Performance Standards for Antimicrobial Susceptibility Testing: Twentieth Informational Supplement

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January 2010

M100-S20 Vol. 30 No. 1 Replaces M100-S19 Vol. 29 No. 3

Performance Standards for Antimicrobial Susceptibility Testing; Twentieth Informational Supplement

This document provides updated tables for the Clinical and Laboratory Standards Institute antimicrobial susceptibility testing standards M02-A10 and M07-A8. An informational supplement for global application developed through the Clinical and Laboratory Standards Institute consensus process.

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Clinical and Laboratory Standards Institute Advancing Quality in Health Care Testing The Clinical and Laboratory Standards Institute (CLSI, formerly NCCLS) is an international, interdisciplinary, nonprofit, standards-developing, and educational organization that promotes the development and use of voluntary consensus standards and guidelines within the health care community. It is recognized worldwide for the application of its unique consensus process in the development of standards and guidelines for patient testing and related health care issues. Our process is based on the principle that consensus is an effective and cost-effective way to improve patient testing and health care services. In addition to developing and promoting the use of voluntary consensus standards and guidelines, we provide an open and unbiased forum to address critical issues affecting the quality of patient testing and health care. PUBLICATIONS A document is published as a standard, guideline, or committee report. Standard A document developed through the consensus process that clearly identifies specific, essential requirements for materials, methods, or practices for use in an unmodified form. A standard may, in addition, contain discretionary elements, which are clearly identified. Guideline A document developed through the consensus process describing criteria for a general operating practice, procedure, or material for voluntary use. A guideline may be used as written or modified by the user to fit specific needs. Report A document that has not been subjected to consensus review and is released by the Board of Directors. CONSENSUS PROCESS The CLSI voluntary consensus process is a protocol establishing formal criteria for

Most documents are subject to two levels of consensus— “proposed” and “approved.” Depending on the need for field evaluation or data collection, documents may also be made available for review at an intermediate consensus level. Proposed A consensus document undergoes the first stage of review by the health care community as a proposed standard or guideline. The document should receive a wide and thorough technical review, including an overall review of its scope, approach, and utility, and a line-by-line review of its technical and editorial content. Approved An approved standard or guideline has achieved consensus within the health care community. It should be reviewed to assess the utility of the final document, to ensure attainment of consensus (ie, that comments on earlier versions have been satisfactorily addressed), and to identify the need for additional consensus documents. Our standards and guidelines represent a consensus opinion on good practices and reflect the substantial agreement by materially affected, competent, and interested parties obtained by following CLSI’s established consensus procedures. Provisions in CLSI standards and guidelines may be more or less stringent than applicable regulations. Consequently, conformance to this voluntary consensus document does not relieve the user of responsibility for compliance with applicable regulations. COMMENTS The comments of users are essential to the consensus process. Anyone may submit a comment, and all comments are addressed, according to the consensus process, by the committee that wrote the document. All comments, including those that result in a change to the document when published at the next consensus level and those that do not result in a change, are addressed by the committee in an appendix to the document. Readers are strongly encouraged to comment in any form and at any time on any document. Address comments to Clinical and Laboratory Standards Institute, 940 West Valley Road, Suite 1400, Wayne, PA 19087, USA.

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Performance Standards for Antimicrobial Susceptibility Testing; Twentieth Informational Supplement Abstract The supplemental information presented in this document is intended for use with the antimicrobial susceptibility testing procedures published in the following Clinical and Laboratory Standards Institute (CLSI)–approved standards: M02-A10—Performance Standards for Antimicrobial Disk Susceptibility Tests; Approved Standard—Tenth Edition; and M07-A8—Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard—Eighth Edition. The standards contain information about both disk (M02) and dilution (M07) test procedures for aerobic bacteria. Clinicians depend heavily on information from the clinical microbiology laboratory for treatment of their seriously ill patients. The clinical importance of antimicrobial susceptibility test results requires that these tests be performed under optimal conditions and that laboratories have the capability to provide results for the newest antimicrobial agents. The tabular information presented here represents the most current information for drug selection, interpretation, and quality control using the procedures standardized in M02 and M07. Users should replace the tables published earlier with these new tables. (Changes in the tables since the most current edition appear in boldface type.) Clinical and Laboratory Standards Institute. Performance Standards for Antimicrobial Susceptibility Testing; Twentieth Informational Supplement. CLSI document M100-S20 (ISBN 1-56238-716-2). Clinical and Laboratory Standards Institute, 940 West Valley Road, Suite 1400, Wayne, Pennsylvania 19087-1898 USA, 2010.

The data in the interpretive tables in this supplement are valid only if the methodologies in M02-A10—Performance Standards for Antimicrobial Disk Susceptibility Tests; Approved Standard—Tenth Edition; and M07-A8—Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard—Eighth Edition are followed.

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M100-S20

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M100-S20 ISBN 1-56238-716-2 ISSN 0273-3099

Performance Standards for Antimicrobial Susceptibility Testing; Twentieth Informational Supplement Volume 30 Number 1 Franklin R. Cockerill, III, MD Matthew A. Wikler, MD, MBA, FIDSA Karen Bush, PhD Michael N. Dudley, PharmD, FIDSA George M. Eliopoulos, MD Dwight J. Hardy, PhD David W. Hecht, MD Janet A. Hindler, MCLS, MT(ASCP) Jean B. Patel, PhD, D(ABMM) Mair Powell, MD, FRCP, FRCPath, MHRA Richard B. Thomson, Jr., PhD John D. Turnidge, MD Melvin P. Weinstein, MD Barbara L. Zimmer, PhD Mary Jane Ferraro, PhD, MPH Jana M. Swenson, MMSc

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Copyright ©2010 Clinical and Laboratory Standards Institute. Except as stated below, neither this publication nor any portion thereof may be adapted, copied, or otherwise reproduced, by any means (electronic, mechanical, photocopying, recording, or otherwise) without prior written permission from Clinical and Laboratory Standards Institute (“CLSI”). CLSI hereby grants permission to each individual member or purchaser to make a single reproduction of this publication for use in its laboratory procedure manual at a single site. To request permission to use this publication in any other manner, contact the Executive Vice President, Clinical and Laboratory Standards Institute, 940 West Valley Road, Suite 1400, Wayne, Pennsylvania 19087-1898, USA.

Suggested Citation CLSI. Performance Standards for Antimicrobial Susceptibility Testing; Twentieth Informational Supplement. CLSI document M100-S20. Wayne, PA: Clinical and Laboratory Standards Institute; 2010. Twentieth Informational Supplement January 2010

Fourteenth Informational Supplement January 2004

Nineteenth Informational Supplement January 2009

Thirteenth Informational Supplement January 2003

Eighteenth Informational Supplement January 2008

Twelfth Informational Supplement January 2002

Seventeenth Informational Supplement January 2007

Eleventh Informational Supplement January 2001

Sixteenth Informational Supplement January 2006

Tenth Informational Supplement January 2000

Fifteenth Informational Supplement January 2005

Ninth Informational Supplement January 1999

ISBN 1-56238-716-2 ISSN 0273-3099

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Vol. 30 No. 1

Committee Membership Area Committee on Microbiology John H. Rex, MD, FACP Chairholder AstraZeneca Cheshire, United Kingdom Mary Jane Ferraro, PhD, MPH Vice-Chairholder Massachusetts General Hospital Boston, Massachusetts, USA Nancy L. Anderson, MMSc, MT(ASCP) Centers for Disease Control and Prevention Atlanta, Georgia, USA Barbara Ann Body, PhD, D(ABMM) Laboratory Corporation of America Burlington, North Carolina, USA Betty (Betz) A. Forbes, PhD, D(ABMM) Medical College of Virginia Campus Richmond, Virginia, USA Thomas R. Fritsche, MD, PhD Marshfield Clinic Marshfield, Wisconsin, USA Freddie Mae Poole, BS, MT(ASCP, ISCLT) FDA Center for Devices and Radiological Health Upper Marlboro, Maryland, USA

Fred C. Tenover, PhD, ABMM Cepheid Sunnyvale, California, USA John D. Turnidge, MD Women’s and Children’s Hospital North Adelaide, Australia

Jana M. Swenson, MMSc Centers for Disease Control and Prevention Young Harris, Georgia, USA Jeffrey L. Watts, PhD, RM(AAM) Pfizer Animal Health Kalamazoo, Michigan, USA

Advisors Donald R. Callihan, PhD BD Diagnostic Systems Sparks, Maryland, USA

Melvin P. Weinstein, MD Robert Wood Johnson University Hospital New Brunswick, New Jersey, USA

James H. Jorgensen, PhD University of Texas Health Science Center San Antonio, Texas, USA

Matthew A. Wikler, MD, MBA, FIDSA Institute for One World Health San Francisco, California, USA

Jean B. Patel, PhD, D(ABMM) Centers for Disease Control and Prevention Atlanta, Georgia, USA

Michael L. Wilson, MD Denver Health Medical Center Denver, Colorado, USA

Michael A. Pfaller, MD University of Iowa College of Medicine Iowa City, Iowa, USA Thomas R. Shryock, PhD Elanco Animal Health Greenfield, Indiana, USA

Gail L. Woods, MD Central Arkansas Veterans Healthcare System Little Rock, Arkansas, USA Barbara L. Zimmer, PhD Siemens Healthcare Diagnostics West Sacramento, California, USA

Subcommittee on Antimicrobial Susceptibility Testing Franklin R. Cockerill, III, MD Chairholder Mayo College of Medicine Rochester, Minnesota, USA Matthew A. Wikler, MD, MBA, FIDSA Vice-Chairholder Institute for One World Health San Diego, California, USA Karen Bush, PhD Indiana University Bloomington, Indiana, USA Michael N. Dudley, PharmD, FIDSA Mpex Pharmaceuticals San Diego, California, USA

George M. Eliopoulos, MD Beth Israel Deaconess Medical Center Boston, Massachusetts, USA

Mair Powell, MD, FRCP, FRCPath MHRA London, United Kingdom

Dwight J. Hardy, PhD University of Rochester Medical Center Rochester, New York, USA

Richard B. Thomson, Jr., PhD Evanston Hospital, Northwestern University Medical School Evanston, Illinois, USA

David W. Hecht, MD Loyola University Medical Center Maywood, Illinois, USA Janet A. Hindler, MCLS, MT(ASCP) UCLA Medical Center Los Angeles, California, USA Jean B. Patel, PhD, D(ABMM) Centers for Disease Control and Prevention Atlanta, Georgia, USA

John D. Turnidge, MD Women’s and Children’s Hospital North Adelaide, Australia Melvin P. Weinstein, MD Robert Wood Johnson Medical School New Brunswick, New Jersey, USA Barbara L. Zimmer, PhD Siemens Healthcare Diagnostics West Sacramento, California, USA

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Committee Membership

January 2010 Advisors Paul G. Ambrose, PharmD, FIDSA ICPD/Orway Research Institute Albany, New York, USA Patricia A. Bradford, PhD Novartis Institutes for Biomedical Research Cambridge, Massachusetts, USA Steven D. Brown, PhD The Clinical Microbiology Institute Wilsonville, Oregon, USA Karen Carroll, MD Johns Hopkins Medical Institutions Baltimore, Maryland, USA Edward M. Cox, Jr., MD, MPH FDA Center for Drug Evaluation and Research Rockville, Maryland, USA William A. Craig, MD Wm. S. Middleton Memorial Veterans Affairs Hospital Madison, Wisconsin, USA Cynthia L. Fowler, MD bioMérieux, Inc. Durham, North Carolina, USA

M100-S20 Yoichi Hirakata, MD, FJSIM, PhD Tohoku University Graduate School of Medicine Sendai, Japan

Sandra S. Richter, MD, D(ABMM) University of Iowa Carver College of Medicine Iowa City, Iowa, USA

Ronald N. Jones, MD JMI Laboratories North Liberty, Iowa, USA

Flavia Rossi, MD University of Sao Paulo Sao Paulo, Brazil

Gunnar Kahlmeter, MD, PhD ESCMID Växjö, Sweden

Dale A. Schwab, PhD, D(ABMM) Quest Diagnostics, Nichols Institute San Juan Capistrano, California, USA

Frederic J. Marsik, PhD, ABMM FDA Center for Drug Evaluation and Research Silver Spring, Maryland, USA

Jana M. Swenson, MMSc Centers for Disease Control and Prevention Atlanta, Georgia, USA

Linda A. Miller, PhD GlaxoSmithKline Collegeville, Pennsylvania, USA

Fred C. Tenover, PhD, ABMM Cepheid Sunnyvale, California, USA

Harriette L. Nadler, PhD DJA Global Pharmaceuticals, Inc. Chadds Ford, Pennsylvania, USA

Joseph G. Toerner, MD, MPH FDA Center for Disease Control and Prevention Silver Spring, Maryland, USA

Freddie Mae Poole, BS, MT(ASCP, ISCLT) FDA Center for Devices and Radiological Health Upper Marlboro, Maryland, USA

Hui Wang, PhD Peking Union Medical College Hospital Beijing, China

Text and Table Working Group Jana M. Swenson, MMSc Chairholder Centers for Disease Control and Prevention Atlanta, Georgia, USA Donald R. Callihan, PhD BD Diagnostic Systems Sparks, Maryland, USA Franklin R. Cockerill, III, MD Mayo Clinic and Mayo College of Medicine Rochester, Minnesota, USA Sharon K. Cullen, BS, RAC Siemens Healthcare Diagnostics West Sacramento, California, USA

Janet A. Hindler, MCLS, MT(ASCP) UCLA Medical Center Los Angeles, California, USA

Susan D. Munro, MT(ASCP) Stanford Hospital and Clinics Palo Alto, California, USA

Judy Johnston, MS Siemens Healthcare Diagnostics West Sacramento, California, USA

Dale A. Schwab, PhD, D(ABMM) Quest Diagnostics, Nichols Institute San Juan Capistrano, California, USA

Ronald N. Jones, MD JMI Laboratories North Liberty, Iowa, USA Dyan Luper, BS, MT(ASCP)SM BD Diagnostic Systems Sparks, Maryland, USA Linda M. Mann, PhD, D(ABMM) Siemens Healthcare Diagnostics West Sacramento, California, USA

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Albert T. Sheldon, Jr., PhD Antibiotic & Antiseptic Consultants Cypress, Texas, USA Richard B. Thomson, Jr., PhD Northwestern University Feinberg School of Medicine Evanston, Illinois, USA Mary K. York, PhD, ABMM MKY Microbiology Consulting Walnut Creek, California, USA

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Vol. 30 No. 1 Quality Control Working Group Steve Brown, PhD Co-Chairholder The Clinical Microbiology Institute Wilsonville, Oregon, USA Sharon K. Cullen, BS, RAC Co-Chairholder Siemens Healthcare Diagnostics West Sacramento, California, USA William Brasso BD Diagnostic Systems Sparks, Maryland, USA Stephen Hawser, PhD IHMA Schaumburg, Illinois, USA Janet A. Hindler, MCLS, MT(ASCP) UCLA Medical Center Los Angeles, California, USA

Michael D. Huband Pfizer Global R&D Groton, Connecticut, USA Ronald N. Jones, MD JMI Laboratories North Liberty, Iowa, USA Ann Macone Paratek Pharmaceuticals, Inc. Boston, Massachusetts, USA Ross Mulder, MT(ASCP) bioMérieux, Inc. Hazelwood, Missouri, USA

Paul E. Oefinger, PhD, D(ABMM) Covance Central Laboratory Services Inc. Indianapolis, Indiana, USA Jean Patel, PhD, D(ABMM) Centers for Disease Control and Prevention Atlanta, Georgia, USA Robert P. Rennie, PhD University of Alberta Hospital Edmonton, Alberta, Canada

Susan D. Munro, MT(ASCP) Stanford Hospital and Clinics Palo Alto, California, USA

Staphylococcal Working Group Fred Tenover, PhD, ABMM Chairholder Cepheid Sunnyvale, California, USA Karen Bush, PhD Indiana University Bloomington, Indiana, USA Patricia A. Bradford, PhD Novartis Institutes for Biomedical Research Cambridge, Massachusetts, USA William A. Craig, MD University of Wisconsin Madison, Wisconsin, USA

Michael N. Dudley, PharmD, FIDSA Mpex Pharmaceuticals San Diego, California, USA

Maria M. Traczewski, BS, MT(ASCP) The Clinical Microbiology Institute Wilsonville, Oregon, USA

George M. Eliopoulos, MD Beth Israel Deaconess Medical Center Boston, Massachusetts, USA

Melvin P. Weinstein, MD Robert Wood Johnson University Hospital New Brunswick, New Jersey, USA

Daniel F. Sahm, PhD Eurofins Medinet Herndon, Virginia, USA Jana Swenson, MMSc Centers for Disease Control and Prevention Atlanta, Georgia, USA

Enterobacteriaceae Working Group Michael N. Dudley, PharmD, FIDSA Chairholder Mpex Pharmaceuticals San Diego, California, USA

Ronald N. Jones, MD JMI Laboratories North Liberty, Iowa, USA

Paul G. Ambrose, PharmD, FIDSA ICPD/Ordway Research Albany, New York, USA

Jean B. Patel, PhD, D(ABMM) Centers for Disease Control and Prevention Atlanta, Georgia, USA

Karen Bush, PhD Indiana University Bloomington, Indiana, USA

David Paterson, MD University of Pittsburgh Pittsburgh, Pennsylvania, USA

William A. Craig, MD University of Wisconsin Madison, Wisconsin, USA

Paul C. Schreckenberger, PhD, D(ABMM), F(AAM) Loyola University Medical Center Maywood, Illinois, USA

Jana Swenson, MMSc Centers for Disease Control and Prevention Atlanta, Georgia, USA Lauri D. Thrupp, MD University of California Irvine Medical Center Orange, California, USA Melvin P. Weinstein, MD Robert Wood Johnson University Hospital New Brunswick, New Jersey, USA Barbara L. Zimmer, PhD Siemens Healthcare Diagnostics West Sacramento, California, USA

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Committee Membership

January 2010 Staff Clinical and Laboratory Standards Institute Wayne, Pennsylvania, USA Lois M. Schmidt, DA Vice President, Standards Development and Marketing Tracy A. Dooley, BS, MLT(ASCP) Staff Liaison Melissa A. Lewis, ELS Editorial Manager Carol DiBerardino, MLA, ELS Assistant Editor

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Contents Abstract ......................................................................................................................................................... 1 Committee Membership................................................................................................................................ 5 Summary of Major Changes in This Document ......................................................................................... 13 Summary of CLSI Processes for Establishing Interpretive Criteria and Quality Control Ranges .............. 17

Subcommittee on Antimicrobial Susceptibility Testing Mission Statement .............................................. 19 Introduction to Tables 1 and 2 for Use With M02-A10 (Disk Diffusion) and M07-A8 (MIC Testing) ..... 20 Table 1. Suggested Groupings of Antimicrobial Agents With FDA Clinical Indications That Should Be Considered for Routine Testing and Reporting on Nonfastidious Organisms by Clinical Microbiology Laboratories in the United States ......................................................................................... 28 Table 1A. Suggested Groupings of Antimicrobial Agents With FDA Clinical Indications That Should Be Considered for Routine Testing and Reporting on Fastidious Organisms by Clinical Microbiology Laboratories in the United States ................................................................................................................ 34 Table 1B. Antimicrobial Agents That Should Be Tested and Reported on Potential Bacterial Agents of Bioterrorism (MIC methods only) ........................................................................................................ 38 Tables 2A–2L. Zone Diameter and MIC Interpretive Standards for: 2A. Enterobacteriaceae .............................................................................................................................. 40 Supplemental Table 2A-S1. Screening and Confirmatory Tests for ESBLs in Klebsiella pneumoniae, Klebsiella oxytoca, Escherichia coli, and Proteus mirabilis for Use With Table 2A……………………46 Supplemental Table 2A-S2. Screening and Confirmatory Tests for Suspected Carbapenemase Production in Enterobacteriaceae for Use With Table 2A…………………………………………………………… 48 2B-1. Pseudomonas aeruginosa ................................................................................................................. 52 2B-2. Acinetobacter spp.............................................................................................................................. 54 2B-3. Burkholderia cepacia ........................................................................................................................ 56 2B-4. Stenotrophomonas maltophilia ......................................................................................................... 57 2B-5. Other Non-Enterobacteriaceae ......................................................................................................... 58 2C. Staphylococcus spp. ............................................................................................................................. 60 Supplemental Table 2C-S3. Screening Tests for β-Lactamase Production, Oxacillin Resistance, mecAMediated Oxacillin Resistance Using Cefoxitin, Vancomycin MIC ≥ 8 μg/mL, Inducible Clindamycin Resistance, and High-Level Mupirocin Resistance in the Staphylococcus aureus Group for Use With Table 2C………….. .................................................................................................................................... 70 9

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Table of Contents

CLSI Reference Methods vs Commercial Methods and CLSI vs FDA Breakpoints ................................. 18

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Contents (Continued) Supplemental Table 2C-S4. Screening Tests for β-Lactamase, mecA-Mediated Oxacillin Resistance Using Cefoxitin, and Inducible Clindamycin Resistance in Coagulase-Negative Staphylococci (except Staphylococcus lugdunensis) for Use With Table 2C…………………………………………………… . 74 2D. Enterococcus spp. ................................................................................................................................ 76 Supplemental Table 2D-S5. Screening Tests for High-Level Aminoglycoside Resistance (HLAR) and Vancomycin Resistance in Enterococcus spp. for Use With Table 2D……………………………………79 2E. Haemophilus influenzae and Haemophilus parainfluenzae ................................................................. 80

Table of Contents

2F. Neisseria gonorrhoeae.......................................................................................................................... 84 2G. Streptococcus pneumoniae ................................................................................................................... 88 2H-1. Streptococcus spp. β-Hemolytic Group ............................................................................................ 92 2H-2. Streptococcus spp. Viridans Group .................................................................................................. 96 2I. Vibrio cholerae ...................................................................................................................................... 99 2J. Neisseria meningitidis ......................................................................................................................... 100 2K. Bacillus anthracis, Yersinia pestis, Burkholderia mallei, Burkholderia pseudomallei, Francisella tularensis, and Brucella spp. ................................................................................................. 104 2L. Helicobacter pylori ............................................................................................................................. 107 Table 3. Disk Diffusion Testing—Acceptable Limits (mm) for Quality Control Strains Used to Monitor Accuracy; Nonfastidious Organisms Using Mueller-Hinton Medium Without Blood or Other Supplements .................................................................................................................................... 108 Table 3A. Disk Diffusion Testing—Acceptable Limits (mm) for Quality Control Strains Used to Monitor Accuracy; Fastidious Organisms ................................................................................................ 110 Table 3B. Disk Diffusion Testing—Reference Guide to Quality Control Testing Frequency ................. 112 Table 3C. Disk Diffusion Quality Control Troubleshooting Guide .......................................................... 114 Table 4. MIC Testing—Acceptable Limits (μg/mL) for Quality Control Strains Used to Monitor Accuracy; Nonfastidious Organisms Using Mueller-Hinton Medium (Cation-Adjusted if Broth) Without Blood or Other Nutritional Supplements .................................................................................... 116 Table 4A. MIC Testing—Acceptable Limits (μg/mL) for Quality Control Strains Used to Monitor Accuracy; Fastidious Organisms Using Dilution Methods ....................................................................... 118 Table 4B. MIC Testing—Acceptable Limits (μg/mL) for Quality Control Strains Used to Monitor Accuracy; Fastidious Organisms Using Agar Dilution ............................................................................. 120

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Contents (Continued) Table 4C. MIC Testing—Acceptable Limits (μg/mL) for Quality Control Strains Used to Monitor Accuracy; Using Cation-Adjusted Mueller-Hinton Broth + 2% Defined Growth Supplement................ 121 Table 4D. MIC Testing—Acceptable Limits (μg/mL) for Quality Control Strains Used to Monitor Accuracy; Using Brucella Broth Media Without Supplements Adjusted to pH 7.1 ± 0.1........................ 122 Table 4E. MIC Testing—Reference Guide to Quality Control Testing Frequency.................................. 123 Table 4F. MIC Testing Quality Control Troubleshooting Guide ............................................................. 124 Table 5. Solvents and Diluents for Preparation of Stock Solutions of Antimicrobial Agents .................. 128

Table 5B. Preparation of Solutions and Media Containing Combinations of Antimicrobial Agents ....... 132 Table 6. Scheme for Preparing Dilutions of Antimicrobial Agents to Be Used in Agar Dilution Susceptibility Tests ................................................................................................................................... 134 Table 7. Scheme for Preparing Dilutions of Antimicrobial Agents to Be Used in Broth Dilution Susceptibility Tests ................................................................................................................................... 135 Table 7A. Scheme for Preparing Dilutions of Water-Insoluble Agents to Be Used in Broth Dilution Susceptibility Tests ................................................................................................................................... 136 Appendix A. Suggestions for Verification of Antimicrobial Susceptibility Test Results and Confirmation of Organism Identification ................................................................................................. 138 Appendix B. Quality Control Strains for Antimicrobial Susceptibility Tests........................................... 140 Appendix C. Cumulative Antimicrobial Susceptibility Report for Bacteroides fragilis Group Organisms ................................................................................................................................................. 143 Glossary I (Part 1). ß-Lactams: Class and Subclass Designation and Generic Name............................... 144 Glossary I (Part 2). Non–ß-lactams: Class and Subclass Designation and Generic Name ....................... 145 Glossary II. Abbreviations/Routes of Administration/Drug Class for Antimicrobial Agents Listed in M100-S20 ................................................................................................................................................. 146 Glossary III. List of Identical Abbreviations Used for More Than One Antimicrobial Agent in US Diagnostic Products .................................................................................................................................. 149 Summary of Comments and Subcommittee Responses ............................................................................ 150 The Quality Management System Approach ............................................................................................ 152 Related CLSI Reference Materials ........................................................................................................... 153

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Table of Contents

Table 5A. Preparation of Stock Solutions for Antimicrobial Agents Provided With Activity Expressed as Units. ................................................................................................................................... 131

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The Clinical and Laboratory Standards Institute consensus process, which is the mechanism for moving a document through two or more levels of review by the health care community, is an ongoing process. Users should expect revised editions of any given document. Because rapid changes in technology may affect the procedures, methods, and protocols in a standard or guideline, users should replace outdated editions with the current editions of CLSI/NCCLS documents. Current editions are listed in the CLSI catalog and posted on our website at www.clsi.org. If your organization is not a member and would like to become one, and to request a copy of the catalog, contact us at: Telephone: +610.688.0100; Fax: +610.688.0700; E-mail: [email protected]; Website: www.clsi.org.

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Summary of Major Changes in This Document This list includes the “major” changes in this document. Other minor or editorial changes have been made to the general formatting and to some of the table footnotes and comments. Boldface type is used to highlight the changes in each table. Additions/Changes/Deletions Major formatting changes: The following table indicates renaming, renumbering, and relocating of several appendixes that were previously positioned at the end of M100-S19.

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New M100-S20 Designation/Location Supplemental Table 2A-S1/end of Table 2A Supplemental Table 2A-S2/end of Table 2A Supplemental Table 2C-S3/end of Table 2C Supplemental Table 2C-S4/end of Table 2C Supplemental Table 2D-S5/end of Table 2D Appendix A/end of M100-S20 before Glossary Appendix B/end of M100-S20 before Glossary

Summary of Changes

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Previous Designation Appendix A (Screening and Confirmatory Tests for ESBLs) Appendix G (Screening and Confirmatory Tests for Carbapenemases) Appendix B (Screening Tests for Staphylococcus aureus Group) Appendix C (Screening Tests for Coagulase-Negative Staphylococci) Appendix D (Screening Tests for Enterococci) Appendix E (Suggestions for Verification of AST Results) Appendix F (QC Strains for AST)

The following are additions or changes unless otherwise noted as a “deletion.” Introduction to Tables 1 and 2 Revised the definition of nonsusceptible (p. 22) Added information on using cephalothin breakpoints ONLY to predict susceptibility to other cephems (p. 30) Added new Section VII describing Screening Tests, to include a summary of the screening tests, their limitations, and any tests needed to confirm results of the screening test (p. 26) Tables 1 and 1A – Drugs Recommended for Testing and Reporting Added cephamycins to the list of antimicrobial agents that should not be reported routinely for bacteria isolated from cerebrospinal fluid (CSF) located in the Warning box following Tables 1 and 1A (pp. 30 and 35) Enterobacteriaceae: Changed Test Report Group for cephalothin from A to U (pp. 28) Acinetobacter spp. Deleted colistin and polymyxin B from Test Report Group C 13

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Summary of Major Changes in This Document (Continued) Tables 1 and 1A – Drugs Recommended for Testing and Reporting (Continued) Staphylococcus spp.: Added information if testing a penicillinase-stable penicillin, oxacillin is the preferred agent and results can be applied to the other penicillinase-stable penicillins, cloxacillin, dicloxacillin, flucloxacillin, methicillin, and nafcillin (p. 32) Modified footnotes in Table 1 to correspond with modifications of comments in Tables 2 as follows: Footnote a) (p. 30) – see Enterobacteriaceae Table 2A comment (11) (p. 42) Footnote k) (p. 31) – see Staphylococcus spp. Table 2C comment (9) (p. 62) Tables 2A through 2L – Interpretive Criteria (Breakpoints) Enterobacteriaceae (Table 2A): Added new (revised) breakpoints for cefazolin, cefotaxime, ceftazidime, ceftizoxime, ceftriaxone, and aztreonam. Also added dosage regimens on which the new breakpoints are based (pp. 42 and 43)

Summary of Changes

Added suggestion that when using the new breakpoints, routine ESBL testing is no longer necessary before reporting cephalosporin, penicillin, or aztreonam results (pp. 41 and 46) Deleted former cefazolin disk diffusion breakpoints and noted that disk diffusion breakpoints to correlate with the new cefazolin MIC breakpoints have not yet been established (p. 42) Added information indicating that results from testing cephalothin should be used ONLY to predict results for select oral cephems. Changed Test/Report Group for cephalothin from A to U (p. 42) Pseudomonas aeruginosa (Table 2B-1): Deleted recommendation to add a report comment suggesting the addition of a second antimicrobial agent (eg, fluoroquinolone, aminoglycoside) for P. aeruginosa infections Staphylococcus spp. (Table 2C): Clarified reporting results for β-lactam agents other than the cephalosporins with anti–methicillinresistant Staphylococcus aureus (MRSA) activity for oxacillin-resistant S. aureus and coagulase-negative staphylococci (p. 60) As related to vancomycin MIC results, modified recommendations for sending isolates of S. aureus and coagulase-negative Staphylococcus to a reference laboratory for confirmation (pp. 65 and 66) Expanded definition of MRSA strains (p. 60) Expanded discussion of limitations of β-lactamase testing for staphylococcal isolates that test susceptible to penicillin but might have the ability to produce β-lactamase (p. 62) Clarified recommendations for reporting results when cefoxitin and oxacillin are tested against S. aureus or S. lugdunensis and either tests resistant (p. 62) Added disk diffusion and MIC “resistant” interpretive criteria for linezolid (p. 68) Further described cross-susceptibility of penicillinase-stable penicillins (p. 62) 14

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Summary of Major Changes in This Document (Continued) Staphylococcus spp. (Table 2C) (Continued): Reemphasized suggestions for performing additional testing of non–S. epidermidis coagulase-negative staphylococcal strains for which the oxacillin MIC is 0.5–2 µg/mL (p. 63) Reemphasized recommendation that oxacillin would be the preferred agent to test if a penicillinase-stable penicillin is tested. (p. 62) Enterococcus spp. (Table 2D): Modified recommendations for performing β-lactamase testing (p. 77) Streptococcus spp. β-hemolytic Group (Table 2H-1): Modified the comment regarding cross susceptibility of penicillin and other β-lactams (p. 93) Streptococcus spp. Viridans Group (Table 2H-2): Deleted suggestion that isolates that test susceptible to penicillin can be considered susceptible to other β-lactams Clarified the organisms covered by Table 2H-2 recommendations (p. 96)

Summary of Changes

Neisseria meningitidis (Table 2J): Added an “or” between cefotaxime and ceftriaxone (p. 101) Tables 3 and 4 – Quality Control Disk Diffusion QC Ranges Changes/Additions (Table 3): (pp. 108–109) Doripenem – Escherichia coli ATCC® 25922 Pseudomonas aeruginosa ATCC® 27853 Razupenem – Escherichia coli ATCC® 25922 Ulifloxacin (prulifloxacin) – Escherichia coli ATCC® 25922 Staphylococcus aureus ATCC® 25923 Pseudomonas aeruginosa ATCC® 27853 Disk Diffusion QC Ranges Changes/Additions (Table 3A): (p. 110) Razupenem – Streptococcus pneumoniae ATCC® 49619 Haemophilus influenzae ATCC® 49247 MIC QC Ranges Changes/Additions (Table 4): (pp. 116–117) Besifloxacin – Staphylococcus aureus ATCC® 29213 Enterococcus faecalis ATCC® 29212 Escherichia coli ATCC® 25922 Pseudomonas aeruginosa ATCC® 27853 Colistin – Escherichia coli ATCC® 25922 Pseudomonas aeruginosa ATCC® 27853 Daptomycin – Staphylococcus aureus ATCC® 29213 15

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Summary of Major Changes in This Document (Continued) MIC QC Ranges Changes/Additions (Table 4) (Continued): Fidaxomicin – Staphylococcus aureus ATCC® 29213 Enterococcus faecalis ATCC® 29212 Polymyxin B – Pseudomonas aeruginosa ATCC® 27853 Razupenem – Escherichia coli ATCC® 25922 Staphylococcus aureus ATCC® 29213 Pseudomonas aeruginosa ATCC® 27853 Enterococcus faecalis ATCC® 29212 Teicoplanin – Enterococcus faecalis ATCC® 29212 Ulifloxacin (prulifloxacin) – Escherichia coli ATCC® 25922 Pseudomonas aeruginosa ATCC® 27853

Summary of Changes

MIC QC Ranges Changes/Additions (Table 4A): (pp. 118–119) Besifloxacin – Haemophilus influenzae ATCC® 49247 Streptococcus pneumoniae ATCC® 49619 Linezolid – Streptococcus pneumoniae ATCC® 49619 Razupenem – Haemophilus influenzae ATCC® 49766 Streptococcus pneumoniae ATCC® 49619 Tetracycline – Streptococcus pneumoniae ATCC® 49619 Solvents and Diluents for Preparation Changes/Additions (Table 5): (pp. 128–129) Added: Besifloxacin Fidaxomicin Razupenem

of

Stock

Solutions

of

Antimicrobial

Agents

Preparation of Solutions and Media Containing Combinations of Antimicrobial Agents (New) Table 5B Explains methods for preparing stock solutions or media containing combinations of antimicrobial agents (pp. 132–133) Cumulative Antimicrobial Susceptibility Report for Bacteroides fragilis Group Organisms (New) Appendix C Provides guidance to laboratories on the percentage of certain anaerobes susceptible or resistant to commonly used antimicrobial agents. This table is also provided in the new M11-S1 Supplement (p. 143). Glossaries I, II, and III: Glossary I – added new antimicrobial subclass for ceftaroline and ceftobiprole (p. 144) Glossaries I and II – added besifloxacin to fluoroquinolone subclass (pp. 145–146) – added razupenem to carbapenem subclass (pp. 144 and 148) – added ulifloxacin (prulifloxacin) to fluoroquinolone subclass (pp. 145 and 148) 16

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Summary of CLSI Processes for Establishing Interpretive Criteria and Quality Control Ranges The Clinical and Laboratory Standards Institute (CLSI) is an international, voluntary, nonprofit, interdisciplinary, standards-developing, and educational organization accredited by the American National Standards Institute (ANSI) that develops and promotes use of consensus-developed standards and guidelines within the health care community. These consensus standards and guidelines are developed to address critical areas of diagnostic testing and patient health care and are developed in an open and consensus seeking forum. CLSI is open to anyone or any organization that has an interest in diagnostic testing and patient care. Information about CLSI can be found at www.clsi.org. The CLSI Subcommittee on Antimicrobial Susceptibility Testing (AST) reviews data from a variety of sources and studies (eg, in vitro, pharmacokinetics/pharmacodynamics, and clinical studies) to establish antimicrobial susceptibility test methods, interpretive criteria, and quality control (QC) parameters. The details of the data required to establish interpretive criteria, QC parameters, and how the data are presented for evaluation are described in CLSI document M23—Development of In Vitro Susceptibility Testing Criteria and Quality Control Parameters. Over time, a microorganism’s susceptibility to an antimicrobial agent may decrease, resulting in a lack of clinical efficacy and/or safety. In addition, microbiological methods and QC parameters may be refined to ensure more accurate and better performance of susceptibility test methods. Because of this, CLSI continually monitors and updates information in its documents. Although CLSI standards and guidelines are developed using the most current information and thinking available at the time, the field of science and medicine is ever changing; therefore, standards and guidelines should be used in conjunction with clinical judgment, current knowledge, and clinically relevant laboratory test results to guide patient treatment. Additional information, updates, and changes in this document can be found in the meeting summary minutes of the Subcommittee on Antimicrobial Susceptibility Testing at www.clsi.org.

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CLSI Reference Methods vs Commercial Methods and CLSI vs FDA Breakpoints (interpretive criteria) It is important for users of M02-A10, M07-A8, and the M100 Informational Supplement to recognize that the standard methods described in CLSI documents are reference methods. These methods may be used for routine antimicrobial susceptibility testing of clinical isolates, for evaluation of commercial devices that will be used in clinical laboratories, or by drug or device manufacturers for testing of new agents or systems. Results generated by reference methods, such as those contained in CLSI documents, may be used by regulatory authorities to evaluate the performance of commercial susceptibility testing devices as part of the approval process. Clearance by a regulatory authority indicates that the commercial susceptibility testing device provides susceptibility results that are substantially equivalent to results generated using reference methods for the organisms and antimicrobial agents described in the device manufacturer’s approved package insert. CLSI breakpoints may differ from those approved by various regulatory authorities for many reasons, including the following: different databases, differences in interpretation of data, differences in doses used in different parts of the world, and public health policies. Differences also exist because CLSI proactively evaluates the need for changing breakpoints. The reasons why breakpoints may change and the manner in which CLSI evaluates data and determines breakpoints are outlined in CLSI document M23—Development of In Vitro Susceptibility Testing Criteria and Quality Control Parameters. Following a decision by CLSI to change an existing breakpoint, regulatory authorities may also review data in order to determine how changing breakpoints may affect the safety and effectiveness of the antimicrobial agent for the approved indications. If the regulatory authority changes breakpoints, commercial device manufacturers may have to conduct a clinical laboratory trial, submit the data to the regulatory authority, and await review and approval. For these reasons, a delay of more than the suggested CLSI “tentative” period of one year may be required if an interpretive breakpoint change is to be implemented by a device manufacturer. In the United States, laboratories that use Food and Drug Administration (FDA)–approved susceptibility testing devices are allowed to use existing FDA interpretive breakpoints. Either FDA or CLSI susceptibility interpretive breakpoints are acceptable to clinical laboratory accrediting bodies. Policies in other countries may vary. Following discussions with appropriate stakeholders such as infectious disease practitioners and the pharmacy department, as well as the Pharmacy and Therapeutics and Infection Control committees of the medical staff, newly approved or revised breakpoints may be implemented by clinical laboratories. CLSI disk diffusion test breakpoints may be implemented as soon as they are published in M100. If a device includes antimicrobial test concentrations sufficient to allow interpretation of susceptibility and resistance to an agent using the CLSI breakpoints, a laboratory could, after appropriate validation, choose to interpret and report results using CLSI breakpoints.

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Subcommittee on Antimicrobial Susceptibility Testing Mission Statement The Subcommittee on Antimicrobial Susceptibility Testing is composed of representatives from the professions, government, and industry, including microbiology laboratories, government agencies, health care providers and educators, and pharmaceutical and diagnostic microbiology industries. Using the CLSI voluntary consensus process, the subcommittee develops standards that promote accurate antimicrobial susceptibility testing and appropriate reporting. The mission of the Subcommittee on Antimicrobial Susceptibility Testing is to

•

Develop standard reference methods for antimicrobial susceptibility tests.

•

Provide QC parameters for standard test methods.

•

Establish interpretive criteria for the results of standard antimicrobial susceptibility tests.

•

Provide suggestions for testing and reporting strategies that are clinically relevant and costeffective.

•

Continually refine standards and optimize detection of emerging resistance mechanisms through development of new or revised methods, interpretive criteria, and QC parameters.

•

Educate users through multimedia communication of standards and guidelines.

•

Foster a dialog with users of these methods and those who apply them.

The ultimate purpose of the subcommittee’s mission is to provide useful information to enable laboratories to assist the clinician in the selection of appropriate antimicrobial therapy for patient care. The standards and guidelines are meant to be comprehensive and to include all antimicrobial agents for which the data meet established CLSI guidelines. The values that guide this mission are quality, accuracy, fairness, timeliness, teamwork, consensus, and trust.

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Introduction to Tables 1 and 2 for Use With M02-A10 (Disk Diffusion) and M07-A8 (MIC Testing) On the following pages, you will find 1.

Tables 1, 1A, and 1B—Suggested groupings of antimicrobial agents that should be considered for routine testing and reporting by clinical microbiology laboratories. These guidelines are based on drugs with clinical indications approved by the US Food and Drug Administration (FDA) in the United States. In other countries, placement of antimicrobial agents in Tables 1, 1A, and 1B should be based on available drugs approved for clinical use by relevant regulatory agencies.

2.

For each organism group, an additional table (Tables 2A through 2L) contains a. Recommended testing conditions. b. Minimal quality control (QC) recommendations. (See also the text documents M02A10, Section 15 and M07-A8, Section 17.) c. General comments for testing the organism group and specific comments for testing particular drug/organism combinations. d. Suggested agents that should be considered for routine testing and reporting by clinical microbiology laboratories, as specified in Tables 1, 1A, and 1B (test/report groups A, B, C, U). e. Additional drugs that have an approved indication for the respective organism group but would generally not warrant routine testing by a clinical microbiology laboratory in the United States (test/report group O for “other”; test/report group Inv. for “investigational” [not yet FDA approved]). f. Zone diameter breakpoints and minimal inhibitory concentration (MIC) interpretive standard criteria.

3.

For some organism groups, a supplemental table summarizing screening tests that may be appropriate for use with isolates within the organism group.

I.

Selecting Antimicrobial Agents for Testing and Reporting

A.

Selection of the most appropriate antimicrobial agents to test and to report is a decision best made by each clinical laboratory in consultation with the infectious disease practitioners and the pharmacy, as well as the pharmacy and therapeutics and infection control committees of the medical staff. The recommendations here for each organism group comprise agents of proven efficacy that show acceptable in vitro test performance. Considerations in the assignment of agents to specific test/report groups include clinical efficacy, prevalence of resistance, minimizing emergence of resistance, cost, FDA clinical indications for use, and current consensus recommendations for first-choice and alternative drugs. Unexpected resistance should be reported (eg, resistance of Enterobacteriaceae to carbapenems). Tests of selected agents may be useful for infection control purposes.

B.

The listing of drugs together in a single box designates clusters of agents for which interpretive results (susceptible, intermediate, or resistant) and clinical efficacy are similar. Within each box, an “or” between agents designates those agents for which cross resistance and cross susceptibility are nearly complete. This means combined major and very major errors are fewer than 3% and minor errors are fewer than 10%, based on a large population of bacteria tested. In addition, to qualify for an “or,” at least 100 strains with resistance to the agents in question must be tested and a result of “resistant” must be obtained with all agents for at least 95% of the strains. “Or” is also used for comparable antimicrobial agents when tested against organisms for which “susceptibleonly” interpretive criteria are provided (eg, cefotaxime or ceftriaxone with Haemophilus

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influenzae). Thus, results from one agent connected by an “or” could be used to predict results for the other agent. For example, Enterobacteriaceae susceptible to cefotaxime can be considered susceptible to ceftriaxone. The results obtained from testing cefotaxime would be reported and a comment could be included on the report that the isolate is also susceptible to ceftriaxone. When no “or” connects agents within a box, testing of one agent cannot be used to predict results for another owing either to discrepancies or insufficient data. C.

D.

Test/Report Groups 1.

As listed in Tables 1, 1A, and 1B, agents in Group A are considered appropriate for inclusion in a routine, primary testing panel, as well as for routine reporting of results for the specific organism groups.

2.

Group B comprises agents that may warrant primary testing. However, they may be reported only selectively, such as when the organism is resistant to agents of the same class, as in Group A. Other indications for reporting the result might include a selected specimen source (eg, a third-generation cephalosporin for enteric bacilli from cerebrospinal fluid [CSF] or trimethoprim-sulfamethoxazole for urinary tract isolates); a polymicrobial infection; infections involving multiple sites; cases of patient allergy, intolerance, or failure to respond to an agent in Group A; or for purposes of infection control.

3.

Group C comprises alternative or supplemental antimicrobial agents that may require testing in those institutions that harbor endemic or epidemic strains resistant to several of the primary drugs (especially in the same class, eg, β-lactams); for treatment of patients allergic to primary drugs; for treatment of unusual organisms (eg, chloramphenicol for extraintestinal isolates of Salmonella spp.); or for reporting to infection control as an epidemiological aid.

4.

Group U (“urine”) lists certain antimicrobial agents (eg, nitrofurantoin and certain quinolones) that are used only or primarily for treating urinary tract infections. These agents should not be routinely reported against pathogens recovered from other sites of infection. Other agents with broader indications may be included in Group U for specific urinary pathogens (eg, P. aeruginosa and ofloxacin).

5.

Group O (“other”) includes agents that have a clinical indication for the organism group, but are generally not candidates for routine testing and reporting in the United States.

6.

Group Inv. (“investigational”) includes agents that are investigational for the organism group and have not yet been approved by the FDA.

Selective Reporting Each laboratory should decide which agents in the tables to report routinely (Group A) and which might be reported only selectively (from Group B), in consultation with the infectious disease practitioners and the pharmacy, as well as the pharmacy and the therapeutics and infection control committees of the medical staff of the hospital. Selective reporting should help improve the clinical relevance of test reports and help minimize the selection of multiresistant nosocomial strains by overuse of broad-spectrum agents. Results for Group B agents not reported routinely should be available on request, or they may be reported for selected specimens. Unexpected resistance, when confirmed, should be reported (eg, resistance to a secondary agent but susceptibility to a primary agent).

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Reporting Results The minimal inhibitory concentration (MIC) values determined as described in M07-A8 may be reported directly to clinicians for patient-care purposes. However, it is essential for an understanding of the data by all clinicians that an interpretive category result also be provided routinely. Zone diameter measurements without an interpretive category should not be reported. Recommended interpretive categories for various MIC and zone diameter values are included in tables for each organism group and are based on evaluation of data as described in CLSI document M23. Recommended MIC and disk diffusion interpretive criteria are based on usual dosage regimens and routes of administration in the United States.

A.

Susceptible, intermediate, or resistant interpretations are reported and defined as follows:

1.

Susceptible (S) The “susceptible” category implies that isolates are inhibited by the usually achievable concentrations of antimicrobial agent when the recommended dosage is used for the site of infection.

2.

Intermediate (I) The “intermediate” category includes isolates with antimicrobial agent MICs that approach usually attainable blood and tissue levels and for which response rates may be lower than for susceptible isolates. The intermediate category implies clinical efficacy in body sites where the drugs are physiologically concentrated (eg, quinolones and β-lactams in urine) or when a higher than normal dosage of a drug can be used (eg, β-lactams). This category also includes a buffer zone, which should prevent small, uncontrolled, technical factors from causing major discrepancies in interpretations, especially for drugs with narrow pharmacotoxicity margins.

3.

Resistant (R) The “resistant” category implies that isolates are not inhibited by the usually achievable concentrations of the agent with normal dosage schedules, and/or that demonstrate MICs or zone diameters that fall in the range where specific microbial resistance mechanisms (eg, βlactamases) are likely, and clinical efficacy of the agent against the isolate has not been reliably shown in treatment studies.

4.

Nonsusceptible (NS) A category used for isolates for which only a susceptible interpretive criterion has been designated because of the absence or rare occurrence of resistant strains. Isolates that have MICs above or zone diameters below the value indicated for the susceptible breakpoint should be reported as nonsusceptible. NOTE 1: An isolate that is interpreted as nonsusceptible does not necessarily mean that the isolate has a resistance mechanism. It is possible that isolates with MICs above the susceptible breakpoint that lack resistance mechanisms may be encountered within the wild-type distribution subsequent to the time the susceptible-only breakpoint is set. NOTE 2: For strains yielding results in the “nonsusceptible” category, organism identification and antimicrobial susceptibility test results should be confirmed. (See Appendix A.)

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For some organism groups excluded from Tables 2A through 2L, the CLSI guideline M45— Methods for Antimicrobial Dilution and Disk Susceptibility Testing of Infrequently Isolated or Fastidious Bacteria provides suggestions for standardized methods for susceptibility testing, including information about drug selection, interpretation, and QC. The organism groups covered in that document are Abiotrophia and Granulicatella spp. (formerly known as nutritionally deficient or nutritionally variant streptococci); the Aeromonas hydrophila complex; Bacillus spp. (not B. anthracis); Campylobacter jejuni/coli; Corynebacterium spp. (including C. diphtheriae); Erysipelothrix rhusiopathiae; the HACEK group: Aggregatibacter spp. (formerly the Aphrophilus cluster of the genus Haemophilus [ie, H. aphrophilus, H. paraphrophilus, H. segnis]), Actinobacillus actinomycetemcomitans, Cardiobacterium spp., Eikenella corrodens, and Kingella spp.; Lactobacillus spp.; Leuconostoc spp.; Listeria monocytogenes; Moraxella catarrhalis; Pasteurella spp.; Pediococcus spp.; and Vibrio spp. For organisms other than those in the groups mentioned above, studies are not yet adequate to develop reproducible, definitive standards to interpret results. These organisms may require different media or different atmospheres of incubation, or they may show marked strain-to-strain variation in growth rate. For these microorganisms, consultation with an infectious disease specialist is recommended for guidance in determining the need for susceptibility testing and in the interpretation of results. Published reports in the medical literature and current consensus recommendations for therapy of uncommon microorganisms may obviate the need for testing. If necessary, a dilution method usually is the most appropriate testing method, and this may require submitting the organism to a reference laboratory. Physicians should be informed of the limitations of results and advised to interpret results with caution.

C.

Policies regarding the generation of cumulative antibiograms should be developed in concert with the infectious disease service, infection control personnel, and the pharmacy and therapeutics committee. Under most circumstances, the percentage of susceptible and intermediate results should not be combined into the same statistics. See CLSI document M39—Analysis and Presentation of Cumulative Antimicrobial Susceptibility Test Data.

III.

Therapy-Related Comments Some of the comments in the tables relate to therapy concerns. These are denoted with an Rx symbol. It may be appropriate to include some of these comments (or modifications thereof) on the patient report. An example would be inclusion of a comment on Enterococcus susceptibility reports from blood cultures that “combination therapy with ampicillin, penicillin, or vancomycin (for susceptible strains) plus an aminoglycoside is usually indicated for serious enterococcal infections, such as endocarditis unless high-level resistance to both gentamicin and streptomycin is documented; such combinations are predicted to result in synergistic killing of the Enterococcus.” Antimicrobial dosage regimens often vary widely among practitioners and institutions. In some cases, the MIC interpretive criteria rely on pharmacokinetic-pharmacodynamic data, using specific human dosage regimens. In cases where specific dosage regimens are important for proper application of breakpoints, a therapy-related comment is included.

IV.

Verification of Patient Results Multiple test parameters are monitored by following the QC recommendations described in this standard. However, acceptable results derived from testing QC strains do not guarantee accurate results when testing patient isolates. It is important to review all of the results obtained from all drugs tested on a patient’s isolate before reporting the results. This should include, but not be limited to, ensuring that 1) the antimicrobial susceptibility results are consistent with the

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identification of the isolate; 2) the results from individual agents within a specific drug class follow the established hierarchy of activity rules (eg, in general, third-generation cephems are more active than first- or second-generation cephems against Enterobacteriaceae); and 3) the isolate is susceptible to those agents for which resistance has not been documented (eg, vancomycin and Streptococcus spp.) and for which only “susceptible” interpretive criteria exist in M100. Unusual or inconsistent results should be verified by checking for the following: 1) transcription errors; 2) contamination of the test (eg, recheck purity plates); 3) for MIC tests, use of a defective panel, plate, or card (eg, broken, underfilled): and 4) previous results on the patient (eg, Did the patient have the same isolate with an unusual antibiogram previously?). If a reason for the unusual or inconsistent result cannot be ascertained, a repeat of the susceptibility test or the identification or both of these is in order. Sometimes, it is helpful to use an alternative test method for the repeat test. A suggested list of results that may require verification is included in Appendix A. Each laboratory must develop its own policies for verification of unusual or inconsistent antimicrobial susceptibility test results. This list should emphasize those results that are likely to affect patient care. V.

Development of Resistance and Testing of Repeat Isolates Isolates that are initially susceptible may become intermediate or resistant after initiation of therapy. Therefore, subsequent isolates of the same species from a similar body site should be tested in order to detect resistance that may have developed. This can occur within as little as three to four days and has been noted most frequently in Enterobacter, Citrobacter, and Serratia spp. with third-generation cephalosporins; in P. aeruginosa with all antimicrobial agents; and in staphylococci with quinolones. For S. aureus, vancomycin-susceptible isolates may become vancomycin intermediate during the course of prolonged therapy. In certain circumstances, testing of subsequent isolates to detect resistance that may have developed might be warranted earlier than within three to four days. The decision to do so requires knowledge of the specific situation and the severity of the patient’s condition (eg, an isolate of Enterobacter cloacae from a blood culture on a premature infant). Laboratory guidelines on when to perform susceptibility testing on repeat isolates should be determined after consultation with the medical staff.

VI.

Warning Some of the comments in the tables relate to dangerously misleading results that can occur when certain antimicrobial agents are tested and reported as susceptible against specific organisms. These are denoted with the word “Warning.”

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“Warning”: The following antimicrobial agent/organism combinations may appear active in vitro but are not effective clinically and should not be reported as susceptible. Location Organism Antimicrobial agents that must not be reported as susceptible Table 2A ESBL-producing K. pneumoniae, K. oxytoca, Penicillins, cephalosporins, and aztreonam E. coli, and P. mirabilis Table 2A Salmonella spp., Shigella spp. 1st- and 2nd-generation cephalosporins, cephamycins, and aminoglycosides Table 2C Oxacillin-resistant Staphylococcus spp. Penicillins, β-lactam/β-lactamase inhibitor combinations, cephems, and carbapenems Table 2D Enterococcus spp. Aminoglycosides (except high concentrations), cephalosporins, clindamycin, and trimethoprimsulfamethoxazole Table 2K Yersinia pestis β-lactam antimicrobial agents

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Screening Tests

Screening tests, as described in this document, characterize an isolate as susceptible or resistant to one or more antimicrobial agents based on a specific resistance mechanism or phenotype. Some screening tests have sufficient sensitivity and specificity such that results of the screen can be reported without additional testing. Others require further testing to confirm the presumptive results obtained with the screen test. A summary of the screening tests is provided here; the details for each screening test, including test specifications, limitations, and additional tests needed for confirmation, are provided in Supplemental Tables 2A-S1, 2A-S2, 2C-S3, 2C-S4, and 2D-S5.

Organism Group Enterobacteriaceae

Staphylococcus aureus

Table Location 2A-S1

Resistance Phenotype or Mechanism ESBL production

2A-S2

Carbapenemase production

2C-S3

β-Lactamase production

Oxacillin resistance

Coagulase-negative staphylococci

Enterococci

Streptococcus pneumoniae

2C-S4

2D-S5

2G

mecA-Mediated oxacillin resistance Vancomycin MIC ≥ 8 µg/mL Inducible clindamycin resistance High-level mupirocin resistance β-Lactamase production

mecA-Mediated oxacillin resistance Inducible clindamycin resistance Vancomycin resistance High-level aminoglycoside resistance (HLAR) Penicillin resistance

Screening Tests Broth microdilution and disk diffusion with various cephalosporins and aztreonam Broth microdilution and disk diffusion with various carbapenems Chromogenic cephalosporin or other method

Agar dilution; MHA with 4% NaCl and 6 µg/mL oxacillin Broth microdilution and disk diffusion with cefoxitin Agar dilution; BHI with 6 µg/mL vancomycin Broth microdilution and disk diffusion with clindamycin and erythromycin Broth microdilution and disk diffusion with mupirocin Chromogenic cephalosporin or other method Disk diffusion with cefoxitin Broth microdilution and disk diffusion with clindamycin and erythromycin Agar dilution with vancomycin Broth microdilution, agar dilution, and disk diffusion with gentamicin and streptomycin Disk diffusion with oxacillin

Further Testing or Confirmation Required? Yes, if screen test positivea Yes, if screen test positive If screen test negative, perform repeat penicillin MIC and induced β-lactamase test (if penicillin MIC < 0.12 µg/mL) on subsequent isolates from same patient No No Yes, if screen test positive No No If screen test negative, perform repeat test on subsequent isolates from same patient No No Yes, if screen test positive No for MIC; yes for disk, if inconclusive Yes, if nonsusceptible

a

If the revised cephalosporin and aztreonam breakpoints are used, ESBL testing is not required; but if the ESBL screen is performed, the confirmatory test must be performed to establish the presence of an ESBL.

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Abbreviations and Acronyms

AST ATCC BHI BLNAR BSC BSL-2 BSL-3 CAMHB CDC CSF DMF DMSO ESBL FDA HLAR HTM KPC LHB MHA MHB MIC MRS MRSA NAD PABA PBP 2a PK-PD QC

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M100-S20

antimicrobial susceptibility testing American Type Culture Collection Brain Heart Infusion β-lactamase negative, ampicillin-resistant biological safety cabinet Biosafety Level 2 Biosafety Level 3 cation-adjusted Mueller-Hinton broth Centers for Disease Control and Prevention cerebrospinal fluid dimethylformamide dimethyl sulfoxide extended-spectrum β-lactamase US Food and Drug Administration high-level aminoglycoside resistance Haemophilus Test Medium Klebsiella pneumoniae carbapenemase lysed horse blood Mueller-Hinton agar Mueller-Hinton broth minimal inhibitory concentration methicillin-resistant staphylococci methicillin-resistant S. aureus nicotinamide adenine dinucleotide para-aminobenzoic acid penicillin-binding protein 2a pharmacokinetics-pharmacodynamics quality control

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Table 1. Suggested Groupings of Antimicrobial Agents With FDA Clinical Indications That Should Be Considered for Routine Testing and Reporting on Nonfastidious Organisms by Clinical Microbiology Laboratories in the United States GROUP A PRIMARY TEST AND REPORT

Enterobacteriaceaeg Ampicilling

Staphylococcus spp. Azithromycind or clarithromycind or erythromycind Clindamycind

Enterococcus spp.n Ampicillin Penicillino

Oxacillin (cefoxitin)k,l

*Cefazolini Gentamicin Tobramycin Amikacin

Amoxicillin-clavulanic acid Ampicillin-sulbactam Piperacillin-tazobactam Ticarcillin-clavulanic acid Cefuroxime

GROUP Be PRIMARY TEST REPORT SELECTIVELY

Pseudomonas aeruginosa Ceftazidime

Cefepime Cefotetan Cefoxitin

Penicillink

Gentamicin Tobramycin Piperacillin

Trimethoprimsulfamethoxazole

Amikacin

*Daptomycin

*Daptomycin

Aztreonam

Linezolid

Linezolid

Cefepime

Telithromycind

Quinupristindalfopristinp

Doxycycline Tetracyclineb

Vancomycin

Ciprofloxacin Levofloxacin

Vancomycin

Imipenem Meropenem Piperacillin-tazobactam Ticarcillin

Rifampinc

Cefotaximeg,h,i or ceftriaxoneg,h,i Ciprofloxacing Levofloxacing Ertapenem Imipenem Meropenem Piperacillin

GROUP Cf SUPPLEMENTAL REPORT SELECTIVELY GROUP U SUPPLEMENTAL FOR URINE ONLY

Table 1 Suggested Nonfastidious Groupings M02 and M07

Trimethoprim-sulfamethoxazoleg Aztreonam Ceftazidimei

Lomefloxacin or ofloxacin

Gentamicin (high-level resistance screen only)

Ciprofloxacin or levofloxacin or ofloxacin

Streptomycin (high-level resistance screen only)

Moxifloxacin Gentamicin Quinupristindalfopristinm

Chloramphenicold,g Tetracyclineb

Cephalothina

Chloramphenicold

Lomefloxacin or ofloxacin

Lomefloxacin Norfloxacin

Ciprofloxacin Levofloxacin Norfloxacin

Norfloxacin

Norfloxacin Nitrofurantoin

Nitrofurantoin Nitrofurantoin Sulfisoxazole Trimethoprim

Sulfisoxazole Trimethoprim

Tetracyclineb

* = MIC testing only; disk diffusion test unreliable.

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GROUP A PRIMARY TEST AND REPORT

Table 1. (Continued) Acinetobacter spp.j Ampicillin-sulbactam

Burkholderia cepaciaj Trimethoprimsulfamethoxazole

Stenotrophomonas maltophilia j Trimethoprimsulfamethoxazole

Ceftazidime Ciprofloxacin Levofloxacin Imipenem Meropenem

Gentamicin Tobramycin Piperacillin

Gentamicin Tobramycin Amikacin

GROUP Be PRIMARY TEST REPORT SELECTIVELY

*Other nonEnterobacteriaceaej Ceftazidime

Piperacillin-tazobactam Ticarcillin-clavulanate

Ceftazidime

*Ceftazidime

Amikacin

*Chloramphenicold

*Chloramphenicold

Aztreonam

*Levofloxacin

Levofloxacin

Cefepime

Meropenem

Minocycline

Minocycline *Ticarcillin-clavulanate

*Ticarcillin-

Ciprofloxacin Levofloxacin Imipenem Meropenem

Cefepime

clavulanate

Piperacillin-tazobactam Ticarcillin-clavulanate

Cefotaxime Ceftriaxone Trimethoprimsulfamethoxazole Doxycycline Minocycline Tetracycline Piperacillin

GROUP U SUPPLEMENTAL FOR URINE ONLY

Cefotaxime Ceftriaxone

Table 1 Suggested Nonfastidious Groupings M02 and M07

GROUP Cf SUPPLEMENTAL REPORT SELECTIVELY

Trimethoprim-sulfamethoxazole

Chloramphenicold

Lomefloxacin or ofloxacin Norfloxacin

Sulfisoxazole Tetracyclineb

* = MIC testing only; disk diffusion test unreliable.

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Table 1. (Continued) “Warning”: The following antimicrobial agents should not be routinely reported for bacteria isolated from CSF that are included in this document. These antimicrobial agents are not the drugs of choice and may not be effective for treating CSF infections caused by these organisms (ie, the bacteria included in Tables 2A through 2L):

Table 1 Suggested Nonfastidious Groupings M02 and M07

agents administered by oral route only 1st- and 2nd-generation cephalosporins (except cefuroxime parenteral) and cephamycins clindamycin macrolides tetracyclines fluoroquinolones NOTE 1:

Selection of the most appropriate antimicrobial agents to test and to report is a decision made best by each clinical laboratory in consultation with the infectious disease practitioners and the pharmacy, as well as the pharmacy and therapeutics and infection control committees of the medical staff. The lists for each organism group comprise agents of proven efficacy that show acceptable in vitro test performance. Considerations in the assignment of agents to Groups A, B, C, and U include clinical efficacy, prevalence of resistance, minimizing emergence of resistance, cost, FDA clinical indications for usage and current consensus recommendations for first-choice and alternative drugs, in addition to the specific comments in footnotes “e” and “f.” Unexpected resistance should be reported (eg, resistance of Enterobacteriaceae to carbapenems). Tests of selected agents may be useful for infection control purposes.

NOTE 2:

The listing of drugs together in a single box designates clusters of agents for which interpretive results (susceptible, intermediate, or resistant) and clinical efficacy are similar. Within each box, an “or” between agents designates those agents for which cross resistance and cross susceptibility are nearly complete. This means combined major and very major errors are fewer than 3% and minor errors are fewer than 10%, based on a large population of bacteria tested. In addition, to qualify for an “or,” at least 100 strains with resistance to the agents in question must be tested and a result of “resistant” must be obtained with all agents for at least 95% of the strains. “Or” is also used for comparable antimicrobial agents when tested against organisms for which “susceptible-only” interpretive criteria are provided (eg, cefotaxime or ceftriaxone with Haemophilus influenzae). Thus, results from one agent connected by an “or” could be used to predict results for the other agent. For example, a non–ESBL-producing isolate of Enterobacteriaceae susceptible to cefotaxime can be considered susceptible to ceftriaxone. The results obtained from testing cefotaxime would be reported and a comment could be included on the report that the isolate is also susceptible to ceftriaxone. When no “or” connects agents within a box, testing of one agent cannot be used to predict results for another either owing to discrepancies or insufficient data.

NOTE 3:

Information in boldface type is considered tentative for one year. Footnotes

General Comments a. Cephalothin interpretive criteria should be used only to predict results to the oral agents, cefadroxil, cefpodoxime, cephalexin, and loracarbef. Older data that suggest that cephalothin results could predict susceptibility to some other cephalosporins may still be correct, but there are no recent data to confirm this. b. Organisms that are susceptible to tetracycline are also considered susceptible to doxycycline and minocycline. However, some organisms that are intermediate or resistant to tetracycline may be susceptible to doxycycline, minocycline, or both.

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Table 1. (Continued) c.

Rx: Rifampin should not be used alone for antimicrobial therapy.

d. Not routinely reported on organisms isolated from the urinary tract. e. Group B represents agents that may warrant primary testing but that should be reported only selectively, such as when the organism is resistant to agents of the same family in Group A. Other indications for reporting the result might include selected specimen sources (eg, selected thirdgeneration cephalosporins for isolates of enteric bacteria from CSF or trimethoprim-sulfamethoxazole for urinary tract isolates); stated allergy or intolerance, or failure to respond to an agent in Group A; polymicrobial infections; infections involving multiple sites with different microorganisms; or reports to infection control for epidemiological aid. f.

Group C represents alternative or supplemental antimicrobial agents that may require testing in those institutions that harbor endemic or epidemic strains resistant to one or more of the primary drugs (especially in the same family, eg, β-lactams), or for treatment of unusual organisms (eg, chloramphenicol for extraintestinal isolates of Salmonella spp.) or reporting to infection control as an epidemiological aid.

Enterobacteriaceae g. When fecal isolates of Salmonella and Shigella spp. are tested, only ampicillin, a fluoroquinolone, and trimethoprim/sulfamethoxazole should be reported routinely. In addition, chloramphenicol and a thirdgeneration cephalosporin should be tested and reported for extraintestinal isolates of Salmonella spp.

i.

Following evaluation of pharmacokinetics-pharmacodynamics (PK-PD) properties and limited clinical data, new (revised) interpretive criteria for cephalosporins (cefazolin, cefotaxime, ceftazidime, ceftizoxime, and ceftriaxone) and aztreonam were established and are listed in Table 2A. Cefepime and cefuroxime (parenteral) were also evaluated; however, no change in interpretive criteria was required for the dosages indicated in Table 2A. When using the new interpretive criteria, routine ESBL testing is no longer necessary before reporting results (ie, it is no longer necessary to edit results for cephalosporins, aztreonam, or penicillins from susceptible to resistant). However, until laboratories implement the new interpretive criteria, ESBL testing should be performed as described in Supplemental Table 2A-S2. ESBL testing may still be useful for epidemiological or infection control purposes. Note that interpretive criteria for drugs with limited availability in many countries (eg, moxalactam, cefonicid, cefamandole, and cefoperazone) were not evaluated. If considering use of these drugs for E. coli, Klebsiella, or Proteus spp., ESBL testing should be performed (see Supplemental Table 2A-S1). If isolates test ESBL positive, the results for moxalactam, cefonicid, cefamandole, and cefoperazone should be reported as resistant.

Pseudomonas aeruginosa and Other Non-Enterobacteriaceae j.

Other non-Enterobacteriaceae include Pseudomonas spp. and other nonfastidious, glucosenonfermenting, gram-negative bacilli but exclude Pseudomonas aeruginosa, Acinetobacter spp., Burkholderia cepacia, B. mallei, B. pseudomallei, and Stenotrophomonas maltophilia, because there are separate lists of suggested drugs to test and report for them.

Staphylococcus spp. k.

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Penicillin-susceptible staphylococci are also susceptible to other penicillins, β-lactam/β-lactamase inhibitor combinations, cephems, and carbapenems approved for use by the FDA for staphylococcal

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Table 1 Suggested Nonfastidious Groupings M02 and M07

h. Cefotaxime and ceftriaxone should be tested and reported on isolates from CSF in place of cephalothin and cefazolin.

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Table 1. (Continued) infections. Penicillin-resistant, oxacillin-susceptible strains are resistant to penicillinase-labile penicillins but susceptible to other penicillinase-stable penicillins, β-lactam/β-lactamase inhibitor combinations, relevant cephems, and carbapenems. Oxacillin-resistant staphylococci are resistant to all currently available β-lactam antimicrobial agents with the exception of the newer cephalosporins with anti-MRSA activity. Thus, susceptibility or resistance to a wide array of βlactam antimicrobial agents may be deduced from testing only penicillin and either cefoxitin or oxacillin. Routine testing of other penicillins, β-lactam/β-lactamase inhibitor combinations, cephems, or carbapenems is not advised. l.

The results of either cefoxitin disk diffusion or cefoxitin MIC tests can be used to predict the presence of mecA-mediated oxacillin resistance in S. aureus and S. lugdunensis. For coagulase-negative staphylococci (except S. lugdunensis), the cefoxitin disk diffusion test is the preferred method for detection of mecA-mediated oxacillin resistance. Cefoxitin is used as a surrogate for detection of oxacillin resistance; report oxacillin as susceptible or resistant based on cefoxitin results. If a penicillinase-stable penicillin is tested, oxacillin is the preferred agent and results can be applied to the other penicillinase-stable penicillins, cloxacillin, dicloxacillin, and flucloxacillin.

m. For reporting against methicillin-susceptible S. aureus. Enterococcus spp. n. Warning: For Enterococcus spp., cephalosporins, aminoglycosides (except for high-level resistance screening), clindamycin, and trimethoprim-sulfamethoxazole may appear active in vitro but are not effective clinically and should not be reported as susceptible.

Table 1 Suggested Nonfastidious Groupings M02 and M07

o. Enterococci susceptible to penicillin are predictably susceptible to ampicillin, amoxicillin, ampicillinsulbactam, amoxicillin-clavulanate, piperacillin, and piperacillin-tazobactam for non–β-lactamaseproducing enterococci. However, enterococci susceptible to ampicillin cannot be assumed to be susceptible to penicillin. If penicillin results are needed, testing of penicillin is required. Rx: Combination therapy with ampicillin, penicillin, or vancomycin (for susceptible strains) plus an aminoglycoside is usually indicated for serious enterococcal infections, such as endocarditis unless high-level resistance to both gentamicin and streptomycin is documented; such combinations are predicted to result in synergistic killing of the Enterococcus. p. For reporting against vancomycin-resistant Enterococcus faecium.

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GROUP A PRIMARY TEST AND REPORT

Table 1A. Suggested Groupings of Antimicrobial Agents With FDA Clinical Indications That Should Be Considered for Routine Testing and Reporting on Fastidious Organisms by Clinical Microbiology Laboratories in the United States f

Haemophilus spp. f,h Ampicillin

Neisseria j gonorrhoeae

l

Trimethoprimsulfamethoxazole

GROUP Bb PRIMARY TEST REPORT SELECTIVELY

Ampicillin-sulbactam Cefuroxime (parenteral)

Streptococcus spp. r β-hemolytic Group e,q Clindamycin a,e,q Erythromycin

Streptococcus spp. r Viridans Group n *Ampicillin n *Penicillin

Penicillin (oxacillin disk) Trimethoprimsulfamethoxazole

Penicillin or o ampicillin

*Cefepime *Cefotaximel *Ceftriaxonel

Cefepime or cefotaxime or ceftriaxone

Cefepime Cefotaxime Ceftriaxone

Vancomycin

Vancomycin

o

e

Clindamycin k Gemifloxacin k Levofloxacin k Moxifloxacin Ofloxacin *Meropeneml

f

Cefotaxime or ceftazidime or f ceftriaxone Chloramphenicol

Meropenem

e,f

Telithromycin d Tetracycline l Vancomycin

f,i

g

Azithromycin g Clarithromycin Aztreonam

Cefixime or cefpodoxime

Amoxicilling clavulanic acid

Cefotaxime or ceftriaxone

g

*Amoxicillin *Amoxicillin-

Chloramphenicol

*Cefuroxime

e

e

a,e

*Daptomycin

g

Ciprofloxacin or levofloxacin or lomefloxacin or moxifloxacin or ofloxacin

Chloramphenicol

Erythromycin

Levofloxacin Ofloxacin

Cefdinir or g cefixime or g cefpodoxime Cefuroxime (oral)

e

Clindamycin

clavulanic acid

Cefoxitin Cefuroxime

Cefaclor g Cefprozil

GROUP CC SUPPLEMENTAL REPORT SELECTIVELY

Streptococcus k pneumoniae a,e Erythromycin

Ciprofloxacin or ofloxacin Penicillin

Chloramphenicol

*Ertapenem *Imipenem

j

e

Linezolid

Linezolid

Quinupristinp dalfopristin

Linezolid

Gemifloxacin Ertapenem or imipenem

Spectinomycin Tetracycline

Rifampin

m

d

Table 1A Suggested Fastidious Groupings M02 and M07

Rifampin g Telithromycin Tetracycline

d

* = MIC testing only; disk diffusion test unreliable.

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Table 1A. (Continued) “Warning”: The following antimicrobial agents should not be routinely reported for bacteria isolated from CSF that are included in this document. These antimicrobial agents are not the drugs of choice and may not be effective for treating CSF infections caused by these organisms (ie, the bacteria included in Tables 2A through 2L): agents administered by oral route only 1st- and 2nd-generation cephalosporins (except cefuroxime parenteral) and cephamycins clindamycin macrolides tetracyclines fluoroquinolones NOTE 1: Selection of the most appropriate antimicrobial agents to test and to report is a decision made best by each clinical laboratory in consultation with the infectious disease practitioners and the pharmacy, as well as the pharmacy and therapeutics and infection control committees of the medical staff. The lists for each organism group comprise agents of proven efficacy that show acceptable in vitro test performance. Considerations in the assignment of agents to Groups A, B, and C include clinical efficacy, prevalence of resistance, minimizing emergence of resistance, cost, FDA clinical indications for usage and current consensus recommendations for first-choice and alternative drugs, in addition to the specific comments in footnotes “b” and “c.” Unexpected resistance should be reported (eg, resistance of Enterobacteriaceae to carbapenems). Tests on selected agents may be useful for infection control purposes. NOTE 2: The listing of drugs together in a single box designates clusters of agents for which interpretive results (susceptible, intermediate, or resistant) and clinical efficacy are similar. Within each box, an “or” between agents designates those agents for which cross resistance and cross susceptibility are nearly complete. This means combined major and very major errors are fewer than 3% and minor errors are fewer than 10%, based on a large population of bacteria tested. In addition, to qualify for an “or,” at least 100 strains with resistance to the agents in question must be tested and a result of “resistant” must be obtained with all agents for at least 95% of the strains. “Or” is also used for comparable antimicrobial agents when tested against organisms for which “susceptible-only” interpretive criteria are provided (eg, cefotaxime or ceftriaxone with Haemophilus influenzae). Thus, results from one agent connected by an “or” could be used to predict results for the other agent. For example, a non–ESBL-producing isolate of Enterobacteriaceae susceptible to cefotaxime can be considered susceptible to ceftriaxone. The results obtained from testing cefotaxime would be reported and a comment could be included on the report that the isolate is also susceptible to ceftriaxone. When no “or” connects agents within a box, testing of one agent cannot be used to predict results for another either owing to discrepancies or insufficient data. NOTE 3: Information in boldface type is considered tentative for one year. Footnotes a. Susceptibility and resistance to azithromycin, clarithromycin, and dirithromycin can be predicted by testing erythromycin. b. Group B represents agents that may warrant primary testing but that should be reported only selectively, such as when the organism is resistant to agents of the same class in Group A. Other indications for reporting the result might include selected specimen sources (eg, third-generation cephalosporin for isolates of Haemophilus influenzae from CSF); stated allergy or intolerance, or failure to respond to an agent in Group A; polymicrobial infections; infections involving multiple sites with different microorganisms; or reports to infection control for epidemiological aid. ©

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Table 1A Suggested Fastidious Groupings M02 and M07

General Comments

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Table 1A. (Continued) c.

Group C represents alternative or supplemental antimicrobial agents that may require testing in those institutions that harbor endemic or epidemic strains resistant to one or more of the primary drugs (especially in the same class, eg, β-lactams), or for treatment of unusual organisms, or reporting to infection control as an epidemiological aid.

d. Organisms that are susceptible to tetracycline are also considered susceptible to doxycycline and minocycline. e. Not routinely reported for organisms isolated from the urinary tract. Haemophilus spp. f.

Only results of testing with ampicillin, one of the third-generation cephalosporins; chloramphenicol; and meropenem should be reported routinely with CSF isolates of H. influenzae.

g. Amoxicillin-clavulanic acid, azithromycin, cefaclor, cefdinir, cefixime, cefpodoxime, cefprozil, cefuroxime, clarithromycin, loracarbef, and telithromycin are oral agents that may be used as empiric therapy for respiratory tract infections due to Haemophilus spp. The results of susceptibility tests with these antimicrobial agents are often not useful for management of individual patients. However, susceptibility testing of Haemophilus spp. with these compounds may be appropriate for surveillance or epidemiological studies. h. The results of ampicillin susceptibility tests should be used to predict the activity of amoxicillin. The majority of isolates of H. influenzae that are resistant to ampicillin and amoxicillin produce a TEM-type β-lactamase. In most cases, a direct β-lactamase test can provide a rapid means of detecting ampicillin and amoxicillin resistance. i.

Clinical indications and relevant pathogens include bacterial meningitis and concurrent bacteremia in association with meningitis caused by H. influenzae (β-lactamase- and non–β-lactamase-producing strains).

Neisseria gonorrhoeae j.

A β-lactamase test detects one form of penicillin resistance in N. gonorrhoeae and also may be used to provide epidemiological information. Strains with chromosomally mediated resistance can be detected only by additional susceptibility testing, such as the disk diffusion method or the agar dilution MIC method.

Table 1A Suggested Fastidious Groupings M02 and M07

Streptococcus pneumoniae k.

S. pneumoniae isolates susceptible to levofloxacin are predictably susceptible to gemifloxacin and moxifloxacin. However, S. pneumoniae susceptible to gemifloxacin or moxifloxacin cannot be assumed to be susceptible to levofloxacin.

l.

Penicillin and cefotaxime or ceftriaxone or meropenem should be tested by a reliable MIC method (such as that described in CLSI document M07-A8) and reported routinely with CSF isolates of S. pneumoniae. Such isolates should also be tested against vancomycin using the MIC or disk method. With isolates from other sites, the oxacillin disk screening test may be used. If the oxacillin zone size is ≤ 19 mm, penicillin or cefotaxime or ceftriaxone or meropenem MICs should be determined.

m. Rx: Rifampin should not be used alone for antimicrobial therapy. Streptococcus spp. n. Rx: Penicillin- or ampicillin-intermediate isolates may require combined therapy with an aminoglycoside for bactericidal action.

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Table 1A. (Continued) o. Susceptibility testing of penicillins and other β-lactams approved by the FDA for treatment of Streptococcus pyogenes or S. agalactiae is not necessary for clinical purposes and need not be performed routinely, because as with vancomycin, resistant strains have not been recognized. Interpretive criteria are provided for pharmaceutical development, epidemiology, or monitoring for emerging resistance. Any strains found to be nonsusceptible should be referred to a reference laboratory for confirmation. p. Report against S. pyogenes. q. Rx: Recommendations for intrapartum prophylaxis for Group B streptococci are penicillin or ampicillin. Although cefazolin is recommended for penicillin-allergic women at low risk for anaphylaxis, those at high risk for anaphylaxis may receive clindamycin or erythromycin. Group B streptococci are susceptible to ampicillin, penicillin, and cefazolin but may be resistant to clindamycin and/or erythromycin. When Group B Streptococcus is isolated from a pregnant woman with severe penicillin allergy (high risk for anaphylaxis), clindamycin and erythromycin should be tested and reported. For this table, the β-hemolytic group includes the large-colony–forming pyogenic strains of streptococci with Group A (S. pyogenes), C, or G antigens and strains with Group B (S. agalactiae) antigen. Small-colony–forming β-hemolytic strains with Group A, C, F, or G antigens (S. anginosus group, previously termed “S. milleri”) are considered part of the viridans group, and interpretive criteria for the viridans group should be used.

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Table 1A Suggested Fastidious Groupings M02 and M07

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Table 1B Suggested Potential Agents of Bioterrorism Groupings M07

January 2010

Vol. 30 No. 1

Table 1B. Antimicrobial Agents That Should Be Testeda and Reported on Potential Bacterial Agents of Bioterrorism (MIC methods only) Bacillus anthracis

Yersinia pestis

Burkholderia mallei

Gentamicin

Ceftazidime

Doxycycline Tetracycline

Streptomycin

Doxycycline Tetracycline

Ciprofloxacin

Doxycycline Tetracycline

Imipenem

Penicillin

b

Burkholderia pseudomallei Amoxicillin-clavulanic acid Ceftazidime Doxycycline Tetracycline

Ciprofloxacin

Imipenem

Chloramphenicol

Trimethoprimsulfamethoxazole

Trimethoprimsulfamethoxazole

Footnotes a.

Extreme caution: Notify public health officials of all isolates presumptively identified as B. anthracis, Y. pestis, B. mallei, B. pseudomallei, or F. tularensis. Confirmation of isolates of these bacteria may require specialized testing available only in reference or public health laboratories.

b.

Organisms that are susceptible to penicillin are also considered susceptible to amoxicillin.

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Table 2A Enterobacteriaceae M02 and M07

Testing Conditions

Minimal QC Recommendations (See Tables 3 and 4 for acceptable QC ranges.)

Medium:

Disk diffusion: MHA Broth dilution: CAMHB Agar dilution: MHA Inoculum: Growth method or direct colony suspension, equivalent to a 0.5 McFarland standard Incubation: 35 ± 2 °C; ambient air; Disk diffusion: 16 to 18 hours Dilution methods: 16 to 20 hours

Escherichia coli ATCC® 25922 Escherichia coli ATCC® 35218 (for β-lactam/β-lactamase inhibitor combinations)

January 2010

40

Table 2A. Zone Diameter and MIC Interpretive Standards for Enterobacteriaceae

Refer to Supplemental Tables 2A-S1 and 2A-S2 at the end of Table 2A for additional recommendations for testing conditions, reporting suggestions, and QC.

General Comments

(2) When fecal isolates of Salmonella and Shigella spp. are tested, only ampicillin, a fluoroquinolone, and trimethoprim-sulfamethoxazole should be reported routinely. In addition, chloramphenicol and a third-generation cephalosporin should be tested and reported for extraintestinal isolates of Salmonella spp. (3) Refer to Table 2K for testing of Y. pestis. NOTE: Information in boldface type is considered tentative for one year.

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(1) For disk diffusion, measure the diameter of the zones of complete inhibition (as judged by the unaided eye), including the diameter of the disk. Hold the Petri plate a few inches above a black, nonreflecting background illuminated with reflected light. The zone margin should be considered the area showing no obvious, visible growth that can be detected with the unaided eye. Ignore faint growth of tiny colonies that can be detected only with a magnifying lens at the edge of the zone of inhibited growth. Strains of Proteus spp. may swarm into areas of inhibited growth around certain antimicrobial agents. With Proteus spp., ignore the thin veil of swarming growth in an otherwise obvious zone of growth inhibition. With trimethoprim and the sulfonamides, antagonists in the medium may allow some slight growth; therefore, disregard slight growth (20% or less of the lawn of growth) and measure the more obvious margin to determine the zone diameter.

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Test/Report Group PENICILLINS A

Antimicrobial Agent

Disk Content

Zone Diameter Breakpoints, nearest whole mm S I R

MIC Interpretive Standard (µg/mL) S I R

Ampicillin

10 μg

≥ 17

14–16

≤ 13

≤8

16

≥ 32

Piperacillin Mecillinam

100 μg 10 μg

≥ 21 ≥ 15

18–20 12–14

≤ 17 ≤ 11

≤ 16 ≤8

32–64 16

≥ 128 ≥ 32

O Carbenicillin O Mezlocillin O Ticarcillin β-LACTAM/β-LACTAMASE COMBINATION B Amoxicillin-clavulanic acid B Ampicillin-sulbactam B Piperacillin-tazobactam

100 μg 75 μg 75 μg

≥ 23 ≥ 21 ≥ 20

20–22 18–20 15–19

≤ 19 ≤ 17 ≤ 14

≤ 16 ≤ 16 ≤ 16

32 32–64 32–64

≥ 64 ≥ 128 ≥ 128

20/10 µg 10/10 µg 100/10 µg

≥ 18 ≥ 15 ≥ 21

14–17 12–14 18–20

≤ 13 ≤ 11 ≤ 17

≤ 8/4 ≤ 8/4 ≤ 16/4

≥ 32/16 ≥ 32/16 ≥ 128/4

75/10 µg

≥ 20

15–19

≤ 14

≤ 16/2

16/8 16/8 32/4– 64/4 32/2– 64/2

B O

B

Ticarcillin-clavulanate

Comments (4) Class representative for ampicillin and amoxicillin. See comment (2). (5) For use against E. coli urinary tract isolates only.

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Table 2A. (Continued)

≥ 128/2

CEPHEMS (PARENTERAL) (including cephalosporins I, II, III, and IV. Please refer to Glossary I.) (6) WARNING: For Salmonella spp. and Shigella spp., first- and second-generation cephalosporins and cephamycins may appear active in vitro but are not effective clinically and should not be reported as susceptible. (7) Following evaluation of pharmacokinetics-pharmacodynamics (PK-PD) properties and limited clinical data, new (revised) interpretive criteria for cephalosporins (cefazolin, cefotaxime, ceftazidime, ceftizoxime, and ceftriaxone) and aztreonam were established and are listed in this table. Cefepime and cefuroxime (parenteral) were also evaluated; however, no change in interpretive criteria was required for the dosages indicated below. When using the new interpretive criteria, routine ESBL testing is no longer necessary before reporting results (eg, it is no longer necessary to edit results for cephalosporins, aztreonam, or penicillins from susceptible to resistant). However, until laboratories implement the new interpretive criteria, ESBL testing should be performed as described in Supplemental Table 2A-S1. ESBL testing may still be useful for epidemiological or infection control purposes. Note that interpretive criteria for drugs with limited availability in many countries (ie, moxalactam, cefonicid, cefamandole, and cefoperazone) were not evaluated. If considering use of these drugs for E. coli, Klebsiella, or Proteus spp., ESBL testing should be performed (see Supplemental Table 2A-S1). If isolates test ESBL positive, the results for moxalactam, cefonicid, cefamandole, and cefoperazone should be reported as resistant. (8) Enterobacter, Citrobacter, and Serratia may develop resistance during prolonged therapy with third-generation cephalosporins. Therefore, isolates that are initially susceptible may become resistant within three to four days after initiation of therapy. Testing of repeat isolates may be warranted.

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Table 2A Enterobacteriaceae M02 and M07

Table 2A Enterobacteriaceae M02 and M07

Product Name: Infobase 2010 - Release Date: February 2010 Table 2A. (Continued)

Cephalothin

30 µg

≥ 18

15–17

≤ 14

≤8

16

≥ 32

B

Cefepime

30 µg

≥ 18

15–17

≤ 14

≤8

16

≥ 32

B B

Cefotaxime or ceftriaxone

30 µg 30 µg

≥ 26 ≥ 23

23–25 20–22

≤ 22 ≤ 19

≤1 ≤1

2 2

≥4 ≥4

B B B

Cefotetan Cefoxitin Cefuroxime (parenteral)

30 μg 30 μg 30 μg

≥ 16 ≥ 18 ≥ 18

13–15 15–17 15–17

≤ 12 ≤ 14 ≤ 14

≤ 16 ≤8 ≤8

32 16 16

≥ 64 ≥ 32 ≥ 32

C

Ceftazidime

30 μg

≥ 21

18–20

≤ 17

≤4

8

≥ 16

O O O O O

Cefamandole Cefmetazole Cefonicid Cefoperazone Ceftizoxime

30 μg 30 μg 30 μg 75 μg 30 μg

≥ 18 ≥ 16 ≥ 18 ≥ 21 ≥ 25

15–17 13–15 15–17 16–20 22–24

≤ 14 ≤ 12 ≤ 14 ≤ 15 ≤ 21

≤8 ≤ 16 ≤8 ≤ 16 ≤1

16 32 16 32 2

≥ 32 ≥ 64 ≥ 32 ≥ 64 ≥4

30 μg

≥ 23

15–22

≤ 14

≤ 8

16–32

≥ 64

30 μg 30 μg

≥ 23 ≥ 18

15–22 15–17

≤ 14 ≤ 14

≤ 4 ≤8

8–16 16

≥ 32 ≥ 32

30 μg 5 μg 5 μg

≥ 18 ≥ 20 ≥ 19

15–17 17–19 16–18

≤ 14 ≤ 16 ≤ 15

≤8 ≤1 ≤1

16 2 2

≥ 32 ≥4 ≥4

O Moxalactam CEPHEMS (ORAL) B Cefuroxime (oral) O Loracarbef

O O O

Cefaclor Cefdinir Cefixime

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(9) Disk diffusion interpretive criteria for cefazolin when using the revised MIC interpretive criteria listed here have not yet been established. (10) MIC interpretive criteria are based on a dosage regimen of at least 1 g every 8 h. See comment (7). (11) Cephalothin interpretive criteria should only be used to predict results to the oral agents, cefadroxil, cefpodoxime, cephalexin, and loracarbef. Older data that suggest that cephalothin results could predict susceptibility to some other cephalosporins may still be correct, but there are no recent data to confirm this. (12) Interpretive criteria are based on a dosage regimen of 1 g every 8 h or 2 g every 12 h. See comment (7). (13) Interpretive criteria are based on a dosage regimen of 1 g every 24 h for ceftriaxone and 1 g every 8 h for cefotaxime. See comment (7).

(14) Interpretive criteria are based on a dosage regimen of 1.5 g every 8 h. See comment (7). (15) Interpretive criteria are based on a dosage regimen of 1 g every 8 h. See comment (7). See comment (7). See comment (7). See comment (7). (16) Interpretive criteria are based on a dosage regimen of 1 g every 12 h. See comment (7). See comment (7).

(17) Because certain strains of Citrobacter, Providencia, and Enterobacter spp. have been reported to give false-susceptible results with cefdinir and loracarbef disks, strains of these genera should not be tested by disk diffusion and reported with these disks. See comment (17). (18) For disk diffusion, not applicable for testing Morganella spp.

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U

Comments

January 2010

42

Zone Diameter Breakpoints, MIC Interpretive Standard nearest whole mm (µg/mL) Test/Report Antimicrobial Disk Group Agent Content S I R S I R CEPHEMS (PARENTERAL) (including cephalosporins I, II, III, and IV. Please refer to Glossary I.) (Continued) A Cefazolin 30 µg – – – ≤1 2 ≥4

Product Name: Infobase 2010 - Release Date: February 2010

Test/Report Antimicrobial Group Agent CEPHEMS (ORAL) (Continued) O Cefpodoxime O Cefprozil

Inv. Cefetamet Inv. Ceftibuten MONOBACTAMS C Aztreonam

Zone Diameter Breakpoints, nearest whole mm

MIC Interpretive Standard (µg/mL)

Disk Content

S

I

R

S

I

R

Comments

10 μg 30 μg

≥ 21 ≥ 18

18–20 15–17

≤ 17 ≤ 14

≤2 ≤8

4 16

≥8 ≥ 32

10 μg 30 μg

≥ 18 ≥ 21

15–17 18–20

≤ 14 ≤ 17

≤4 ≤8

8 16

≥ 16 ≥ 32

See comment (18). (19) Because certain strains of Providencia spp. have been reported to give false-susceptible results with cefprozil disks, strains of this genus should not be tested and reported with this disk. See comment (18). (20) Indicated for urine isolates only.

30 µg

≥ 21

18–20

≤ 17

≤4

8

≥ 16

(22) Interpretive criteria are based on a dosage regimen of 1 g every 8 h. See comment (7).

CARBAPENEMS

For Use With M02-A10 and M07-A8

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Table 2A. (Continued)

(21) Enterobacteriaceae that are resistant to one or multiple agents in cephalosporin subclass lll and that demonstrate elevated MICs or reduced disk zone diameters to carbapenems may produce a carbapenemase despite the fact that the MICs or zone diameters may fall within the current susceptible range. Screening tests using MIC or zone diameter cutoffs and a confirmatory test, the modified Hodge test, which has shown sensitivity and specificity exceeding 90% in the detection of carbapenemase production in Enterobacteriaceae, are shown in Supplemental Table 2A-S2 at the end of Table 2A. Proteus spp., Providencia spp., and Morganella spp. may have elevated MICs to imipenem by mechanisms other than production of carbapenemases; thus, the usefulness of the imipenem MIC screen test for the detection of carbapenemases in these three genera is not established. The clinical efficacy of the carbapenems in the treatment of infections due to carbapenemase-producing Enterobacteriaceae that test susceptible using established susceptibility Interpretive criteria have not been confirmed. For isolates with confirmed carbapenemase production, MICs should be determined and reported but without an interpretation. Clinicians and infection control practitioners caring for patients with infections due to these isolates should be informed, and alternative antimicrobial agents should be considered. B Ertapenem B Imipenem B Meropenem AMINOGLYCOSIDES

10 µg 10 µg 10 µg

≥ 19 ≥ 16 ≥ 16

16–18 14–15 14–15

≤ 15 ≤ 13 ≤ 13

≤2 ≤4 ≤4

4 8 8

≥ 8 ≥ 16 ≥ 16

(23) WARNING: For Salmonella spp. and Shigella spp., aminoglycosides may appear active in vitro but are not effective clinically and should not be reported as susceptible. 10 μg 10 μg 30 μg 30 μg 30 μg 10 μg

≥ 15 ≥ 15 ≥ 17 ≥ 18 ≥ 15 ≥ 15

13–14 13–14 15–16 14–17 13–14 12–14

≤ 12 ≤ 12 ≤ 14 ≤ 13 ≤ 12 ≤ 11

≤4 ≤4 ≤ 16 ≤ 16 ≤8 –

8 8 32 32 16 –

≥ 16 ≥ 16 ≥ 64 ≥ 64 ≥ 32 –

(24) There are no MIC interpretive standards.

43

(25) Organisms that are susceptible to tetracycline are also considered susceptible to doxycycline and minocycline. However, some organisms that are intermediate or resistant to tetracycline may be susceptible to doxycycline, minocycline, or both. C Tetracycline ≥ 15 12–14 ≤ 11 8 30 μg ≤4 ≥ 16 O Doxycycline ≥ 14 11–13 ≤ 10 8 30 μg ≤4 ≥ 16 O Minocycline ≥ 16 13–15 ≤ 12 8 30 μg ≤4 ≥ 16

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Table 2A Enterobacteriaceae M02 and M07  

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A Gentamicin A Tobramycin B Amikacin O Kanamycin O Netilmicin O Streptomycin TETRACYCLINES

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Table 2A Enterobacteriaceae M02 and M07

Table 2A. (Continued) Disk Content

S

I

MIC Interpretive Standard (µg/mL) R

S

I

Comments

R

(26) Fluoroquinolone-susceptible strains of Salmonella that test resistant to nalidixic acid may be associated with clinical failure or delayed response in fluoroquinolone-treated patients with extraintestinal salmonellosis. Extraintestinal isolates of Salmonella should also be tested for resistance to nalidixic acid. For isolates that test susceptible to fluoroquinolones and resistant to nalidixic acid, the physician should be informed that the isolate may not be eradicated by fluoroquinolone treatment. A consultation with an infectious disease practitioner is recommended. See comment (2). B Ciprofloxacin B Levofloxacin U Lomefloxacin or U ofloxacin U Norfloxacin O Enoxacin O Gatifloxacin O Gemifloxacin O Grepafloxacin Inv. Fleroxacin QUINOLONES O Cinoxacin O Nalidixic acid

5 µg 5 µg 10 µg 5 µg 10 µg 10 µg 5 µg 5 µg 5 µg 5 µg

≥ 21 ≥ 17 ≥ 22 ≥ 16 ≥ 17 ≥ 18 ≥ 18 ≥ 20 ≥ 18 ≥ 19

16–20 14–16 19–21 13–15 13–16 15–17 15–17 16–19 15–17 16–18

≤ 15 ≤ 13 ≤ 18 ≤ 12 ≤ 12 ≤ 14 ≤ 14 ≤ 15 ≤ 14 ≤ 15

≤1 ≤2 ≤2 ≤2 ≤4 ≤2 ≤2 ≤ 0.25 ≤1 ≤2

2 4 4 4 8 4 4 0.5 2 4

≥ 4 ≥ 8 ≥ 8 ≥ 8 ≥ 16 ≥8 ≥8 ≥1 ≥4 ≥8

100 µg 30 µg

≥ 19 ≥ 19

15–18 14–18

≤ 14 ≤ 13

≤ 16 ≤ 16

32 –

≥ 64 ≥ 32

January 2010

44

Test/Report Antimicrobial Group Agent FLUOROQUINOLONES

Zone Diameter Breakpoints, nearest whole mm

(27) FDA-approved for Klebsiella pneumoniae.

See comments (20) and (26). FOLATE PATHWAY INHIBITORS B Trimethoprimsulfamethoxazole U Sulfonamides

1.25/ 23.75 µg 250 or 300 µg

≥ 16

11–15

≤ 10

≤ 2/38

–

≥ 4/76

See comment (2).

≥ 17

13–16

≤ 12

≤ 256

–

≥ 512

(29) Sulfisoxazole can be used to represent any of the currently available sulfonamide preparations.

Trimethoprim

5 µg

≥ 16

11–15

≤ 10

≤8

–

≥ 16

Chloramphenicol

30 µg

≥ 18

13–17

≤ 12

≤8

16

≥ 32

(30) Not routinely reported on isolates from the urinary tract.

FOSFOMYCINS O Fosfomycin

200 µg

≥ 16

13–15

≤ 12

≤ 64

128

≥ 256

(31) Indicated for use against E. coli urinary tract isolates only. (32) The 200-μg fosfomycin disk contains 50 μg of glucose-6-phosphate. (33) The approved MIC susceptibility testing method is agar dilution. Agar media should be supplemented with 25 μg/mL of glucose-6phosphate. Broth dilution should not be performed.

NITROFURANS U Nitrofurantoin

300 µg

≥ 17

15–16

≤ 14

≤ 32

64

≥ 128

U PHENICOLS C

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See comment (20). (28) In addition to testing urine isolates, nalidixic acid may be used to test for reduced fluoroquinolone susceptibility in isolates from patients with extraintestinal Salmonella infections.

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45

Supplemental Table 2A-S1

Product Name: Infobase 2010 - Release Date: February 2010 Screening and Confirmatory Tests for ESBLs

Supplemental Table 2A-S1. Screening and Confirmatory Tests for ESBLs in Klebsiella pneumoniae, Klebsiella oxytoca, Escherichia coli, and Proteus mirabilisa for Use With Table 2A

Incubation conditions Incubation length Results

Standard disk diffusion recommendations 35 ± 2 °C; ambient air

Standard broth dilution recommendations 35 ± 2 °C; ambient air

Standard disk diffusion recommendations 35 ± 2 °C; ambient air

Standard broth dilution recommendations 35 ± 2 °C; ambient air

16–18 hours

16–20 hours

16–18 hours

16–20 hours

For K. pneumoniae, K. oxytoca, and E. coli: Cefpodoxime zone ≤ 17 mm Ceftazidime zone ≤ 22 mm Aztreonam zone ≤ 27 mm Cefotaxime zone ≤ 27 mm Ceftriaxone zone ≤ 25 mm

Growth at or above the screening concentrations may indicate ESBL production (ie, for E. coli, K. pneumoniae, and K. oxytoca, MIC ≥ 8 μg/mL for cefpodoxime or MIC ≥ 2 μg/mL for ceftazidime, aztreonam, cefotaxime, or ceftriaxone; and for P. mirabilis, MIC ≥ 2 μg/mL for cefpodoxime, ceftazidime, or cefotaxime).

A ≥ 5-mm increase in a zone diameter for either antimicrobial agent tested in combination with clavulanic acid vs its zone when tested alone = ESBL (eg, ceftazidime zone = 16; ceftazidimeclavulanic acid zone = 21).

A ≥ 3 twofold concentration decrease in an MIC for either antimicrobial agent tested in combination with clavulanic acid vs its MIC when tested alone = ESBL (eg, ceftazidime MIC = 8 μg/mL; ceftazidime-clavulanic acid MIC = 1 μg/mL).

a For P. mirabilis : Cefpodoxime zone Ceftazidime zone Cefotaxime zone

≤ 22 mm ≤ 22 mm ≤ 27 mm

Zones above may indicate ESBL production.

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Inoculum

January 2010

46

NOTE: Following evaluation of PK-PD properties and limited clinical data, new (revised) interpretive criteria for cephalosporins (cefazolin, cefotaxime, ceftazidime, ceftizoxime, and ceftriaxone) and aztreonam were established and are listed in Table 2A. Cefepime and cefuroxime (parenteral) were also evaluated; however, no change in interpretive criteria was required with the dosages included in Table 2A. When using the new interpretive criteria, routine ESBL testing is no longer necessary before reporting results (ie, it is no longer necessary to edit results for cephalosporins, aztreonam, or penicillins to resistant). However, until laboratories implement the new interpretive criteria, ESBL testing should be performed as described in the following table. ESBL testing may still be useful for epidemiological or infection control purposes. Test Initial Screen Test Phenotypic Confirmatory Test Test method Disk diffusion Broth microdilution Disk diffusion Broth microdilution b Medium MHA CAMHBb MHA CAMHB Antimicrobial Ceftazidime 0.25– For K. pneumoniae, For K. pneumoniae, K. Ceftazidime 30 μg c concentration K. oxytoca, and E. coli: oxytoca, and E. coli: 128 μg/mL Ceftazidime-clavulanic acid 30/10 μg Ceftazidime-clavulanic acid 0.25/4– Cefpodoxime 10 μg or Cefpodoxime 4 μg/mL or 128/4 μg/mL Ceftazidime 30 μg or Ceftazidime 1 μg/mL or and Aztreonam 30 μg or Aztreonam 1 μg/mL or and 30 μg Cefotaxime 30 μg or Cefotaxime 1 μg/mL or Cefotaxime c Cefotaxime-clavulanic acid 30/10 μg Ceftriaxone 30 μg Ceftriaxone 1 μg/mL Cefotaxime 0.25– a a 64 μg/mL (Confirmatory testing requires use of For P. mirabilis : For P. mirabilis : Cefotaxime-clavulanic acid 0.25/4– Cefpodoxime 10 μg or Cefpodoxime 1 μg/mL or both cefotaxime and ceftazidime, alone 64/4 μg/mL Ceftazidime 30 μg or Ceftazidime 1 μg/mL or and in combination with clavulanic acid.) Cefotaxime 30 μg Cefotaxime 1 μg/mL (Confirmatory testing requires use of both cefotaxime and ceftazidime, (The use of more than one (The use of more than one alone and in combination with antimicrobial agent for screening antimicrobial agent for clavulanic acid.) improves the sensitivity of detection.) screening improves the sensitivity of detection.)

Product Name: Infobase 2010 - Release Date: February 2010

Test Test Method Reporting

Disk diffusion

Initial Screen Test Broth microdilution

Phenotypic Confirmatory Test Disk diffusion Broth microdilution For all confirmed ESBL-producing strains: If laboratories have not yet implemented the new cephalosporin and aztreonam interpretive criteria, the test interpretation should be reported as resistant for all penicillins, cephalosporins, and aztreonam. If the laboratory has implemented the new cephalosporin and aztreonam interpretive criteria, then test interpretations for these agents do not need to be changed.

QC recommendations

When testing ESBL-screening antimicrobial agents, K. pneumoniae ATCC® 700603 is provided as a supplemental QC strain (eg, for training, competency, or test evaluation). Either strain, K. pneumoniae ® ® ATCC 700603 or E. coli ATCC 25922, may then be used for routine QC (eg, weekly or daily).

When testing ESBL-screening antimicrobial agents, K. pneumoniae ATCC® 700603 is provided as a supplemental QC strain (eg, for training, competency, or test evaluation). Either strain, K. ® pneumoniae ATCC 700603 ® or E. coli ATCC 25922, may then be used for routine QC (eg, weekly or daily).

When performing the ESBL confirmatory tests, K. pneumoniae ® ® ATCC 700603 and E. coli ATCC 25922 should be tested routinely (eg, weekly or daily).

When performing the ESBL confirmatory tests, K. pneumoniae ATCC® 700603 and E. coli ATCC® 25922 should be tested routinely (eg, weekly or daily).

E. coli ATCC® 25922 (see control limits in Table 3)

E. coli ATCC® 25922 = No growth (also refer to control limits listed in Table 3).

® E. coli ATCC 25922: ≤ 2-mm increase in zone diameter for antimicrobial agent tested alone vs its zone when tested in combination with clavulanic acid.

® E. coli ATCC 25922: 90%) and specificity (>90%) in detecting Klebsiella pneumoniae carbapenemase (KPC)–type carbapenemases in these isolates. The sensitivity and specificity of the test for detecting low-level metallo-β-lactamase production are not known. 3. No data exist on the usefulness of these tests for the detection of carbapenemase production in nonfermenting gram-negative bacilli.

3 1

2

Inhibition of E. coli ATCC® 25922 by ertapenem Enhanced growth of E. coli ATCC® 25922. Carbapenemase produced by K. pneumoniae ATCC ® BAA-1705 inactivated ertapenem that diffused into the media. Thus, there is no longer sufficient ertapenem here to inhibit E. coli ATCC® 25922 and an indentation of the zone is noted.

Figure 1. The MHT Performed on a Small MHA Plate. (1) K. pneumoniae ATCC® BAA-1705, positive result; (2) K. pneumoniae ATCC® BAA-1706, negative result; and (3) a clinical isolate, positive result.

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E. coli ATCC® 25922

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Supplemental Table 2A-S2. (Continued)

Figure 2. The MHT Performed on a Large MHA Plate With Ertapenem. (1) K. pneumoniae ATCC® BAA-1705, positive result; (2) K. pneumoniae ® ATCC BAA-1706, negative result; (3–8) clinical isolates; (6) negative result; (3, 4, 5, 7, 8) positive result.

51

This document is

Supplemental Table 2A-S2 Screening and Confirmatory Tests for Suspected Carbapenemase Production protected by international copyright  

laws.

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Figure 3. An Example of an Indeterminate Result. (1) A clinical isolate with an indeterminate result; and (2) a clinical isolate with a negative result.

Table 2B-1 Product Name: Infobase 2010 - Release Date: February 2010 Pseudomonas aeruginosa M02 and M07

 

Testing Conditions

Minimal QC Recommendations (See Tables 3 and 4 for acceptable QC ranges.)

Medium:

Disk diffusion: MHA Broth dilution: CAMHB Agar dilution: MHA Inoculum: Growth method or direct colony suspension, equivalent to a 0.5 McFarland standard Incubation: 35 ± 2 °C; ambient air; Disk diffusion: 16 to 18 hours Dilution methods: 16 to 20 hours

Escherichia coli ATCC® 25922 ® Pseudomonas aeruginosa ATCC 27853 ® Escherichia coli ATCC 35218 (for β-lactam/β-lactamase inhibitor combinations)

January 2010

52

Table 2B-1. Zone Diameter and MIC Interpretive Standards for Pseudomonas aeruginosa

General Comments (1) For disk diffusion, measure the diameter of the zones of complete inhibition (as judged by the unaided eye), including the diameter of the disk. Hold the Petri plate a few inches above a black, nonreflecting background illuminated with reflected light. The zone margin should be considered the area showing no obvious, visible growth that can be detected with the unaided eye. Ignore faint growth of tiny colonies that can be detected only with a magnifying lens at the edge of the zone of inhibited growth.

(3) P. aeruginosa may develop resistance during prolonged therapy with all antimicrobial agents. Therefore, isolates that are initially susceptible may become resistant within three to four days after initiation of therapy. Testing of repeat isolates may be warranted. NOTE:

Information in boldface type is considered tentative for one year.

Test/Report Group PENICILLINS

Antimicrobial Agent

Disk Content

Zone Diameter Breakpoints, nearest whole mm S

I

MIC Interpretive Standard (µg/mL) R

S

I

R

Comments

(4) Rx: The susceptible category for these drugs implies the need for high-dose therapy for serious infections caused by P. aeruginosa. For these infections, monotherapy has been associated with clinical failure. A B O O O

Piperacillin Ticarcillin Azlocillin Carbenicillin Mezlocillin

100 μg 75 μg 75 μg 100 μg 75 μg

≥ 18 ≥ 15 ≥ 18 ≥ 17 ≥ 16

– – – 14–16 –

≤ 17 ≤ 14 ≤ 17 ≤ 13 ≤ 15

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≤ 64 ≤ 64 ≤ 64 ≤ 128 ≤ 64

– – – 256 –

≥ 128 ≥ 128 ≥ 128 ≥ 512 ≥ 128

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(2) The susceptibility of P. aeruginosa isolated from patients with cystic fibrosis can be reliably determined by disk diffusion or dilution methods, but may require extended incubation for up to 24 hours before reporting as susceptible.

Product Name: Infobase 2010 - Release Date: February 2010

Test/Report Antimicrobial Disk Group Agent Content β-LACTAM/β-LACTAMASE INHIBITOR COMBINATIONS

Zone Diameter Breakpoints, nearest whole mm S

I

MIC Interpretive Standard (µg/mL) R

See comment (4). B Piperacillin-tazobactam – 100/10 μg ≥ 18 ≤ 17 ≤ 64/4 O Ticarcillin-clavulanic acid – 75/10 μg ≥ 15 ≤ 14 ≤ 64/2 CEPHEMS (PARENTERAL) (Including cephalosporins I, II, III, and IV. Please refer to Glossary I.) A Ceftazidime 15–17 30 μg ≥ 18 ≤ 14 ≤8 B Cefepime 15–17 30 μg ≥ 18 ≤ 14 ≤8 O Cefoperazone 16–20 75 μg ≥ 21 ≤ 15 ≤ 16 O Cefotaxime 15–22 30 μg ≥ 23 ≤ 14 ≤8 O Ceftriaxone 14–20 30 μg ≥ 21 ≤ 13 ≤8 O Ceftizoxime 15–19 30 μg ≥ 20 ≤ 14 ≤8 O Moxalactam 15–22 30 μg ≥ 23 ≤ 14 ≤8 MONOBACTAMS B Aztreonam 16–21 30 μg ≥ 22 ≤ 15 ≤8 CARBAPENEMS B Imipenem 14–15 10 μg ≥ 16 ≤ 13 ≤4 B Meropenem 10 μg ≥ 16 ≤ 13 ≤4 14–15 LIPOPEPTIDES O Colistin – 10 μg ≥ 11 ≤ 10 ≤2 O Polymyxin B 300 units – ≥ 12 ≤ 11 ≤2 AMINOGLYCOSIDES A Gentamicin 13–14 10 μg ≥ 15 ≤ 12 ≤4 A Tobramycin 13–14 10 μg ≥ 15 ≤ 12 ≤4 B Amikacin 15–16 30 μg ≥ 17 ≤ 14 ≤ 16 O Netilmicin 13–14 30 μg ≥ 15 ≤ 12 ≤8 FLUOROQUINOLONES B Ciprofloxacin 5 μg ≥ 21 ≤ 15 ≤1 16–20 B Levofloxacin 14–16 5 μg ≥ 17 ≤ 13 ≤2 Lomefloxacin or U 10 μg ≥ 22 ≤ 18 ≤2 19–21 ofloxacin U 5 μg ≥ 16 ≤ 12 ≤2 13–15 Norfloxacin U 10 μg ≥ 17 ≤ 12 ≤4 13–16 O

Gatifloxacin

5 μg

≥ 18

15–17

≤ 14

Table 2B-1 Pseudomonas aeruginosa document isM07 protected M02 and  

by international copyright laws.

≤2

I

R

– –

≥ 128/4 ≥ 128/2

16 16 32 16–32 16–32 16–32 16–32

≥ 32 ≥ 32 ≥ 64 ≥ 64 ≥ 64 ≥ 64 ≥ 64

16

≥ 32

8 8

≥ 16 ≥ 16

4 4

≥8 ≥8

8 8 32 16

≥ 16 ≥ 16 ≥ 64 ≥ 32

2 4 4 4 8

≥4 ≥8 ≥8 ≥8 ≥ 16

4

≥8

Comments

(5) These interpretive criteria apply to isolates from the urinary tract only.

M100-S20

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This

S

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Table 2B-1. (Continued)

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Table 2B-2 Acinetobacter spp. M02 and M07

Table 2B-2. Zone Diameter and MIC Interpretive Standards for Acinetobacter spp.

Minimal QC Recommendations (See Tables 3 and 4 for acceptable QC ranges.)

Medium:

Disk diffusion: MHA Broth dilution: CAMHB Agar dilution: MHA Inoculum: Growth method or direct colony suspension, equivalent to a 0.5 McFarland standard Incubation: 35 ± 2 °C; ambient air; 20 to 24 hours, all methods

Escherichia coli ATCC® 25922 ® Pseudomonas aeruginosa ATCC 27853 ® Escherichia coli ATCC 35218 (for β-lactam/β-lactamase inhibitor combinations)

January 2010

54

Testing Conditions

General Comments (1) For disk diffusion, measure the diameter of the zones of complete inhibition (as judged by the unaided eye), including the diameter of the disk. Hold the Petri plate a few inches above a black, nonreflecting background illuminated with reflected light. The zone margin should be considered the area showing no obvious, visible growth that can be detected with the unaided eye. Ignore faint growth of tiny colonies that can be detected only with a magnifying lens at the edge of the zone of inhibited growth. With trimethoprim and the sulfonamides, antagonists in the medium may allow some slight growth; therefore, disregard slight growth (20% or less of the lawn of growth) and measure the more obvious margin to determine the zone diameter. NOTE:

Information in boldface type is considered tentative for one year.

B B

MIC Interpretive Standard (µg/mL)

S

I

R

S

I

R

≥ 21 ≥ 21 ≥ 20

18–20 18–20 15–19

≤ 17 ≤ 17 ≤ 14

≤ 16 ≤ 16 ≤ 16

32–64 32–64 32–64

≥ 128 ≥ 128 ≥ 128

≥ 15

12–14

≤ 11

≤ 8/4 ≤ 16/4

16/8 32/4– 64/4 32/2– 64/2

≥ 32/16 ≥ 128/4

16 16 16–32 16–32

≥ 32 ≥ 32 ≥ 64 ≥ 64

8 8

≥ 16 ≥ 16

– –

≥4 ≥4

Piperacillin-tazobactam

100/10 μg

≥ 21

18–20

≤ 17

Ticarcillin-clavulanic acid

75/10 μg

≥ 20

15–19

≤ 14

≤ 16/2

CEPHEMS (PARENTERAL) (Including cephalosporins I, II, III, and IV. Please refer to Glossary I.) A Ceftazidime ≤8 15–17 30 μg ≥ 18 ≤ 14 B Cefepime ≤8 15–17 30 μg ≥ 18 ≤ 14 B Cefotaxime 30 μg ≥ 23 15–22 ≤ 14 ≤8 B Ceftriaxone ≤8 14–20 30 μg ≥ 21 ≤ 13 CARBAPENEMS 14–15 A Imipenem ≥ 16 ≤ 13 ≤4 10 μg 14–15 A Meropenem ≥ 16 ≤ 13 ≤4 10 μg LIPOPEPTIDES O Polymyxin B –– – – – ≤2 O – – – Colistin ≤2

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Comments

≥ 128/2

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Test/Report Antimicrobial Disk Group Agent Content PENICILLINS B Piperacillin 100 μg O Mezlocillin 75 μg O Ticarcillin 75 μg β-LACTAM/β-LACTAMASE INHIBITOR COMBINATIONS A Ampicillin-sulbactam 10/10 μg

Zone Diameter Breakpoints, nearest whole mm

Product Name: Infobase 2010 - Release Date: February 2010

Test/Report Antimicrobial Group Agent AMINOGLYCOSIDES A Gentamicin A Tobramycin B Amikacin O Netilmicin TETRACYCLINES

Zone Diameter Breakpoints, nearest whole mm

MIC Interpretive Standard (µg/mL)

Disk Content

S

I

R

S

I

R

10 μg 10 μg 30 μg –

≥ 15 ≥ 15 ≥ 17 –

13–14 13–14 15–16 –

≤ 12 ≤ 12 ≤ 14 –

≤4 ≤4 ≤ 16 ≤8

8 8 32 16

≥ 16 ≥ 16 ≥ 64 ≥ 32

Comments

(2) Organisms that are susceptible to tetracycline are also considered susceptible to doxycycline and minocycline. However, some organisms that are intermediate or resistant to tetracycline may be susceptible to doxycycline or minocycline or both. B Tetracycline B Doxycycline B Minocycline FLUOROQUINOLONES A Ciprofloxacin A Levofloxacin O Gatifloxacin FOLATE PATHWAY INHIBITORS TrimethoprimB sulfamethoxazole

30 μg 30 μg 30 μg

≥ 15 ≥ 13 ≥ 16

12–14 10–12 13–15

≤ 11 ≤9 ≤ 12

≤4 ≤4 ≤4

8 8 8

≥ 16 ≥ 16 ≥ 16

5 μg 5 μg 5 μg

≥ 21 ≥ 17 ≥ 18

16–20 14–16 15–17

≤ 15 ≤ 13 ≤ 14

≤1 ≤2 ≤2

2 4 4

≥4 ≥8 ≥8

≥ 16

11–15

≤ 10

≤ 2/38

–

≥ 4/76

1.25/23.75 μg

M100-S20

55

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Table 2B-2. (Continued)

Table 2B-2 Acinetobacter spp. M02 and M07

Product Name: Infobase 2010 - Release Date: February 2010

Table 2B-3 Burkholderia cepacia M02 and M07

Table 2B-3. Zone Diameter and MIC Interpretive Standards for Burkholderia cepacia Minimal QC Recommendations (See Tables 3 and 4 for acceptable QC ranges.)

Medium:

Disk diffusion: MHA Broth dilution: CAMHB Agar dilution: MHA Inoculum: Growth method or direct colony suspension, equivalent to a 0.5 McFarland standard Incubation: 35 ± 2 °C; ambient air; all methods, 20 to 24 hours

Escherichia coli ATCC® 25922 ® Pseudomonas aeruginosa ATCC 27853 ® Escherichia coli ATCC 35218 (for β-lactam/β-lactamase inhibitor combinations)

January 2010

56

Testing Conditions

General Comments (1) For disk diffusion, measure the diameter of the zones of complete inhibition (as judged by the unaided eye), including the diameter of the disk. Hold the Petri plate a few inches above a black, nonreflecting background illuminated with reflected light. The zone margin should be considered the area showing no obvious, visible growth that can be detected with the unaided eye. Ignore faint growth of tiny colonies that can be detected only with a magnifying lens at the edge of the zone of inhibited growth. With trimethoprim and the sulfonamides, antagonists in the medium may allow some slight growth; therefore, disregard slight growth (20% or less of the lawn of growth) and measure the more obvious margin to determine the zone diameter. NOTE:

Information in boldface type is considered tentative for one year. MIC Interpretive Standard (µg/mL)

Test/Report Antimicrobial Disk Group Agent Content S I R S CEPHEMS (PARENTERAL) (Including cephalosporins I, II, III, and IV. Please refer to Glossary I.) B Ceftazidime 18–20 ≤8 30 μg ≥ 21 ≤ 17 CARBAPENEMS 16–19 B Meropenem ≥ 20 ≤ 15 ≤4 10 μg TETRACYCLINES ≤4 B Minocycline 15–18 30 μg ≥ 19 ≤ 14 FOLATE PATHWAY INHIBITORS ≤ 2/38 A Trimethoprim11–15 1.25/23.75 μg ≥ 16 ≤ 10 sulfamethoxazole β-LACTAM/β-LACTAMASE INHIBITOR COMBINATIONS B Ticarcillin-clavulanic – – – – ≤ 16/2 acid FLUOROQUINOLONES B Levofloxacin – – – – ≤2 PHENICOLS – – – – B Chloramphenicol ≤8

This document is protected by international copyright laws.

I

R

16

≥ 32

8

≥ 16

8

≥ 16

–

≥ 4/76

32/2– 64/2

≥ 128/2

4

≥8

16

≥ 32

Comments

(2) Not routinely reported on isolates from the urinary tract.

Vol. 30 No. 1

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Zone Diameter Breakpoints, nearest whole mm

Product Name: Infobase 2010 - Release Date: February 2010

Testing Conditions

Minimal QC Recommendations (See Tables 3 and 4 for acceptable QC ranges.)

Medium:

Disk diffusion: MHA Broth dilution: CAMHB Agar dilution: MHA Inoculum: Growth method or direct colony suspension, equivalent to a 0.5 McFarland standard Incubation: 35 ± 2 °C; ambient air; all methods, 20 to 24 hours

Escherichia coli ATCC® 25922 Pseudomonas aeruginosa ATCC® 27853 Escherichia coli ATCC® 35218 (for β-lactam/β-lactamase inhibitor combinations)

For Use With M02-A10 and M07-A8

Clinical and Laboratory Standards Institute. All rights reserved.

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Table 2B-4. Zone Diameter and MIC Interpretive Standards for Stenotrophomonas maltophilia

General Comments (1) For disk diffusion, measure the diameter of the zones of complete inhibition (as judged by the unaided eye), including the diameter of the disk. Hold the Petri plate a few inches above a black, nonreflecting background illuminated with reflected light. The zone margin should be considered the area showing no obvious, visible growth that can be detected with the unaided eye. Ignore faint growth of tiny colonies that can be detected only with a magnifying lens at the edge of the zone of inhibited growth. With trimethoprim and the sulfonamides, antagonists in the medium may allow some slight growth; therefore, disregard slight growth (20% or less of the lawn of growth) and measure the more obvious margin to determine the zone diameter. NOTE: Information in boldface type is considered tentative for one year.

Test/Report Antimicrobial Disk Group Agent Content β-LACTAM/β-LACTAMASE INHIBITOR COMBINATIONS B Ticarcillin-clavulanic acid –

Zone Diameter Breakpoints, nearest whole mm

MIC Interpretive Standard (µg/mL)

I

R

S

I

R

–

–

–

≤ 16/2

32/2– 64/2

≥ 128/2

≤8

16

≥ 32

≤4

8

≥ 16

≤2

4

≥8

≤ 2/38

–

≥ 4/76

≤8

16

≥ 32

CEPHEMS (PARENTERAL) (Including cephalosporins I, II, III, and IV. Please refer to Glossary I.) B Ceftazidime – – – – TETRACYCLINES B Minocycline 15–18 30 μg ≥ 19 ≤ 14 FLUOROQUINOLONES Levofloxacin ≥ 17 ≤ 13 5 μg B 14–16 FOLATE PATHWAY INHIBITORS A Trimethoprim11–15 1.25/23.75 μg ≥ 16 ≤ 10 sulfamethoxazole PHENICOLS

57

B

Chloramphenicol

–

–

–

–

 

This document is protected by international

Table 2B-4 Stenotrophomonas maltophilia M02 and M07 copyright laws.

Comments

(2) Not routinely reported on isolates from the urinary tract.

M100-S20

S

Table 2B-5 Product Name: Infobase 2010 Release Date: February 2010 Other- Non-Enterobacteriaceae M07 Table 2B-5. MIC Interpretive Standards (μg/mL) for Other Non-Enterobacteriaceae (Refer to Comment 1) Minimal QC Recommendations (See Tables 3 and 4 for acceptable QC ranges.)

Medium:

Broth dilution: CAMHB Agar dilution: MHA Inoculum: Growth method or direct colony suspension, equivalent to a 0.5 McFarland standard Incubation: 35 ± 2 °C; ambient air; 16 to 20 hours

Escherichia coli ATCC® 25922 Pseudomonas aeruginosa ATCC® 27853 Escherichia coli ATCC® 35218 (for β-lactam/β-lactamase inhibitor combinations)

January 2010

58 Testing Conditions

General Comments (1)

Other non-Enterobacteriaceae include Pseudomonas spp. (not P. aeruginosa) and other nonfastidious, glucose-nonfermenting, gram-negative bacilli but exclude P. aeruginosa, Acinetobacter spp., Burkholderia cepacia, B. mallei, B. pseudomallei, and Stenotrophomonas maltophilia. Refer to Tables 2B-2, 2B-3, and 2B-4 for testing of Acinetobacter spp., B. cepacia, and S. maltophilia, respectively, and Table 2K for testing of Burkholderia mallei and B. pseudomallei.

NOTE:

Information in boldface type is considered tentative for one year.

B

Piperacillin-tazobactam

–

MIC Interpretive Standard (µg/mL)

S

I

R

S

I

R

– – – –

– – – –

– – – –

≤ 16 ≤ 16 ≤ 16 ≤ 16

32–64 32–64 32–64 32

≥ 128 ≥ 128 ≥ 128 ≥ 64

–

–

–

≤ 16/2

≥ 128/2

–

–

–

≤ 16/4

32/2– 64/2 32/4– 64/4

This document is protected by international copyright laws.

Comments

≥ 128/4

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Test/Report Antimicrobial Disk Group Agent Content PENICILLINS A Piperacillin – O Mezlocillin – O Ticarcillin – O Carbenicillin – β-LACTAM/β-LACTAMASE INHIBITOR COMBINATIONS B Ticarcillin-clavulanic acid –

Zone Diameter Breakpoints, nearest whole mm

Product Name: Infobase 2010 - Release Date: February 2010

Zone Diameter Breakpoints, nearest whole mm

MIC Interpretive Standard (µg/mL)

Test/Report Antimicrobial Disk Group Agent Content S I R S CEPHEMS (PARENTERAL) (Including cephalosporins I, II, III, and IV. Please refer to Glossary I.) A Ceftazidime – – – – ≤8 B Cefepime – – – – ≤8 C Cefotaxime – – – – ≤8 C Ceftriaxone – – – – ≤8 O Cefoperazone – – – – ≤ 16 O Ceftizoxime – – – – ≤8 O Moxalactam – – – – ≤8 MONOBACTAMS B Aztreonam – – – – ≤8 CARBAPENEMS B Imipenem – – – – ≤4 B Meropenem – – – – ≤4 LIPOPEPTIDES O Colistin – – – – ≤2 O Polymyxin B – – – – ≤2 AMINOGLYCOSIDES A Gentamicin – – – – ≤4 A Tobramycin – – – – ≤4 B Amikacin – – – – ≤ 16 O Netilmicin – – – – ≤8 TETRACYCLINES

I

R

16 16 16–32 16–32 32 16–32 16–32

≥ 32 ≥ 32 ≥ 64 ≥ 64 ≥ 64 ≥ 64 ≥ 64

16

≥ 32

8 8

≥ 16 ≥ 16

4 4

≥8 ≥8

8 8 32 16

≥ 16 ≥ 16 ≥ 64 ≥ 32

Comments

PHENICOLS C

This document is

Chloramphenicol

–

–

–

Table 2B-5 Other Non-Enterobacteriaceae protected by international copyright M07

–

laws.

≤8

16

≥ 32

(5) Not routinely reported on isolates from the urinary tract.

M100-S20

59

(2) Organisms that are susceptible to tetracycline are also considered susceptible to doxycycline and minocycline. However, some organisms that are intermediate or resistant to tetracycline may be susceptible to doxycycline, minocycline, or both. U Tetracycline – – – – 8 ≤4 ≥ 16 O Doxycycline – – – – 8 ≤4 ≥ 16 O Minocycline – – – – 8 ≤4 ≥ 16 FLUOROQUINOLONES B Ciprofloxacin – – – – 2 ≤1 ≥4 B Levofloxacin – – 4 ≤2 ≥8 U Lomefloxacin or – – – – 4 ≤2 ≥8 U ofloxacin – – – – 4 ≤2 ≥8 U Norfloxacin – – – – 8 ≤4 ≥ 16 O Gatifloxacin – – – – 4 (3) These interpretive criteria apply to isolates ≤2 ≥8 from the urinary tract only. FOLATE PATHWAY INHIBITORS B Trimethoprim– – – – – ≤ 2/38 ≥ 4/76 sulfamethoxazole (4) Sulfisoxazole can be used to represent any of U Sulfonamides – – – – – ≤ 256 ≥ 512 the currently available sulfonamide preparations.

For Use With M07-A8—MIC Testing

Clinical and Laboratory Standards Institute. All rights reserved.

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Table 2B-5. (Continued)

Table 2C

Product Name: Infobase 2010 - Release Date: February 2010 Staphylococcus spp.

M02 and M07 Table 2C. Zone Diameter and MIC Interpretive Standards for Staphylococcus spp.

60

Minimal QC Recommendations (See Tables 3 and 4 for acceptable QC ranges.)

Medium:

Disk diffusion: MHA Broth dilution: CAMHB; CAMHB + 2% NaCl for oxacillin, methicillin, and nafcillin; CAMHB supplemented to 50 µg/mL calcium for daptomycin Agar dilution: MHA; MHA + 2% NaCl for oxacillin, methicillin, and nafcillin. Agar dilution has not been validated for daptomycin. Inoculum: Direct colony suspension, equivalent to a 0.5 McFarland standard Incubation: 35 ± 2 °C; ambient air; Disk diffusion: 16 to 18 hours; 24 hours (coagulase-negative staphylococci and cefoxitin); Dilution methods: 16 to 20 hours; All methods: 24 hours for oxacillin, methicillin, nafcillin, and vancomycin. Testing at temperatures above 35 °C may not detect MRS.

Staphylococcus aureus ATCC® 25923 (Disk diffusion) Staphylococcus aureus ATCC® 29213 (MIC) Escherichia coli ATCC® 35218 (for β-lactam/β-lactamase inhibitor combinations)

January 2010

Testing Conditions

Refer to Supplemental Tables 2C-S3 and 2C-S4 at the end of Table 2C for additional recommendations for testing conditions, reporting suggestions, and QC.

General Comments

(2)

Historically, resistance to the penicillinase-stable penicillins (see Glossary I) has been referred to as “methicillin resistance” or “oxacillin resistance.” MRSAs are those strains of S. aureus that express mecA or another mechanism of methicillin resistance, such as changes in affinity of penicillin binding proteins for oxacillin (modified S. aureus [MOD-SA] strains).

(3)

For oxacillin-susceptible S. aureus and coagulase-negative staphylococci, results for parenteral and oral cephems, β-lactam/β-lactamase inhibitor combinations, and carbapenems, if tested, should be reported according to the results generated using routine interpretive criteria. See comment (4) for reporting β-lactam results on oxacillin-resistant strains.

(4)

WARNING: For oxacillin-resistant S. aureus and coagulase-negative staphylococci (MRS), other β-lactam agents, ie, penicillins, β-lactam/β-lactamase inhibitor combinations, cephems (with the exception of the newer “cephalosporins with anti-MRSA activity”), and carbapenems, may appear active in vitro but are not effective clinically. Results for β-lactam agents other than the cephalosporins with anti-MRSA activity should be reported as resistant or should not be reported. This is because most cases of documented MRS infections have responded poorly to β-lactam therapy, or because convincing clinical data have yet to be presented that document clinical efficacy for those agents.

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For disk diffusion, measure the diameter of the zones of complete inhibition (as judged by the unaided eye), including the diameter of the disk. Hold the Petri plate a few inches above a black, nonreflecting background illuminated with reflected light, except for linezolid, oxacillin, and vancomycin, which should be read with transmitted light (plate held up to light source). The zone margin should be considered the area showing no obvious, visible growth that can be detected with the unaided eye. Ignore faint growth of tiny colonies that can be detected only with a magnifying lens at the edge of the zone of inhibited growth. With trimethoprim and the sulfonamides, antagonists in the medium may allow some slight growth; therefore, disregard slight growth (20% or less of the lawn of growth) and measure the more obvious margin to determine the zone diameter. Any discernable growth within the zone of inhibition is indicative of oxacillin, linezolid, or vancomycin resistance.

©

(1)

Product Name: Infobase 2010 - Release Date: February 2010

(5)

Detection of oxacillin resistance: Tests for mecA or for the protein expressed by mecA, the penicillin-binding protein 2a (PBP 2a, also called PBP2'), are the most accurate methods for prediction of resistance to oxacillin and can be used to confirm results for isolates of staphylococci from serious infections. Isolates of staphylococci that carry the mecA gene, or that produce PBP 2a (the mecA gene product), should be reported as oxacillin resistant. Isolates that do not carry mecA or do not produce PBP 2a should be reported as oxacillin susceptible. Because of the rare occurrence of resistance mechanisms other than mecA, if MIC tests are performed in addition to disk diffusion, isolates for which oxacillin MICs are ≥ 4 μg/mL and are mecA negative or PBP 2a negative should be reported as oxacillin resistant. These isolates may test as susceptible to cefoxitin by disk diffusion.

(6)

Routine testing of urine isolates of S. saprophyticus is not advised, because infections respond to concentrations achieved in urine of antimicrobial agents commonly used to treat acute, uncomplicated urinary tract infections (eg, nitrofurantoin, trimethoprim ± sulfamethoxazole, or a fluoroquinolone).

(7)

For some organism/antimicrobial agent combinations, the absence or rare occurrence of resistant strains precludes defining any results categories other than “susceptible.” For strains yielding results suggestive of a “nonsusceptible” category, organism identification and antimicrobial susceptibility test results should be confirmed. (See Appendix A.)

(8)

For screening tests for β-lactamase production, oxacillin resistance, mecA-mediated oxacillin resistance using cefoxitin, reduced susceptibility to vancomycin, and inducible clindamycin resistance, refer to Supplemental Table 2C-S3 at the end of Table 2C for S. aureus group and Supplemental Table 2C-S4 for coagulase-negative staphylococci at the end of Table 2C. In addition, further explanation on the use of cefoxitin for prediction of mecAmediated oxacillin resistance can be found in Section 12 of M07-A8 and Section 11 of M02-A10.

NOTE:

For Use With M02-A10 and M07-A8

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Table 2C. (Continued)

Information in boldface type is considered tentative for one year.

M100-S20

61 Table 2C Staphylococcus spp. M02 and M07

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Table 2C

Product Name: spp. Infobase 2010 - Release Date: February 2010 Staphylococcus M02 and M07 Table 2C. (Continued) Antimicrobial Agent

Disk Content

MIC Interpretive Standard (µg/mL) S I R

Comments

(9) Penicillin-susceptible staphylococci are also susceptible to other penicillins, β-lactam/β-lactamase inhibitor combinations, cephems, and carbapenems approved for use by the FDA for staphylococcal infections. Penicillin-resistant, oxacillin-susceptible strains are resistant to penicillinase-labile penicillins but susceptible to other penicillinase-stable penicillins, βlactam/β-lactamase inhibitor combinations, relevant cephems, and carbapenems. Oxacillin-resistant staphylococci are resistant to all currently available β-lactam antimicrobial agents with the exception of the newer cephalosporins with anti-MRSA activity. Thus, susceptibility or resistance to a wide array of β-lactam antimicrobial agents may be deduced from testing only penicillin and either cefoxitin or oxacillin. Routine testing of other penicillins, β-lactam/β-lactamase inhibitor combinations, cephems, or carbapenems is not advised.

January 2010

62

Test/Report Group PENICILLINS

Zone Diameter Breakpoints, nearest whole mm S I R

(10) If a penicillinase-stable penicillin is tested, oxacillin is the preferred agent and results can be applied to the other penicillinase-stable penicillins, cloxacillin, dicloxacillin, flucloxacillin, methicillin, and nafcillin. See comment (4). A Penicillin

–

≤ 28

≤ 0.12

–

≥ 0.25

Clinical and Laboratory Standards Institute. All rights reserved.

A

Oxacillin

1 μg oxacillin

≥ 13

11-12

≤ 10

≤2 (oxacillin

–

≥4 (oxacillin)

1 μg oxacillin

–

–

–

–

≥ 22

–

≤ 21

≤2 (oxacillin) ≤4 (cefoxitin)

≥4 (oxacillin) ≥8 (cefoxitin)

For S. aureus and S. lugdunensis. 30 µg cefoxitin

–

(11) Penicillin-resistant strains of staphylococci produce β-lactamase, and the testing of penicillin instead of ampicillin is preferred. Penicillin should be used to test the susceptibility of all staphylococci to all penicillinase-labile penicillins, such as ampicillin, amoxicillin, azlocillin, carbenicillin, mezlocillin, piperacillin, and ticarcillin. An induced β-lactamase test should be performed on staphylococcal isolates with penicillin MICs ≤ 0.12 µg/mL or zone diameters ≥ 29 mm before reporting the isolate as penicillin susceptible. However, the prevalence of penicillinsusceptible S. aureus strains is low. Isolates that test as susceptible to penicillin may still produce β-lactamase, which is usually detected by an induced β-lactamase test. Occasional isolates are not detected by induced β-lactamase testing. Thus, for serious infections, laboratories should consider performing MIC tests for penicillin and testing for induced β-lactamase production on subsequent isolates from the same patient. A positive βlactamase test predicts resistance to penicillin, ampicillin, amoxicillin, carbenicillin, ticarcillin, mezlocillin, and piperacillin. For oxacillin-resistant staphylococci, report penicillin as resistant or do not report. See Supplemental Table 2C-S3 and Table 2CS4 at the end of Table 2C. For S. aureus.

For S. lugdunensis. For S. aureus and S. lugdunensis. (12) Cefoxitin is used as a surrogate for oxacillin resistance; report oxacillin susceptible or resistant based on the cefoxitin result. If both cefoxitin and oxacillin are tested against S. aureus or S. lugdunensis and either result is resistant, the organism should be reported as oxacillin resistant. See comment (9).

This document is protected by international copyright laws.

Vol. 30 No. 1

≥ 29

©

10 units

Product Name: Infobase 2010 - Release Date: February 2010

Test/Report Group A

Antimicrobial Agent Oxacillin For coagulasenegative staphylococci except S. lugdunensis.

Disk Content 1 μg oxacillin

Zone Diameter Breakpoints, nearest whole mm S –

I –

MIC Interpretive Standard (µg/mL) R –

S ≤ 0.25 (oxacillin)

I –

R ≥ 0.5 (oxacillin)

Comments For coagulase-negative staphylococci lugdunensis.

except

S.

(13) Oxacillin interpretive criteria may overcall resistance for some coagulase-negative staphylococci because some non–S. epidermidis strains for which the oxacillin MICs are 0.5 to 2 µg/mL lack mecA. For serious infections with coagulase-negative staphylococci other than S. epidermidis, testing for mecA or for PBP 2a or with cefoxitin disk diffusion may be appropriate for strains for which the oxacillin MICs are 0.5 to 2 µg/mL. 30 μg cefoxitin

≥ 25

–

≤ 24

–

–

–

For Use With M02-A10 and M07-A8

Clinical and Laboratory Standards Institute. All rights reserved.

©

Table 2C. (Continued)

See comment (12). See comment (9).

M100-S20

63 Table 2C Staphylococcus spp. M02 and M07

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2C ProductStaphylococcus Name:Table Infobase 2010 - Release Date: February 2010 spp. M02 and M07

Table 2C. (Continued) MIC Interpretive Standard (µg/mL)

Disk Content

S

I

R

S

I

R

Comments (14) Class representative for ampicillin and amoxicillin. (15) For oxacillin-resistant staphylococci, report ampicillin as resistant or do not report. (16) For use with S. aureus only. See comment (16).

O

Ampicillin

10 μg

≥ 29

–

≤ 28

≤ 0.25

–

≥ 0.5

O O

Methicillin Nafcillin

5 μg 1 μg

≥ 14 ≥ 13

10–13 11–12

≤9 ≤ 10

≤8 ≤2

– –

≥ 16 ≥4

– 16/8 – –

≥ 8/4 ≥ 32/16 ≥ 16/4 ≥ 16/2

January 2010

64

Test/Report Antimicrobial Group Agent PENICILLINS (Continued)

Zone Diameter Breakpoints, nearest whole mm

β-LACTAM/β-LACTAMASE INHIBITOR COMBINATIONS (17) For oxacillin-resistant staphylococci, report as resistant or do not report. See comments (4) and (9). O Amoxicillin-clavulanic acid – 20/10 μg ≥ 20 ≤ 19 ≤ 4/2 O Ampicillin-sulbactam 12–14 10/10 μg ≥ 15 ≤ 11 ≤ 8/4 O Piperacillin-tazobactam – 100/10 μg ≥ 18 ≤ 17 ≤ 8/4 O Ticarcillin-clavulanic acid – 75/10 μg ≥ 23 ≤ 22 ≤ 8/2 CEPHEMS (PARENTERAL) (Including cephalosporins I, II, III, and IV. Please refer to Glossary I.) See comment (17). 30 μg 30 μg 30 μg 30 μg 30 μg 75 μg 30 μg 30 μg 30 μg 30 μg 30 μg 30 μg 30 μg 30 μg

≥ 18 ≥ 18 ≥ 18 ≥ 16 ≥ 18 ≥ 21 ≥ 23 ≥ 16 ≥ 18 ≥ 20 ≥ 21 ≥ 18 ≥ 18 ≥ 23

15–17 15–17 15–17 13–15 15–17 16–20 15–22 13–15 15–17 15–19 14–20 15–17 15–17 15–22

≤ 14 ≤ 14 ≤ 14 ≤ 12 ≤ 14 ≤ 15 ≤ 14 ≤ 12 ≤ 14 ≤ 14 ≤ 13 ≤ 14 ≤ 14 ≤ 14

≤8 ≤8 ≤8 ≤ 16 ≤8 ≤ 16 ≤8 ≤ 16 ≤8 ≤8 ≤8 ≤8 ≤8 ≤8

16 16 16 32 16 32 16–32 32 16 16–32 16–32 16 16 16–32

≥ 32 ≥ 32 ≥ 32 ≥ 64 ≥ 32 ≥ 64 ≥ 64 ≥ 64 ≥ 32 ≥ 64 ≥ 64 ≥ 32 ≥ 32 ≥ 64

30 μg 5 μg 10 μg 30 μg 30 μg 30 μg

≥ 18 ≥ 20 ≥ 21 ≥ 18 ≥ 23 ≥ 18

15–17 17–19 18–20 15–17 15–22 15–17

≤ 14 ≤ 16 ≤ 17 ≤ 14 ≤ 14 ≤ 14

≤8 ≤1 ≤2 ≤8 ≤4 ≤8

16 2 4 16 8–16 16

≥ 32 ≥4 ≥8 ≥ 32 ≥ 32 ≥ 32

See comment (15). See comments (4) and (9). O Cefaclor O Cefdinir O Cefpodoxime O Cefprozil O Cefuroxime (oral) O Loracarbef

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See comments (4) and (9). O Cefamandole O Cefazolin O Cefepime O Cefmetazole O Cefonicid O Cefoperazone O Cefotaxime O Cefotetan O Ceftazidime O Ceftizoxime O Ceftriaxone O Cefuroxime (parenteral) O Cephalothin O Moxalactam CEPHEMS (ORAL)

Product Name: Infobase 2010 - Release Date: February 2010

Test/Report Group CARBAPENEMS

Antimicrobial Agent

Zone Diameter Breakpoints, nearest whole mm

MIC Interpretive Standard (µg/mL)

Disk Content

S

I

R

S

I

R

10 μg 10 μg 10 μg

≥ 19 ≥ 16 ≥ 16

16–18 14–15 14–15

≤ 15 ≤ 13 ≤ 13

≤2 ≤4 ≤4

4 8 8

≥8 ≥ 16 ≥ 16

–

–

–

–

≤2

4–8

≥ 16

Comments

See comment (17). See comments (4) and (9). O Ertapenem O Imipenem O Meropenem GLYCOPEPTIDES

B

Vancomycin

For Use With M02-A10 and M07-A8

Clinical and Laboratory Standards Institute. All rights reserved.

©

Table 2C. (Continued)

For S. aureus. (18) MIC tests should be performed to determine the susceptibility of all isolates of staphylococci to vancomycin. The disk test does not differentiate vancomycin-susceptible isolates of S. aureus from vancomycin-intermediate isolates, nor does the test differentiate among vancomycin-susceptible, intermediate, and resistant isolates of coagulasenegative staphylococci, all of which will give similar size zones of inhibition. (19) The vancomycin 30-µg disk test detects S. aureus isolates containing the vanA vancomycin resistance gene (VRSA). Such isolates will show no zone of inhibition around the disk (zone = 6 mm). The identification of isolates showing no zone of inhibition should be confirmed. Isolates of staphylococci producing vancomycin zones of ≥ 7 mm should not be reported as susceptible without performing a vancomycin MIC test. (20) Send any S. aureus for which the vancomycin is ≥ 8 μg/mL to a reference laboratory. (21) Disk testing is not reliable for testing vancomycin.

65

This

Table 2C Staphylococcus spp. document isM07 protected M02 and

by international copyright laws.

M100-S20

Also refer to Supplemental Table 2C-S3 for S. aureus at the end of Table 2C, Section 12.1.3 in M07-A8, and Section 11.1.3 in M02-A10.

Table 2C

Product Name: Infobase Staphylococcus spp. 2010 - Release Date: February 2010 M02 and M07 Table 2C. (Continued) Test/Report Antimicrobial Group Agent GLYCOPEPTIDES (Continued)

B

Vancomycin

MIC Interpretive Standard (µg/mL)

Disk Content

S

I

R

S

I

R

–

–

–

–

≤4

8–16

≥ 32

Comments

January 2010

66

Zone Diameter Breakpoints, nearest whole mm

For coagulase-negative staphylococci. See comments (18) and (21). (22) Send any coagulase-negative Staphylococcus for which the vancomycin MIC is ≥ 32 μg/mL to a reference laboratory. See also Section 12.1.3 in M07-A8 and Section 11.1.3 in M02-A10.

Inv.

30 μg

≥ 14

11–13

≤ 10

≤8

16

≥ 32

(23) Teicoplanin disk diffusion interpretive criteria were not reevaluated concurrent with the reevaluation of vancomycin disk diffusion interpretive criteria during recent studies. Therefore, the ability of these teicoplanin interpretive criteria to differentiate teicoplaninintermediate and teicoplanin-resistant staphylococci from teicoplanin-susceptible strains is not known.

Daptomycin

–

–

–

–

≤1

–

–

(24) Disk testing is not reliable for testing daptomycin. See comment (7).

LIPOPEPTIDES B

AMINOGLYCOSIDES C

Gentamicin

10 μg

≥ 15

13–14

≤ 12

≤4

8

≥ 16

O

Amikacin

30 μg

≥ 17

15–16

≤ 14

≤ 16

32

≥ 64

O

Kanamycin

30 μg

≥ 18

14–17

≤ 13

≤ 16

32

≥ 64

O

Netilmicin

30 μg

≥ 15

13–14

≤ 12

≤8

16

≥ 32

O

Tobramycin

10 μg

≥ 15

13–14

≤ 12

≤4

8

≥ 16

MACROLIDES (25) Not routinely reported on organisms isolated from the urinary tract. A A A O

Azithromycin or clarithromycin or erythromycin Dirithromycin

15 μg 15 μg 15 μg 15 μg

≥ 18 ≥ 18 ≥ 23 ≥ 19

14–17 14–17 14–22 16–18

≤ 13 ≤ 13 ≤ 13 ≤ 15

≤2 ≤2 ≤ 0.5 ≤2

4 4 1–4 4

≥8 ≥8 ≥8 ≥8

Telithromycin

15 μg

≥ 22

19–21

≤ 18

≤1

2

≥4

KETOLIDES B

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Teicoplanin

Product Name: Infobase 2010 - Release Date: February 2010

Test/Report Group TETRACYCLINES

Antimicrobial Agent

Disk Content

Zone Diameter Breakpoints, nearest whole mm S

I

MIC Interpretive Standard (µg/mL) R

I

R

Comments

(26) Organisms that are susceptible to tetracycline are also considered susceptible to doxycycline and minocycline. However, some organisms that are intermediate or resistant to tetracycline may be susceptible to doxycycline, minocycline, or both. B Tetracycline B Doxycycline O Minocycline FLUOROQUINOLONES

30 μg 30 μg 30 μg

≥ 19 ≥ 16 ≥ 19

15–18 13–15 15–18

≤ 14 ≤ 12 ≤ 14

≤4 ≤4 ≤4

8 8 8

≥ 16 ≥ 16 ≥ 16

(27) Staphylococcus spp. may develop resistance during prolonged therapy with quinolones. Therefore, isolates that are initially susceptible may become resistant within three to four days after initiation of therapy. Testing of repeat isolates may be warranted. C C C C U U O O O O Inv.

Ciprofloxacin or levofloxacin or ofloxacin Moxifloxacin Lomefloxacin Norfloxacin Enoxacin

5 μg 5 μg 5 μg 5 μg 10 μg 10 μg 10 μg

≥ 21 ≥ 19 ≥ 18 ≥ 24 ≥ 22 ≥ 17 ≥ 18

16–20 16–18 15–17 21–23 19–21 13–16 15–17

≤ 15 ≤ 15 ≤ 14 ≤ 20 ≤ 18 ≤ 12 ≤ 14

≤1 ≤1 ≤1 ≤ 0.5 ≤2 ≤4 ≤2

2 2 2 1 4 8 4

≥4 ≥4 ≥4 ≥2 ≥8 ≥ 16 ≥8

Gatifloxacin Grepafloxacin Sparfloxacin Fleroxacin

5 μg 5 μg 5 μg 5 μg

≥ 23 ≥ 18 ≥ 19 ≥ 19

20–22 15–17 16–18 16–18

≤ 19 ≤ 14 ≤ 15 ≤ 15

≤ 0.5 ≤1 ≤ 0.5 ≤2

1 2 1 4

≥2 ≥4 ≥2 ≥8

Table 2C Staphylococcus spp. document is protected M02 and M07

(28) FDA approved for S. saprophyticus and S. epidermidis (but not for S. aureus).

M100-S20

67

This

S

For Use With M02-A10 and M07-A8

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Table 2C. (Continued)

by international copyright laws.

Table 2C Product Name: Infobase 2010 - Release Date: February 2010 Staphylococcus spp. M02 and M07

Test/Report Antimicrobial Group Agent NITROFURANTOINS U Nitrofurantoin LINCOSAMIDES A Clindamycin

Zone Diameter Breakpoints, nearest whole mm

MIC Interpretive Standard (µg/mL)

Disk Content

S

I

R

S

I

R

300 μg

≥ 17

15–16

≤ 14

≤ 32

64

≥ 128

2 μg

≥ 21

15–20

≤ 14

≤ 0.5

1–2

≥4

Comments

January 2010

68

Table 2C. (Continued)

(29) Inducible clindamycin resistance can be detected by disk diffusion using the D-zone test and by broth microdilution using a single well containing a combination of erythromycin and clindamycin. See Supplemental Tables 2C-S3 and 2C-S4, Section 12 in M02-A10, and Section 13 in M07-A8 for current recommendations. See comment (25).

FOLATE PATHWAY INHIBITORS A Trimethoprimsulfamethoxazole U Sulfonamides

≥ 16

11–15

≤ 10

≤ 2/38

–

≥ 4/76

250 or 300 μg

≥ 17

13–16

≤ 12

≤ 256

–

≥ 512

5 μg

≥ 16

11–15

≤ 10

≤8

–

≥ 16

30 μg

≥ 18

13–17

≤ 12

≤8

16

≥ 32

See comment (25).

5 μg

≥ 20

17–19

≤ 16

≤1

2

≥4

(31) Rx: Rifampin should not be used alone for antimicrobial therapy.

15 μg

≥ 19

16–18

≤ 15

≤1

2

≥4

(32) For reporting against methicillin-susceptible S. aureus.

30 μg

≥ 21

–

≤ 20

≤4

–

≥8

(33) When testing linezolid, disk diffusion zones should be examined using transmitted light. Organisms with resistant results by disk diffusion should be confirmed using an MIC method.

U

Trimethoprim

PHENICOLS C Chloramphenicol ANSAMYCINS B Rifampin STREPTOGRAMINS C Quinupristindalfopristin OXAZOLIDINONES B Linezolid

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(30) Sulfisoxazole can be used to represent any of the currently available sulfonamide preparations.

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1.25/23.75 μg

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69

Supplemental Table 2C-S3 Screening Tests for Staphylococcus aureus Group

Product Name: Infobase 2010 - Release Date: February 2010

70

Screen Test Organism group

Oxacillin Resistance S. aureus

mecA-Mediated Oxacillin Resistance Using Cefoxitin S. aureus and S. lugdunensis

Vancomycin MIC ≥ 8 μg/mL S. aureus

Agar dilution

Disk diffusion

Broth microdilution a CAMHB

Agar dilution

Disk diffusion

Brain Heart Infusion (BHI) agar

MHA or blood agar purity plate used with MIC tests 15-µg erythromycin disk and 2-µg clindamycin disk spaced 15–26 mm apart Standard disk diffusion Recommendations

NA

MHA with 4% NaCl

MHA

Antimicrobial concentration

NA

6 μg/mL oxacillin

30 µg cefoxitin disk

4 µg/mL cefoxitin

6 μg/mL vancomycin

Inoculum

Induced growth (ie, growth taken from the zone margin surrounding an oxacillin or cefoxitin disk test on either MHA or a blood agar plate after 16–18 hours of incubation).

Direct colony suspension to obtain 0.5 McFarland turbidity. Using a 1-μL loop that was dipped in the suspension, spot an area 10 to 15 mm in diameter. Alternatively, using a swab dipped in the suspension and expressed, spot a similar area or streak an entire quadrant. 33–35 °C; ambient air. (Testing at temperatures above 35 °C may not detect MRSA.) 24 hours; read with transmitted light

Standard disk diffusion recommendations

Standard broth microdilution recommendations

Direct colony suspension to obtain 0.5 McFarland turbidity. Preferably, using a micropipette, spot a 10 μL drop onto agar surface. Alternatively, using a swab dipped in the suspension and the excess liquid expressed, spot an area 10 to 15 mm in diameter or streak a portion of the plate.

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Room temperature

Incubation length

Up to 1 hour for nitrocefin-based test or follow manufacturer’s directions

109

Incubation conditions

Inducible Clindamycin Resistance S. aureus and S. lugdunensis resistant to erythromycin and susceptible or intermediate to clindamycin

High-level b,c Mupirocin Resistance S. aureus

Broth microdilution a CAMHB

Disk diffusion

4 µg/mL erythromycin and 0.5 µg/mL clindamycin in same well

200-µg mupirocin disk

Single mupirocin 256-μg/mL well

Standard broth microdilution recommendations

Standard disk diffusion recommendations

Standard broth microdilution recommendations

MHA

Broth microdilution a CAMHB

or heavily inoculated area of purity plate

33–35 °C; ambient air. (Testing at temperatures above 35 °C may not detect MRSA.)

33–35 °C; ambient air. (Testing at temperatures above 35 °C may not detect MRSA.)

35 ± 2 °C; ambient air

35 ± 2 °C; ambient air

35 ± 2 °C; ambient air

35 ± 2 °C; ambient air

35 ± 2 °C; ambient air

16–18 hours

16–20 hours

24 hours; read with transmitted light

16–18 hours

18–24 hours

24 hours; read with transmitted light

24 hours; read with transmitted light

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Test method

β-Lactamase S. aureus and S. lugdunensis with penicillin MICs ≤ 0.12 µg/mL or zones ≥ 29 mm Nitrocefin-based test

January 2010

Supplemental Table 2C-S3. Screening Tests for β-Lactamase Production, Oxacillin Resistance, mecA-Mediated Oxacillin Resistance Using Cefoxitin, Vancomycin MIC ≥ 8 μg/mL, Inducible Clindamycin Resistance, and High-Level Mupirocin Resistance in the Staphylococcus aureus Group for Use With Table 2C

Product Name: Infobase 2010 - Release Date: February 2010

Screen Test Test method Results

β-Lactamase Nitrocefin-based test Nitrocefin-based test: conversion from yellow to red/pink = β-lactamase positive.

Oxacillin Resistance Agar dilution Examine carefully with transmitted light for > 1 colony or light film of growth.

mecA-Mediated Oxacillin Resistance Using Cefoxitin Disk diffusion Broth microdilution >4 µg/mL = ≤ 21 mm = mecA mecA positive positive ≥ 22 mm = mecA negative

≤ 4 µg/mL = mecA negative

> 1 colony = oxacillin resistant.

Further testing and reporting

β-Lactamasepositive staphylococci are resistant to penicillin, amino-, carboxy-, and ureidopenicillins.

Oxacillinresistant staphylococci are resistant to all β-lactam agents; other βlactam agents should be reported as resistant or should not be reported.

Vancomycin MIC ≥ 8 μg/mL Agar dilution Examine carefully with transmitted light for > 1 colony or light film of growth. > 1 colony = presumptive reduced susceptibility to vancomycin.

Cefoxitin is used as a surrogate for mecA-mediated oxacillin resistance. Isolates that test as mecA positive should be reported as oxacillin (not cefoxitin) resistant; other β-lactam agents should be reported as resistant or should not be reported. Because of the rare occurrence of oxacillin resistance mechanisms other than mecA, isolates that test as mecA negative but for which the oxacillin MICs are resistant (MIC ≥ 4 µg/mL) should be reported as oxacillin resistant.

Disk diffusion Flattening of the zone of inhibition adjacent to the erythromycin disk (referred to as a Dzone) = inducible clindamycin resistance.

Broth microdilution Any growth = inducible clindamycin resistance; No growth = no inducible clindamycin resistance

Hazy growth within the zone of inhibition around clindamycin = clindamycin resistance even if no D-zone apparent. Report isolates with inducible clindamycin resistance as “clindamycin resistant.” A comment that “This isolate is presumed to be resistant based on detection of inducible clindamycin resistance. Clindamycin may still be effective in some patients” may be included.

High-level b,c Mupirocin Resistance Disk diffusion Broth microdilution For single 256Examine carefully µg/mL well: with transmitted light for light growth within the Growth = highzone of inhibition. level mupirocin resistance No zone = highlevel mupirocin No growth = the resistance absence of highlevel mupirocin Any zone = the resistance absence of highlevel mupirocin resistance

Report isolates with no zone as high-level mupirocin resistant.

Report growth in the 256-µg/mL well as high-level mupirocin resistant.

Report any zone of inhibition as the absence of highlevel resistance.

Report no growth in the 256-µg/mL well as the absence of highlevel resistance.

71

M100-S20

Perform a vancomycin MIC using a validated MIC method to determine vancomycin MICs on S. aureus that grow on BHI– vancomycin screening agar. Testing on BHI – vancomycin screening agar does not reliably detect all vancomycinintermediate S. aureus strains. Some strains for which the vancomycin MICs are 4 μg/mL will fail to grow.

Inducible Clindamycin Resistance

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Supplemental Table 2C-S3. (Continued)

Supplemental Table 2C-S3 Screening Tests for Staphylococcus aureus Group

Supplemental Table 2C-S3 Screening Tests for Staphylococcus aureus Group

Product Name: Infobase 2010 - Release Date: February 2010

72

Screen Test Test method QC recommendations

β-Lactamase Nitrocefin-based test S. aureus ATCC 29213 – positive

®

®

S. aureus ATCC 25923 – negative

(or see manufacturer’s recommendations)

Oxacillin Resistance Agar dilution

mecA-Mediated Oxacillin Resistance Using Cefoxitin Disk diffusion Broth microdilution

S. aureus ® ATCC 29213 – Susceptible

S. aureus ATCC 25923 – mecA negative (zone 23-29 mm)

®

S. aureus ATCC 43300 – mecA positive (zone ≤ 21 mm)

®

S. aureus ® ATCC 43300 – Resistant

Vancomycin MIC ≥ 8 μg/mL Agar dilution

S. aureus ® ATCC 29213 – mecA negative (MIC 1-4 µg/mL) S. aureus ® ATCC 43300 – mecA positive (MIC >4 µg/mL)

Enterococcus faecalis ATCC® 29212 – Susceptible E. faecalis ATCC® 51299 – Resistant

Inducible Clindamycin Resistance Disk diffusion Broth microdilution S. aureus ATCC® 25923 for routine QC of disks; See Table 3 for use of supplemental QC strains

S. aureus ATCC® BAA976 or S. aureus ATCC® 29213 – no growth S. aureus ATCC® BAA-977 – growth

High-level b,c Mupirocin Resistance Disk diffusion Broth microdilution ®

S. aureus ATCC 25923 (200-µg disk) – mupA negative (zone 29 to 38 mm) ®

S. aureus ATCC BAA1708 – mupA positive (no zone)

®

S. aureus ATCC 29213 – mupA negative (MIC 0.06– 0.5 µg/mL)

January 2010

Supplemental Table 2C-S3. (Continued)

®

E. faecalis ATCC 29212 – mupA negative (MIC 16 to 128 µg/mL) ®

S. aureus ATCC BAA1708 – mupA positive (growth in 256-µg/mL well)

Footnotes

c.

CAMHB = cation-adjusted Mueller-Hinton broth. Although not formally validated by CLSI document M23–based analyses, some studies have linked a lack of response to mupirocin-based decolonization regimens with isolates for which the mupirocin MICs are ≥ 512. Although this document does not provide guidance on interpretive criteria for mupirocin, disk-based testing and the MIC screening test described here identify isolates for which the mupirocin MICs are ≥ 512 µg/mL. References: Simor AE. Randomized controlled trial of chlorhexidine gluconate for washing intranasal mupirocin, and rifampin and doxycycline versus no treatment for the eradication of methicillinresistant Staphylococcus aureus colonization. Clin Infect Dis. 2007;44:178-185; Harbarth S, Dharan S, Liassine N, Herrault P, Auckenthaler R, Pittet D. Randomized, placebo-controlled, double-blind trial to evaluate the efficacy of mupirocin for eradicating carriage of methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother. 1999;43:1412-1416; and Walker ES, Vasquez JE, Dula R, Bullock H, Sarubbi FA. Mupirocin-resistant, methicillin-resistant Staphylococcus aureus; does mupirocin remain effective? Infect Control Hosp Epidemiol. 2003;24:342-346.

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a. b.

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73

Supplemental Table 2C-S4 Screening Tests for CoagulaseNegative Staphylococci

Product Name: Infobase 2010 - Release Date: February 2010

Screen Test Organism group

mecA-Mediated Oxacillin Resistance Using Cefoxitin Coagulase-negative staphylococcia

Disk diffusion

Disk diffusion

Broth microdilution

Medium

NA

MHA

MHA or blood agar purity plate used with MIC tests

CAMHB

Antimicrobial concentration

NA

30-µg cefoxitin disk

15-µg erythromycin and 2-µg clindamycin disks spaced 15– 26 mm apart

4 µg/mL erythromycin and 0.5 µg/mL clindamycin in same well

Inoculum

Induced growth (ie, growth taken from the zone margin surrounding an oxacillin or cefoxitin disk test on either MHA or a blood agar plate after 16–18 hours of incubation)

Standard disk diffusion Procedure

Standard disk diffusion procedure

Standard broth microdilution procedure

Room temperature

33–35 °C; ambient air

Incubation conditions

Inducible Clindamycin Resistance Coagulase-negative staphylococcia resistant to erythromycin and susceptible or intermediate to clindamycin.

b

or heavily inoculated area of purity plate 35 ± 2 °C; ambient air

35 ± 2 °C; ambient air

(Testing at temperatures higher than 35 °C may not detect MRS.) Incubation length

Up to 1 hour for nitrocefinbased test or follow manufacturer’s directions.

24 hours (may be reported after 18 hours if resistant)

16–18 hours

18–24 hours

Results

Nitrocefin-based test: conversion from yellow to red/pink = β-lactamase positive.

≤ 24 mm = mecA positive;

Flattening of the zone of inhibition adjacent to the erythromycin disk (referred to as a D-zone) = inducible clindamycin resistance.

Any growth = inducible clindamycin resistance;

≥ 25 mm = mecA negative.

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Hazy growth within the zone of inhibition around clindamycin = clindamycin resistance, even if no D-zone is apparent.

no growth = no inducible clindamycin resistance.

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Test method

β-Lactamase Coagulase-negative a staphylococci with penicillin MICs ≤ 0.12 µg/mL or zones ≥ 29 mm Nitrocefin-based test

January 2010

74

Supplemental Table 2C-S4. Screening Tests for β-Lactamase, mecA-Mediated Oxacillin Resistance Using Cefoxitin, and Inducible Clindamycin Resistance in Coagulase-Negative Staphylococci (except Staphylococcus lugdunensis) for Use With Table 2C

Product Name: Infobase 2010 - Release Date: February 2010

Test method Further testing and reporting

QC recommendations

β-Lactamase Nitrocefin-based test β-Lactamase– positive staphylococci are resistant to penicillin, amino-, carboxyand ureidopenicillins.

®

S. aureus ATCC 29213 – positive

®

S. aureus ATCC 25923 – negative

mecA-Mediated Oxacillin Resistance Using Cefoxitin Disk diffusion Cefoxitin is used as a surrogate for mecAmediated oxacillin resistance. Isolates that test as mecA positive should be reported as oxacillin (not cefoxitin) resistant; other β-lactam agents should be reported as resistant or should not be reported. Because of the rare occurrence of resistance mechanisms other than mecA, isolates that test as mecA negative but for which the oxacillin MICs are resistant (MICs ≥ 4 µg/mL) should be reported as oxacillin resistant. For serious infections with coagulase-negative staphylococci other than S. epidermidis, testing for mecA or the protein expressed by mecA may be appropriate for strains for which the oxacillin MICs are 0.5 to 2 µg/mL. ® S. aureus ATCC 25923 – mecA negative (zone 23-29 mm) ® S. aureus ATCC 43300 – mecA positive (zone ≤ 21 mm)

Inducible Clindamycin Resistance Disk diffusion Broth microdilution Report isolates with inducible clindamycin resistance as “clindamycin resistant.” A comment that “This isolate is presumed to be resistant based on detection of inducible clindamycin resistance. Clindamycin may still be effective in some patients” may be included.

S. aureus ATCC® 25923 for routine QC of disks; see Table 3 for use of supplemental QC strains.

For Use With M02-A10 and M07-A8

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Supplemental Table 2C-S4. (Continued) Screen Test

S. aureus ATCC® BAA-976 or S. ® aureus ATCC 29213 – no growth S. aureus ATCC® BAA-977 – growth

(or see manufacturer’s recommendations)

Footnotes a. Except S. lugdunensis, which is included in the S. aureus group. See the preceding table. b. CAMHB = cation-adjusted Mueller-Hinton broth

M100-S20

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Supplemental Table 2C-S4 Screening Tests for CoagulaseNegative Staphylococci

Table 2D Product Name: Infobase 2010 - Release Date: February 2010

Enterococcus spp. M02 and M07

Table 2D. Zone Diameter and MIC Interpretive Standards for Enterococcus spp.

Medium:

Inoculum: Incubation:

Minimal QC Recommendations (See Tables 3 and 4 for acceptable QC ranges.)

Disk diffusion: MHA Broth dilution: CAMHB; CAMHB supplemented to 50 µg/mL calcium for daptomycin Agar dilution: MHA; agar dilution has not been validated for daptomycin Growth method or direct colony suspension, equivalent to a 0.5 McFarland standard 35 ± 2 °C; ambient air; Disk diffusion: 16 to 18 hours; Dilution methods: 16 to 20 hours; All methods: 24 hours for vancomycin

Disk diffusion: Staphylococcus aureus ATCC® 25923

January 2010

76

Testing Conditions

Dilution methods: Enterococcus faecalis ATCC® 29212

Refer to Supplemental Table 2D-S5 at the end of Table 2D for additional recommendations for testing conditions, reporting suggestions, and QC.

General Comments For disk diffusion, measure the diameter of the zones of complete inhibition (as judged by the unaided eye), including the diameter of the disk. Hold the Petri plate a few inches above a black, nonreflecting background illuminated with reflected light, except for vancomycin, which should be read with transmitted light (plate held up to light source). The zone margin should be considered the area showing no obvious, visible growth that can be detected with the unaided eye. Ignore faint growth of tiny colonies that can be detected only with a magnifying lens at the edge of the zone of inhibited growth. Any discernable growth within the zone of inhibition is indicative of vancomycin resistance.

(2)

WARNING: For Enterococcus spp., cephalosporins, aminoglycosides (except for high-level resistance screening), clindamycin, and trimethoprimsulfamethoxazole may appear active in vitro, but they are not effective clinically, and isolates should not be reported as susceptible.

(3)

Synergy between ampicillin, penicillin, or vancomycin and an aminoglycoside can be predicted for enterococci by using a high-level aminoglycoside (gentamicin and streptomycin) screening test. Other aminoglycosides need not be tested, because their activities against enterococci are not superior to gentamicin and streptomycin.

(4)

For some organism/antimicrobial agent combinations, the absence or rare occurrence of resistant strains precludes defining any results categories other than “susceptible.” For strains yielding results suggestive of a “nonsusceptible” category, organism identification and antimicrobial susceptibility test results should be confirmed. (See Appendix A.)

NOTE:

Information in boldface type is considered tentative for one year.

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(1)

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Test/Report Group PENICILLINS A A

Antimicrobial Agent Penicillin Ampicillin

Zone Diameter Breakpoints, nearest whole mm

MIC Interpretive Standard (µg/mL)

Disk Content

S

I

R

S

I

R

Comments

10 units 10 μg

≥ 15 ≥ 17

– –

≤ 14 ≤ 16

≤8 ≤8

– –

≥ 16 ≥ 16

(5) Ampicillin is the class representative for ampicillin and amoxicillin. Ampicillin results may be used to predict susceptibility to amoxicillin-clavulanic acid, ampicillin-sulbactam, piperacillin, and piperacillin-tazobactam among non–β-lactamase–producing enterococci. Ampicillin susceptibility can be used to predict imipenem susceptibility, providing the species is confirmed to be E. faecalis. (6) Enterococci susceptible to penicillin are predictably susceptible to ampicillin, amoxicillin, ampicillin-sulbactam, amoxicillinclavulanate, piperacillin, and piperacillin-tazobactam for non–βlactamase–producing enterococci. However, enterococci susceptible to ampicillin cannot be assumed to be susceptible to penicillin. If penicillin results are needed, testing of penicillin is required.

For Use With M02-A10 and M07-A8

Table 2D. (Continued)

(7) Rx: Combination therapy of ampicillin, penicillin, or vancomycin (for susceptible strains), plus an aminoglycoside, is usually indicated for serious enterococcal infections, such as endocarditis, unless high-level resistance to both gentamicin and streptomycin is documented; such combinations are predicted to result in synergistic killing of the Enterococcus. (8) Penicillin or ampicillin resistance among enterococci due to βlactamase production has been reported very rarely. Penicillin or ampicillin resistance due to β-lactamase production is not reliably detected with routine disk or dilution methods but is detected using a direct, nitrocefin-based β-lactamase test. Because of the rarity of β-lactamase–positive enterococci, this test need not be performed routinely, but can be used in selected cases. A positive β-lactamase test predicts resistance to penicillin, as well as amino- and ureidopenicillins (see Glossary I).

GLYCOPEPTIDES B Vancomycin

≥ 17

15–16

≤ 14

≤4

8–16

≥ 32

Teicoplanin

30 μg

≥ 14

11–13

≤ 10

≤8

16

≥ 32

Daptomycin

–

–

–

–

≤4

–

–

(9) When testing vancomycin against enterococci, plates should be held a full 24 hours for accurate detection of resistance. For isolates for which the vancomycin MICs are 8 to 16 µg/mL, perform biochemical tests for identification as listed under the “Vancomycin Resistance” test found in Supplemental Table 2D-S5 at the end of Table 2D. Zones should be examined using transmitted light; the presence of a haze or any growth within the zone of inhibition indicates resistance. Organisms with intermediate zones should be tested by an MIC method as described in CLSI document M07-A8. See also the Vancomycin Resistance test described in Supplemental Table 2D-S5 at the end of Table 2D. See comments (3) and (7).

77

Inv. LIPOPEPTIDES B

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Table 2D Enterococcus spp. copyright laws. M02 and M07

(10) Disk testing is not reliable for testing daptomycin. See comment (4).

M100-S20

30 μg

Table 2D Product Name: Infobase 2010 - Release Date: February 2010

Enterococcus spp. M02 and M07

Table 2D. (Continued)

MIC Interpretive Standard (µg/mL)

Disk Content

S

I

R

S

I

R

Comments

15 μg

≥ 23

14–22

≤ 13

≤ 0.5

1–4

≥8

(11) Not routinely reported on isolates from the urinary tract.

TETRACYCLINES

January 2010

78

Test/Report Antimicrobial Group Agent MACROLIDES O Erythromycin

Zone Diameter Breakpoints, nearest whole mm

(12) Organisms that are susceptible to tetracycline are also considered susceptible to doxycycline and minocycline. However, some organisms that are intermediate or resistant to tetracycline may be susceptible to doxycycline, minocycline, or both. U Tetracycline O Doxycycline O Minocycline FLUOROQUINOLONES U Ciprofloxacin U Levofloxacin U Norfloxacin O Gatifloxacin NITROFURANTOINS U Nitrofurantoin ANSAMYCINS O Rifampin

≥ 19 ≥ 16 ≥ 19

15–18 13–15 15–18

≤ 14 ≤ 12 ≤ 14

≤4 ≤4 ≤4

8 8 8

≥ 16 ≥ 16 ≥ 16

5 μg 5 μg 10 μg 5 μg

≥ 21 ≥ 17 ≥ 17 ≥ 18

16–20 14–16 13–16 15–17

≤ 15 ≤ 13 ≤ 12 ≤ 14

≤1 ≤2 ≤4 ≤2

2 4 8 4

≥4 ≥8 ≥ 16 ≥8

300 μg

≥ 17

15–16

≤ 14

≤ 32

64

≥ 128

5 μg

≥ 20

17–19

≤ 16

≤1

2

≥4

(14) Rx: Rifampin should not be used alone for antimicrobial therapy.

200 μg

≥ 16

13–15

≤ 12

≤ 64

128

≥ 256

(15) Indicated for use against E. faecalis urinary tract isolates only.

(13) These interpretive criteria apply to urinary tract isolates only.

(16) The approved MIC testing method is agar dilution. Agar media should be supplemented with 25 µg/mL of glucose-6-phosphate. Broth dilution testing should not be performed. (17) The 200-μg fosfomycin disk contains 50 μg of glucose-6-phosphate. PHENICOLS O Chloramphenicol STREPTOGRAMINS B Quinupristin-dalfopristin OXAZOLIDINONES B Linezolid

30 μg

≥ 18

13–17

≤ 12

≤8

16

≥ 32

See comment (11).

15 μg

≥ 19

16–18

≤ 15

≤1

2

≥4

(18) For reporting against vancomycin-resistant E. faecalis.

30 μg

≥ 23

21–22

≤ 20

≤2

4

≥8

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FOSFOMYCINS O Fosfomycin

30 μg 30 μg 30 μg

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Screen Test Test method Medium Antimicrobial concentration Inoculum

Disk diffusion MHA 120-µg gentamicin disk Standard disk diffusion recommendations

Gentamicin HLAR Broth microdilution a BHI broth Gentamicin, 500 μg/mL Standard broth dilution recommendations

Incubation conditions Incubation length

35 ± 2 °C; ambient air 16–18 hours

Results

6 mm = Resistant;

Disk diffusion MHA 300-µg streptomycin disk Standard disk diffusion recommendations

35 ± 2 °C; ambient air 24 hours

Agar dilution a BHI agar Gentamicin, 500 µg/mL 10 μL of a 0.5 McFarland suspension spotted onto agar surface 35 ± 2 °C; ambient air 24 hours

Any growth = Resistant

>1 colony = Resistant

6 mm = Resistant;

35 ± 2 °C; ambient air 16–18 hours

7–9 mm = Inconclusive;

7–9 mm = Inconclusive;

≥ 10 mm = Susceptible.

≥ 10 mm = Susceptible

MIC correlates: R = >500 µg/mL S = ≤ 500 µg/mL

MIC correlates: R = >1000 µg/mL (broth) and >2000 µg/mL (agar);

Streptomycin HLAR Broth microdilution a BHI broth Streptomycin, 1000 µg/mL Standard broth dilution recommendations 35 ± 2 °C; ambient air 24–48 hours (if susceptible at 24 hours, reincubate) Any growth = Resistant

Agar dilution a BHI agar Streptomycin, 2000 μg/mL 10 μL of a 0.5 McFarland suspension spotted onto agar surface 35 ± 2 °C; ambient air 24–48 hours (if susceptible at 24 hours, reincubate) >1 colony = Resistant

S = ≤ 500 µg/mL (broth) and ≤ 1000 µg/mL (agar) Resistant: is not synergistic with cell wall–active agent (eg, ampicillin, penicillin, and vancomycin).

Further testing and reporting

Susceptible: is synergistic with cell wall–active agent (eg, ampicillin, penicillin, and vancomycin) that is also susceptible. If disk diffusion result is inconclusive: perform an agar dilution or broth microdilution test to confirm.

®

79

E. faecalis ATCC 29212: 16–23 mm

®

E. faecalis ATCC 29212 – Susceptible ® E. faecalis ATCC 51299 – Resistant

E. faecalis ® ATCC 29212 – Susceptible E. faecalis ® ATCC 51299 – Resistant

®

E. faecalis ATCC 29212: 14–20 mm

®

E. faecalis ATCC 29212 – Susceptible ® E. faecalis ATCC 51299 – Resistant

®

E. faecalis ATCC 29212 – Susceptible ® E. faecalis ATCC 51299 – Resistant

35 ± 2 °C; ambient air 24 hours >1 colony = Presumptive vancomycin resistance

Perform vancomycin MIC and test for motility and pigment production to distinguish species with acquired resistance (VanA and VanB) from those with intrinsic, intermediate-level resistance to vancomycin (VanC), such as Enterococcus gallinarum and Enterococcus casseliflavus, which often grow on the vancomycin screen plate. In contrast to other enterococci, E. casseliflavus and E. gallinarum with vancomycin MICs of 8–16 μg/mL (intermediate) differ from vancomycin-resistant enterococci (VRE) for infection control purposes. ® E. faecalis ATCC 29212 – Susceptible ®

E. faecalis ATCC 51299 – Resistant

Footnote BHI = Brain Heart Infusion; even though not as widely available, dextrose phosphate agar and broth have been shown in limited testing to perform comparably.

Supplemental Table 2D-S5 Screening Tests for HLAR and Vancomycin Resistance

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Vancomycin Resistance Agar dilution a BHI agar Vancomycin, 6 μg/mL 1–10 μL of a 0.5 McFarland suspension spotted onto agar surface

For Use With M02-A10 and M07-A8

Supplemental Table 2D-S5. Screening Tests for High-Level Aminoglycoside Resistance (HLAR) and Vancomycin Resistance in Enterococcus spp. for Use With Table 2D

Table 2E Product Name: Infobase 2010 - Release Date: February 2010 Haemophilus spp. M02 and M07 Table 2E. Zone Diameter and MIC Interpretive Standards for Haemophilus influenzae and Haemophilus parainfluenzae

Medium: Inoculum: Incubation:

Minimal QC Recommendations (See Tables 3A and 4A for acceptable QC ranges.)

Disk diffusion: Haemophilus Test Medium (HTM) Broth dilution: HTM broth Direct colony suspension, equivalent to a 0.5 McFarland standard 35 ± 2 °C; Disk diffusion: 5% CO2; 16 to 18 hours Broth dilution: ambient air; 20 to 24 hours

Haemophilus influenzae ATCC® 49247 Haemophilus influenzae ATCC® 49766 ® Escherichia coli ATCC 35218 (when testing amoxicillin-clavulanic acid)

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80

Testing Conditions

General Comments (1) For disk diffusion, measure the diameter of the zones of complete inhibition (as judged by the unaided eye), including the diameter of the disk. Hold the Petri plate a few inches above a black, nonreflecting background illuminated with reflected light. The zone margin should be considered the area showing no obvious, visible growth that can be detected with the unaided eye. Ignore faint growth of tiny colonies that can be detected only with a magnifying lens at the edge of the zone of inhibited growth. With trimethoprim and the sulfonamides, antagonists in the medium may allow some slight growth; therefore, disregard slight growth (20% or less of the lawn of growth) and measure the more obvious margin to determine the zone diameter.

(3) Amoxicillin-clavulanic acid, azithromycin, clarithromycin, cefaclor, cefprozil, loracarbef, cefdinir, cefixime, cefpodoxime, cefuroxime, and telithromycin are oral agents that may be used as empiric therapy for respiratory tract infections due to Haemophilus spp. The results of susceptibility tests with these antimicrobial agents are often not useful for management of individual patients. However, susceptibility testing of Haemophilus spp. with these compounds may be appropriate for surveillance or epidemiological studies. (4) To make Haemophilus Test Medium (HTM): Prepare a fresh hematin stock solution by dissolving 50 mg of hematin powder in 100 mL of 0.01 mol/L NaOH with heat and stirring until the powder is thoroughly dissolved. Add 30 mL of the hematin stock solution and 5 g of yeast extract to 1 L of Mueller-Hinton agar (MHA) and autoclave. After autoclaving and cooling, add 3 mL of a nicotinamide adenine dinucleotide (NAD) stock solution (50 mg of NAD dissolved in 10 mL of distilled water, filter sterilized) aseptically. (5) For some organism/antimicrobial agent combinations, the absence or rare occurrence of resistant strains precludes defining any results categories other than “susceptible.” For strains yielding results suggestive of a “nonsusceptible” category, organism identification and antimicrobial susceptibility test results should be confirmed. (See Appendix A.) NOTE: Information in boldface type is considered tentative for one year.

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(2) For isolates of H. influenzae from CSF, only results of testing with ampicillin, one of the third-generation cephalosporins, chloramphenicol, and meropenem should be reported routinely.

Product Name: Infobase 2010 - Release Date: February 2010

Test/Report Group PENICILLINS A

Antimicrobial Agent Ampicillin

Zone Diameter Breakpoints, nearest whole mm

MIC Interpretive Standard (µg/mL)

Disk Content

S

I

R

S

I

R

10 μg

≥ 22

19–21

≤ 18

≤1

2

≥4

See comment (2). (6) The results of ampicillin susceptibility tests should be used to predict the activity of amoxicillin. The majority of isolates of H. influenzae that are resistant to ampicillin and amoxicillin produce a TEM-type β-lactamase. In most cases, a direct β-lactamase test can provide a rapid means of detecting resistance to ampicillin and amoxicillin. (7) Rare β-lactamase–negative, ampicillinresistant (BLNAR) strains of H. influenzae should be considered resistant to amoxicillin-clavulanic acid, ampicillin-sulbactam, cefaclor, cefetamet, cefonicid, cefprozil, cefuroxime, loracarbef, and piperacillin-tazobactam, despite apparent in vitro susceptibility of some BLNAR strains to these agents.

β-LACTAM/β-LACTAMASE INHIBITOR COMBINATIONS B Ampicillin-sulbactam – 10/10 μg ≥ 20 ≤ 19 ≤ 2/1 C Amoxicillin-clavulanic acid – 20/10 μg ≥ 20 ≤ 19 ≤ 4/2 O Piperacillin-tazobactam – – 100/10 μg ≥ 21 ≤ 1/4 CEPHEMS (PARENTERAL) (Including cephalosporins I, II, III, and IV. Please refer to Glossary I.) B Cefotaxime or – – 30 μg ≥ 26 ≤2 B ceftazidime or – – 30 μg ≥ 26 ≤2 B ceftriaxone – – 30 μg ≥ 26 ≤2 B Cefuroxime 17–19 30 μg ≥ 20 ≤ 16 ≤4 O Cefonicid 17–19 30 μg ≥ 20 ≤ 16 ≤4 O Cefamandole – – – – ≤4 O Cefepime – – 30 μg ≥ 26 ≤2 O Ceftizoxime – – 30 μg ≥ 26 ≤2

Table 2E Haemophilus spp. M02 is andprotected M07 document

– – –

≥ 4/2 ≥ 8/4 ≥ 2/4

See comment (7). See comments (3) and (7). See comment (7).

– – – 8 8 8 – –

– – –

See comments (2) and (5).

≥ 16 ≥ 16 ≥ 16 – –

See comment (7). See comment (7). See comment (7). See comment (5). See comment (5).

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Table 2E. (Continued)

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2E Product Name:Table Infobase 2010 - Release Date: February 2010 Haemophilus spp. M02 and M07

MIC Interpretive Standard (µg/mL)

Disk Content

S

I

R

S

I

R

30 μg 30 μg 5 μg 5 μg 10 μg 30 μg 30 μg 30 μg 10 μg

≥ 20 ≥ 18 ≥ 20 ≥ 21 ≥ 21 ≥ 20 ≥ 19 ≥ 28 ≥ 18

17–19 15–17 – – – 17–19 16–18 – 15–17

≤ 16 ≤ 14 – – –

16 16 – – – 8 16 – 8

≥ 32 ≥ 32 – – –

≤ 16 ≤ 15 – ≤ 14

≤8 ≤8 ≤1 ≤1 ≤2 ≤4 ≤8 ≤2 ≤4

30 μg

≥ 26

–

–

≤2

–

–

See comment (5).

10 μg 10 μg 10 μg

≥ 20 ≥ 19 ≥ 16

– – –

– – –

≤ 0.5 ≤ 0.5 ≤4

– – –

– – –

See comments (2) and (5). See comment (5).

15 μg 15 μg

≥ 12 ≥ 13

– 11–12

– ≤ 10

≤4 ≤8

– 16

– ≥ 32

See comment (5).

15 μg

≥ 15

12–14

≤ 11

≤4

8

≥ 16

See comment (3).

30 μg

≥ 29

26–28

≤ 25

≤2

4

≥8

(8) Organisms that are susceptible to tetracycline are also considered susceptible to doxycycline and minocycline.

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≥ 16 ≥ 32 – ≥ 16

Comments See comments (3) and (7). See comments (3) and (5).

See comments (3) and (7). See comment (5). See comment (7).

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Test/Report Antimicrobial Group Agent CEPHEMS (ORAL) C Cefaclor C Cefprozil Cefdinir or C cefixime or C cefpodoxime C C Cefuroxime O Loracarbef O Ceftibuten Inv. Cefetamet MONOBACTAMS C Aztreonam CARBAPENEMS B Meropenem C Ertapenem or C imipenem MACROLIDES C Azithromycin C Clarithromycin KETOLIDES C Telithromycin TETRACYCLINES C Tetracycline

Zone Diameter Breakpoints, nearest whole mm

January 2010

82

Table 2E. (Continued)

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Test/Report Antimicrobial Group Agent FLUOROQUINOLONES C Ciprofloxacin or C levofloxacin or C lomefloxacin or C moxifloxacin or C ofloxacin C Gemifloxacin O Gatifloxacin O Grepafloxacin O Sparfloxacin O Trovafloxacin Inv. Fleroxacin FOLATE PATHWAY INHIBITORS A Trimethoprimsulfamethoxazole PHENICOLS B Chloramphenicol

Disk Content

Zone Diameter Breakpoints, nearest whole mm S

I

MIC Interpretive Standard (µg/mL) R

S

I

Comments

R See comment (5).

5 μg 5 μg 10 μg 5 μg 5 μg 5 μg 5 μg 5 μg – 10 μg 5 μg

≥ 21 ≥ 17 ≥ 22 ≥ 18 ≥ 16 ≥ 18 ≥ 18 ≥ 24 – ≥ 22 ≥ 19

– – – – –

– – – – –

≤1 ≤2 ≤2 ≤1 ≤2

– – – – –

– – – – –

– – – – – –

– – – – – –

≤ 0.12

– – – – – –

– – – – – –

1.25/23.75 μg

≥ 16

11–15

≤ 10

≤ 0.5/9.5

1/19– 2/38

≥ 4/76

30 μg

≥ 29

26–28

≤ 25

≤2

4

≥8

≤1

≤ 0.5 ≤ 0.25 ≤1 ≤2

For Use With M02-A10 and M07-A8

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Table 2E. (Continued)

See comment (2). (9) Not routinely reported on isolates from the urinary tract.

ANSAMYCINS C Rifampin

5 μg

≥ 20

17–19

≤ 16

2

≥4

(10) Rx: Rifampin should not be used alone for antimicrobial therapy.

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Table 2F Neisseria gonorrhoeae M02 and M07

Testing Conditions Medium:

Inoculum: Incubation:

Minimal QC Recommendations (See Tables 3A and 4B for acceptable QC ranges.)

Disk diffusion: GC agar base and 1% defined growth supplement. (The use of a cysteine-free growth supplement is not required for disk diffusion testing.) Agar dilution: GC agar base and 1% defined growth supplement. (The use of a cysteine-free growth supplement is required for agar dilution tests with carbapenems and clavulanate. Cysteine-containing defined growth supplement does not significantly alter dilution test results with other drugs). Direct colony suspension, equivalent to a 0.5 McFarland standard 36 ± 1 ºC (do not exceed 37 ºC); 5% CO2; all methods, 20 to 24 hours

Neisseria gonorrhoeae ATCC® 49226

January 2010

84

Table 2F. Zone Diameter and MIC Interpretive Standards for Neisseria gonorrhoeae

General Comments

(2) The clinical effectiveness of cefmetazole, cefotetan, cefoxitin, and spectinomycin for treating organisms that produce intermediate results with these agents is unknown. (3) For disk diffusion testing of N. gonorrhoeae, an intermediate result for an antimicrobial agent indicates either a technical problem that should be resolved by repeat testing or a lack of clinical experience in treating organisms with these zones. Strains with intermediate zones to agents other than cefmetazole, cefotetan, cefoxitin, and spectinomycin have a documented lower clinical cure rate (85% to 95%) compared with > 95% for susceptible strains. (4) The recommended medium for testing N. gonorrhoeae consists of GC agar to which a 1% defined growth supplement (1.1 g L-cysteine, 0.03 g guanine HCl, 3 mg thiamine HCl, 13 mg para-aminobenzoic acid (PABA), 0.01 g B12, 0.1 g cocarboxylase, 0.25 g NAD, 1 g adenine, 10 g L-glutamine, 100 g glucose, 0.02 g ferric nitrate [in 1 L H2O]) is added after autoclaving. (5) For some organism/antimicrobial agent combinations, the absence or rare occurrence of resistant strains precludes defining any results categories other than “susceptible.” For strains yielding results suggestive of a “nonsusceptible” category, organism identification and antimicrobial susceptibility test results should be confirmed. (See Appendix A.) NOTE: Information in boldface type is considered tentative for one year.

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(1) For disk diffusion, measure the diameter of the zones of complete inhibition (as judged by the unaided eye), including the diameter of the disk. Hold the Petri plate a few inches above a black, nonreflecting background illuminated with reflected light. The zone margin should be considered the area showing no obvious, visible growth that can be detected with the unaided eye. Ignore faint growth of tiny colonies that can be detected only with a magnifying lens at the edge of the zone of inhibited growth.

Product Name: Infobase 2010 - Release Date: February 2010

Test/Report Group PENICILLINS C

Antimicrobial Agent Penicillin

Zone Diameter Breakpoints, nearest whole mm

MIC Interpretive Standard (µg/mL)

Disk Content

S

I

R

S

I

R

10 units

≥ 47

27–46

≤ 26

≤ 0.06

0.12-1

≥2

Comments See comment (3). (6) A positive β-lactamase test predicts resistance to penicillin, ampicillin, and amoxicillin. (7) A β-lactamase test detects one form of penicillin resistance in N. gonorrhoeae and also may be used to provide epidemiological information. Strains with chromosomally mediated resistance can be detected only by the disk diffusion method or the agar dilution MIC method.

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Table 2F. (Continued)

(8) Gonococci with 10-unit penicillin disk zone diameters of ≤ 19 mm are likely to be β-lactamase– producing strains. However, the β-lactamase test remains preferable to other susceptibility methods for rapid, accurate recognition of this plasmidmediated penicillin resistance. CEPHEMS (PARENTERAL) (Including cephalosporins I, II, III, and IV. Please refer to Glossary I.) C Cefotaxime or – – 30 μg ≥ 31 ≤ 0.5 C ceftriaxone – – 30 μg ≥ 35 ≤ 0.25 C Cefoxitin 30 μg ≥ 28 ≤ 23 ≤2 24–27 C Cefuroxime 30 μg ≥ 31 ≤ 25 ≤1 26–30

– – 4 2

– – ≥8 ≥4

See comment (5). See comment (2). See comment (3).

O O

Cefepime Cefmetazole

30 μg 30 μg

≥ 31 ≥ 33

– 28–32

– ≤ 27

≤ 0.5 ≤2

– 4

– ≥8

See comment (5). See comment (2).

O

Cefotetan

30 μg

≥ 26

20–25

≤ 19

≤2

4

≥8

See comment (2).

30 μg 30 μg

≥ 31 ≥ 38

– –

– –

≤ 0.5 ≤ 0.5

– –

– –

See comment (5). See comment (5).

5 μg 10 μg 10 μg

≥ 31 ≥ 29 ≥ 29

– – –

– – –

≤ 0.25 ≤ 0.5 ≤ 0.5

– – –

– – –

See comment (5).

O Ceftazidime O Ceftizoxime CEPHEMS (ORAL) C Cefixime or C cefpodoxime Inv. Cefetamet TETRACYCLINES

See comment (5).

(9) Organisms that are susceptible to tetracycline are also considered susceptible to doxycycline and minocycline. Tetracycline

30 μg

≥ 38

31–37

≤ 30

85

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≤ 0.25

0.5–1

≥2

(10) Gonococci with 30-μg tetracycline disk zone diameters of ≤ 19 mm usually indicate a plasmidmediated tetracycline-resistant N. gonorrhoeae (TRNG) isolate. Resistance in these strains should be confirmed by a dilution test (MIC ≥ 16 μg/mL).

Table 2F Neisseria gonorrhoeae M02 and M07

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C

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Table 2F Neisseria gonorrhoeae M02 and M07

Test/Report Antimicrobial Group Agent FLUOROQUINOLONES C Ciprofloxacin or C ofloxacin O Enoxacin O Gatifloxacin O Grepafloxacin O Lomefloxacin O Trovafloxacin Inv. Fleroxacin AMINOCYCLITOLS C Spectinomycin

Disk Content

Zone Diameter Breakpoints, nearest whole mm S

I

MIC Interpretive Standard (µg/mL) R

S

I

Comments

R

January 2010

86

Table 2F. (Continued)

See comment (3). 5 μg 5 μg 10 μg 5 μg 5 μg 10 μg 10 μg 5 μg

≥ 41 ≥ 31 ≥ 36 ≥ 38 ≥ 37 ≥ 38 ≥ 34 ≥ 35

28–40 25–30 32–35 34–37 28–36 27–37 – 29–34

≤ 27 ≤ 24 ≤ 31 ≤ 33 ≤ 27 ≤ 26 – ≤ 28

≤ 0.06 ≤ 0.25 ≤ 0.5 ≤ 0.125 ≤ 0.06 ≤ 0.12 ≤ 0.25 ≤ 0.25

0.12–0.5 0.5–1 1 0.25 0.12–0.5 0.25–1 – 0.5

≥1 ≥2 ≥2 ≥ 0.5 ≥1 ≥2 – ≥1

100 μg

≥18

15–17

≤ 14

≤ 32

64

≥ 128

See comment (5).

See comment (2).

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Table 2G Streptococcus pneumoniae M02 and M07

Product Name: Infobase 2010 - Release Date: February 2010 Table 2G. Zone Diameter and MIC Interpretive Standards for Streptococcus pneumoniae

Minimal QC Recommendations (See Tables 3A and 4A for acceptable QC ranges.)

Medium:

Disk diffusion: MHA with 5% sheep’s blood Broth dilution: CAMHB with LHB (2.5 to 5% v/v) (see M07-A8 for instructions for preparation of LHB) Inoculum: Direct colony suspension, equivalent to a 0.5 McFarland standard Incubation: 35 ± 2 °C Disk diffusion: 5% CO2; 20 to 24 hours Dilution methods: ambient air; 20 to 24 hours

Streptococcus pneumoniae ATCC® 49619

January 2010

88

Testing Conditions

General Comments

(2) Amoxicillin, ampicillin, cefepime, cefotaxime, ceftriaxone, cefuroxime, ertapenem, imipenem, and meropenem may be used to treat pneumococcal infections; however, reliable disk diffusion susceptibility tests with these agents do not yet exist. Their in vitro activity is best determined using an MIC method. (3) Penicillin and cefotaxime or ceftriaxone or meropenem should be tested by a reliable MIC method (such as that described in CLSI document M07-A8) and reported routinely with CSF isolates of S. pneumoniae. Such isolates should also be tested against vancomycin using the MIC or disk method. (4) For some organism/antimicrobial agent combinations, the absence or rare occurrence of resistant strains precludes defining any results categories other than “susceptible.” For strains yielding results suggestive of a “nonsusceptible” category, organism identification and antimicrobial susceptibility test results should be confirmed. (See Appendix A.) NOTE:

Information in boldface type is considered tentative for one year.

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(1) For disk diffusion, measure the diameter of the zones of complete inhibition (as judged by the unaided eye), including the diameter of the disk. The zone margin should be considered the area showing no obvious, visible growth that can be detected with the unaided eye. Measure the zones from the upper surface of the agar illuminated with reflected light, with the cover removed. Ignore faint growth of tiny colonies that can be detected only with a magnifying lens at the edge of the zone of inhibited growth. With trimethoprim and the sulfonamides, antagonists in the medium may allow some slight growth; therefore, disregard slight growth (20% or less of the lawn of growth) and measure the more obvious margin to determine the zone diameter.

Product Name: Infobase 2010 - Release Date: February 2010

Test/Report Group PENICILLINS

Antimicrobial Agent

Disk Content

Zone Diameter Breakpoints, nearest whole mm S

I

MIC Interpretive Standard (µg/mL) R

S

I

Comments

R

(5) For nonmeningitis isolates, the penicillin MIC can predict susceptibility to other β-lactams as follows: Penicillin MICs ≤ 0.06 µg/mL (or oxacillin zones ≥ 20 mm) indicate susceptibility to ampicillin (oral or parenteral), ampicillin-sulbactam, cefaclor, cefdinir, cefditoren, cefpodoxime, cefprozil, ceftizoxime, cefuroxime, imipenem, loracarbef, and meropenem. Penicillin MICs ≤ 2 µg/mL indicate susceptibility to: amoxicillin, amoxicillin-clavulanic acid, cefepime, cefotaxime, ceftriaxone, and ertapenem. See comment (3). A Penicillin

A

A

Penicillin parenteral (nonmeningitis)

Penicillin parenteral (meningitis)

1 μg oxacillin

≥ 20

–

–

–

–

–

–

–

–

–

≤2

4

≥8

–

–

–

–

≤ 0.06

–

≥ 0.12

(6) Isolates of pneumococci with oxacillin zone sizes of ≥ 20 mm are susceptible (MIC ≤ 0.06 μg/mL) to penicillin. Penicillin and cefotaxime or ceftriaxone or meropenem MICs should be determined for those isolates with oxacillin zone diameters of ≤ 19 mm, because zones of ≤ 19 mm occur with penicillin–resistant, intermediate, or certain susceptible strains. For isolates with oxacillin zones ≤ 19 mm, do not report penicillin as resistant without performing a penicillin MIC test. (7) Rx: Doses of intravenous penicillin of at least 2 million units every four hours in adults with normal renal function (12 million units per day) can be used to treat nonmeningeal pneumococcal infections due to strains with penicillin MICs ≤ 2 µg/mL. Strains with an intermediate MIC of 4 µg/mL may require penicillin doses of 18 to 24 million units per day.

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Table 2G. (Continued)

(8) For all isolates other than those from CSF, report interpretations for both meningitis and nonmeningitis. (9) Rx: Use of penicillin in meningitis requires therapy with maximum doses of intravenous penicillin (eg, at least 3 million units every four hours in adults with normal renal function). (10) For CSF isolates, report only meningitis interpretations.

Penicillin (oral penicillin V)

–

–

–

–

≤ 0.06

0.12–1

≥2

C

Amoxicillin (nonmeningitis) Amoxicillin-clavulanic acid (nonmeningitis)

–

–

–

–

≤2

4

≥8

≤ 2/1

4/2

≥ 8/4

C

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Table 2G Streptococcus pneumoniae M02 and M07

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A

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Table 2G Streptococcus pneumoniae M02 and M07

90

Zone Diameter Breakpoints, nearest whole mm

MIC Interpretive Standard (µg/mL)

Test/Report Antimicrobial Disk Group Agent Content S I R S CEPHEMS (PARENTERAL) (Including cephalosporins I, II, III, and IV. Please refer to Glossary I.) O Cefepime (meningitis) – – – – ≤ 0.5

I

R

Comments

1

≥2

(11) For CSF isolates, report only meningitis interpretations. There is not an FDA–approved indication for the use of cefepime for meningitis. (12) In the United States, only report interpretations for nonmeningitis and include the nonmeningitis notation on the report. (13) For CSF isolates, report only meningitis interpretations.

B

Cefepime (nonmeningitis)

–

–

–

–

≤1

2

≥4

B B

Cefotaxime (meningitis) Ceftriaxone (meningitis)

– –

– –

– –

– –

≤ 0.5 ≤ 0.5

1 1

≥2 ≥2

January 2010

Table 2G. (Continued)

(14) Rx: Use of cefotaxime or ceftriaxone in meningitis requires therapy with maximum doses. B B

Cefotaxime (nonmeningitis) Ceftriaxone (nonmeningitis)

– –

– –

– –

≤1 ≤1

2 2

≥4 ≥4

–

–

–

–

≤ 0.5

1

≥2

– – – – – –

– – – – – –

– – – – – –

– – – – – –

≤1 ≤1 ≤ 0.5 ≤ 0.5 ≤2 ≤2

2 2 1 1 4 4

≥4 ≥4 ≥2 ≥2 ≥8 ≥8

– – –

– – –

– – –

– – –

≤ 0.25 ≤1 ≤ 0.12

0.5 2 0.25–0.5

≥1 ≥4 ≥1

30 μg

≥ 17

–

–

≤1

–

–

See comment (3). (15) For all isolates other than those from CSF, report interpretations for both meningitis and nonmeningitis.

See comment (3).

See comments (3) and (4).

(16) Susceptibility and resistance to azithromycin, clarithromycin, and dirithromycin can be predicted by using erythromycin. (17) Not routinely reported on isolates from the urinary tract. A O O O

Erythromycin Azithromycin Clarithromycin Dirithromycin

15 μg 15 μg 15 μg 15 μg

≥ 21 ≥ 18 ≥ 21 ≥ 18

16–20 14–17 17–20 14–17

≤ 15 ≤ 13 ≤ 16 ≤ 13

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≤ 0.25 ≤ 0.5 ≤ 0.25 ≤ 0.5

0.5 1 0.5 1

≥1 ≥2 ≥1 ≥2

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C Cefuroxime (parenteral) CEPHEMS (ORAL) C Cefuroxime (oral) O Cefaclor O Cefdinir O Cefpodoxime O Cefprozil O Loracarbef CARBAPENEMS B Meropenem C Ertapenem C Imipenem GLYCOPEPTIDES B Vancomycin MACROLIDES

– –

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Test/Report Antimicrobial Group Agent KETOLIDES B Telithromycin TETRACYCLINES B Tetracycline FLUOROQUINOLONES Gemifloxacin B Levofloxacin B Moxifloxacin B Ofloxacin B O Gatifloxacin O Grepafloxacin O Sparfloxacin O Trovafloxacin FOLATE PATHWAY INHIBITORS A Trimethoprimsulfamethoxazole PHENICOLS C Chloramphenicol ANSAMYCINS C Rifampin LINCOSAMIDES B Clindamycin STREPTOGRAMINS O Quinupristin-dalfopristin OXAZOLIDINONES C Linezolid

Zone Diameter Breakpoints, nearest whole mm

MIC Interpretive Standard (µg/mL)

Disk Content

S

I

R

S

I

R

15 μg

≥ 19

16–18

≤ 15

≤1

2

≥4

30 μg

≥ 23

19–22

≤ 18

≤2

4

≥8

5 μg 5 μg 5 μg 5 μg 5 μg 5 μg 5 μg 10 μg

≥ 23 ≥ 17 ≥ 18 ≥ 16 ≥ 21 ≥ 19 ≥ 19 ≥ 19

20–22 14–16 15–17 13–15 18–20 16–18 16–18 16–18

≤ 19 ≤ 13 ≤ 14 ≤ 12 ≤ 17 ≤ 15 ≤ 15 ≤ 15

≤ 0.12 ≤2 ≤1 ≤2 ≤1 ≤ 0.5 ≤ 0.5 ≤1

0.25 4 2 4

≥ 0.5 ≥8 ≥4 ≥8

1.25/ 23.75 μg

≥ 19

16–18

≤ 15

≤ 0.5/9.5

1/19– 2/38

≥ 4/76

30 μg

≥ 21

–

≤ 20

≤4

–

≥8

See comment (17).

5 μg

≥ 19

17–18

≤ 16

≤1

2

≥4

(19) Rx: Rifampin should not be used alone for antimicrobial therapy.

2 μg

≥ 19

16–18

≤ 15

≤ 0.25

0.5

≥1

See comment (17).

15 μg

≥ 19

16–18

≤ 15

≤1

2

≥4

30 μg

≥ 21

–

–

≤2

–

–

2 1 1 2

Comments

(18) Organisms that are susceptible to tetracycline are also considered susceptible to doxycycline and minocycline.

≥4

≥2 ≥2

≥4

See comment (4).

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Table 2G. (Continued)

Table 2G Streptococcus pneumoniae M02 and M07

Table 2H-1 Product Name: Infobase 2010 - Release Date: February 2010

Streptococcus spp. β-Hemolytic Group M02 and M07

Testing Conditions Medium:

Inoculum: Incubation:

Minimal QC Recommendations (See Tables 3A and 4A for acceptable QC ranges.)

Disk diffusion: MHA with 5% sheep’s blood Broth dilution: CAMHB with LHB (2.5 to 5% v/v); the CAMHB should be supplemented to 50 µg/mL calcium for daptomycin (see M07-A8 for instructions for preparation of LHB) Agar dilution MHA with sheep’s blood (5% v/v) (when testing a sulfonamide, LHB should be used); agar dilution has not been validated for daptomycin Direct colony suspension, equivalent to a 0.5 McFarland standard 35 ± 2 °C; Disk diffusion: 5% CO2; 20 to 24 hours Dilution methods: ambient air; 20 to 24 hours (CO2 if necessary for growth with agar dilution)

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Table 2H-1. Zone Diameter and MIC Interpretive Standards for Streptococcus spp. β-Hemolytic Group

Streptococcus pneumoniae ATCC® 49619

General Comments For disk diffusion, measure the diameter of the zones of complete inhibition (as judged by the unaided eye), including the diameter of the disk. The zone margin should be considered the area showing no obvious, visible growth that can be detected with the unaided eye. Measure the zones from the upper surface of the agar illuminated with reflected light, with the cover removed. Ignore faint growth of tiny colonies that can be detected only with a magnifying lens at the edge of the zone of inhibited growth.

(2)

For this table, the β-hemolytic group includes the large colony–forming pyogenic strains of streptococci with Group A (S. pyogenes), C, or G antigens and strains with Group B (S. agalactiae) antigen. Small colony–forming β-hemolytic strains with Group A, C, F, or G antigens (S. anginosus group, previously termed “S. milleri”) are considered part of the viridans group, and interpretive criteria for the viridans group should be used (see Table 2H-2).

(3)

Susceptibility testing of penicillins and other β-lactams approved by the FDA for treatment of Group A (S. pyogenes) and Group B streptococci (S. agalactiae) is not necessary for clinical purposes and need not be performed routinely, because as with vancomycin, resistant strains have not been recognized. Interpretive criteria are provided for pharmaceutical development, epidemiology, or monitoring for emerging resistance. Any strains found to be nonsusceptible should be referred to a reference laboratory for confirmation.

(4)

Interpretive criteria for streptococci are proposed based on population distributions of various species, pharmacokinetics of the antimicrobial agents, previously published literature, and the clinical experience of certain members of the subcommittee. Systematically collected clinical data were not available for review with many of the compounds in the group.

(5)

For some organism/antimicrobial agent combinations, the absence or rare occurrence of resistant strains precludes defining any results categories other than “susceptible.” For strains yielding results suggestive of a “nonsusceptible” category, organism identification and antimicrobial susceptibility test results should be confirmed. (See Appendix A.)

NOTE: Information in boldface type is considered tentative for one year.

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Test/Report Group PENICILLINS

Antimicrobial Agent

Disk Content

Zone Diameter Breakpoints, nearest whole mm S

I

MIC Interpretive Standard (µg/mL) R

S

I

Comments

R

(6) For the following organism groups, an organism that is susceptible to penicillin can be considered susceptible to the listed antimicrobial agents when used for approved indications and need not be tested against those agents. For β-hemolytic streptococci (Groups A, B, C, G): ampicillin, amoxicillin, amoxicillin-clavulanic acid, ampicillin-sulbactam, cefazolin, cefepime, cephradine, cephalothin, cefotaxime, ceftriaxone, ceftizoxime, imipenem, ertapenem, and meropenem. In addition, for group A streptococci only: cefaclor, cefdinir, cefprozil, ceftibuten, cefuroxime, cefpodoxime, and cephapirin. A A

Penicillin or ampicillin

10 units 10 μg

≥ 24 ≥ 24

– –

– –

≤ 0.12 ≤ 0.25

CEPHEMS (PARENTERAL) (Including cephalosporins I, II, III, and IV. Please refer to Glossary I.) B Cefepime or – – 30 μg ≥ 24 ≤ 0.5 B cefotaxime or – – 30 μg ≥ 24 ≤ 0.5 B ceftriaxone – – 30 μg ≥ 24 ≤ 0.5 CARBAPENEMS O Ertapenem – – – – ≤1 O Meropenem – – – – ≤ 0.5 GLYCOPEPTIDES B Vancomycin – – 30 μg ≥ 17 ≤1 LIPOPEPTIDES C Daptomycin – – – – ≤1

– –

See comment (5). (7) Strains of β–hemolytic streptococci with penicillin MICs of greater than 0.12 μg/mL or ampicillin MICs of greater than 0.25 μg/mL have not been observed; submit such strains to a reference laboratory. See comment (6). See comment (5).

– – –

– – –

– –

– –

–

–

See comment (5).

–

–

See comment (5).

See comment (5).

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Table 2H-1. (Continued)

Table 2H-1 Streptococcus spp. β-Hemolytic Group copyright laws. M02 and M07

Table 2H-1 Product Name: Infobase 2010 - Release Date: FebruaryStreptococcus 2010 spp. β-Hemolytic Group M02 and M07

Table 2H-1. (Continued) Antimicrobial Agent

Disk Content

S

I

MIC Interpretive Standard (µg/mL) R

S

I

R

Comments

(10) Rx: Recommendations for intrapartum prophylaxis for Group B streptococci are penicillin or ampicillin. Although cefazolin is recommended for penicillin-allergic women at low risk for anaphylaxis, those at high risk for anaphylaxis may receive clindamycin or erythromycin. Group B streptococci are susceptible to ampicillin, penicillin, and cefazolin but may be resistant to clindamycin and/or erythromycin. When a Group B Streptococcus is isolated from a pregnant woman with severe penicillin allergy (high risk for anaphylaxis), clindamycin and erythromycin should be tested and reported.

(8) Susceptibility and resistance to azithromycin, clarithromycin, and dirithromycin can be predicted by testing erythromycin.

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Test/Report Group MACROLIDES

Zone Diameter Breakpoints, nearest whole mm

(9) Not routinely reported on isolates from the urinary tract. A

Erythromycin

FLUOROQUINOLONES C Levofloxacin C Ofloxacin O Gatifloxacin O Grepafloxacin O Trovafloxacin PHENICOLS C Chloramphenicol LINCOSAMIDES A Clindamycin

≥ 21

16–20

≤ 15

≤ 0.25

0.5

≥1

15 μg 15 μg 15 μg

≥ 18 ≥ 21 ≥ 18

14–17 17–20 14–17

≤ 13 ≤ 16 ≤ 13

≤ 0.5 ≤ 0.25 ≤ 0.5

1 0.5 1

≥2 ≥1 ≥2

30 μg

≥ 23

19–22

≤ 18

≤2

4

≥8

5 μg 5 μg 5 μg 5 μg 10 μg

≥ 17 ≥ 16 ≥ 21 ≥ 19 ≥ 19

14–16 13–15 18–20 16–18 16–18

≤ 13 ≤ 12 ≤ 17 ≤ 15 ≤ 15

≤2 ≤2 ≤1 ≤ 0.5 ≤1

4 4 2 1 2

≥8 ≥8 ≥4 ≥2 ≥4

30 μg

≥ 21

18–20

≤ 17

≤4

8

≥ 16

See comment (9).

2 μg

≥ 19

16–18

≤ 15

≤ 0.25

0.5

≥1

See comments (9) and (10).

(11) Organisms that are susceptible to tetracycline are also considered susceptible to doxycycline and minocycline.

(12) Inducible clindamycin resistance can be detected by disk diffusion using the D-zone test. See Section 12 in M02-A10 and Section 13 in M07-A8. STREPTOGRAMINS C Quinupristin-dalfopristin OXAZOLIDINONES C Linezolid

15 μg

≥ 19

16–18

≤ 15

≤1

2

≥4

30 μg

≥ 21

–

–

≤2

–

–

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(13) Report against S. pyogenes. See comment (5).

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O Azithromycin O Clarithromycin O Dirithromycin TETRACYCLINES O Tetracycline

15 μg

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Table 2H-2

Product Name: Infobase 2010 - Release Date: February 2010 Streptococcus spp. Viridans Group M02 and M07

Testing Conditions Medium:

Inoculum: Incubation:

Minimal QC Recommendations (See Tables 3A and 4A for acceptable QC ranges.)

Disk diffusion: MHA with 5% sheep’s blood Broth dilution: CAMHB with LHB (2.5 to 5% v/v); the CAMHB should be supplemented to 50 µg/mL calcium for daptomycin (see M07-A8 for instructions for preparation of LHB) Agar dilution MHA with sheep’s blood (5% v/v) (when testing a sulfonamide, LHB should be used); agar dilution has not been validated for daptomycin Direct colony suspension, equivalent to a 0.5 McFarland standard 35 ± 2 °C; Disk diffusion: 5% CO2; 20 to 24 hours Dilution methods: ambient air; 20 to 24 hours (CO2 if necessary for growth with agar dilution)

Streptococcus pneumoniae ATCC® 49619

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Table 2H-2. Zone Diameter and MIC Interpretive Standards for Streptococcus spp. Viridans Group

General Comments For disk diffusion, measure the diameter of the zones of complete inhibition (as judged by the unaided eye), including the diameter of the disk. The zone margin should be considered the area showing no obvious, visible growth that can be detected with the unaided eye. Measure the zones from the upper surface of the agar illuminated with reflected light, with the cover removed. Ignore faint growth of tiny colonies that can be detected only with a magnifying lens at the edge of the zone of inhibited growth.

(2)

The viridans group of streptococci includes the following five groups, with several species within each group: mutans group, salivarius group, bovis group, anginosus group (previously "S. milleri" group), and mitis group. The anginosus group includes small colony–forming β-hemolytic strains with groups A, C, F, and G antigens. For detailed information on the species within the groups, please refer to recent clinical microbiology literature.

(3)

Interpretive criteria for streptococci other than S. pneumoniae are proposed based on population distributions of various species, pharmacokinetics of the antimicrobial agents, previously published literature, and the clinical experience of certain members of the subcommittee. Systematically collected clinical data were not available for review with many of the compounds in the group.

(4)

For some organism/antimicrobial agent combinations, the absence or rare occurrence of resistant strains precludes defining any results categories other than “susceptible.” For strains yielding results suggestive of a “nonsusceptible” category, organism identification and antimicrobial susceptibility test results should be confirmed. (See Appendix A.)

NOTE: Information in boldface type is considered tentative for one year.

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Test/Report Group PENICILLINS A A

Antimicrobial Agent Penicillin Ampicillin

Zone Diameter Breakpoints, nearest whole mm

MIC Interpretive Standard (µg/mL)

Disk Content

S

I

R

S

I

R

Comments

–

–

–

–

≤ 0.12 ≤ 0.25

0.25–2 0.5–4

≥4 ≥8

(5) Disk testing is not reliable for testing penicillin and ampicillin. (6) Viridans streptococci isolated from normally sterile body sites (eg, CSF, blood, bone) should be tested for penicillin susceptibility using an MIC method. (7) Rx: Penicillin- or ampicillin-intermediate isolates may require combined therapy with an aminoglycoside for bactericidal action.

2 2 2

≥4 ≥4 ≥4

– –

– –

See comment (4). See comment (4).

–

–

See comment (4).

–

–

(8) Disk testing is not reliable for testing daptomycin. See comment (4).

CEPHEMS (PARENTERAL) (Including cephalosporins I, II, III, and IV. Please refer to Glossary I.) 22–23 Cefepime B ≤1 30 μg ≤ 21 ≥ 24 Cefotaxime B ≤1 26–27 30 μg ≤ 25 ≥ 28 Ceftriaxone B ≤1 25–26 30 μg ≤ 24 ≥ 27 CARBAPENEMS – O Ertapenem – – – ≤1 – O Meropenem – – – ≤ 0.5 GLYCOPEPTIDES B Vancomycin – – 30 μg ≥ 17 ≤1 LIPOPEPTIDES O Daptomycin – – – – ≤1

MACROLIDES (9) Susceptibility and resistance to azithromycin, clarithromycin, and dirithromycin can be predicted by testing erythromycin. (10) Not routinely reported on isolates from the urinary tract. C Erythromycin 16–20 0.5 15 μg ≥ 21 ≤ 15 ≤ 0.25 ≥1 O Azithromycin 14–17 1 15 μg ≥ 18 ≤ 13 ≤ 0.5 ≥2 O Clarithromycin 17–20 0.5 15 μg ≥ 21 ≤ 16 ≤ 0.25 ≥1 O Dirithromycin 14–17 1 15 μg ≥ 18 ≤ 13 ≤ 0.5 ≥2 TETRACYCLINES O Tetracycline 19–22 4 30 μg ≥ 23 ≤ 18 ≤2 ≥8

5 μg 5 μg 5 μg 5 μg 10 μg

≥ 17 ≥ 16 ≥ 21 ≥ 19 ≥ 19

14–16 13–15 18–20 16–18 16–18

≤ 13 ≤ 12 ≤ 17 ≤ 15 ≤ 15

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≤2 ≤2 ≤1 ≤ 0.5 ≤1

4 4 2 1 2

≥8 ≥8 ≥4 ≥2 ≥4

(11) Organisms that are susceptible to tetracycline are also considered susceptible to doxycycline and minocycline.

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Table 2H-2. (Continued)

Table 2H-2 Product Name: Infobase 2010 - Release Date: February 2010 Streptococcus spp. Viridans Group M02 and M07

Antimicrobial Test/Report Agent Group PHENICOLS C Chloramphenicol LINCOSAMIDES C Clindamycin STREPTOGRAMINS O Quinupristin-dalfopristin OXAZOLIDINONES C Linezolid

Zone Diameter Breakpoints, nearest whole mm

MIC Interpretive Standard (µg/mL)

Disk Content

S

I

R

S

I

R

30 μg

≥ 21

18–20

≤ 17

≤4

8

≥ 16

See comment (10).

2 μg

≥ 19

16–18

≤ 15

≤ 0.25

0.5

≥1

See comment (10).

15 μg

≥ 19

16–18

≤ 15

≤1

2

≥4

30 μg

≥ 21

–

–

≤2

–

–

Comments

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Table 2H-2. (Continued)

See comment (4).

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Table 2I. Zone Diameter and MIC Interpretive Standards for Vibrio cholerae

Medium: Inoculum: Incubation:

Minimal QC Recommendations (See Tables 3 and 4 for acceptable QC ranges.)

Disk diffusion: MHA Broth dilution: CAMHB Agar dilution: MHA Growth method or direct colony suspension, equivalent to a 0.5 McFarland standard 35 ± 2 °C; ambient air; Disk diffusion: 16 to 18 hours Dilution methods: 16 to 20 hours

Escherichia coli ATCC® 25922

General Comments (1)

For disk diffusion, measure the diameter of the zones of complete inhibition (as judged by the unaided eye), including the diameter of the disk. Hold the Petri plate a few inches above a black, nonreflecting background illuminated with reflected light. The zone margin should be considered the area showing no obvious, visible growth that can be detected with the unaided eye. Ignore faint growth of tiny colonies that can be detected only with a magnifying lens at the edge of the zone of inhibited growth. With trimethoprim and the sulfonamides, antagonists in the medium may allow some slight growth; therefore, disregard slight growth (20% or less of the lawn of growth) and measure the more obvious margin to determine the zone diameter.

(2)

The results of disk diffusion tests for ampicillin, tetracycline, trimethoprim-sulfamethoxazole, and sulfonamides (ie, percentage of susceptible, intermediate, and resistant) correlate well with results determined by broth microdilution.

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Testing Conditions

Information in boldface type is considered tentative for one year.

Test/Report Group PENICILLINS A

Antimicrobial Agent Ampicillin

Zone Diameter Breakpoints, nearest whole mm

MIC Interpretive Standard (µg/mL)

Disk Content

S

I

R

S

I

R

10 μg

≥ 17

14–16

≤ 13

≤8

16

≥ 32

Comments (3) Class representative amoxicillin.

for

ampicillin

and

TETRACYCLINES

Table 2I Vibrio cholerae document isM07 protected M02 and

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This

(4) Tetracycline results can be used to predict the likely susceptibility of isolates to doxycycline; disk diffusion tests should not be used with doxycycline, because there is poor correlation with MIC test results. C Tetracycline 15–18 8 30 μg ≥ 19 ≤ 14 ≤4 ≥ 16 O Doxycycline – – – – 8 ≤4 ≥ 16 FOLATE PATHWAY INHIBITORS B Trimethoprim1.25/ 11–15 – ≥ 16 ≤ 10 ≤ 2/38 ≥ 4/76 sulfamethoxazole 23.75 μg C Sulfonamides 13–16 – (5) Sulfisoxazole can be used to represent any of 250 μg or ≥ 17 ≤ 12 ≤ 256 ≥ 512 the currently available sulfonamide preparations. 300 μg PHENICOLS C Chloramphenicol 13–17 16 (6) Use with caution for disk diffusion because the 30 μg ≥ 18 ≤ 12 ≤8 ≥ 32 disk diffusion test may misclassify many organisms (higher minor error rate). (7) Not routinely reported on isolates from the urinary tract.

Product Name: Infobase 2010 - Release Date: February 2010 Table 2J. Zone Diameter and MIC Interpretive Standards for Neisseria meningitidis

Minimal QC Recommendations (See Tables, 3, 3A, 4, and 4A for acceptable QC ranges.)

Medium:

Disk diffusion: MHA with 5% sheep’s blood Broth microdilution: CAMHB supplemented with 2.5 to 5% LHB (see M07-A8 for preparation of LHB) Agar dilution: MHA supplemented with 5% defibrinated sheep’s blood Inoculum: Direct colony suspension from a 20 to 24 hours growth from chocolate agar incubated at 35 °C; 5% CO2; equivalent to a 0.5 McFarland standard. Colonies grown on sheep blood agar may be used for inoculum preparation. However, the 0.5 McFarland suspension obtained from sheep’s blood agar will contain approximately 50% fewer CFU/mL. This must be taken into account when preparing the final dilution before panel inoculation, as guided by colony counts. Incubation: 35 ± 2 °C; 5% CO2; 20 to 24 hours

Streptococcus pneumoniae ATCC® 49619 in 5% CO2 for disk diffusion and in either ambient air or 5% CO2 for broth microdilution, except that azithromycin QC tests must be incubated in ambient air.

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Testing Conditions

Table 2J Neisseria meningitidis M02 and M07

E. coli ATCC® 25922 (incubated either in ambient air or 5% CO2) should be used for ciprofloxacin, nalidixic acid, minocycline, and sulfisoxazole.

General Comments Important: For complete information on safety precautions, see Biosafety in Microbiological and Biomedical Laboratories. 5th ed. Washington, DC: US Government Printing Office; 2007. http://www.cdc.gov/OD/ohs/biosfty/bmbl5/bmbl5toc.htm. Caution: Perform all antimicrobial susceptibility testing of N. meningitidis in a biological safety cabinet (BSC). Manipulating suspensions of N. meningitidis outside a BSC is associated with a high risk for contracting meningococcal disease. Laboratory-acquired meningococcal disease is associated with a case fatality rate of 50%. Exposure to droplets or aerosols of N. meningitidis is the most likely risk for laboratory-acquired infection. Rigorous protection from droplets or aerosols is mandated when microbiological procedures (including antimicrobial susceptibility testing) are performed on all N. meningitidis isolates.

(2)

Recommended precautions: Specimens for N. meningitidis analysis and cultures of N. meningitidis not associated with invasive disease may be handled in Biosafety Level 2 (BSL-2) facilities, with rigorous application of BSL-2 standard practices, special practices, and safety equipment. All sterile-site isolates of N. meningitidis should be manipulated within a BSC. If a BSC is unavailable, manipulation of these isolates should be minimized, limited to Gram staining or serogroup identification using phenolized saline solution while wearing a laboratory coat and gloves and working behind a full face splash shield. Use Biosafety Level 3 (BSL-3) practices, procedures, and containment equipment for activities with a high potential for droplet or aerosol production and for activities involving production quantities or high concentrations of infectious materials. If BSL-2 or BSL-3 facilities are not available, forward isolates to a reference or public health laboratory with a minimum of BSL-2 facilities.

(3) Laboratorians who are exposed routinely to potential aerosols of N. meningitidis should consider vaccination according to the current recommendations of the Centers for Disease Control and Prevention (CDC) Advisory Committee on Immunization Practices (www.cdc.gov). Vaccination will decrease but not eliminate the risk of infection, because it is less than 100% effective and does not provide protection against serogroup B, a frequent cause of laboratoryacquired cases. (4) For disk diffusion, measure the diameter of the zones of complete inhibition (as judged by the unaided eye), including the diameter of the disk. Measure the zones from the upper surface of the agar illuminated with reflected light, with the cover removed. Ignore faint growth of tiny colonies that can be detected only with a magnifying lens at the edge of the zone of inhibited growth. With trimethoprim and the sulfonamides, antagonists in the medium may allow some slight growth; therefore, disregard slight growth (20% or less of the lawn of growth) and measure the more obvious margin to determine the zone diameter.

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(5) Interpretive criteria are based on population distributions of MICs of various agents, pharmacokinetics of the agents, previously published literature, and the clinical experience of certain members of the subcommittee. Systematically collected clinical data were not available to review with many of the antimicrobial agents in this table. (6) For some organism/antimicrobial agent combinations, the absence or rare occurrence of resistant strains precludes defining any results categories other than “susceptible.” For strains yielding results suggestive of a “nonsusceptible” category, organism identification and antimicrobial susceptibility test results should be confirmed. (See Appendix A.) (7) With azithromycin, interpretive criteria were developed initially using MICs determined by incubation in ambient air for the pharmacodynamic calculations. NOTE:

Information in boldface type is considered tentative for one year.

Test/Report Group PENICILLINS C C

Antimicrobial Agent

Disk Content

MIC Interpretive Standard (µg/mL)

S

I

R

S

I

R

Comments

– –

– –

– –

≤ 0.06 ≤ 0.12

0.12– 0.25 0.25–1

≥ 0.5 ≥2

(8) Disk diffusion tests with ampicillin and penicillin are unreliable for N. meningitidis. MIC tests should be used for this organism.

30 μg 30 μg

≥ 34 ≥ 34

– –

– –

≤ 0.12 ≤ 0.12

– –

– –

See comment (6). See comment (6).

10 μg

≥ 30

–

–

≤ 0.25

–

–

See comment (6).

15 μg

≥ 20

–

–

≤2

–

–

See comments (6) and (7). (9) May be appropriate only for prophylaxis of meningococcal case contacts. These interpretive criteria do not apply to therapy of patients with invasive meningococcal disease.

Penicillin Ampicillin

CEPHEMS C Cefotaxime or C ceftriaxone CARBAPENEMS C Meropenem MACROLIDES C Azithromycin

Zone Diameter Breakpoints, nearest whole mm

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Table 2J. (Continued)

Table 2J Neisseria meningitidis M02 and M07

Table 2J Neisseria meningitidis M02 and M07

Product Name: Infobase 2010 - Release Date: February 2010 Table 2J. (Continued) MIC Interpretive Standard (µg/mL)

Disk Content

S

I

R

S

I

R

30 μg

≥ 26

–

–

≤2

–

–

Comments See comments (6) and (9).

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Test/Report Antimicrobial Group Agent TETRACYCLINES C Minocycline FLUOROQUINOLONES

Zone Diameter Breakpoints, nearest whole mm

(10) For surveillance purposes, a nalidixic acid MIC ≥ 8 μg/mL or a zone ≤ 25 mm may correlate with diminished fluoroquinolone susceptibility. C Ciprofloxacin 33–34 0.06 See comment (9). 5 μg ≥ 35 ≤ 32 ≤ 0.03 ≥ 0.12 C Levofloxacin FOLATE PATHWAY INHIBITORS C Sulfisoxazole C Trimethoprimsulfamethoxazole

PHENICOLS C

Chloramphenicol

–

–

–

≤ 0.03

0.06

≥ 0.12

– 1.25/ 23.75 μg

– ≥ 30

– 26–29

– ≤ 25

≤2 ≤ 0.12/ 2.4

4 0.25/4.75

≥8 ≥ 0.5/ 9.5

See comment (9). (11) This is the preferred disk for detection of sulfonamide resistance. Trimethoprimsulfamethoxazole testing predicts susceptibility and resistance to trimethoprim-sulfamethoxazole and sulfonamides. Sulfonamides may be appropriate only for prophylaxis of meningococcal case contacts.

30 μg

≥ 26

20–25

≤ 19

≤2

4

≥8

(12) Not routinely reported on isolates from the urinary tract.

5 μg

≥ 25

20–24

≤ 19

≤ 0.5

1

≥2

See comment (9).

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ANSAMYCINS C Rifampin

–

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Table 2K Potential Bacterial Agents of Bioterrorism M07

Testing Conditions Medium:

Broth dilution: unsupplemented Brucella broth pH adjusted to 7.1 ± 0.1 for Brucella spp.; cation-adjusted Mueller-Hinton broth (CAMHB) + 2% defined growth supplement for F. tularensis; CAMHB for all other organisms Inoculum: Growth method or direct colony suspension in CAMHB, equivalent to a 0.5 McFarland standard; for F. tularensis, prepare inoculum as a direct colony suspension from a chocolate agar plate Incubation: 35 ± 2 °C; ambient air; 16 to 20 hours; for Y. pestis, incubate 24 hours and if unacceptable growth in the control well reincubate an additional 24 hours; for F. tularensis and Brucella spp., incubate 48 hours (see comment 8)

Minimal QC Recommendations (See Table 4 [CAMHB], Table 4C [CAMHB + 2% defined growth supplement], and Table 4D [Brucellabroth] for acceptable QC ranges.) Escherichia coli ATCC® 25922 (all organisms) Escherichia coli ATCC® 35218 (for amoxicillin-clavulanic acid and B. pseudomallei) Staphylococcus aureus ATCC® 29213 (for B. anthracis and F. tularensis) Pseudomonas aeruginosa ATCC® 27853 (for B. mallei/pseudomallei and F. tularensis) ® Streptococcus pneumoniae ATCC 49619 (for Brucella spp. only)

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Table 2K. MIC Interpretive Standards (μg/mL) for Potential Bacterial Agents of Bioterrorism: Bacillus anthracis, Yersinia pestis, Burkholderia mallei, Burkholderia pseudomallei, Francisella tularensis, and Brucella spp.

General Comments Important: For complete information on safety precautions, see Biosafety in Microbiological and Biomedical Laboratories. 5th ed. Washington, DC: US Government Printing Office; 2007. http://www.cdc.gov/OD/ohs/biosfty/bmbl5/bmbl5toc.htm.

(2) Recommended precautions: Use BSL-2 practices, containment equipment, and facilities for activities using clinical materials and diagnostic quantities of infectious cultures. Use BSL-3 practices, containment equipment, and facilities for work involving production quantities or concentrations of cultures, and for activities with a high potential for aerosol production. If BSL-2 or BSL-3 facilities are not available, forward isolates to a reference or public health laboratory with a minimum of BSL-2 facilities for susceptibility testing. (3) Interpretive criteria are based on microorganism MIC population distributions, pharmacokinetics, and pharmacodynamics of the antimicrobial agents, and/or animal model data. (4) Test method and interpretive criteria for B. anthracis do not apply to other Bacillus spp. (5) WARNING: For Y. pestis, studies have demonstrated that although β-lactam antimicrobial agents may appear active in vitro, they lack efficacy in animal models of infection. Y. pestis should be reported as resistant to these antimicrobial agents. Rx: Retrospective clinical data suggest that β-lactam antimicrobial agents are not effective clinically. (6) The recommended medium for testing F. tularensis consists of cation-adjusted Mueller-Hinton broth (CAMHB) to which a 2% defined growth supplement (25.9 g L-cysteine HCl, 1.1 g L-cystine, 1 g adenine, 0.03 g guanine HCl, 0.01 g vitamin B12, 0.1 g cocarboxylase, 0.25 g NAD, 10 g L-glutamine, 0.02 g ferric nitrate, 100 g glucose, 3 mg thiamine HCl, and 13 mg PABA acid [in 1 L H2O]) is added after autoclaving. The pH of the medium should be adjusted to 7.1 ± 0.1.

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(1) Extreme Caution: Notify public health officials of all isolates presumptively identified as B. anthracis, Y. pestis, B. mallei, B. pseudomallei, or F. tularensis. Confirmation of isolates of these bacteria may require specialized testing, which is available only in reference or public health laboratories.

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(7) For some organism/antimicrobial agent combinations, the absence or rare occurrence of resistant strains precludes defining any results categories other than “susceptible.” For strains yielding results suggestive of a “nonsusceptible” category, organism identification and antimicrobial susceptibility test results should be confirmed. (See Appendix A.) (8) Incubation in 5% CO2 may be required for growth of some strains of Brucella spp., especially B. abortus. Incubation of broth in CO2 may increase the MIC of aminoglycosides and decrease the MIC of tetracyclines, usually by one doubling dilution.

Organism Group PENICILLINS B. anthracis

Antimicrobial Agent Penicillin

Zone Diameter Breakpoints, nearest whole mm

MIC Interpretive Standard (µg/mL)

Disk Content

S

I

R

S

I

R

Comments

–

–

–

–

≤ 0.12

–

≥ 0.25

(9) Class representative for amoxicillin. (10) B. anthracis strains may contain inducible β-lactamases. In vitro penicillinase induction studies suggest that penicillin MICs may increase during therapy. This finding is supported by reduced response rates to penicillin in animal treatment studies of B. anthracis infection. However, β-lactamase testing of clinical isolates of B. anthracis is unreliable and should not be performed. If MIC susceptibility testing using CLSI methods indicates that B. anthracis isolates are susceptible to penicillin, amoxicillin may still be considered for prophylactic use in children and pregnant women. (References: MMWR 21 October 2001 and websites: www.cdc.gov or www.bt.cdc.gov/agent/anthrax/exposure/index.asp)

16/8

≥ 32/16

16

≥ 32

β-LACTAM/β-LACTAMASE INHIBITOR COMBINATIONS – – – – B. pseudomallei Amoxicillin-clavulanic acid ≤ 8/4 CEPHEMS (PARENTERAL) (Including cephalosporins I, II, III, and IV. Please refer to Glossary I.) Ceftazidime – – – – B. mallei ≤8 B. pseudomallei

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Table 2K. (Continued)

CARBAPENEMS

B. mallei B. pseudomallei

Imipenem

–

–

–

–

≤4

8

≥ 16

– – – –

– – – –

– – – –

– – – –

≤4 ≤4 ≤4 ≤8

8 8 – –

≥ 16 ≥ 16 – –

AMINOGLYCOSIDES

Y. pestis F. tularensis Brucella spp.

Gentamicin Streptomycin Gentamicin Streptomycin

Table 2K Potential Bacterial Agents of Bioterrorism M07

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See comment (7). See comments (7) and (8). (11) The streptomycin-susceptible breakpoint is ≤ 16 μg/mL when the test is incubated in CO2 and ≤ 8 μg/mL when it is incubated in air.

Table 2K Potential Bacterial Agents of Bioterrorism M07

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Table 2K. (Continued) Antimicrobial Agent

Disk Content

S

I

MIC Interpretive Standard (µg/mL)

R

S

I

R

Comments

TETRACYCLINES

(12) Organisms that are susceptible to tetracycline are also considered susceptible to doxycycline. Tetracycline

–

–

–

–

≤1

–

–

See comments (7) and (8).

Doxycycline

–

–

–

–

≤1

–

–

See comments (7) and (8).

B. mallei

Tetracycline

–

–

–

–

≤4

8

≥ 16

B. pseudomallei Y. pestis F. tularensis

Doxycycline

–

–

–

–

≤4

8

≥ 16

Tetracycline Doxycycline

– –

– –

– –

– –

≤4 ≤4

– –

– –

See comment (7). See comment (7).

– – – – – –

– – – – – –

– – – – – –

– – – – – –

≤ 0.25 ≤ 0.25 ≤ 0.25 ≤ 0.25 ≤ 0.5 ≤ 0.5

– – – – – –

– – – – – –

See comment (7). See comment (7). See comment (7). See comment (7). See comment (7). See comment (7).

Trimethoprim-sulfamethoxazole

–

–

–

–

≤ 2/38

–

≥ 4/76

Trimethoprim-sulfamethoxazole

–

–

–

–

≤ 2/38

–

–

Chloramphenicol Chloramphenicol

– –

– –

– –

– –

≤8 ≤8

16 –

≥ 32 –

B. anthracis Brucella spp.

January 2010

106 Organism Group

Zone Diameter Breakpoints, nearest whole mm

FLUOROQUINOLONES

B. anthracis Y. pestis

FOLATE PATHWAY INHIBITORS

B. pseudomallei Y. pestis Brucella spp.

See comments (7) and (8).

PHENICOLS

Y. pestis F. tularensis

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F. tularensis

Ciprofloxacin Levofloxacin Ciprofloxacin Levofloxacin Ciprofloxacin Levofloxacin

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Testing Conditions

Minimal QC Recommendations (See Table 4B for acceptable QC ranges.)

Medium:

Agar dilution: MHA and aged (≥ 2 weeks old) sheep’s blood (5% v/v) Inoculum: A saline suspension equivalent to a 2.0 McFarland standard (containing 1 × 107 to 1 × 108 CFU/mL), to be prepared from a 72-hour-old subculture from a blood agar plate. The inoculum (1 to 3 μL per spot) is replicated directly onto the antimicrobial agent-containing agar dilution plates. Incubation: 35 ± 2 °C; three days; microaerobic atmosphere produced by a gas-generating system suitable for campylobacters.

Helicobacter pylori ATCC® 43504

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Table 2L. MIC Interpretive Standards for Helicobacter pylori

NOTE: Information in boldface type is considered tentative for one year.

Test/Report Group MACROLIDES A

Antimicrobial Agent Clarithromycin

Zone Diameter Breakpoints, nearest whole mm

MIC Interpretive Standard (µg/mL)

Disk Content

S

I

R

S

I

R

Comments

–

–

–

–

≤ 0.25

0.5

≥ 1.0

(1) These interpretive criteria presume that clarithromycin will be used in an FDA-approved regimen that includes a proton-pump inhibitor or an H2 antagonist (these treatments include omeprazole, lansoprazole, or ranitidine bismuth citrate).

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Table 3 Nonfastidious Quality Control M02

Table 3. Disk Diffusion Testing—Acceptable Limits (mm) for Quality Control Strains Used to Monitor Accuracy; Nonfastidious Organisms Using Mueller-Hinton Medium Without Blood or Other Supplements Antimicrobial Agent Amikacin Amoxicillin-clavulanic acid Ampicillin Ampicillin-sulbactam Azithromycin Azlocillin Aztreonam Carbenicillin Cefaclor Cefamandole Cefazolin Cefdinir Cefditoren Cefepime Cefetamet Cefixime Cefmetazole Cefonicid Cefoperazone Cefotaxime Cefotetan Cefoxitin Cefpodoxime Cefprozil Ceftaroline Ceftazidime Ceftibuten Ceftizoxime Ceftobiprole Ceftriaxone Cefuroxime Cephalothin Chloramphenicol Cinoxacin Ciprofloxacin Clarithromycin Clinafloxacin c Clindamycin Colistin d Daptomycin Dirithromycin Doripenem Doxycycline Enoxacin Ertapenem c Erythromycin Faropenem Fleroxacin e Fosfomycin Garenoxacin Gatifloxacin Gemifloxacin f Gentamicin Grepafloxacin Iclaprim Imipenem Kanamycin Levofloxacin Linezolid Linopristin-flopristin Lomefloxacin

Disk Content 30 μg 20/10 μg 10 μg 10/10 μg 15 μg 75 μg 30 μg 100 μg 30 μg 30 μg 30 μg 5 μg 5 μg 30 μg 10 μg 5 μg 30 μg 30 μg 75 μg 30 μg 30 μg 30 μg 10 μg 30 μg 30 μg 30 μg 30 μg 30 μg 30 μg 30 μg 30 μg 30 μg 30 μg 100 μg 5 μg 15 μg 5 μg 2 μg 10 μg 30 μg 15 μg 10 μg 30 μg 10 μg 10 μg 15 μg 5 μg 5 μg 200 μg 5 μg 5 μg 5 μg 10 μg 5 μg 5 μg 10 μg 30 μg 5 μg 30 μg 10 μg 10 μg

Escherichia coli ® a ATCC 25922 19–26 18–24 16–22 19–24 – – 28–36 23–29 23–27 26–32 21–27 24–28 22–28 31–37 24–29 23–27 26–32 25–29 28–34 29–35 28–34 23–29 23–28 21–27 26–34 25–32 27–35 30–36 30–36 29–35 20–26 15–21 21–27 26–32 30–40 – 31–40 – 11–17 – – 27–35 18–24 28–36 29–36 – 20–26 28–34 22–30 28–35 30–37 29–36 19–26 28–36 14–22 26–32 17–25 29–37 – – 27–33 ©

108

Staphylococcus aureus ® ATCC 25923 20–26 28–36 27–35 29–37 21–26 – – – 27–31 26–34 29–35 25–32 20–28 23–29 – – 25–34 22–28 24–33 25–31 17–23 23–29 19–25 27–33 26–35 16–20 – 27–35 26–34 22–28 27–35 29–37 19–26 – 22–30 26–32 28–37 24–30 – 18–23 18–26 33–42 23–29 22–28 24–31 22–30 27–34 21–27 25–33 30–36 27–33 27–33 19–27 26–31 25–33 – 19–26 25–30 25–32 25–31 23–29

Pseudomonas aeruginosa ® ATCC 27853 18–26 – – – – 24–30 23–29 18–24 – – – – – 24–30 – – – – 23–29 18–22 – – – – – 22–29 – 12–17 24–30 17–23 – – – – 25–33 – 27–35 – 11–17 – – 28–35 – 22–28 13–21 – – 12–20 – 19–25 20–28 19–25 16–21 20–27 – 20–28 – 19–26 – – 22–28

Escherichia coli ® b ATCC 35218 – 17–22 6 13–19 – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – –

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Antimicrobial Agent Loracarbef Mecillinam Meropenem Methicillin Mezlocillin Minocycline Moxalactam Moxifloxacin Nafcillin Nalidixic acid Netilmicin Nitrofurantoin Norfloxacin Ofloxacin Oxacillin Penicillin Piperacillin Piperacillin-tazobactam Polymyxin B Quinupristin-dalfopristin Razupenem Rifampin Sparfloxacin f Streptomycin h Sulfisoxazole Teicoplanin Telavancin Telithromycin Tetracycline Ticarcillin Ticarcillin-clavulanic acid Tigecycline Tobramycin h Trimethoprim h Trimethoprim-sulfamethoxazole Trospectomycin Trovafloxacin g Ulifloxacin (prulifloxacin) Vancomycin NOTE:

Disk Content 30 μg 10 μg 10 μg 5 μg 75 μg 30 μg 30 μg 5 μg 1 μg 30 μg 30 μg 300 μg 10 μg 5 μg 1 μg 10 units 100 μg 100/10 μg 300 units 15 μg 10 μg 5 μg 5 μg 10 μg 250 μg or 300 μg 30 μg 30 μg 15 μg 30 μg 75 μg 75/10 μg 15 μg 10 μg 5 μg 1.25/23.75 μg 30 μg 10 μg 5 μg 30 μg

Escherichia coli ® a ATCC 25922 23–29 24–30 28–34 – 23–29 19–25 28–35 28–35 – 22–28 22–30 20–25 28–35 29–33 – – 24–30 24–30 13–19 – 21–26 8–10 30–38 12–20 15–23 – – – 18–25 24–30 24–30 20–27 18–26 21–28 23–29 10–16 29–36 32–38 –

Staphylococcus aureus ® ATCC 25923 23–31 – 29–37 17–22 – 25–30 18–24 28–35 16–22 – 22–31 18–22 17–28 24–28 18–24 26–37 – 27–36 – 21–28 – 26–34 27–33 14–22 24–34 15–21 16–20 24–30 24–30 – 29–37 20–25 19–29 19–26 24–32 15–20 29–35 20–26 17–21

Pseudomonas aeruginosa ® ATCC 27853 – – 27–33 – 19–25 – 17–25 17–25 – – 17–23 – 22–29 17–21 – – 25–33 25–33 14–18 – – – 21–29 – – – – – – 21–27 20–28 9–13 19–25 – – – 21–27 27–33 –

Escherichia coli ® b ATCC 35218 – – – – – – – – – – – – – – – – 12–18 24–30 – – – – – – – – – – – 6 21–25 – – – – – – – –

Information in boldface type is considered tentative for one year. Footnotes

a. b. c.

d. e. f. g. h.

©

ATCC is a registered trademark of the American Type Culture Collection. Because this strain may lose its plasmid, careful organism maintenance is required; refer to M02-A10, Section 15.4. ® When disk approximation tests are performed with erythromycin and clindamycin, S. aureus ATCC BAA-977 (containing ® inducible ermA-mediated resistance) and S. aureus ATCC BAA-976 (containing msrA-mediated macrolide-only efflux) are ® recommended as supplemental QC strains (eg, for training, competency assessment, or test evaluation). S. aureus ATCC ® BAA-977 should demonstrate inducible clindamycin resistance (ie, a positive D-zone test), whereas S. aureus ATCC BAA-976 ® should not demonstrate inducible clindamycin resistance. S. aureus ATCC 25923 should be used for routine QC (eg, weekly or daily) of erythromycin and clindamycin disks using standard MHA. Some lots of MHA are deficient in calcium and give small zones. The 200-μg fosfomycin disk contains 50 μg of glucose-6-phosphate. ® For control limits of gentamicin 120-μg and streptomycin 300-μg disks, use E. faecalis ATCC 29212 (gentamicin: 16–23 mm; streptomycin: 14–20 mm). Ulifloxacin is the active metabolite of the prodrug prulifloxacin. Only ulifloxacin should be used for antimicrobial susceptibility testing. These agents can be affected by excess levels of thymidine and thymine. See M02-A10, Section 7.1.3 for guidance should a problem with QC occur.

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Table 3 Nonfastidious Quality Control M02

Table 3. (Continued)

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Table 3A Fastidious Quality Control M02

Table 3A. Disk Diffusion Testing—Acceptable Limits (mm) for Quality Control Strains Used to Monitor Accuracy; Fastidious Organisms Antimicrobial Agent c Amoxicillin-clavulanic acid Ampicillin Ampicillin-sulbactam Azithromycin Aztreonam Cefaclor Cefdinir Cefditoren Cefepime Cefetamet Cefixime Cefmetazole Cefonicid Cefotaxime Cefotetan Cefoxitin Cefpodoxime Cefprozil Ceftaroline Ceftazidime Ceftibuten Ceftizoxime d Ceftobiprole Ceftriaxone Cefuroxime Cephalothin Chloramphenicol Ciprofloxacin Clarithromycin Clinafloxacin Clindamycin e Daptomycin Dirithromycin Doripenem Enoxacin Ertapenem Erythromycin Faropenem Fleroxacin Garenoxacin Gatifloxacin Gemifloxacin Grepafloxacin Iclaprim Imipenem Levofloxacin Linezolid Linopristin-flopristin Lomefloxacin Loracarbef Meropenem Moxifloxacin Nitrofurantoin Norfloxacin Ofloxacin Oxacillin Penicillin Piperacillin-tazobactam Quinupristin-dalfopristin Razupenem Rifampin

Disk Content 20/10 μg 10 μg 10/10 μg 15 μg 30 μg 30 μg 5 μg 5 μg 30 μg 10 μg 5 μg 30 μg 30 μg 30 μg 30 μg 30 μg 10 μg 30 μg 30 μg 30 μg 30 μg 30 μg 30 μg 30 μg 30 μg 30 μg 30 μg 5 μg 15 μg 5 μg 2 μg 30 μg 15 μg 10 μg 10 μg 10 μg 15 μg 5 μg 5 μg 5 μg 5 μg 5 μg 5 μg 5 μg 10 μg 5 μg 30 μg 10 μg 10 μg 30 μg 10 μg 5 μg 300 μg 10 μg 5 μg 1 μg 10 units 100/10 μg 15 μg 10 μg 5 μg

Haemophilus influenzae ® a ATCC 49247 15–23 13–21 14–22 13–21 30–38 – – 25–34 25–31 23–28 25–33 16–21 – 31–39 – – 25–31 – 29–39 27–35 29–36 29–39 28–36 31–39 – – 31–40 34–42 11–17 34–43 – – – 21–31 – 20–28 – 15–22 30–38 33–41 33–41 30–37 32–39 24–33 21–29 32–40 – 25–31 33–41 – 20–28 31–39 – – 31–40 – – 33–38 15–21 24–30 22–30

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110

Haemophilus influenzae ® ATCC 49766 – – – – – 25–31 24–31 – – – – – 30–38 – – – – 20–27 – – – – 30–38 – 28–36 – – – – – – – – – – 27–33 – – – – – – – – – – – – – 26–32 – – – – – – – – – – –

Neisseria gonorrhoeae ® ATCC 49226 – – – – – – 40–49 – 37–46 35–43 37–45 31–36 – 38–48 30–36 33–41 35–43 – – 35–43 – 42–51 – 39–51 33–41 – – 48–58 – – – – – – 43–51 – – – 43–51 – 45–56 – 44–52 – – – – – 45–54 – – – – – 43–51 – 26–34 – – – –

Streptococcus pneumoniae ® b ATCC 49619 – 30–36 – 19–25 – 24–32 26–31 27–35 28–35 – 16–23 – – 31–39 – – 28–34 25–32 31–41 – – 28–34 33–39 30–35 – 26–32 23–27 – 25–31 27–34 19–25 19–26 18–25 30–38 – 28–35 25–30 27–35 – 26–33 24–31 28–34 21–28 21–29 – 20–25 25–34 22–28 – 22–28 28–35 25–31 23–29 15–21 16–21 f ≤ 12 24–30 – 19–24 29–36 25–30

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Table 3A. (Continued) Antimicrobial Agent Sparfloxacin Spectinomycin Telavancin Telithromycin Tetracycline Tigecycline Trimethoprimsulfamethoxazole Trospectomycin Trovafloxacin Vancomycin

Disk Content 5 μg 100 μg 30 μg 15 μg 30 μg 15 μg 1.25/23.75 μg

Haemophilus influenzae ® a ATCC 49247 32–40 – – 17–23 14–22 23–31 24–32

Haemophilus influenzae ® ATCC 49766 – – – – – – –

Neisseria gonorrhoeae ® ATCC 49226 43–51 23–29 – – 30–42 30–40 –

Streptococcus pneumoniae ® b ATCC 49619 21–27 – 17–24 27–33 27–31 23–29 20–28

30 μg 10 μg 30 μg

22–29 32–39 –

– – –

28–35 42–55 –

– 25–32 20–27

Disk Diffusion Testing Conditions for Clinical Isolates and Performance of Quality Control Streptococci and Neisseria meningitidis MHA supplemented with 5% defibrinated sheep’s blood

Organism

Haemophilus influenzae

Neisseria gonorrhoeae

Medium

HTM

GC agar base and 1% defined growth supplement. The use of a cysteine-free growth supplement is not required for disk diffusion testing.

Inoculum

Direct colony suspension

Direct colony suspension

Direct colony suspension

Incubation characteristics

5% CO2; 16–18 hours; 35 °C

5% CO2; 20–24 hours; 35 °C

5% CO2; 20–24 hours; 35 °C

NOTE: Information in boldface type is considered tentative for one year. Footnotes a.

ATCC is a registered trademark of the American Type Culture Collection.

b.

Despite the lack of reliable disk diffusion interpretive criteria for S. pneumoniae with certain β-lactams, Streptococcus ® pneumoniae ATCC 49619 is the strain designated for QC of all disk diffusion tests with all Streptococcus spp.

c.

When testing Haemophilus on HTM, the acceptable limits for QC strain E. coli ATCC 35218 are 17 to 22 mm for amoxicillinclavulanic acid when incubated in ambient air.

d.

Either H. influenzae ATCC 49247 or 49766 may be used for routine QC testing.

e.

Some lots of MHA are deficient in calcium and give small zones.

f.

Deterioration in oxacillin disk content is best assessed with QC organism S. aureus ATCC 25923, with an acceptable zone diameter of 18 mm to 24 mm.

®

®

Table 3A Fastidious Quality Control M02

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Table 3B QC Testing Frequency M02

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Table 3B. Disk Diffusion Testing—Reference Guide to Quality Control Testing Frequency This table summarizes the suggested frequency of testing CLSI-recommended ATCC®a QC strains to be performed by the user of antimicrobial susceptibility tests. It applies only to antimicrobial agents for which 20 or 30 consecutive test days of QC testing produced satisfactory results.

Test Modification Disks Use new shipment or lot number Use new manufacturer Media (prepared agar plates) Use new shipment or lot number Use new manufacturer Inoculum Preparation Convert inoculum preparation/ standardization to use of a device that has its own QC protocol

Number of Days of Consecutive QC Testing Requiredb 1 5 20 or 30

Comments

X X X X X

Convert inoculum preparation/ standardization to a method that is dependent on user technique

X

Measuring Zones Change method of measuring zones

X

Example: Convert from visual adjustment of turbidity to use of a photometric device for which a QC procedure is provided Example: Convert from visual adjustment of turbidity to another method that is not based on a photometric device Example: Convert from manual zone measurements to automated zone reader In addition, perform inhouse validation studies

Instrument/Software (eg, automated zone reader) Software update that affects AST results Repair of instrument that affects AST results

X

X

Monitoring all drugs, not just those implicated in software modification Depending on extent of repair (eg, critical component such as the photographic device), additional testing may be appropriate (eg, five days)

NOTE 1: Addition of any NEW antimicrobial agent requires 20 or 30 consecutive days of satisfactory testing (see M02-A10, Section 15.7) before use of this guide. NOTE 2: QC can be performed before or concurrent with testing patient isolates. Patient results can be reported for that day if QC results are within the acceptable limits. NOTE 3: Manufacturers of commercial or in-house prepared tests should follow their own internal procedures and applicable regulations. NOTE 4: For troubleshooting out-of-range results, refer to M02-A10, Section 15.8. NOTE 5: Broth, saline, and/or water used to prepare an inoculum does not require routine QC. Footnotes a. ATCC is a registered trademark of the American Type Culture Collection. b. Does not eliminate the need for routine weekly or daily QC testing.

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Table 3C. Disk Diffusion Quality Control Troubleshooting Guide This table provides guidance for troubleshooting and corrective action for out-of-range QC, primarily using antimicrobial susceptibility tests with MHA. Refer to M02-A10, Section 15, Quality Control and Quality Assurance Procedures for additional information. Out-of-range QC tests should first be repeated. If the issue is unresolved, this troubleshooting guide provides additional suggestions for troubleshooting out-ofrange QC results. In addition, if unresolved, manufacturers should be notified of potential product problems. General Comments

Table 3C QC Troubleshooting M02

(1)

QC organism maintenance: avoid repeated subcultures. Retrieve new QC strain from stock. If using lyophilized strains, follow ®a ® the maintenance recommendations of the manufacturer. Store E. coli ATCC 35218 and K. pneumoniae ATCC 700603 stock cultures at -60 °C or below and prepare working stock cultures weekly. Antimicrobial Agent QC Strain Observation Probable Cause Comments/Action

Aminoglycosides

Any

Zone too small

pH of media too low

Aminoglycosides Aminoglycosides

Any P. aeruginosa ® ATCC 27853 P. aeruginosa ® ATCC 27853 ® E. coli ATCC 35218

Zone too large Zone too small

pH of media too high Ca++ and/or Mg++ content too high Ca++ and/or Mg++ content too low Clavulanic acid is labile. Disk has lost potency.

Aminoglycosides Amoxicillin-clavulanic acid

®

Ampicillin

E. coli ATCC 35218

β-lactam group

Any

Aztreonam Cefotaxime Cefpodoxime Ceftazidime Ceftriaxone Cefotaxime/clavulanic acid Ceftazidime/clavulanic acid Penicillins

K. pneumoniae ® ATCC 700603

Zone too large Zone too small

Spontaneous loss of the plasmid encoding the βlactamase

Zone too large (should be no zone — resistant) Zone initially acceptable but decreases and possibly out of range over time Zone too large

Disk has lost potency

Spontaneous loss of the plasmid encoding the βlactamase

Acceptable pH range = 7.2–7.4 Avoid CO2 incubation, which lowers pH. Acceptable pH range = 7.2–7.4 Use alternative lot of media. Use alternative lot of media. Use alternative lot of disks. Check storage conditions and package integrity. See comment (1) on QC organism maintenance. Use alternative lot of disks. Check storage conditions and package integrity. Imipenem, clavulanic acid, and cefaclor are especially labile. See comment (1) on QC organism maintenance.

K. pneumoniae ® ATCC 700603

Negative ESBL confirmatory test

Spontaneous loss of the plasmid encoding the βlactamase

See comment (1) on QC organism maintenance.

Any

Zone too large

pH of media too low

Penicillins Carbenicillin

Any P. aeruginosa ® ATCC 27853

Zone too small Zone too small

Ticarcillin-clavulanic acid

E. coli ATCC 35218

®

Zone too small

pH of media too high QC strain develops resistance after repeated subculture Clavulanic acid is labile. Disk has lost potency.

Acceptable pH range = 7.2–7.4 Avoid CO2 incubation, which lowers pH. Acceptable pH range = 7.2–7.4 See comment (1) on QC organism maintenance.

Clindamycin

S. aureus ® ATCC 25923

Zone too small

pH of media too low

Clindamycin

S. aureus ® ATCC 25923 S. aureus ® ATCC 25923 S. aureus ® ATCC 25923

Zone too large

pH of media too high

Zone too small Zone too small

Ca++ content of media too low pH of media too low

S. aureus ® ATCC 25923

Zone too large

pH of media too high

Daptomycin Macrolides Macrolides

©

114

Use alternative lot of disks. Check storage conditions and package integrity. Acceptable pH range = 7.2–7.4 Avoid CO2 incubation, which lowers pH. Acceptable pH range = 7.2–7.4 Use an alternative lot of media. Acceptable pH range = 7.2–7.4 Avoid CO2 incubation, which lowers pH. Acceptable pH range = 7.2–7.4

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M100-S20

Table 3C. (Continued) QC Strain

Observation

Probable Cause

Quinolones

Any

Zone too small

pH of media too low

Quinolones Tetracyclines

Any Any

Zone too large Zone too large

pH of media too high pH of media too low

Tetracyclines Tetracyclines

Any Any

Zone too small Zone too small

Tetracyclines

Any

Zone too large

Sulfonamides Trimethoprim Trimethoprimsulfamethoxazole Various

E. faecalis ® ATCC 29212

Zone ≤20 mm

pH of media too high Ca++ and/or Mg++ content too high Ca++ and/or Mg++ content too low Media too high in thymidine content

Any

Many zones too large

Inoculum too light Error in inoculum preparation Media depth too thin MHA nutritionally unacceptable

Various

Any

Many zones too small

Inoculum too heavy Error in inoculum preparation Media depth too thick MHA nutritionally unacceptable

Various

Any

One or more zones too small or too large

Various

S. pneumoniae ® ATCC 49619

Zones too large. Lawn of growth scanty.

Various

Any

One QC strain is out of range, but other QC organism(s) are in range with the same antimicrobial agent

Measurement error Transcription error Random defective disk Disk not pressed firmly against agar Inoculum source plate too old and contains too many nonviable cells. Plate used to prepare inoculum should be 18–20 hours. One QC organism may be a better indicator of a QC problem.

Various

Any

Various

Any

Two QC strains out of range with the same antimicrobial agent Zones overlap

Indicative of a problem with the disk Too many disks per plate

Comments/Action Acceptable pH range = 7.2–7.4 Avoid CO2 incubation, which lowers pH. Acceptable pH range = 7.2–7.4 Acceptable pH range = 7.2–7.4 Avoid CO2 incubation, which lowers pH. Acceptable pH range = 7.2–7.4 Use alternative lot of media. Use alternative lot of media. Use alternative lot of media.

Repeat using McFarland 0.5 turbidity standard or standardizing device. Check expiration date and proper storage if using barium sulfate or latex standards. Use agar with depth approximately 4 mm. Recheck alternate lots of MHA. Repeat using McFarland 0.5 turbidity standard or standardizing device. Check expiration date and proper storage if using barium sulfate or latex standards. Use agar with depth approximately 4 mm. Recheck alternate lots of MHA. Recheck readings for measurement or transcription errors. Retest. If retest results out of range and no errors detected, initiate corrective action. Subculture QC strain and repeat QC test or retrieve new QC strain from stock. Retest this strain to confirm reproducibility of acceptable results. Evaluate with alternative strains with known MICs. Initiate corrective action with problem QC strain/antimicrobial agents. Use alternative lot of disks. Check storage conditions and package integrity. Place no more than 12 disks on a 150-mm plate and 5 disks on a 100mm plate; for some fastidious bacteria that produce large zones, use fewer.

Footnote a. ATCC is a registered trademark of the American Type Culture Collection.

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Table 3C QC Troubleshooting M02

Antimicrobial Agent

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Table 4 Nonfastidious Quality Control M07

Table 4. MIC Testing—Acceptable Limits (μg/mL) for Quality Control Strains Used to Monitor Accuracy; Nonfastidious Organisms Using Mueller-Hinton Medium (Cation-Adjusted if Broth) Without Blood or Other Nutritional Supplements Antimicrobial Agent Amikacin Amoxicillin-clavulanic acid Ampicillin Ampicillin-sulbactam Azithromycin Azlocillin Aztreonam Besifloxacin Carbenicillin Cefaclor Cefamandole Cefazolin Cefdinir Cefditoren Cefepime Cefetamet Cefixime Cefmetazole Cefonicid Cefoperazone Cefotaxime Cefotetan Cefoxitin Cefpodoxime Cefprozil Ceftaroline Ceftazidime Ceftibuten Ceftizoxime Ceftobiprole Ceftriaxone Cefuroxime Cephalothin Chloramphenicol Cinoxacin c Ciprofloxacin Clarithromycin Clinafloxacin d Clindamycin Colistin e Dalbavancin f Daptomycin Dirithromycin Doripenem Doxycycline Enoxacin Ertapenem d Erythromycin Faropenem Fidaxomicin Fleroxacin g Fosfomycin Garenoxacin Gatifloxacin Gemifloxacin h Gentamicin Grepafloxacin Iclaprim Imipenem Kanamycin Levofloxacin Linezolid Linopristin-flopristin Lomefloxacin

Staphylococcus aureus ® a ATCC 29213 1–4 0.12/0.06–0.5/0.25 0.5–2 – 0.5–2 2–8 – 0.015–0.06 2–8 1–4 0.25–1 0.25–1 0.12–0.5 0.25–2 1–4 – 8–32 0.5–2 1–4 1–4 1–4 4–16 1–4 1–8 0.25–1 0.12–0.5 4–16 – 2–8 0.12–1 1–8 0.5–2 0.12–0.5 2–16 – 0.12–0.5 0.12–0.5 0.008–0.06 0.06–0.25 – 0.03–0.12 0.12–1 1–4 0.015–0.06 0.12–0.5 0.5–2 0.06–0.25 0.25–1 0.03–0.12 2–16 0.25–1 0.5–4 0.004–0.03 0.03–0.12 0.008–0.03 0.12–1 0.03–0.12 0.06–0.25 0.015–0.06 1–4 0.06–0.5 1–4 0.06–0.25 0.25–2

Enterococcus faecalis ® ATCC 29212 64–256 0.25/0.12–1.0/0.5 0.5–2 – – 1–4 – 0.06–0.25 16–64 – – – – – – – – – – – – – – – – – – – – 0.06–0.5 – – – 4–16 – 0.25–2 – 0.03–0.25 4–16 – 0.03–0.12 1–4 – 1–4 2–8 2–16 4–16 1–4 – 1–4 2–8 32–128 0.03–0.25 0.12–1.0 0.015–0.12 4–16 0.12–0.5 0.004–0.03 0.5–2 16–64 0.25–2 1–4 0.5–2 2–8

©

116

Escherichia coli ® ATCC 25922 0.5–4 2/1–8/4 2–8 2/1–8/4 – 8–32 0.06–0.25 0.06–0.25 4–16 1–4 0.25–1 1–4 0.12–0.5 0.12–1 0.015–0.12 0.25–1 0.25–1 0.25–1 0.25–1 0.12–0.5 0.03–0.12 0.06–0.25 2–8 0.25–1 1–4 0.03–0.12 0.06–0.5 0.12–0.5 0.03–0.12 0.03–0.12 0.03–0.12 2–8 4–16 2–8 2–8 0.004–0.015 – 0.002–0.015 – 0.5–2 – – – 0.015–0.06 0.5–2 0.06–0.25 0.004–0.015 – 0.25–1 – 0.03–0.12 0.5–2 0.004–0.03 0.008–0.03 0.004–0.015 0.25–1 0.004–0.03 1–4 0.06–0.25 1–4 0.008–0.06 – – 0.03–0.12

Pseudomonas aeruginosa ® ATCC 27853 1–4 – – – – 2–8 2–8 1–4 16–64 – – – – – 1–8 – – > 32 – 2–8 8–32 – – – – – 1–4 – 16–64 1–4 8–64 – – – – 0.25–1 – 0.06–0.5 – 0.5–4 – – – 0.12–0.5 – 2–8 2–8 – – – 1–4 2–8 0.5–2 0.5–2 0.25–1 0.5–2 0.25–2.0 – 1–4 – 0.5–4 – – 1–4

Escherichia coli ® b ATCC 35218 – 4/2–16/8 > 32 8/4–32/16 – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – –

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Staphylococcus Enterococcus Escherichia Pseudomonas Escherichia aureus faecalis coli aeruginosa coli Antimicrobial ® a ® ® ® ® b ATCC 29213 ATCC 29212 ATCC 25922 ATCC 27853 ATCC 35218 Agent Loracarbef 0.5–2 – 0.5–2 >8 – i Mecillinam – – – – 0.03–0.25 Meropenem 0.03–0.12 2–8 0.008–0.06 0.25–1 – Methicillin 0.5–2 > 16 – – – Mezlocillin 1–4 1–4 2–8 8–32 – c Minocycline 0.06–0.5 1–4 0.25–1 – – Moxalactam 4–16 – 0.12–0.5 8–32 – Moxifloxacin 0.015–0.12 0.06–0.5 0.008–0.06 1–8 – Nafcillin 0.12–0.5 2–8 – – – c Nalidixic acid – – 1–4 – – Netilmicin 4–16 0.5–8 – ≤ 0.25 ≤ 0.5–1 Nitrofurantoin 8–32 4–16 4–16 – – Norfloxacin 0.5–2 2–8 0.03–0.12 1–4 – Ofloxacin 0.12–1 1–4 0.015–0.12 1–8 – e Oritavancin 0.015–0.12 0.008–0.03 – – – Oxacillin 0.12–0.5 8–32 – – – Penicillin 0.25–2 1–4 – – – Piperacillin 1–4 1–4 1–4 1–8 >64 Piperacillin-tazobactam 0.25/4–2/4 1/4–4/4 1/4–4/4 1/4–8/4 0.5/4–2/4 Polymyxin B – – 0.25–2 1–4 – Quinupristin-dalfopristin 0.25–1 2–8 – – – Razupenem 0.008–0.03 0.25–1 0.06–0.5 – – Rifampin 0.004–0.015 0.5–4 4–16 16–64 – Sparfloxacin 0.03–0.12 0.12–0.5 0.004–0.015 0.5–2 – c,k Sulfisoxazole 32–128 32–128 8–32 – – Sulopenem 0.015–0.12 2–8 0.015–0.06 – – Teicoplanin 0.25–1 0.25–1 – – – Telavancin 0.12–1 0.12–0.5 – – – Telithromycin 0.06–0.25 0.015–0.12 – – – Tetracycline 0.12–1 8–32 0.5–2 8–32 – Ticarcillin 2–8 16–64 4–16 8–32 >128 l Ticarcillin-clavulanic acid 0.5/2–2/2 16/2–64/2 4/2–16/2 8/2–32/2 8/2–32/2 m Tigecycline 0.03–0.25 0.03–0.12 0.03–0.25 – – Tobramycin 0.12–1 8–32 0.25–1 0.25–1 – k Trimethoprim 1–4 0.12–0.5 0.5–2 > 64 – Trimethoprim8/152–32/608 – ≤ 0.5/9.5 ≤ 0.5/9.5 ≤ 0.5/9.5 sulfamethoxazole Trospectomycin 2–16 2–8 8–32 – – Trovafloxacin 0.008–0.03 0.06–0.25 0.004–0.015 0.25–2 – j Ulifloxacin (prulifloxacin) – – 0.004–0.015 0.12–0.5 – n Vancomycin 0.5–2 1–4 – – – NOTE 1: These MICs were obtained in several reference laboratories by dilution methods. If four or fewer concentrations are tested, QC may be more difficult. NOTE 2: Information in boldface type is considered tentative for one year. Footnotes a. b. c. d.

e. f. g. h. i. j. k. l. m. n. ©

ATCC is a registered trademark of the American Type Culture Collection. Because this strain may lose its plasmid, careful organism maintenance is required; refer to M07-A8, Section 16.4. QC limits for E. coli ATCC® 25922 with ciprofloxacin, nalidixic acid, minocycline, and sulfisoxazole when tested in CAMHB with 2.5% to 5% lysed horse blood (LHB) incubated either in ambient air or 5% CO2 are the same as those listed in Table 3. When the erythromycin/clindamycin combination well for detection of inducible clindamycin resistance is used, S. aureus ATCC® BAA-977 (containing inducible ermA-mediated resistance) and S. aureus ATCC® 29213 or S. aureus ATCC® BAA-976 (containing msrA-mediated macrolide-only efflux) are recommended for QC purposes. S. aureus ATCC® BAA-977 should demonstrate inducible clindamycin resistance (ie, growth in the well), whereas S. aureus ATCC® 29213 and S. aureus ATCC® BAA-976 should not demonstrate inducible clindamycin resistance (ie, no growth in the well). QC ranges reflect MICs obtained when CAMHB is supplemented with 0.002% polysorbate-80. QC ranges reflect MICs obtained when MHB is supplemented with calcium to a final concentration of 50 μg/mL. Agar dilution has not been validated for daptomycin. The approved MIC susceptibility testing method is agar dilution. Agar media should be supplemented with 25 μg/mL of glucose-6-phosphate. Broth dilution should not be performed. For control organisms for gentamicin and streptomycin high-level aminoglycoside screen tests for enterococci, see Supplemental Table 2D-S5 at the end of Table 2D. This test should be performed by agar dilution only. Ulifloxacin is the active metabolite of the prodrug prulifloxacin. Only ulifloxacin should be used for antimicrobial susceptibility testing. Very medium-dependent, especially with enterococci. The QC limits for E. coli ATCC® 35218 when using HTM are 16/2 to 64/2 μg/mL. For broth microdilution testing of tigecycline, when MIC panels are prepared, the medium must be prepared fresh on the day of use. The medium must be no more than 12 hours old at the time the panels are made; however, the panels may then be frozen for later use. For QC organisms for vancomycin screen test for enterococci, see Supplemental Table 2D-S5 at the end of Table 2D.

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Table 4 Nonfastidious Quality Control M07

Table 4. (Continued)

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Table 4A Fastidious Quality Control M07

Table 4A. MIC Testing—Acceptable Limits (μg/mL) for Quality Control Strains Used to Monitor Accuracy; Fastidious Organisms Using Dilution Methods Antimicrobial Agent b Amoxicillin Amoxicillinb clavulanic acid Ampicillin Ampicillinsulbactam Azithromycin Aztreonam Besifloxacin Cefaclor Cefamandole Cefdinir Cefditoren Cefepime Cefetamet Cefixime Cefmetazole Cefonicid Cefotaxime Cefotetan Cefoxitin Cefpirome Cefpodoxime Cefprozil Ceftaroline Ceftazidime Ceftibuten Ceftizoxime c Ceftobiprole Ceftriaxone Cefuroxime Cephalothin Chloramphenicol d Ciprofloxacin Clarithromycin Clinafloxacin Clindamycin e Dalbavancin f Daptomycin Dirithromycin Doripenem Doxycycline Enoxacin Ertapenem Erythromycin Faropenem Fleroxacin Garenoxacin Gatifloxacin Gemifloxacin Gentamicin Grepafloxacin Iclaprim Imipenem Levofloxacin Linezolid Linopristinflopristin Lomefloxacin Loracarbef Meropenem Metronidazole Moxifloxacin d Nalidixic acid Nitrofurantoin

118

Haemophilus influenzae ® a ATCC 49247 – 2/1–16/8

Haemophilus influenzae ® ATCC 49766 – –

Streptococcus pneumoniae ® ATCC 49619 0.03–0.12 0.03/0.015–0.12/0.06

2–8 2/1–8/4

– –

0.06–0.25 –

1–4 0.12–0.5 0.015–0.06 – – – 0.06–0.25 0.5–2 0.5–2 0.12–1 2–16 – 0.12–0.5 – – 0.25–1 0.25–1 – 0.03–0.12 0.12–1 0.25–1 0.06–0.5 0.12–1 0.06–0.25 – – 0.25–1 0.004–0.03 4–16 0.001–0.008 – – – 8–32 – – – – – – 0.03–0.12 0.002–0.008 0.004–0.03 0.002–0.008 – 0.002–0.015 0.12–1 – 0.008–0.03 – 0.25–2

– – – 1–4 0.25–1 0.12–0.5 – – – – – 0.06–0.25 – – – – – 1–4 – – – – 0.016–0.06 – 0.25–1 – – – – – – – – – 0.06–0.25 – – 0.015–0.06 – 0.12–0.5 – – – – – – – 0.25–1 – – –

0.06–0.25 – 0.03–0.12 1–4 – 0.03–0.25 0.015–0.12 0.03–0.25 0.5–2 – – – 0.03–0.12 – – – 0.03–0.12 0.25–1 0.008–0.03 – – 0.12–0.5 0.004–0.03 0.03–0.12 0.25–1 0.5–2 2–8 – 0.03–0.12 0.03–0.12 0.03–0.12 0.008–0.03 0.06–0.5 0.06–0.25 0.03–0.12 0.015–0.12 – 0.03–0.25 0.03–0.12 0.03–0.25 – 0.015–0.06 0.12–0.5 0.008–0.03 – 0.06–0.5 0.03–0.12 0.03–0.12 0.5–2 0.25–2 0.12–0.5

0.03–0.12 – – – 0.008–0.03 – –

– 0.5–2 0.03–0.12 – – – –

– 2–8 0.06–0.25 – 0.06–0.25 – 4–16

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Table 4A. (Continued) Antimicrobial Agent Norfloxacin Ofloxacin e Oritavancin Penicillin Piperacillintazobactam Quinupristindalfopristin Razupenem Rifampin Sparfloxacin Spectinomycin Sulopenem Telavancin Telithromycin Tetracycline g Tigecycline Trimethoprimsulfamethoxazole Trospectomycin Trovafloxacin Vancomycin

Haemophilus influenzae ® a ATCC 49247 – 0.015–0.06 – – 0.06/4–0.5/4

Haemophilus influenzae ® ATCC 49766 – – – – –

Streptococcus pneumoniae ® ATCC 49619 2–8 1–4 0.001–0.004 0.25–1 –

2–8

–

0.25–1

– 0.25–1 0.004–0.015 – – – 1–4 4–32 0.06–0.5 0.03/0.59– 0.25/4.75 0.5–2 0.004–0.015 –

0.008–0.03 – – – 0.06–0.25 – – – – –

0.008–0.06 0.015–0.06 0.12–0.5 – 0.03–0.12 0.004–0.03 0.004–0.03 0.06–0.5 0.015–0.12 0.12/2.4– 1/19 1–4 0.06–0.25 0.12–0.5

– – –

Testing Conditions for Clinical Isolates and Performance of Quality Control Organism

Haemophilus influenzae

Medium

Broth dilution: HTM broth

Direct colony suspension, equivalent to a 0.5 McFarland standard Incubation 35 °C; ambient Characteristics air; 20–24 hours NOTE 1: Information in boldface type is considered tentative for one year. NOTE 2: For four-dilution ranges, results at the extremes of the acceptable ranges should be suspect. Verify control validity with data from other control strains. Footnotes a. b. c. d. e. f. g.

©

ATCC is a registered trademark of the American Type Culture Collection. ® QC limits for E. coli ATCC 35218 when tested on HTM are 4/2 to 16/8 μg/mL for amoxicillin-clavulanic acid and ≥ 256 μg/mL for amoxicillin; testing amoxicillin may help to determine if the isolate has maintained its ability to produce β-lactamase. ® Either H. influenzae ATCC 49247 or 49766 may be used for routine QC testing. ® QC limits for E. coli ATCC 25922 with ciprofloxacin, nalidixic acid, minocycline, and sulfisoxazole when tested in CAMHB with 2.5 to 5% LHB incubated either in ambient air or 5% CO2 are the same as those listed in Table 3. QC ranges reflect MICs obtained when CAMHB is supplemented with 0.002% polysorbate-80. QC ranges reflect MICs obtained when MHB is supplemented with calcium to a final concentration of 50 μg/mL. Agar dilution has not been validated for daptomycin. For broth microdilution testing of tigecycline, when MIC panels are prepared, the medium must be prepared fresh on the day of use. The medium must not be more than 12 hours old at the time the panels are made; however, the panels may then be frozen for later use.

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Table 4A Fastidious Quality Control M07

Inoculum

Streptococcus pneumoniae, Streptococci, and Neisseria meningitidis Broth dilution: CAMHB with LHB (2.5–5% v/v) Direct colony suspension, equivalent to a 0.5 McFarland standard 35 °C; ambient air; 20–24 hours

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Table 4B. MIC Testing—Acceptable Limits (μg/mL) for Quality Control Strains Used to Monitor Accuracy; Fastidious Organisms Using Agar Dilution Antimicrobial Agent Amoxicillin Cefdinir Cefepime Cefetamet Cefixime Cefmetazole Cefotaxime Cefotetan Cefoxitin Cefpodoxime Ceftazidime Ceftizoxime Ceftriaxone Cefuroxime Ciprofloxacin Clarithromycin Doxycycline Enoxacin Erythromycin Fleroxacin Gatifloxacin Gentamicin Grepafloxacin Lomefloxacin Meropenem Metronidazole Moxifloxacin Ofloxacin Penicillin Sparfloxacin Spectinomycin Telithromycin Tetracycline Trospectomycin Trovafloxacin

Neisseria gonorrhoeae ® a ATCC 49226 – 0.008–0.03 0.015–0.06 0.015–0.25 0.004–0.03 0.5–2 0.015–0.06 0.5–2 0.5–2 0.03–0.12 0.03–0.12 0.008–0.03 0.004–0.015 0.25–1 0.001–0.008 – – 0.015–0.06 – 0.008–0.03 0.002–0.015 – 0.004–0.03 0.008–0.03 – – 0.008–0.03 0.004–0.015 0.25–1 0.004–0.015 8–32 – 0.25–1 1–4 0.004–0.015

Helicobacter pylori ® ATCC 43504 0.015–0.12 – – – – – – – – – – – – – – 0.015–0.12 – – – – – – – – – 64–256 – – – – – 0.06–0.5 0.12–1.0 – –

Testing Conditions for Clinical Isolates and Performance of Quality Control Organism Medium

Inoculum

Table 4B Fastidious Quality Control Agar Dilution M07

Incubation Characteristics

Neisseria gonorrhoeae Agar dilution: GC agar base and 1% defined growth supplement. The use of a cysteinefree supplement is required for agar dilution tests with carbapenems and clavulanate. Cysteine-containing defined growth supplements do not significantly alter dilution test results with other drugs. Direct colony suspension, equivalent to a 0.5 McFarland standard

36 ± 1 °C (do not exceed 37 °C); 5% CO2; 2024 hours

Helicobacter pylori Agar dilution: MHA with aged (≥ 2-week-old) sheep’s blood (5% v/v).

A saline suspension equivalent to a 2.0 7 McFarland standard (containing 1 × 10 to 8 1 × 10 CFU/mL), to be prepared from a 72-hour-old subculture from a blood agar plate. The inoculum (1–3 μL per spot) is replicated directly on the antimicrobial agentcontaining agar dilution plates. 35 ± 2 °C; three days; microaerobic atmosphere produced by gas-generating system suitable for campylobacters

NOTE 1: Information in boldface type is considered tentative for one year. NOTE 2: For four-dilution ranges, results at the extremes of the acceptable ranges should be suspect. Verify control validity with data from other control strains. Footnote a.

120

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For Use With M07-A8—MIC Testing

M100-S20

Table 4C. MIC Testing—Acceptable Limits (μg/mL) for Quality Control Strains Used to Monitor Accuracy; Using Cation-Adjusted Mueller-Hinton Broth + 2% Defined Growth Supplementa Antimicrobial Agent Chloramphenicol Ciprofloxacin Doxycycline Gentamicin Levofloxacin Nalidixic acid Streptomycin Tetracycline Trimethoprimsulfamethoxazole

Staphylococcus aureus ® b ATCC 29213 24 hours 4–16 0.25–1 0.12–1 0.25–1 0.12-0.5 – 8–32 0.25–2 ≤ 0.25/4.75

Staphylococcus aureus ® ATCC 29213 48 hours 4–32 0.25–1 0.25–2 0.25–1 0.12-0.5 – 8–64 0.5–4 ≤ 0.25/4.75

Escherichia coli ® ATCC 25922 24 hours 2–8 0.004–0.015 1–4 0.25–2 0.008-0.03 1–8 8–32 1–4 ≤ 0.5/9.5

Escherichia coli ® ATCC 25922 48 hours 4–16 0.004–0.03 1–8 0.25–2 0.008–-0.06 2–8 8-32 2–8 ≤ 0.5/9.5

Pseudomonas aeruginosa ® ATCC 27853 24 hours – 0.12–1 4–32 0.5–2 0.5–2 – 32–128 8–32 –

Pseudomonas aeruginosa ® ATCC 27853 48 hours – 0.25–1 4–32 0.5–4 0.5–4 – 32–256 8–64 –

NOTE: Francisella tularensis MIC results read after 24 hours of incubation should use 24-hour QC ranges; results read after 48 hours should use only the 48-hour QC ranges. Footnotes a. Add 2% defined growth supplement (25.9 g L-cysteine HCl, 1.1 g L-cystine, 1 g adenine, 0.03 g guanine HCl, 0.01 g vitamin B12, 0.1 g cocarboxylase, 0.25 g NAD, 10 g L-glutamine, 0.02 g ferric nitrate, 100 g glucose, 3 mg thiamine HCl, and 13 mg PABA acid [in 1 L H2O]) to CAMHB after autoclaving. The pH of medium should be adjusted to 7.1 ± 0.1. b. ATCC is a registered trademark of the American Type Culture Collection.

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Table 4C QC Monitoring for CAMHB + 2% Defined Growth Supplement M07

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Table 4D. MIC Testing—Acceptable Limits (μg/mL) for Quality Control Strains Used to Monitor Accuracy; Using Brucella Broth Media Without Supplements Adjusted to pH 7.1 ± 0.1

Antimicrobial Agent Azithromycin Chloramphenicol Ciprofloxacin Doxycycline Gentamicin Levofloxacin Rifampin Streptomycin Tetracycline Trimethoprim– sulfamethoxazole

Escherichia coli ®a ATCC 25922 24 hours – 2–8 – 0.5–2 1–8 – 4–16 4–32 0.5–2 –

Escherichia coli ® ATCC 25922 48 hours – 4–16 – 1–4 1–8 – 4–16 4–32 0.5–4 –

Staphylococcus aureus ® ATCC 29213 24 hours 2–8 4–16 0.25–1 0.12–0.5 – 0.06–0.5 – 8–64 0.12–1 –

Staphylococcus aureus ATCC® 29213 48 hours 2–16 4–16 0.25–1 0.12–0.5 – 0.12–0.5 – 8–64 0.25–1 –

Streptococcus pneumoniae ATCC® 49619 24 hours 0.25–1 1–8 0.25–1 0.03–0.12 – 0.25–1 0.008–0.03 16–64 0.03–0.25 0.5/9.5–2/38

Streptococcus pneumoniae ATCC® 49619 48 hours 0.25–1 2–8 0.25–2 0.03–0.25 – 0.25–2 0.008–0.06 16–128 0.06–0.5 0.5/9.5–2/38

Table 4D QC Monitoring Using Brucella Broth Media M07

Footnote a.

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Table 4E. MIC Testing—Reference Guide to Quality Control Testing Frequency This table summarizes the suggested frequency of testing CLSI-recommended ATCC®a QC strains to be performed by the user of antimicrobial susceptibility tests. It applies only to antimicrobial agents for which 20 or 30 consecutive test days of QC testing produced satisfactory results.

Test Modification MIC Tests(s)

Number of Days of Consecutive QC Testing b Required 1 5 20 or 30

Use new shipment or lot number

X

Expand dilution range

X

Reduce dilution range

X

Use new method (same company)

X

Comments

Example: Convert from breakpoint to expanded range MIC panels. Example: Convert from expanded dilution range to breakpoint panels. Examples: Convert from visual to instrument reading of panel. Convert from overnight to rapid MIC test.

X

Use new manufacturer of broth or agar Inoculum Preparation

X

Convert inoculum preparation/ standardization to use of a device that has its own QC protocol

X

Convert inoculum preparation/ standardization to a method that is dependent on user technique

X

Example: Convert from visual adjustment of turbidity to use of a photometric device for which a QC procedure is provided. Example: Convert from visual adjustment of turbidity to another method that is not based on a photometric device.

Instrument/Software Software update that affects AST results Repair of instrument that affects AST results

X X

Monitor all drugs, not just those implicated in software modification. Depending on extent of repair (eg, critical component such as the optics), additional testing may be appropriate (eg, five days).

NOTE 1: Addition of any new antimicrobial agent requires 20 or 30 consecutive days of satisfactory testing (see M07-A8, Section 16.7.2) before using this guide. NOTE 2: QC can be performed before or concurrent with testing patient isolates. Patient results can be reported for that day if QC results are within the acceptable limits. NOTE 3: Manufacturers of commercial or in-house prepared tests should follow their own internal procedures and applicable regulations. NOTE 4: Acceptable MIC QC limits for FDA-cleared antimicrobial susceptibility tests may differ slightly from acceptable CLSI QC limits. Users of each device should use the manufacturer’s procedures and QC limits as indicated in the instructions for use. NOTE 5: For troubleshooting out-of-range results, refer to M07-A8, Section 16.9. NOTE 6: Broth, saline, and/or water used to prepare an inoculum does not require routine QC. Footnotes a. ATCC is a registered trademark of the American Type Culture Collection. b. Does not eliminate the need for routine weekly or daily QC testing. ©

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123

Table 4E QC Testing Frequency M07

Use new manufacturer of MIC test

In addition, perform in-house validation studies. In addition, perform in-house validation studies.

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Table 4F. MIC Testing Quality Control Troubleshooting Guide This table provides guidance for troubleshooting and corrective action for out-of-range QC primarily using antimicrobial susceptibility tests with CAMHB broth microdilution. Refer to M07-A8 MIC, Section 16, Quality Control and Quality Assurance Procedures. Out-of-range QC tests should first be repeated. If the issue is unresolved, this troubleshooting guide provides additional suggestions for troubleshooting out-of-range QC results and unusual clinical isolate results. In addition, if unresolved, manufacturers should be notified of potential product problems. General Comments (1)

QC organism maintenance: Avoid repeated subcultures. Retrieve new QC strain from stock. If using lyophilized strains, follow ®a ® the maintenance recommendations of the manufacturer. Store E. coli ATCC 35218 and K. pneumoniae ATCC 700603 stock cultures at −60 °C or below and prepare working stock cultures weekly.

Antimicrobial Agent

Observation

Probable Cause

Any

MIC too high

pH of media too low

Aminoglycosides Aminoglycosides

MIC too low MIC too high

Amoxicillinclavulanic acid

Any P. aeruginosa ® ATCC 27853 P. aeruginosa ® ATCC 27853 ® E. coli ATCC 35218

β-lactam group

Any

Aztreonam Cefotaxime Cefpodoxime Ceftazidime Ceftriaxone Cefotaxime/ clavulanic acid Ceftazidime/ clavulanic acid Carbapenems

K. pneumoniae ® ATCC 700603

MIC initially acceptable but increases possibly out-of-range over time MIC too low

pH of media too high Ca++ and/or Mg++ content too high Ca++ and/or Mg++ content too low Clavulanic acid is labile. Antimicrobial agent is degrading. Antimicrobial agent is degrading.

Aminoglycosides

MIC too low MIC too high

Comments/Suggested Actions Acceptable pH range = 7.2–7.4 Avoid CO2 incubation, which lowers pH. Acceptable pH range = 7.2–7.4 Acceptable range = Ca++ 20–25 mg/L Mg++ 10–12.5 mg/L Acceptable range = Ca++ 20–25 mg/L Mg++ 10–12.5 mg/L Use alternative lot. Check storage and package integrity. Use alternative lot. Check storage and package integrity. Imipenem, cefaclor, and clavulanic acid are especially labile.

Spontaneous loss of the plasmid encoding the β-lactamase.

See General Comment (1) on QC organism maintenance.

K. pneumoniae ® ATCC 700603

Negative ESBL confirmatory test

Spontaneous loss of the plasmid encoding the β-lactamase.

See General Comment (1) on QC organism maintenance.

P. aeruginosa ® ATCC 27853 P. aeruginosa ® ATCC 27853

MIC too high

Zn++ concentration in media is too high Antimicrobial agent is degrading

Use alternative lot.

Penicillin

S. aureus ® ATCC 29213

MIC too high

Penicillins

Any

MIC too low

Penicillins Carbenicillin

Any P. aeruginosa ® ATCC 27853

MIC too high MIC too high

Ticarcillinclavulanic acid

E. coli ® ATCC 35218

MIC too high

Clindamycin

S. aureus ® ATCC 29213 E. faecalis ® ATCC 29212

MIC too high

Carbapenems

Table 4F QC Troubleshooting M07

QC Strain

Aminoglycosides

124

MIC too high

QC strain is a βlactamase producer; overinoculation may yield increased MICs pH of media too low pH of media too high QC strain develops resistance after repeated subculture Clavulanic acid is labile. Antimicrobial agent is degrading. pH of media too low

©

Use alternative lot. Check storage and package integrity. Repeated imipenem results of 4 μg/mL with P. aeruginosa ® ATCC 27853 may be indicative of deterioration of the drug. Repeat with a carefully adjusted inoculum.

Acceptable pH range = 7.2–7.4 Avoid CO2 incubation, which lowers pH. Acceptable pH range = 7.2–7.4 See comment (1) on QC organism maintenance. Use alternative lot. Check storage and package integrity. Acceptable pH range = 7.2–7.4 Avoid CO2 incubation, which lowers pH.

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Table 4F. (Continued) QC Strain

Observation

Probable Cause

Comments/Suggested Actions

S. aureus ® ATCC 29213 E. faecalis ® ATCC 29212 S. aureus ® ATCC 29213 E. faecalis ® ATCC 29212

MIC too low

pH of media too high

Acceptable pH range = 7.2–7.4

MICs too high

Ca++ content too low

MICs too low

Ca++ content too high

Acceptable Ca++ content 50 µg/mL in CAMHB Adjust Ca++ concentration in or try alternative lots.

MIC too high

pH of media too low

Acceptable pH range = 7.2–7.4 Avoid CO2 incubation, which lowers pH.

MIC too low

pH of media too high

Acceptable pH range = 7.2–7.4

Quinolones

S. aureus ® ATCC 29213 E. faecalis ® ATCC 29212 S. aureus ® ATCC 29213 E. faecalis ® ATCC 29212 Any

MIC too high

pH of media too low

Quinolones Tetracyclines Tetracyclines Tetracyclines

Any Any Any Any

MIC too low MIC too low MIC too high MIC too high

Tetracyclines

Any

MIC too low

Tigecycline

Any

MIC too high

pH of media too high pH of media too low pH of media too high Ca++ and/or Mg++ content too high Ca++ and/or Mg++ content too low CAMHB has not been freshly prepared

Various

Any

Many MICs too low

Inoculum too light; error in inoculum preparation

Various

Any

CAMHB not optimal

Various

Any

Many MICs too high or too low Many MICs too high

Acceptable pH range = 7.2–7.4 Avoid CO2 incubation, which lowers pH. Acceptable pH range = 7.2–7.4 Acceptable pH range = 7.2–7.4 Acceptable pH range = 7.2–7.4 Acceptable range = Ca++ 20–25 mg/L Mg++ 10–12.5 mg/L Acceptable range = Ca++ 20–25 mg/L Mg++ 10–12.5 mg/L Reference panels must be used or frozen within 12 hours of CAMHB preparation. Repeat using McFarland 0.5 turbidity standard or standardizing device. Check expiration date and proper storage if using barium sulfate or latex standards. Check steps in inoculum preparation and inoculation procedure. Perform colony count check of growth control well immediately after inoculation and ® before incubation (E. coli ATCC 25922 5 closely approximates 5 × 10 CFU/mL). Use alternative lot.

Various

Any

Skipped wells

Various

Any

Several MICs too high or too low

Contamination. Improper inoculation of panel or inadequate mixing of inoculum. Actual concentration of drug in wells inaccurate. Volume of broth in wells inaccurate. Possible reading/transcription error

Clindamycin

Daptomycin

Macrolides and Ketolides Macrolides and Ketolides

©

Inoculum too heavy

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Repeat using McFarland 0.5 turbidity standard or standardizing device. Check expiration date and proper storage if using barium sulfate or latex standards. Check steps in inoculum preparation and inoculation procedure. Perform colony count check of growth control well immediately after inoculation and ® before incubation (E. coli ATCC 25922 5 closely approximates 5 × 10 CFU/mL). Repeat QC test. Use alternative lot.

Recheck readings. Use alternative lot.

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Table 4F QC Troubleshooting M07

Antimicrobial Agent

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Table 4F. (Continued) Antimicrobial Agent

QC Strain

Observation

Various

S. pneumoniae ® ATCC 49619

MICs too low

Various

Any

One QC strain is out of range, but other QC strains are in range with the same antimicrobial agent

Various

Any

Various

Any

Two QC strains out of range with the same antimicrobial agent One QC result out of range, but the antimicrobial agent is not an agent reported for patient results (eg, not on hospital formulary)

Probable Cause

Comments/Suggested Actions

Inoculum source plate too old and contains too many nonviable cells. Plate used to prepare inoculum should be 18–20 hours. MHB with LHB not optimal. One QC organism may be a better indicator of a QC problem (eg, P. aeruginosa ® ATCC 27853 is a better indicator of imipenem deterioration than E. coli ® ATCC 25922).

Subculture QC strain and repeat QC test; or subculture new QC strain from stock culture. Use alternative lot.

Indicative of a problem with the antimicrobial agent. May be a systemic problem.

Determine if the in-range QC strain has an on-scale end point for the agent in question. Retest this strain to confirm reproducibility of acceptable results. Evaluate with alternative strains with known MICs. Initiate corrective action with problem QC strain/antimicrobial agent(s). Initiate corrective action.

If antimicrobial agent is not normally reported, no repeat is necessary if adequate controls are in place to prevent reporting of the out-of-range antimicrobial agent. Carefully check antimicrobial agents of the same class for similar trend toward out-of-control results. If the antimicrobial agent in question is consistently out-of-control, contact the manufacturer.

Footnote

Table 4F QC Troubleshooting M07

a. ATCC is a registered trademark of the American Type Culture Collection.

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Table 5. Solvents and Diluents for Preparation of Stock Solutions of Antimicrobial Agents Antimicrobial Agent

Diluent

Water

Amoxicillin

Phosphate buffer, pH 6.0, 0.1 mol/L

Phosphate buffer, pH 6.0, 0.1 mol/L

Ampicillin

Phosphate buffer, pH 8.0, 0.1 mol/L

Phosphate buffer, pH 6.0, 0.1 mol/L

Azithromycin

95% ethanol or glacial acetic acid

Azlocillin

Water

e,f

Broth media

Aztreonam

Saturated solution sodium bicarbonate

Water

Besifloxacin

Methanol

Water

Carbenicillin

Water

Cefaclor

Water

Cefadroxil

Phosphate buffer, pH 6.0, 0.1 mol/L

Cefamandole

Water

Cefazolin

Phosphate buffer, pH 6.0, 0.1 mol/L

Phosphate buffer, pH 6.0, 0.1 mol/L

Cefdinir

Phosphate buffer, pH 6.0, 0.1 mol/L

Water

Cefditoren

Phosphate buffer, pH 6.0, 0.1 mol/L

Water

Cefepime

Phosphate buffer, pH 6.0, 0.1 mol/L

Phosphate buffer, pH 6.0, 0.1 mol/L

Cefetamet

Phosphate buffer, pH 6.0, 0.1 mol/L

Water

Cefixime

Phosphate buffer, pH 7.0, 0.1 mol/L

Phosphate buffer, pH 7.0, 0.1 mol/L

Cefmetazole

Water

Cefonicid

Water

Cefoperazone

Water

Cefotaxime

Water

Cefotetan

DMSO

Cefoxitin

Water

Cefpodoxime

0.10% (11.9 mmol/L) aqueous sodium bicarbonate

Cefprozil

Water

Water

e,g

Water

Ceftaroline

0.85% physiological saline

Ceftazidime

Sodium carbonate

Ceftibuten

1/10 vol DMSO

Ceftizoxime

Water

Ceftobiprole

DMSO plus glacial acetic acid

Ceftriaxone

Water

0.85% physiological saline

d

Water

g

g

Water

Water e,i

Water, vortex vigorously

Cefuroxime

Phosphate buffer, pH 6.0, 0.1 mol/L

Cephalexin

Phosphate buffer, pH 6.0, 0.1 mol/L

Water

Cephalothin

Phosphate buffer, pH 6.0, 0.1 mol/L

Water

Cephapirin

Phosphate buffer, pH 6.0, 0.1 mol/L

Water

Cephradine

Phosphate buffer, pH 6.0, 0.1 mol/L

Water

Chloramphenicol

95% ethanol

Water

Cinoxacin

1/2 volume of water, then add 1 mol/L NaOH, dropwise to dissolve

Water

Phosphate buffer, pH 6.0, 0.1 mol/L

Ciprofloxacin

Water

Clarithromycin

Methanol or glacial acetic acid

Phosphate buffer, pH 6.5, 0.1 mol/L

Clavulanic acid

Phosphate buffer, pH 6.0, 0.1 mol/L

Phosphate buffer, pH 6.0, 0.1 mol/L

e

Clinafloxacin

Water

Clindamycin

Water

Colistin

Table 5 Solvents and Diluents M07

Solvent

Amikacin

a

e,f

Water

Water g

g,h

Dalbavancin

DMSO

DMSO

Daptomycin

Water

Water

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Table 5. (Continued) Antimicrobial Agent Dirithromycin

Solvent Glacial acetic acid

Diluent

f

Water

Doripenem

0.85% physiological saline

Doxycycline

Water

0.85% physiological saline

Enoxacin

1/2 volume of water, then 0.1 mol/L NaOH dropwise to dissolve

Water

Ertapenem

Phosphate buffer, pH 7.2, 0.01 mol/L

Phosphate buffer, pH 7.2, 0.01 mol/L

Erythromycin

95% ethanol or glacial acetic acid

Faropenem

Water

Fidaxomicin

DMSO

Water

Fleroxacin

1/2 volume of water, then 0.1 mol/L NaOH dropwise to dissolve

Water

Garenoxacin

Water (with stirring)

Gatifloxacin

Water (with stirring)

e,f

Water Water

g

Gemifloxacin

Water

Gentamicin

Water

Iclaprim

DMSO

Water

Imipenem

Phosphate buffer, pH 7.2, 0.01 mol/L

Phosphate buffer, pH 7.2, 0.01 mol/L

Kanamycin Levofloxacin

Water 1/2 volume of water, then 0.1 mol/L NaOH dropwise to dissolve

Water

Linezolid

Water

Linopristin-flopristin

DMF

Lomefloxacin

Water

Loracarbef

Water

g

l

Mecillinam

Water

Meropenem

Water

Water

Methicillin

Water

Metronidazole

DMSO

Mezlocillin

Water

Minocycline

Water

Moxalactam b (diammonium salt)

0.04 mol/L HCI (let sit for 1.5 to 2 hours)

e,g

Water

Moxifloxacin

Water

Mupirocin

Water

Nafcillin

Water

Nalidixic acid

1/2 volume of water, then add 1 mol/L NaOH dropwise to dissolve

Nitrofurantoin

Water

Water c

Norfloxacin Ofloxacin Oritavancin

Phosphate buffer, pH 8.0, 0.1 mol/L

Phosphate buffer, pH 8.0, 0.1 mol/L

1/2 volume of water, then 0.1 mol/L NaOH dropwise to dissolve 1/2 volume of water, then 0.1 mol/L NaOH dropwise to dissolve

Water

0.002% polysorbate-80 in water

Oxacillin

Water

Penicillin

Water

Piperacillin

Water

j

Polymyxin B

Water

Quinupristin-dalfopristin

Water

Razupenem

Phosphate buffer, pH 7.2, 0.01 mol/L

Rifampin

Methanol (maximum concentration = 640 μg/mL) Water

Spectinomycin

Water

Streptomycin

Water

©

0.002% polysorbate-80 in water

j

Water

e

Sparfloxacin

Water

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Phosphate buffer, pH 7.2, 0.01 mol/L Water (with stirring)

129

Table 5 Solvents and Diluents M07

Netilmicin

Phosphate buffer, pH 6.0, 0.1 mol/L

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Table 5. (Continued) Antimicrobial Agent

Solvent

Diluent

Sulbactam

Water

Sulfonamides

1/2 volume hot water and minimal amount of 2.5 mol/L NaOH to dissolve

Water

0.01 M phosphate buffer, pH 7.2, vortex to dissolve

0.01 M phosphate buffer, pH 7.2

Sulopenem

k

Tazobactam

Water

Teicoplanin

Water

Telavancin

DMSO

Water

Telithromycin

Glacial acetic acid

Tetracycline

Water

Ticarcillin

Phosphate buffer, pH 6.0, 0.1 mol/L

Phosphate buffer, pH 6.0, 0.1 mol/L

Tigecycline

Water

Water

Tobramycin

Water

Trimethoprim

0.05 mol/L lactic or hydrochloric acid, 10% of final volume

Trimethoprim (if lactate)

Water

Trospectomycin Ulifloxacin (prulifloxacin)

DMSO

Vancomycin

Water

g

Water

e

f

Water

e

Water (may require heat)

Water g

Water

NOTE: Information in boldface type is considered tentative for one year. Footnotes a. b. c. d.

e. f. g. h.

i. j.

Table 5 Solvents and Diluents M07

k. l.

The formulation of colistin used in antimicrobial susceptibility tests is colistin sulfate and not colistin methane sulfonate (sulfomethate). The diammonium salt of moxalactam is very stable, but it is almost pure R isomer. Moxalactam for clinical use is a 1:1 mixture of R and S isomers. Therefore, the salt is dissolved in 0.04 mol/L HCl and allowed to react for 1.5 to 2 hours to convert it to equal parts of both isomers. Alternatively, nitrofurantoin is dissolved in dimethyl sulfoxide (DMSO). Anhydrous sodium carbonate is used at a weight of exactly 10% of the ceftazidime to be used. The sodium carbonate is dissolved in solution in most of the required water. The antimicrobial agent is dissolved in this sodium carbonate solution, and water is added to the desired volume. The solution is to be used as soon as possible, but it can be stored up to six hours at no more than 25 °C. These compounds are potentially toxic. Consult the material safety data sheets (MSDSs) available from the product manufacturer before using any of these materials. For glacial acetic acid, use 1/2 volume of water, then add glacial acetic acid dropwise until dissolved, not to exceed 2.5 μL/mL. Dimethyl sulfoxide (DMSO). Starting stock solutions of dalbavancin should be prepared at concentrations no higher than 1600 µg/mL. Intermediate 100x concentrations should then be diluted in DMSO. Final 1:100 dilutions should then be made directly into CAMHB supplemented with 0.002% (v/v) polysorbate-80, so the final concentration of DMSO in the wells is no greater than 1%. See also Table 7A. For each 1.5 mg of ceftobiprole, add 110 μL of a 10:1 mixture of DMSO and glacial acetic acid. Vortex vigorously for one minute, then intermittently for 15 minutes. Dilute to 1.0 mL with distilled water. Starting stock solutions of oritavancin should be prepared at concentrations no higher than 1600 μg/mL in 0.002% polysorbate-80 in water. Intermediate 100× oritavancin concentrations should then be prepared in 0.002% polysorbate-80 in water. Final 1:100 dilutions should be made directly into CAMHB supplemented with 0.002% polysorbate-80, so the final concentration of polysorbate-80 in the wells is 0.002%. Must be made FRESH on the day of use. Dimethylformamide (DMF) to 25% of final volume/water

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Antimicrobial Agent Potassium Penicillin G

Pure Agent (reference) 0.625 µg/unit(1)

Sodium Penicillin G

0.6 µg/unit(1)

Multiply the activity expressed in units/mg by 0.6 µg/unit.

Polymyxin B

10 000 units/mg =

Multiply the activity expressed in units/mg by 0.1 µg/unit.

Calculation for µg/mg Multiply the activity expressed in units/mg by 0.625 µg/unit.

10 units/µg = 0.1 µg/unit(2)

For Use With M07-A8—MIC Testing

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Table 5A. Preparation of Stock Solutions for Antimicrobial Agents Provided With Activity Expressed as Units Example Activity units/mg × 0.625 µg/unit = Activity µg/mg (eg, 1592 units/mg × 0.625 µg/unit = 995 µg/mg) Activity units/mg × 0.6 µg/unit = Activity µg/mg (eg, 1477 units/mg × 0.6 µg/unit = 886.2 µg/mg) Activity units/mg × 0.1 µg/unit = Activity µg/mg (eg, 8120 units/mg × 0.1 µg/unit = 812 µg/mg) Divide the activity expressed in units/mg by 10 units/µg.

Activity units/mg / 10 units/µg = Activity µg/mg (eg, 8120 units/mg / 10 units/mg = 812 µg/mg)

Colistin sulfatea

30 000 units/mg =

Multiply the activity expressed in units/mg by 0.03333 µg/unit.

30 units/µg = 0.03333 µg/unit(2)

Activity units/mg × 0.03333 µg/unit = Activity µg/mg (eg, 20 277 units/mg × 0.03333 µg/unit = 676 µg/mg)

Divide the activity expressed in units/mg by 30 units/mg.

Activity units/mg / 30 units/µg = Activity µg/mg (eg, 20 277 units/mg / 30 units/µg = 676 µg/mg)

Streptomycin

785 units/mg(3)

Divide the number of units given for the powder by 785. This will give the percent purity of the powder. Multiply the percent purity by 850, which is the amount in the purest form of streptomycin. This will equal the activity factor in µg/mg.

([Potency units/mg] / [785 units/mg]) × (850 µg/mg) = Potency µg/mg [eg, (751 units/mg / 785 units/mg) × 850 µg/mg = 813 µg/mg] If powder contains 2.8% water: 813 × (1–0.028) = potency 813 × 0.972 = 790 µg/mg

Footnote a

Do not use colistin methanesulfonate for in vitro antimicrobial susceptibility tests.

References for Table 5A:

131

Kucers A, Crowe SM, Grayson ML, Hoy JF. Penicillin G (Pen G). The Use of Antibiotics. 5th ed. Oxford, UK: Butterworth-Heinemann; 1997:3-70. Kucers A, Crowe SM, Grayson ML, Hoy JF. Polymyxins. The Use of Antibiotics. 5th ed. Oxford, UK: Butterworth-Heinemann; 1997:667-675. United States Department of Agriculture, OPHS, Laboratory QA/QC Division. Bioassay for the detection, identification and quantitation of antimicrobial residues in meat and poultry tissue. 2004;1-58, vol. MLG 34.01.

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Table 5A Stock Solutions M07

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Table 5B Solutions and Media M07

132

Antimicrobial Agent Amoxicillinclavulanic acid

Combination Tested 2:1 ratio (amoxicillin:clavulanic acid).

Preparation Prepare 10× starting concentration as 2:1 ratio and dilute as needed.

Ampicillinsulbactam Piperacillintazobactam

2:1 ratio (ampicillin:sulbactam).

Same as amoxicillin-clavulanic acid. Prepare 10× starting concentration of piperacillin at twice the concentration needed and dilute as usual using serial twofold dilutions. Add an equal volume of tazobactam 80 µg/mL to each of the diluted tubes.

Ticarcillinclavulanic acid

Fixed concentration of clavulanic acid at 2 µg/mL.

Fixed concentration of tazobactam at 4 µg/mL.

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For a starting concentration of 128/4 in the panel, prepare a 10× stock concentration of piperacillin at 2560 µg/mL and dilute by serial twofold increments down to the final concentration needed in the panel. Prepare a stock concentration of tazobactam at 80 µg/mL. Then add an equal volume of the tazobactam 80 µg/mL solution to each diluted tube of piperacillin. For example, 5 mL of 2560 µg/mL piperacillin + 5 mL of 80 µg/mL tazobactam = 10 mL of 1280/40 µg/mL piperacillin-tazobactam. Dilute 1:10 with broth to achieve the final concentration in microdilution wells. For a starting concentration of 128/4 in the panel, prepare a 10× stock concentration of ticarcillin at 2560 µg/mL and dilute by serial twofold increments down to the final concentration needed. Prepare a stock concentration of clavulanic acid at 40 µg/mL. Then add an equal volume of the clavulanic acid 40 µg/mL solution to each diluted tube of ticarcillin. For example, 5 mL of 2560 µg/mL ticarcillin + 5 mL of 40 µg/mL clavulanic acid = 10 mL of 1280/20 µg/mL ticarcillin-clavulanic acid. Dilute 1:10 with broth to achieve the final concentration in microdilution wells.

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Prepare 10× starting concentration of ticarcillin at twice the concentration needed and dilute as usual using serial twofold dilutions. Add an equal volume of clavulanic acid 40 µg/mL to each of the diluted tubes.

Example For a starting concentration of 128/64 in the panel, prepare a 10× stock concentration of 2560 µg/mL for amoxicillin and 1280 µg/mL for clavulanic acid. Then combine equal amounts of each to the first dilution tube, which will then contain 1280/640 µg/mL of the combination. Dilute 1:10 with broth to achieve the final concentration in microdilution wells.

January 2010

Table 5B. Preparation of Solutions and Media Containing Combinations of Antimicrobial Agents

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Antimicrobial Agent Trimethoprimsulfamethoxazole

Quinupristindalfopristin

Combination Tested 1:19 ratio (trimethoprim:sulfamethoxazole)

Preparation Prepare a 10× starting concentration of trimethoprim at 1600 µg/mL (or at 1280 µg/mL that will require dilution to 160 µg/mL). Prepare a 10× starting concentration of sulfamethoxazole at a log2 multiple of 1520 µg/mL (eg, 1520, 3040, or 6080 µg/mL) depending on the starting concentration needed.

Example For a starting concentration of 8/152 in the panel, prepare a 10× concentration of trimethoprim at 160 µg/mL. Prepare a 10× starting concentration of sulfamethoxazole at 3040 µg/mL. Add an equal volume of the 160 µg/mL trimethoprim and the 3040 µg/mL sulfamethoxazole to the first dilution tube and then dilute by serial twofold dilutions as usual. For example, 5 mL of 160 µg/mL trimethoprim and 5 mL of 3040 µg/mL sulfamethoxazole = 10 mL of 80/1520 trimethoprimsulfamethoxazole. Dilute 1:10 with broth to achieve the final concentration in microdilution wells.

Preparation usually not required because drug powder is received as combination.

For Use With M07-A8—MIC Testing

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Table 5B. (Continued)

Linopristinflopristin NOTE: To prepare intermediate dilutions of antimicrobial agents, a convenient formula to use is C1 ×V1 = C2 × V2, where C1 is the concentration of stock solution of the antimicrobial agent (usually 1280 µg/mL or greater); V1 is the unknown volume that will be needed to make the intermediate concentration; C2 is the intermediate concentration needed; and V2 is the volume of the intermediate stock solution needed. For example: To prepare 20 mL of a 40 µg/mL solution from a 1280 µg/mL stock solution: C1 × V1 = C2 × V2 1280 µg/mL × V1 = 40 µg/mL × 20 mL V1 = 40 µg/mL × 20 mL 1280 µg/mL V1 = 0.625 mL Therefore, add 0.625 mL of the 1280 µg/mL stock solution to 19.375 mL of diluent (usually water) for a final volume of 20 mL of a 40 µg/mL solution.

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Table 5B Solutions and Media M07

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Table 6. Scheme for Preparing Dilutions of Antimicrobial Agents to Be Used in Agar Dilution Susceptibility Tests Antimicrobial Solution

Step

Table 6 Dilution Scheme for Agar Dilution Tests M07

1 2 3 4 5 6 7 8 9 10 11 12

Concentration (μg/mL) 5120 5120 5120 5120 640 640 640 80 80 80 10 10 10

Source Stock Stock Stock Stock Step 3 Step 3 Step 3 Step 6 Step 6 Step 6 Step 9 Step 9 Step 9

Volume (mL) – 2 1 1 2 1 1 2 1 1 2 1 1

Diluent (mL) – 2 3 7 2 3 7 2 3 7 2 3 7

Intermediate Concentration (μg/mL) 5120 2560 1280 640 320 160 80 40 20 10 5 2.5 1.25

Final Concentration at 1:10 Dilution in Agar (μg/mL) 512 256 128 64 32 16 8 4 2 1 0.5 0.25 0.125

Log2 9 8 7 6 5 4 3 2 1 0 −1 −2 −3

NOTE: This table is modified from Ericsson HM, Sherris JC. Antibiotic sensitivity testing. Report of an international collaborative study. Acta Pathol Microbiol Scand. 1971;217 (suppl B):1-98.

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Table 7. Scheme for Preparing Dilutions of Antimicrobial Agents to Be Used in Broth Dilution Susceptibility Tests Antimicrobial Solution b

Step

Concentration (μg/mL)

Volume (mL)

Source

CAMHB Volumea (mL)

a

+

=

Final Concentration (μg/mL)

Log2

1

5120

Stock

1

9

512

9

2 3 4 5 6 7 8 9 10 11 12 13

512 512 512 64 64 64 8 8 8 1 1 1

Step 1 Step 1 Step 1 Step 4 Step 4 Step 4 Step 7 Step 7 Step 7 Step 10 Step 10 Step 10

1 1 1 1 1 1 1 1 1 1 1 1

1 3 7 1 3 7 1 3 7 1 3 7

256 128 64 32 16 8 4 2 1 0.5 0.25 0.125

8 7 6 5 4 3 2 1 0 −1 −2 −3

NOTE: This table is modified from Ericsson HM, Sherris JC. Antibiotic sensitivity testing. Report of an international collaborative study. Acta Pathol Microbiol Scand. 1971;217 (suppl B):1-90. Footnotes The volumes selected can be any multiple of these figures, depending on the number of tests to be performed.

b.

Adjustment with cations, if necessary, occurs before this step.

Table 7 Dilution Scheme for Broth Dilution Tests M07

a.

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Table 7A. Scheme for Preparing Dilutions of Water-Insoluble Agents to Be Used in Broth Dilution Susceptibility Tests Antimicrobial Solution

Step 1 2 3 4 5 6 7 8 9 10 11 12 13 14

Concentration (µg/mL) 1600 1600 1600 1600 200 200 200 25 25 25 3.1 3.1 3.1 0.4

Source Stock Stock Stock Stock Step 4 Step 4 Step 4 Step 7 Step 7 Step 7 Step 10 Step 10 Step 10 Step 13

Volume (mL) 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5

+

Solvent (mL) (eg, DMSO*) 0.5 1.5 3.5 0.5 1.5 3.5 0.5 1.5 3.5 0.5 1.5 3.5 0.5

Intermediate Concentration (μg/mL) = 1600 800 400 200 100 50 25 12.5 6.25 3.1 1.6 0.8 0.4 0.2

=

Final Concentration at 1:100 (μg/mL) 16 8.0 4.0 2.0 1.0 0.5 0.25 0.125 0.0625 0.03 0.016 0.008 0.004 0.002

Log2 4 3 2 1 0 −1 −2 −3 −4 −5 −6 −7 −8 −9

Table 7A Broth Dilution Tests M07

*Dimethyl sulfoxide

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Appendix A Suggested Test Result Verification and Organism Identification

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Appendix A. Suggestions for Verification of Antimicrobial Susceptibility Test Results and Confirmation of Organism Identification This table reflects the drugs listed for testing against the respective organisms in Tables 2A through 2J and gives some examples to consider for verification protocols at a given institution. The list includes phenotypes that 1) have never been documented; 2) are uncommon in some geographic areas; and/or 3) represent results that could easily occur from technical errors and that may have significant clinical consequences. NOTE: For critical results, communicate preliminary findings to the laboratory director or supervisor.

Category Ia Phenotypes That Have Not Been Reported, Are Uncommon, and/or Organism or Group Result From Technical Errors Gram-negative organisms Carbapenem – I or R Enterobacteriaceae (any) Ampicillin, cefazolin, or Citrobacter freundii Enterobacter spp. cephalothin – S Serratia marcescens Escherichia coli Klebsiella spp. Ampicillin – S Ampicillin – S Proteus vulgaris Providencia spp. Salmonella spp. Pseudomonas aeruginosa Stenotrophomonas maltophilia Haemophilus influenzae

Neisseria gonorrhoeae Neisseria meningitidis

Any organism

138

Carbapenem – S Aztreonam – NS Carbapenem – NS 3rd-Generation cephalosporinc – NS Fluoroquinolone – NS 3rd-Generation cephalosporin – NS

Category IIb Phenotypes That May Be Uncommon at a Given Institution and/or Result From Technical Errors

Amikacin – R Fluoroquinolone – R

ESBL confirmed positive ESBL confirmed positive 3rd-Generation cephalosporin – I or Rd fluoroquinolone I or R or nalidixic acid – Rd Concurrent gentamicin and tobramycin and amikacin – R Trimethoprim-sulfamethoxazole – R Ampicillin – R and β-lactamase-negative amoxicillin-clavulanic acid – R Fluoroquinolone – R

Azithromycin – NS 3rd-Generation cephalosporinc – NS Meropenemc – NS Minocycline c – NS Chloramphenicol – I or R Fluoroquinolones – I or R Rifampin – I or R Resistant to all agents routinely tested

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Appendix A. (Continued) a

Category I Phenotypes That Have Not Been Reported, Are Uncommon, and/or Result From Technical Errors

Organism or Group Gram-positive organisms Enterococcus spp. Daptomycin – NS Ampicillin or penicillin – R E. faecalis Daptomycin – NS Linezolid – R Quinupristin-dalfopristin – S Daptomycin – NS E. faecium Linezolid – R

S. aureus

Staphylococcus, coagulase-negative S. pneumoniae Streptococcus, beta group

Streptococcus, viridans group Any organism

Daptomycin – NS Linezolid – NS Quinupristin-dalfopristin – I or R Vancomycin – I or R Daptomycin – NS Linezolid – NS Vancomycin – I or R Fluoroquinolone – R Linezolidc – NS Vancomycinc – NS Ampicillin or penicillinc – NS 3rd-Generation cephalosporinc – NS Daptomycinc – NS Linezolidc – NS Vancomycinc – NS Daptomycinc – NS Linezolid – NS Vancomycinc – NS Resistant to all agents routinely tested

Category IIb Phenotypes That May Be Uncommon at a Given Institution and/or Result From Technical Errors Vancomycin – R High-level aminoglycoside – R (particularly if isolate from sterile body site) High-level aminoglycoside – R (particularly if isolate from sterile body site) Quinupristin-dalfopristin – R Oxacillin – R

Penicillin – R 3rd-Generation cephalosporin – R

Penicillin – I or R

Footnotes Category I When results listed in this category are observed on individual patient isolates, they should be verified by one or more of the following: 1. Ensuring that the unusual results are not due to transcription errors, contamination, or use of a defective panel, plate, or card. 2. Checking previous reports on the patient to determine if the isolate was encountered and verified earlier. 3. Confirming the identification of the isolate. 4. Repeating the susceptibility test to confirm results. Sometimes, it is helpful to use an alternative test method for the repeat test. 5. For isolates that show results other than susceptible for those antimicrobial agents for which only susceptible interpretive criteria are provided in Tables 2A to 2J (listed with an “NS” above) and for staphylococci with vancomycin-intermediate or vancomycin-resistant results: 1) confirm the organism identification; 2) confirm the antimicrobial susceptibility test results; 3) save the isolate; and 4) submit the isolate to a reference laboratory that will test it by a CLSI reference dilution method.

a

b

Category II When results listed in this category are observed on individual patient isolates, the verification steps as outlined for Category I should be considered if the resistance is uncommon in a given institution.

c

For these antimicrobial agent/organism combinations, resistance has not been documented to date.

d

When submitting reports to a public health laboratory, include antimicrobial susceptibility results for Salmonella spp. that are intermediate or resistant to 3rd-generation cephalosporins and/or intermediate or resistant to fluoroquinolone or resistant to nalidixic acid. ©

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Appendix A Suggested Test Result Verification and Organism Identification

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Appendix B Quality Control Strains

Appendix B. Quality Control Strains for Antimicrobial Susceptibility Tests

E. faecalis ATCC® 51299 E. coli ® ATCC 25922

E. coli ® ATCC 35218 H. influenzae ATCC® 49247 H. influenzae ATCC® 49766

Organism Characteristics

• Resistant to vancomycin (VanB) and high-level aminoglycosides • β-Lactamase negative

• β-lactam/β-lactamase inhibitor combinations • Haemophilus spp.

• Haemophilus spp.

• Ampicillin susceptible

• Haemophilus spp. (more reproducible with selected βlactams)

• Contains SHV-18 ESBLb,e,f

• ESBL screen and confirmatory tests • N. gonorrhoeae

• Haemophilus spp. (more reproducible with selected βlactams) • H. pylori • ESBL screen and confirmatory tests • N. gonorrhoeae

• β-Lactamase negative • mecA Negative • Little value in MIC testing due to its extreme susceptibility to most drugs

Other • Assess suitability of medium for sulfonamide or trimethoprim MIC testsd

• Vancomycin agar HLAR

• Contains plasmid-encoded TEM-1 β-lactamase (nonESBL)a,b,e,f • BLNAR

• CMRNG, chromosomally mediated penicillin resistant • Contains inducible AmpC β-lactamase

Screening Tests • Vancomycin agar HLAR

• Nonfastidious gramnegative bacteria • Neisseria meningitidis

• Nonfastidious gramnegative bacteria

• Nonfastidious gramnegative bacteria • Potential agents of bioterrorism

• Assess suitability of cation content in each batch/lot of MuellerHinton for gentamicin MIC and disk diffusion

• Nonfastidious grampositive bacteria

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S. aureus ATCC® 25923

MIC Tests • Nonfastidious grampositive bacteria

• Nonfastidious gramnegative bacteria • Neisseria meningitidis • Potential agents of bioterrorism • β-Lactam/β-lactamase inhibitor combinations

©

H. pylori ATCC® 43504 K. pneumoniae ® ATCC 700603 N. gonorrhoeae ATCC® 49226 P. aeruginosa ® c ATCC 27853

Disk Diffusion Tests

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140

Quality Control Strain E. faecalis ATCC® 29212

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Organism Characteristics • Weak β-lactamase producing strain • mecA negative

Quality Control Strain S. aureus ® ATCC 29213

Disk Diffusion Tests

• Oxacillin-resistant, mecA positive • High-level mupirocin resistance mediated by the mupA gene • Penicillin intermediate by altered penicillinbinding protein

S. aureus ® ATCC 43300 S. aureus ® ATCC BAA-1708 S. pneumoniae ® ATCC 49619

MIC Tests • Nonfastidious grampositive bacteria • Potential agents of bioterrorism

Screening Tests • Oxacillin agar

• Cefoxitin disk testing

• Cefoxitin MIC testing

• Oxacillin agar

• Screening test for highlevel mupirocin resistance

• Screening test for highlevel mupirocin resistance

• S. pneumoniae • Streptococcus spp. • N. meningitidis

• • • •

g

Other • Assess suitability of cation content in each batch/lot of MuellerHinton for daptomycin disk diffusion

S. pneumoniae Streptococcus spp. N. meningitidis Potential agents of bioterrorism

Supplemental QC Strains E. faecalis ® ATCC 33186

For Use With M02-A10 and M07-A8

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Appendix B. (Continued)

• Alternative to E. faecalis ® ATCC 29212 to assess suitability of medium for sulfonamide or d trimethoprim MIC tests • Assess each batch/lot for growth capabilities of HTM

H. influenzae ® ATCC 10211 • KPC-producing strain • Modified Hodge test positive

K. pneumoniae ® ATCC BAA-1706

• Resistant to carbapenems by mechanisms other than carbapenemase • Modified Hodge test negative

S. aureus ® ATCC BAA-976

• Contains msrAmediated macrolideonly resistance

S. aureus ® ATCC BAA-977

• Contains inducible ermA-mediated resistance

b

• Phenotypic confirmatory test for carbapenemase production (modified Hodge test) • Phenotypic confirmatory test for carbapenemase production (modified Hodge test)

141

• Assess disk approximation tests with erythromycin and clindamycin (D-zone test negative) • Assess disk approximation tests with erythromycin and clindamycin (D-zone test positive)

• QC – see Tables 2C-S3, 2C-S4, 3, and 4

• Routine QC for inducible clindamycin test by MIC method – see Tables 2CS3, 2C-S4, 3, and 4

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K. pneumoniae ® ATCC BAA-1705

Appendix B Quality Control Strains

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Appendix B Quality Control Strains

Footnotes a

b

c d e ©

f

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® E. coli ATCC 35218 is recommended only as a control organism for β-lactamase inhibitor combinations, such as those containing clavulanic acid, sulbactam, or tazobactam. This strain contains a plasmid-encoded β-lactamase (non-ESBL); subsequently, the organism is resistant to many penicillinase-labile drugs but susceptible to β-lactam/β-lactamase inhibitor combinations. The plasmid must be present in the QC strain for the QC test to be valid; however, the plasmid may be lost during storage at refrigerator or freezer temperatures. To ensure the plasmid is present, test the strain with a β-lactam agent alone (either ampicillin, amoxicillin, piperacillin, or ticarcillin) in addition to a β-lactam/β-lactamase inhibitor agent (eg, amoxicillin-clavulanate). If the strain loses the plasmid, it will be susceptible to the β-lactam agent when tested alone, indicating that the QC test is invalid and a new culture of E. coli ATCC® 35218 must be used. Careful attention to organism maintenance (eg, minimal subcultures) and storage (eg, −60 °C or below) is especially important for QC strains E. coli ATCC® 35218, K. pneumoniae ATCC® 700603, and K. pneumoniae ATCC® BAA-1705, because spontaneous loss of the plasmid encoding the βlactamase or carbapenemase has been documented. Plasmid loss leads to QC results outside the acceptable limit, such as decreased MICs for E. coli ATCC® 35218 with enzyme-labile penicillins (eg, ampicillin, piperacillin, and ticarcillin), decreased MICs for K. pneumoniae ATCC® 700603 with cephalosporins and aztreonam, and false-negative modified Hodge test (MHT) with K. pneumoniae ATCC® BAA-1705. Develops resistance to β-lactam antimicrobial agents after repeated transfers onto laboratory media. Minimize by removing new culture from storage at least monthly or whenever the strain begins to show resistance. End points should be easy to read (as 80% or greater reduction in growth as compared with the control) if media have acceptable levels of thymidine. Rasheed JK, Anderson GJ, Yigit H, et al. Characterization of the extended-spectrum beta-lactamase reference strain, Klebsiella pneumoniae K6 ® (ATCC 700603), which produces the novel enzyme SHV-18. Antimicrob Agents Chemother. 2000;44:2382-2388. Queenan AM, Foleno B, Gownley C, Wira E, Bush K. Effects of inoculum and beta-lactamase activity in AmpC- and extended-spectrum betalactamase (ESBL)-producing Escherichia coli and Klebsiella pneumoniae clinical isolates tested by using NCCLS ESBL methodology. J Clin Microbiol. 2004;42:269-275. QC strains are tested regularly (eg, daily or weekly) to ensure the test system is working and produces results that fall within specified limits listed in M100. The QC strains recommended in this document should be included if a laboratory performs CLSI reference disk diffusion or MIC testing as described herein. For commercial test systems, manufacturer’s recommendations should be followed for all QC procedures. Supplemental QC strains are used to assess particular characteristics of a test or test system in select situations or may represent alternative QC strains. For example, Haemophilus influenzae ATCC® 10211 is more fastidious than H. influenzae ATCC® 49247 or H. influenzae ATCC® 49766, and is used to ensure HTM can adequately support the growth of clinical isolates of H. influenzae and H. parainfluenzae. Supplemental QC strains may possess susceptibility or resistance characteristics specific for one or more special tests listed in M02-A10 and M07-A8. They can be used to assess a new test, for training new personnel, for competency assessment, etc. It is not necessary to include supplemental QC strains in routine daily or weekly AST QC programs.

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142

Appendix B. (Continued)

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Percent Susceptible (%S) and Percent Resistant (%R) Breakpoints in µg/mL

%S

%R

≤ 8/4

≥ 32/16

%S

%R

≤ 32/4 ≥ 128/4

Metronidazoleb

Moxifloxacin

Clindamycin

Meropenem

Imipenem

Ertapenem

Cefoxitin

Piperacillintazobactam

Ampicillinsulbactam

Anaerobic Organisms

Number of Strains

Isolates collected from US hospitals 1 January 2006 – 31 December 2008

%S

%R

%S

%R

%S

%R

%S

%R

%S

%R

%S

%R

%S

%R

≤ 16

≥ 64

≤4

≥ 16

≤4

≥ 16

≤4

≥ 16

≤2

≥8

≤2

≥8

≤8

≥ 32

89

3

98

2

82

7

96

2

98

2

97

2

78

18

59

32

100

0

B. thetaiotaomicron Parabacteroides (Bacteroides) distasonis

217

85

3

92

2

32

15

97

1

99

0

99

1

42

42

39

41

100

0

81

68

12

94

2

40

12

94

0

99

0

99

0

36

41

48

43

100

0

B. ovatus

61

92

0

100

0

41

13

98

0

100

0

100

0

56

39

13

70

100

0

B. vulgatus

44

75

5

100

0

82

9

98

2

100

0

98

2

50

50

26

57

100

0

B. uniformis

43

93

2

91

0

51

12

98

0

100

0

100

0

43

49

33

49

100

0

B. eggerthii

32

91

3

100

0

47

0

100

0

100

0

100

0

38

59

22

59

100

0

B. fragilis group without B. fragilis

478

83

4

93

1

42

13

97

1

100

0

99

1

38

51

33

50

100

0

B. fragilis group (all 7 species listed)

1083

86

4

95

2

64

10

96

2

98

1

97

2

56

37

47

41

100

0

 

605

143

Data were generated from unique isolates from patient specimens submitted to three referral laboratories: Tufts New England Medical Center, Boston, MA; Loyola University Medical Center, Maywood, IL; and R.M. Alden Research Laboratory, Culver City, CA. Testing was performed by the agar dilution method. b Resistance to metronidazole occurs infrequently.

Appendix C Cumulative Susceptibility copyright laws. Report for B. fragilis Group

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Appendix C. Cumulative Antimicrobial Susceptibility Report for Bacteroides fragilis Group Organisms

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Glossary I (Part 1). β-Lactams: Class and Subclass Designation and Generic Name Antimicrobial Class

Penicillins

e

Antimicrobial Subclass a Penicillin a Aminopenicillin Ureidopenicillin

a

a

Carboxypenicillin

Penicillinase-stable b penicillins

Amidinopenicillin β-Lactam/β-lactamase inhibitor combinations Cephems (parenteral)

c,e

Cephalosporin I

Cephalosporin II

c,e

Cephalosporin III

c,e

c,e

Cephalosporin IV Cephalosporins with anti-MRSA activity d Cephamycin

Glossary I

Cephems (oral)

Monobactams Penems

e

Oxacephem e Cephalosporin

Carbacephem Carbapenem

Penem a

Agents Included; Generic Names Penicillin Amoxicillin Ampicillin Azlocillin Mezlocillin Piperacillin Carbenicillin Ticarcillin Cloxacillin Dicloxacillin Methicillin Nafcillin Oxacillin Mecillinam Amoxicillin-clavulanic acid Ampicillin-sulbactam Piperacillin-tazobactam Ticarcillin-clavulanic acid Cefazolin Cephalothin Cephapirin Cephradine Cefamandole Cefonicid Cefuroxime (parenteral) Cefoperazone Cefotaxime Ceftazidime Ceftizoxime Ceftriaxone Cefepime Ceftaroline Ceftobiprole Cefmetazole Cefotetan Cefoxitin Moxalactam Cefaclor Cefadroxil Cefdinir Cefditoren Cefetamet Cefixime Cefpodoxime Cefprozil Ceftibuten Cefuroxime (oral) Cephalexin Cephradine Loracarbef Aztreonam Doripenem Ertapenem Imipenem Meropenem Razupenem Faropenem Sulopenem

Penicillinase labile; hydrolyzed by staphylococcal penicillinase. Not hydrolyzed by staphylococcal penicillinase. c Cephalosporin I, II, III, and IV are sometimes referred to as 1st-, 2nd-, 3rd-, and 4th-generation cephalosporins, respectively. Cephalosporin III and IV are also referred to as “extended-spectrum cephalosporins.” This does not imply activity against ESBLproducing gram-negative bacteria. d Although often referred to as a 2nd-generation cephalosporin, cephamycins are not included with the other cephalosporins with regard to reporting of ESBL-producing strains. e For all confirmed ESBL-producing strains, the test interpretation should be reported as resistant for this antimicrobial class or subclass. b

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Glossary I (Part 2). Non–β-lactams: Class and Subclass Designation and Generic Name Antimicrobial Subclass

Aminoglycosides

Ansamycins Quinolones

Quinolone Fluoroquinolone

Folate pathway inhibitors

Fosfomycins Glycopeptides

Glycopeptide Lipoglycopeptide

Glycylcyclines Ketolides Lincosamides Lipopeptides Polymyxins Macrolides

Nitrofurans Nitroimidazoles Oxazolidinones Phenicols Pseudomonic acid Streptogramins Tetracyclines

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Agents Included; Generic Names Spectinomycin Trospectinomycin Amikacin Gentamicin Kanamycin Netilmicin Streptomycin Tobramycin Rifampin Cinoxacin Garenoxacin Nalidixic acid Besifloxacin Ciprofloxacin Clinafloxacin Enoxacin Fleroxacin Gatifloxacin Gemifloxacin Grepafloxacin Levofloxacin Lomefloxacin Moxifloxacin Norfloxacin Ofloxacin Sparfloxacin Trovafloxacin Ulifloxacin (prulifloxacin) Iclaprim Sulfonamides Trimethoprim Trimethoprim-sulfamethoxazole Fosfomycin Vancomycin Dalbavancin Oritavancin Teicoplanin Telavancin Tigecycline Telithromycin Clindamycin Daptomycin Colistin Polymyxin B Azithromycin Clarithromycin Dirithromycin Erythromycin Nitrofurantoin Metronidazole Linezolid Chloramphenicol Mupirocin Linopristin-flopristin Quinupristin-dalfopristin Doxycycline Minocycline Tetracycline

Glossary I

Antimicrobial Class Aminocyclitols

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Glossary II. Abbreviations/Routes of Administration/Drug Class for Antimicrobial Agents Listed in M100-S20 Antimicrobial Agent Amikacin Amoxicillin Amoxicillin-clavulanic acid Ampicillin Ampicillin-sulbactam Azithromycin Azlocillin Aztreonam Besifloxacin Carbenicillin (indanyl salt) Carbenicillin Cefaclor Cefadroxil Cefamandole Cefazolin Cefdinir Cefditoren Cefepime Cefetamet Cefixime Cefmetazole Cefonicid Cefoperazone Cefotaxime Cefotetan Cefoxitin Cefpodoxime Cefprozil Ceftaroline Ceftazidime Ceftibuten Ceftizoxime Ceftobiprole Ceftriaxone Cefuroxime (oral)

Glossary II

Cefuroxime (parenteral) Cephalexin Cephalothin

146

Agent Abbreviationa

AN, AK, Ak, AMI, AMK AMX, Amx, AMOX, AC AMC, Amc, A/C, AUG, Aug, XL, AML AM, Am, AMP SAM, A/S, AMS, AB AZM, Azi, AZI, AZ AZ, Az, AZL ATM, AZT, Azt, AT, AZM BES CB, Cb, BAR

Routes of Administrationb Topical PO IM IV X X

Aminoglycoside

X

Penicillin

X

β-Lactam/β-lactamase Inhibitor Penicillin β-Lactam/β-lactamase Inhibitor Macrolide Penicillin Monobactam

X

X

X X

X X X X X X

X X

CEC, CCL, Cfr, FAC, CF CFR, FAD MA, CM, Cfm, FAM CZ, CFZ, Cfz, FAZ, KZ CDR, Cdn, DIN, CD, CFD CDN FEP, Cpe, PM, CPM CAT, FET CFM, FIX, Cfe, IX CMZ, CMZS, CMT CID, Cfc, FON, CPO CFP, Cfp, CPZ, PER, FOP, CP CTX, TAX, Cft, FOT, CT CTT, CTN, Ctn, CTE, TANS, CN FOX, CX, Cfx, FX CPD, Cpd, POD, PX CPR, CPZ, FP CPT CAZ, Caz, TAZ, TZ CTB, TIB, CB ZOX, CZX, CZ, Cz, CTZ, TIZ BPR CRO, CTR, FRX, Cax, AXO, TX CXM, CFX, ROX, Crm, FUR, XM CN, LEX, CFL CF, Cf, CR, CL, CEP, CE, KF

Drug Class

Fluoroquinolone Penicillin

X

X

Cephem

X

Cephem Cephem Cephem Cephem

X X

X X

X

X

X X X

X X X

Cephem Cephem Cephem Cephem Cephem Cephem Cephem

X X

X X

Cephem Cephem

X

X

X

X X

X

X

Cephem Cephem Cephem Cephem Cephem Cephem Cephem

X

X X

Cephem Cephem

X X X X

X X

X

X

Cephem X

X

X X

©

Cephem Cephem

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Glossary II. (Continued)

Cephapirin Cephradine Chloramphenicol Cinoxacin Ciprofloxacin Clarithromycin Clinafloxacin Clindamycin Colistin Dalbavancin Daptomycin Dicloxacillin Dirithromycin Doripenem Ertapenem Erythromycin Faropenem Fleroxacin Fosfomycin Garenoxacin Gatifloxacin Gemifloxacin Gentamicin Gentamicin synergy Grepafloxacin Iclaprim Imipenem Kanamycin Levofloxacin Linezolid Linopristinflopristin Lomefloxacin Loracarbef Mecillinam Meropenem Methicillin Mezlocillin Minocycline Moxalactam Moxifloxacin Mupirocin Nafcillin Nalidixic acid Netilmicin Nitrofurantoin Norfloxacin Ofloxacin Oritavancin Oxacillin

©

a

Agent Abbreviation

CP, HAP RAD, CH C, CHL, CL CIN, Cn CIP, Cp, CI CLR, CLM, CLA, Cla, CH CFN, CLX, LF CC, CM, CD, Cd, CLI, DA CL, CS, CT DAL DAP DX, DIC DTM, DT DOR ETP E, ERY, EM FAR, FARO FLE, Fle, FLX, FO FOS, FF, FO, FM GRN GAT GEM GM, Gm, CN, GEN GM500, HLG, Gms GRX, Grx, GRE, GP ICL IPM, IMI, Imp, IP K, KAN, HLK, KM LVX, Lvx, LEV, LEVO, LE LNZ, LZ, LZD LFE LOM, Lmf LOR, Lor, LO MEC MEM, Mer, MERO, MRP, MP DP, MET, ME, SC MZ, Mz, MEZ MI, MIN, Min, MN, MNO, MC, MH MOX MXF MUP, MOP, MU NF, NAF, Naf NA, NAL NET, Nt, NC F/M, FD, Fd, FT, NIT, NI, F NOR, Nxn, NX OFX, OFL, Ofl, OF ORI OX, Ox, OXS, OXA

Routes of Administrationb Topical PO IM IV X X X X X X X X X X X

X

X X X X X

X X X X X X X

X X X X X

Fluoroquinolone Folate pathway inhibitor Carbapenem Aminoglycoside Fluoroquinolone

X X X X X X

X X X X X X

Cephem Cephem Phenicol Quinolone Fluoroquinolone Macrolide Fluoroquinolone Lincosamide Lipopeptide Glycopeptide Lipopeptide Penicillin Macrolide Carbapenem Carbapenem Macrolide Penem Fluoroquinolone Fosfomycin Quinolone Fluoroquinolone Fluoroquinolone Aminoglycoside

X X X

Drug Class

X

Oxazolidinone Streptogramin

X X X X

Fluoroquinolone Cephem Penicillin Carbapenem

X X

X X X

Penicillin Penicillin Tetracycline

X

X X

X

X

X

X

Cephem Fluoroquinolone Pseudomonic acid Penicillin Quinolone Aminoglycoside Nitrofurantoin

X X

X

X

X

X X X

X X

X X X

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Fluoroquinolone Fluoroquinolone Lipoglycopeptide Penicillin

Glossary II

Antimicrobial Agent

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Vol. 30 No. 1 Agent Abbreviationa

Penicillin Piperacillin Piperacillin-tazobactam

P, PEN, PV PIP, PI, PP, Pi TZP, PTZ, P/T, PTc

Polymyxin B Quinupristin-dalfopristin Razupenem Rifampin Sparfloxacin Spectinomycin Streptomycin

PB SYN, Syn, QDA, RP RZM RA, RIF, Rif, RI, RD SPX, Sfx, SPA, SO SPT, SPE, SC S, STR, StS, SM, ST2000, HLS SSS, S3

Streptomycin synergy Sulfonamides Sulopenem Teicoplanin Telavancin Telithromycin Tetracycline Ticarcillin Ticarcillin-clavulanic acid Tigecycline Tobramycin Trimethoprim Trimethoprimsulfamethoxazole Trospectinomycin Trovafloxacin Ulifloxacin (prulifloxacin) Vancomycin

Routes of Administrationb PO IM IV X X X X X X X X X X

X X X X X

SLP, SULO TEC, TPN, Tei, TEI, TP, TPL TLV TEL TE, Te, TET, TC TIC, TC, TI, Ti TIM, Tim, T/C, TCC, TLc

X X X

X X

X X X

X X X

TGC NN, TM, TO, To, TOB TMP, T, TR, W

X

SXT, SxT, T/S, TS, COT

X

TVA, Tva, TRV, TV PRU VA, Va, VAN

X X X

X

X X X X X X

X

X X X

Drug Class Penicillin Penicillin β-Lactam/βlactamase inhibitor combination Lipopeptide Streptogramin Carbapenem Ansamycin Fluoroquinolone Aminocyclitol Aminoglycoside Folate pathway antagonist (some PO only) Penem Glycopeptide Glycopeptide Ketolide Tetracycline Penicillin β-Lactam/βlactamase inhibitor Glycylcycline Aminoglycoside Folate pathway inhibitor Folate pathway inhibitor Aminocyclitol Fluoroquinolone Fluoroquinolone Glycopeptide

Glossary II

PO = per OS (oral); IM = intramuscular; IV = intravenous. a Abbreviations assigned to one or more diagnostic products in the United States. If no diagnostic product is available, abbreviation is that of the manufacturer. b As available in the United States.

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Agent Abbreviation AZM AZ CB, Cb CFR, Cfr CF, Cf CM CFM, Cfm CZ, Cz CD, Cd CPZ CP, Cp CN, Cn CFX, Cfx CL CH DX FO SC SO TC

©

Glossary III

Glossary III. List of Identical Abbreviations Used for More Than One Antimicrobial Agent in US Diagnostic Products Antimicrobial Agents for Which Respective Abbreviation Is Used Azithromycin, Aztreonam Azithromycin, Azlocillin Ceftibuten, Carbenicillin Cefaclor, Cefadroxil Cefaclor, Cephalothin Clindamycin, Cefamandole Cefixime, Cefamandole Ceftizoxime, Cefazolin Clindamycin, Cefdinir Cefprozil, Cefoperazone Cephapirin, Cefoperazone, Ciprofloxacin Cephalexin, Cefotetan, Cinoxacin, Gentamicin Cefoxitin, Cefuroxime Cephalothin, Chloramphenicol Clarithromycin, Cephradine Doxycycline, Dicloxacillin Fleroxacin, Fosfomycin Spectinomycin, Methicillin Sparfloxacin, Oxacillin Tetracycline, Ticarcillin

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Vol. 30 No. 1

Clinical and Laboratory Standards Institute consensus procedures include an appeals process that is described in detail in Section 8 of the Administrative Procedures. For further information, contact CLSI or visit our website at www.clsi.org.

Summary of Comments and Subcommittee Responses M100-S19: Performance Standards for Antimicrobial Susceptibility Testing; Nineteenth Informational Supplement NOTE: All comments received are answered by the subcommittee and the responses are published in M02 and M07. Between the three-year cycle of text revisions, any comments received are published in M100. All comments are then published in the next revisions of M02 and M07. 1.

The CLSI standard says that organisms should be taken from noninhibitory media such as TSA blood plates for AST. What other media are acceptable, eg, CAN, choc, PEA? Not EMB/MAC, I presume. I believe some manufacturers of selective media state that AST can be done directly from those plates. This may be worth clarifying in the CLSI documents.

•

Only nonselective media, eg, blood and chocolate agar, should be used to prepare inoculum for CLSI reference methods. We have no data that would support the use of selective media for inoculum preparation. Users of commercial systems should follow the manufacturer’s recommendations for media requirements for inoculum preparation.

2.

In the CLSI standards (M100-S18) in the MIC QC tables (pp. 142–145), the ranges quoted for the specific organisms have two sections for amoxicillin/clavulanic acid (eg, ATCC 29213 0.12/0.06–0.5/0.25 and in the M11-A6 ATCC 25285 0.25/0.125–1/0.5. Can you please tell me what the two values relate to? I can find nothing in the footnotes for any of the compounds that are quoted in this way—does the explanation for the amoxicillin/clavulanic acid apply to other compounds eg, piperacillin/tazobactam, trimethoprim/ sulfamethoxazole, and ampicillin/sulbactam and ticarcillin/clavulanic acid.

•

A new table (Table 5B) was added to M100-S20 that explains the preparation of combinations of antimicrobial agents.

3.

Where in the documents would I find the information about the ratios/concentrations of β-lactamase inhibitors to be used in the β-lactam/β-lactamase inhibitor combinations (eg, testing amoxicillin/clavulanic at 2:1 vs piperacillin/tazobactam at constant 4 ug/mL)? I have been searching in both M07 and M100 but I cannot find where it is spelled out. The only reference I see is the QC tables, where they give the double concentrations, but it is not obvious for someone who does not know how to test them.

•

See the response to comment 2 above.

4.

In Table 2D for enterococci, it currently states that ampicillin susceptibility can be used to predict imipenem susceptibility providing that the species is confirmed to be E. faecalis. Can we use the ampicillin results to predict results for other carbapenems?

•

No. No data are available that correlate in vitro susceptibility of ampicillin with that of doripenem, ertapenem, or meropenem for enterococci.

5.

Is the acceptable range appropriate for an antimicrobial agent and quality control strain when it encompasses the susceptible, intermediate, and resistant interpretive categories?

•

Interpretive criteria are established to interpret results with clinical isolates and are independent from acceptable QC ranges. Thus, it is possible for a QC range to overlap the S, I, and R breakpoints.

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M100-S20

The “routine” QC strains (E. coli ATCC® 25922, P. aeruginosa ATCC® 27853) have been historically used wherever possible to minimize the number of QC strains that need to be maintained and tested. Some QC strains are selected based on their expression of resistance (eg, Klebsiella pneumoniae ATCC® 700603 for ESBL, Staphylococcus aureus ATCC® BAA-976 for inducible clindamycin resistance). The purpose of testing QC strains is to ensure that the reagents are reliable and the test is performed accurately. The important question for QC strains is whether or not the result is within the acceptable range, not whether the interpretive category is S, I, or R. For additional information on the characteristics of QC strains, refer to Appendix F in CLSI document M100-S19 (now Appendix B in CLSI document M100-S20). 6.

There are now acceptable ranges listed for ampicillin, piperacillin, and ticarcillin with E. coli ATCC® 35218 in Table 4. Is a laboratory expected to test all of these antimicrobial agents with E. coli ATCC® 35218 and, if so, with what frequency?

•

According to M100-S19, Appendix F (now Appendix B in M100-S20, footnote a), E. coli ATCC® 35218 is recommended as a QC strain when β-lactam/β-lactamase inhibitor combinations are tested. The plasmid-encoded β-lactamase with this strain may be lost during storage. To ensure that the plasmid has not been lost (and the QC test is valid), E. coli ATCC® 35218 should also be tested with a β-lactam agent (eg, ampicillin, amoxicillin, piperacillin, ticarcillin). If the strain loses the plasmid, it will test susceptible to the β-lactam agent. In this case, the QC test is invalid and a new culture of E. coli ATCC® 35218 must be used. Therefore, when QC is performed with E. coli ATCC® 35218 for one or more β-lactam/β-lactamase inhibitor combination agents, one of the β-lactam agents should also be tested to confirm that the E. coli ATCC® 35218 isolate tested is satisfactory and the QC test is valid. Acceptable QC ranges are currently available for amoxicillin with Haemophilus Test Media (Table 4A), ampicillin, piperacillin, and ticarcillin with Mueller-Hinton broth (Table 4), and ampicillin and ticarcillin with Mueller-Hinton agar (Table 3).

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The Quality Management System Approach Clinical and Laboratory Standards Institute (CLSI) subscribes to a quality management system approach in the development of standards and guidelines, which facilitates project management; defines a document structure via a template; and provides a process to identify needed documents. The approach is based on the model presented in the most current edition of CLSI document HS01—A Quality Management System Model for Health Care. The quality management system approach applies a core set of “quality system essentials” (QSEs), basic to any organization, to all operations in any health care service’s path of workflow (ie, operational aspects that define how a particular product or service is provided). The QSEs provide the framework for delivery of any type of product or service, serving as a manager’s guide. The QSEs are Documents and Records Organization Personnel

Equipment Purchasing and Inventory Process Control

Information Management Occurrence Management Assessments—External and Internal

Process Improvement Customer Service Facilities and Safety

Facilities and Safety

Customer Service

Process Improvement

Assessments —External and Internal

Occurrence Management

Information Management

Process Control

Purchasing and Inventory

Equipment

Personnel

Organization

Documents and Records

M100-S20 addresses the QSEs indicated by an “X.” For a description of the other documents listed in the grid, please refer to the Related CLSI Reference Materials section on the following page.

M02 M07 M11 M23 M27 M31 M37 M39 M45

M07

Adapted from CLSI document HS01—A Quality Management System Model for Health Care.

Path of Workflow A path of workflow is the description of the necessary steps to deliver the particular product or service that the organization or entity provides. For example, CLSI document GP26⎯Application of a Quality Management System Model for Laboratory Services defines a clinical laboratory path of workflow, which consists of three sequential processes: preexamination, examination, and postexamination. All clinical laboratories follow these processes to deliver the laboratory’s services, namely quality laboratory information. M100-S20 addresses the clinical laboratory path of workflow steps indicated by an “X.” For a description of the other documents listed in the grid, please refer to the Related CLSI Reference Materials section on the following page.

M27 M31

X M02 M07 M11 M27 M31

X M02 M07 M11 M27 M31

Sample management

X M02 M07 M11 M27 M31

Results reporting and archiving

Interpretation

M02 M07

Postexamination

Results review and follow-up

Examination

Examination Sample receipt/processing

Sample transport

Sample collection

Examination ordering

Preexamination

M27

Adapted from CLSI document HS01—A Quality Management System Model for Health Care.

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Related CLSI Reference Materials∗ M02-A10

Performance Standards for Antimicrobial Disk Susceptibility Tests; Approved Standard—Tenth Edition (2009). This standard contains the current Clinical and Laboratory Standards Institute-recommended methods for disk susceptibility testing, criteria for quality control testing, and updated tables for interpretive zone diameters.

M07-A8

Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard—Eighth Edition (2009). This document addresses reference methods for the determination of minimal inhibitory concentrations (MICs) of aerobic bacteria by broth macrodilution, broth microdilution, and agar dilution.

M11-A7

Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria; Approved Standard—Seventh Edition (2007). This standard provides reference methods for the determination of minimal inhibitory concentrations (MICs) of anaerobic bacteria by broth microdilution and agar dilution.

M23-A3

Development of In Vitro Susceptibility Testing Criteria and Quality Control Parameters; Approved Guideline—Third Edition (2008). This document addresses the required and recommended data needed for the selection of appropriate interpretive criteria and quality control ranges for antimicrobial agents.

M27-A3

Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts; Approved Standard— Third Edition (2008). This document addresses the selection and preparation of antifungal agents; implementation and interpretation of test procedures; and quality control requirements for susceptibility testing of yeasts that cause invasive fungal infections.

M31-A3

Performance Standards for Antimicrobial Disk and Dilution Susceptibility Tests for Bacteria Isolated From Animals; Approved Standard—Third Edition (2008). This document provides the currently recommended techniques for antimicrobial agent disk and dilution susceptibility testing, criteria for quality control testing, and interpretive criteria for veterinary use.

M37-A3

Development of In Vitro Susceptibility Testing Criteria and Quality Control Parameters for Veterinary Antimicrobial Agents; Approved Guideline—Third Edition (2008). This document addresses the required and recommended data needed for selection of appropriate interpretive standards and quality control guidance for new veterinary antimicrobial agents.

M39-A3

Analysis and Presentation of Cumulative Antimicrobial Susceptibility Test Data; Approved Guideline— Third Edition (2009). This document describes methods for recording and analysis of antimicrobial susceptibility test data, consisting of cumulative and ongoing summaries of susceptibility patterns of clinically significant microorganisms.

M45-A

Methods for Antimicrobial Dilution and Disk Susceptibility Testing of Infrequently Isolated or Fastidious Bacteria; Approved Guideline (2006). This document provides guidance to clinical microbiology laboratories for standardized susceptibility testing of infrequently isolated or fastidious bacteria that are not presently included in CLSI documents M02, M07, or M11. The tabular information in this document presents the most current information for drug selection, interpretation, and quality control for the infrequently isolated or fastidious bacterial pathogens included in this guideline.

∗

CLSI documents are continually reviewed and revised through the CLSI consensus process; therefore, readers should refer to the most current editions.

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Product Name: Infobase 2010 - Release Date: February 2010 Carolinas Healthcare System (NC) Carpermor S.A. de C.V. (Mexico) Catholic Health Initiatives (KY) Cedars-Sinai Medical Center (CA) Central Baptist Hospital (KY) Centre Hospitalier Anna-Laberge (Canada) Chaleur Regional Hospital (Canada) Chang Gung Memorial Hospital (Taiwan) Changhua Christian Hospital (Taiwan) Charleston Area Medical Center (WV) The Charlotte Hungerford Hospital (CT) Chatham – Kent Health Alliance (Canada) Chester County Hospital (PA) Children’s Healthcare of Atlanta (GA) Children’s Hospital and Regional Medical Center (WA) Children’s Hospital of Central California (CA) Children’s Hospital Medical Center (OH) Children’s Hospital of Orange County (CA) Children’s Hospital of Philadelphia (PA) Children’s Hospitals and Clinics (MN) Children’s Medical Center (OH) Children’s Medical Center (TX) Children’s Memorial Hospital (IL) The Children’s Mercy Hospital (MO) Childrens Hospital Los Angeles (CA) Childrens Hospital of Wisconsin (WI) Christiana Care Health Services (DE) CHU Sainte-Justine (Quebec, Canada) CHU – Saint Pierre (Belgium) CHUM Hopital Saint-Luc (Canada) City of Hope National Medical Center (CA) Clarian Health – Clarian Pathology Laboratory (IN) Clinical Labs of Hawaii (HI) Clinton Memorial Hospital (OH) Colchester East Hants Health Authority (Canada) College of Physicians and Surgeons of Alberta (Canada) Columbia Regional Hospital (MO) Commonwealth of Virginia (DCLS) (VA) Community Hospital (IN) Community Medical Center (NJ) Community Memorial Hospital (WI) Complexe Hospitalier de la Sagamie (Canada) Consultants Laboratory of WI LLC (WI) Contra Costa Regional Medical Center (CA) Cook Children’s Medical Center (TX) Cornwall Community Hospital (Canada) Covance CLS (IN) The Credit Valley Hospital (Canada) Creighton Medical Lab (NE) Creighton University Medical Center (NE) Crozer-Chester Medical Center (PA) Cumberland Medical Center (TN) Darwin Library NT Territory Health Services (Australia) David Grant Medical Center (CA) Davies Community Hospital (IN) DCL Medical Laboratories (IN) Deaconess Hospital Laboratory (IN) Dean Medical Center (WI) DHHS NC State Lab of Public Health (NC) Diagnostic Laboratory Services, Inc. (HI) Diagnostic Services of Manitoba (Canada) Diagnósticos da América S/A (Brazil) Diaz Gill-Medicina Laboratorial S.A. (Paraguay) Dimensions Healthcare System Prince George’s Hospital Center (MD) DMC University Laboratories (MI) Dr. Everette Chalmers Regional Hospital (Canada) DRAKE Center (OH) DUHS Clinical Laboratories Franklin Site (NC) Dunn Memorial Hospital (IN) DynaLIFE, Canada E. A. Conway Medical Center (LA) East Central Health (Canada) East Georgia Regional Medical Center (GA) East Texas Medical Center-Pittsburg (TX) Eastern Health - Health Sciences Centre (Canada) Eastern Health Pathology (Australia) Easton Hospital (PA) Edward Hospital (IL) Effingham Hospital (GA)

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OFFICERS Gerald A. Hoeltge, MD, President Cleveland Clinic

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University of the Ryukyus (Japan) University of Virginia Medical Center (VA) UPMC Bedford Memorial (PA) U.S. Naval Hospital Guantanamo Bay US Naval Hospital Naples (FPO) USC University Hospital (CA) UW Health (WI) UZ-KUL Medical Center (Belgium) VA (Bay Pines) Medical Center (FL) VA (Chillicothe) Medical Center (OH) VA (Cincinnati) Medical Center (OH) VA (Dayton) Medical Center (OH) VA (Decatur) Medical Center (GA) VA (Hampton) Medical Center (VA) VA (Miami) Medical Center (FL) VA New Jersey Health Care System (NJ) VA (San Diego) Medical Center (CA) VA (Sheridan) Medical Center (WY) Valley Health (VA) Vancouver Coastal Health Regional Laboratory (BC, Canada) Vancouver Island Health Authority (SI) (Canada) Vanderbilt University Medical Center (TN) Veterans Hospital (FL) Via Christi Regional Medical Center (KS) Virga Jessezieukenhuis (Belgium) Virginia Beach General Hospital (VA) Virginia Regional Medical Center, (MN) Virtua – West Jersey Hospital (NJ) WakeMed (NC) Walter Reed Army Medical Center (DC) Warren Hospital (NJ) Washington Hospital Center (DC) Waterbury Hospital (CT) Waterford Regional Hospital (Ireland) Wayne Memorial Hospital (NC) West China Second University Hospital, Sichuan University (China) West Jefferson Medical Center (LA) West Shore Medical Center (MI) West Valley Medical Center Laboratory (ID) Western Baptist Hospital (KY) Western Healthcare Corporation (Canada) Western Pennsylvania Hospital (PA) Wheaton Franciscan and Midwest Clinical Laboratories (WI) Wheeling Hospital (WV) William Beaumont Army Medical Center (TX) William Osler Health Centre (Canada) Winchester Hospital (MA) Winn Army Community Hospital (GA) Wishard Health Sciences (IN) Womack Army Medical Center (NC) York Hospital (PA) Zulekha Hospital Dubai (United Arab Emirates)

BOARD OF DIRECTORS Maria Carballo Health Canada

Luann Ochs, MS BD Diagnostics – TriPath

Russel K. Enns, PhD Cepheid

Timothy J. O’Leary, MD, PhD Department of Veterans Affairs

Prof. Naotaka Hamasaki, MD, PhD Nagasaki International University

Robert Rej, PhD New York State Department of Health

Mary Lou Gantzer, PhD, Secretary Siemens Healthcare Diagnostics

Christopher M. Lehman, MD University of Utah Health Sciences Center

Donald St.Pierre FDA Center for Devices and Radiological Health

W. Gregory Miller, PhD, Treasurer Virginia Commonwealth University

Valerie Ng, PhD, MD Alameda County Medical Center/ Highland General Hospital

Michael Thein, PhD Roche Diagnostics GmbH

Janet K.A. Nicholson, PhD, President-Elect Centers for Disease Control and Prevention

Robert L. Habig, PhD, Immediate Past President Habig Regulatory Consulting Glen Fine, MS, MBA, CAE, Executive Vice President

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James A. Thomas ASTM International

Product Name: Infobase 2010 - Release Date: February 2010

This document is protected by international copyright laws.

Product Name: Infobase 2010 - Release Date: February 2010

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