Clinical and Laboratory Standards Institute

Clinical and Laboratory Standards Institute Advancing Quality in Healthcare Testing 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 healthcare 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 healthcare issues. Our process is based on the principle that consensus is an effective and cost-effective way to improve patient testing and healthcare services.

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A document is published as a standard, guideline, or committee report.

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The CLSI voluntary consensus process is a protocol establishing formal criteria for:

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• the acceptance of a document as a consensus standard or guideline.

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 healthcare 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.

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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 responded to 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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M45-A ISBN 1-56238-607-7

Volume 26 Number 19 ISSN 0273-3099

Methods for Antimicrobial Dilution and Disk Susceptibility Testing of Infrequently Isolated or Fastidious Bacteria; Approved Guideline James H. Jorgensen, PhD Jean B. Patel, PhD, D(ABMM) Janet Hindler, MCLS, MT(ASCP) Paul C. Schreckenberger, PhD, D(ABMM) Diane M. Citron, M(ASCP) John D. Turnidge, MD Franklin R. Cockerill, III, MD Robert D. Walker, PhD Thomas R. Fritsche, PhD, MD David F. Welch, PhD, D(ABMM) Guido Funke, MD

Abstract If the susceptibility of a bacterial pathogen to antimicrobial agents cannot be predicted based on the identity of the organism alone, in vitro antimicrobial susceptibility testing of the organism isolated from the disease processes is indicated. Susceptibility testing is particularly necessary in those situations where the etiologic agent belongs to a bacterial species for which resistance to commonly used antimicrobial agents has been documented, or could arise. A variety of laboratory techniques can be used to measure the in vitro susceptibility of bacteria to antimicrobial agents. This document describes the standard microdilution and agar disk diffusion methods. It also includes a series of procedures designed to standardize test performance. The performance, applications, and limitations of the current CLSI-recommended methods are described. 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. As more information becomes available, changes will be incorporated into future revisions of this document. Clinical and Laboratory Standards Institute (CLSI). Methods for Antimicrobial Dilution and Disk Susceptibility Testing of Infrequently Isolated or Fastidious Bacteria; Approved Guideline. CLSI document M45-A (ISBN 1-56238-607-7). Clinical and Laboratory Standards Institute, 940 West Valley Road, Suite 1400, Wayne, Pennsylvania 19087-1898 USA, 2006.

(Formerly NCCLS)

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 healthcare 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, which is distributed to member organizations, and to nonmembers on request. 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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This publication is protected by copyright. No part of it may be reproduced, stored in a retrieval system, transmitted, or made available in any form or by any means (electronic, mechanical, photocopying, recording, or otherwise) without prior written permission from Clinical and Laboratory Standards Institute, except as stated below. Clinical and Laboratory Standards Institute hereby grants permission to reproduce limited portions of this publication for use in laboratory procedure manuals at a single site, for interlibrary loan, or for use in educational programs provided that multiple copies of such reproduction shall include the following notice, be distributed without charge, and, in no event, contain more than 20% of the document’s text.

Reproduced with permission, from CLSI publication M45-A—Methods for Antimicrobial Dilution and Disk Susceptibility Testing of Infrequently Isolated or Fastidious Bacteria; Approved Guideline (ISBN 1-56238-607-7). Copies of the current edition may be obtained from Clinical and Laboratory Standards Institute, 940 West Valley Road, Suite 1400, Wayne, Pennsylvania 19087-1898, USA.

Permission to reproduce or otherwise use the text of this document to an extent that exceeds the exemptions granted here or under the Copyright Law must be obtained from Clinical and Laboratory Standards Institute by written request. To request such permission, address inquiries to the Executive Vice President, Clinical and Laboratory Standards Institute, 940 West Valley Road, Suite 1400, Wayne, Pennsylvania 19087-1898, USA. Copyright ©2006. Clinical and Laboratory Standards Institute. Suggested Citation (Clinical and Laboratory Standards Institute. Methods for Antimicrobial Dilution and Disk Susceptibility Testing of Infrequently Isolated or Fastidious Bacteria; Approved Guideline. CLSI document M45-A [ISBN 1-56238-607-7]. Clinical and Laboratory Standards Institute, 940 West Valley Road, Suite 1400, Wayne, Pennsylvania 19087-1898 USA, 2006.) Proposed Guideline October 2005 Approved Guideline May 2006 ISBN 1-56238-607-7 ISSN 0273-3099

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Committee Membership Area Committee on Microbiology Mary Jane Ferraro, PhD, MPH Chairholder Massachusetts General Hospital Boston, Massachusetts James H. Jorgensen, PhD Vice-Chairholder University of Texas Health Science Center San Antonio, Texas Donald R. Callihan, PhD BD Diagnostic Systems Sparks, Maryland Freddie Mae Poole FDA Center for Devices and Radiological Health Rockville, Maryland David L. Sewell, PhD Veterans Affairs Medical Center Portland, Oregon Thomas R. Shryock, PhD Elanco Animal Health Greenfield, Indiana

Jana M. Swenson, MMSc Centers for Disease Control and Prevention Atlanta, Georgia Michael L. Wilson, MD Denver Health Medical Center Denver, Colorado Advisors Ellen Jo Baron, PhD Stanford Univ. Hospital & Medical School Stanford, California Lynne S. Garcia, MS LSG & Associates Santa Monica, California Richard L. Hodinka, PhD Children’s Hospital of Philadelphia Philadelphia, Pennsylvania Michael A. Pfaller, MD University of Iowa College of Medicine Iowa City, Iowa

Robert P. Rennie, PhD University of Alberta Hospital Edmonton, Alberta, Canada John H. Rex, MD, FACP AstraZeneca Cheshire, United Kingdom Melvin P. Weinstein, MD Robert Wood Johnson Medical School New Brunswick, New Jersey Matthew A. Wikler, MD, MBA, FIDSA Mpex Pharmaceuticals, Inc. San Diego, California Gail L. Woods, MD University of Arkansas for Medical Sciences Little Rock, Arkansas

Subcommittee on Antimicrobial Susceptibility Testing Matthew A. Wikler, MD, MBA, FIDSA Chairholder Mpex Pharmaceuticals San Diego, California Franklin R. Cockerill, III, MD Mayo Clinic/Mayo Foundation Rochester, Minnesota William A. Craig, MD University of Wisconsin Madison, Wisconsin Michael N. Dudley, PharmD Mpex Pharmaceuticals San Diego, California George M. Eliopoulos, MD Beth Israel Deaconess Medical Center Boston, Massachusetts David W. Hecht, MD Loyola University Medical Center Maywood, Illinois Janet F. Hindler, MCLS, MT(ASCP) UCLA Medical Center Los Angeles, California Donald E. Low, MD Mount Sinai Hospital Toronto, Ontario, Canada Daniel J. Sheehan, PhD Pfizer Inc. New York, New York

Fred C. Tenover, PhD, ABMM Centers for Disease Control and Prevention Atlanta, Georgia 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 Barbara L. Zimmer, PhD Dade Behring MicroScan West Sacramento, California Advisors Patricia A. Bradford, PhD Wyeth Research Pearl River, New York John S. Bradley, MD Children’s Hospital and Health Center San Diego, California Steven D. Brown, PhD The Clinical Microbiology Institute Wilsonville, Oregon Karen Bush, PhD Johnson & Johnson Pharmaceutical Research and Development, L.L.C. Raritan, New Jersey

Prof. José María Casellas Universidad Nacional de Rosario Victoria, Argentina Edward M. Cox, Jr., MD, MPH FDA Center for Drug Evaluation and Research Rockville, Maryland Lawrence V. Friedrich, PharmD Cubist Pharmaceuticals Mt. Pleasant, South Carolina Mark J. Goldberger, MD, MPH FDA Center for Drug Evaluation and Research Rockville, Maryland Dwight J. Hardy, PhD University of Rochester Medical Center Rochester, New York Yoichi Hirakata, MD, PhD Nagasaki University School of Medicine and Dentistry Nagasaki, Japan Ronald N. Jones, MD JMI Laboratories North Liberty, Iowa Gunnar Kahlmeter, MD, PhD ESCMID Växjö, Sweden

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Advisors (Continued) Frederic J. Marsik, PhD, ABMM FDA Center for Drug Evaluation and Research Rockville, Maryland John E. McGowan, Jr., MD Emory University, Rollins School of Public Health Atlanta, Georgia Linda A. Miller, PhD GlaxoSmithKline Collegeville, Pennsylvania Mary R. Motyl, PhD, D(ABMM) Merck & Company, Inc. Rahway, New Jersey Susan D. Munro, MT(ASCP) Stanford Hospital and Clinics Stanford, California

Charles H. Nightingale, PhD Hartford Hospital Hartford, Connecticut Jean B. Patel, PhD, D(ABMM) Centers for Disease Control and Prevention Atlanta, Georgia David Paterson, MD University of Pittsburgh Pittsburgh, Pennsylvania John H. Powers, III, MD, FACP FDA Center for Drug Evaluation and Research Rockville, Maryland L. Barth Reller, MD Duke University Medical Center Durham, North Carolina Daniel F. Sahm, PhD Focus Bio-Inova, Inc. Herndon, Virginia

Dale A. Schwab, PhD, D(ABMM) Quest Diagnostics, Nichols Institute San Juan Capistrano, California Sally Selepak, MT(ASCP) FDA Center for Devices and Radiological Health Rockville, Maryland Jana M. Swenson, MMSc Centers for Disease Control and Prevention Atlanta, Georgia George H. Talbot, MD Talbot Advisors LLC Wayne, Pennsylvania

Working Group on Susceptibility Testing of Infrequently Encountered or Fastidious Bacteria James H. Jorgensen, PhD Chairholder University of Texas Health Science Ctr. San Antonio, Texas Janet F. Hindler, MCLS, MT(ASCP) Vice-Chairholder UCLA Medical Center Los Angeles, California Diane M. Citron, M(ASCP) Santa Monica – UCLA Medical Center R.M. Alden Research Laboratory Santa Monica, California Franklin R. Cockerill, III, MD Mayo Clinic/Mayo Foundation Rochester, Minnesota Thomas R. Fritsche, PhD, MD JMI Laboratories North Liberty, Iowa Guido Funke, MD Gartner & Colleagues Laboratories Ravensburg, Germany Jean B. Patel, PhD, D(ABMM) Centers for Disease Control and Prevention Atlanta, Georgia Paul C. Schreckenberger, PhD, D(ABMM) Loyola University Medical Center Maywood, Illinois

John D. Turnidge, MD Women’s and Children’s Hospital North Adelaide, Australia Robert D. Walker, PhD FDA Center for Veterinary Medicine Laurel, Maryland David F. Welch, PhD, D(ABMM) University of Texas Southwestern Medical Center Dallas, Texas Advisors Paul G. Ambrose, PharmD Institute for Clinical Pharmacodynamics Ordway Research Institute Albany, New York Anton F. Ehrhardt, PhD Cubist Pharmaceuticals Lexington, Massachusetts Frederic J. Marsik, PhD, ABMM FDA Center for Drug Evaluation and Research Rockville, Maryland Patrick McDermott, PhD FDA Center for Veterinary Medicine Laurel, Maryland Jana M. Swenson, MMSc Centers for Disease Control and Prevention Atlanta, Georgia

Fred C. Tenover, PhD, ABMM Centers for Disease Control and Prevention Atlanta, Georgia Mary K. York, PhD, ABMM MKY Microbiology Consulting Walnut Creek, California Staff Clinical and Laboratory Standards Institute Wayne, Pennsylvania John J. Zlockie, MBA Vice President, Standards Tracy A. Dooley, BS, MLT(ASCP) Staff Liaison Donna M. Wilhelm Editor Melissa A. Lewis Assistant Editor

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Contents

Abstract ....................................................................................................................................................i

Committee Membership........................................................................................................................ iii

Foreword................................................................................................................................................ix

1 Scope..........................................................................................................................................1

2 Introduction................................................................................................................................1

3 Standard Precautions..................................................................................................................4

4 Definitions .................................................................................................................................4

5 Indications for Performing Susceptibility Tests.........................................................................4

6 Methods for Dilution Antimicrobial Susceptibility Testing of Infrequently Isolated or Fastidious Bacteria ................................................................................................................5

6.1 Selection of Antimicrobial Agents................................................................................5 6.2 Antimicrobial Agents....................................................................................................5 6.3 Interpretive Categories..................................................................................................5

7 Methods for Antimicrobial Disk Diffusion Susceptibility Testing of Infrequently Isolated or Fastidious Bacteria.....................................................................................................................6

8 Therapy-Related Comments ......................................................................................................6

9 Quality Control ..........................................................................................................................6

9.1 Minimum Laboratory Requirements for Testing Infrequently Isolated or Fastidious Bacteria ......................................................................................................................................7

10 Detection of Resistance to Some β-Lactams by a Direct β-Lactamase Test .............................7

References...............................................................................................................................................8

Table 1. Abiotrophia species and Granulicatella species (Formerly Known as Nutritionally Deficient or Nutritionally Variant Streptococci)—Information and Interpretive Criteria for Broth Microdilution Susceptibility Testing............................................................................................................................10

Table 2. Aeromonas hydrophila Complex (Includes A. caviae, A. hydrophila, A. jandaei, A. schubertii, and A. veronii, Two Biotypes) and Plesiomonas shigelloides—Information and Interpretive Criteria for Broth Microdilution and Disk Diffusion Susceptibility Testing ....................12

Table 3. Bacillus species (Not B. anthracis)—Information and Interpretive Criteria for Broth Microdilution Susceptibility Testing ....................................................................................................14

Table 4. Campylobacter jejuni/coli—Information and Interpretive Criteria for Broth Microdilution and Disk Diffusion Susceptibility Testing ............................................................................................16

Table 5. Corynebacterium species (Including C. diphtheriae)—Information and Interpretive Criteria for Broth Microdilution Susceptibility Testing........................................................................18

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Contents (Continued)

Table 6. Erysipelothrix rhusiopathiae—Information and Interpretive Criteria for Broth Microdilution Susceptibility Testing............................................................................................................................20

Table 7. HACEK Group: the Aphrophilus Cluster of the Genus Haemophilus (i.e., H. aphrophilus, H. paraphrophilus, H. segnis), Actinobacillus actinomycetemcomitans, Cardiobacterium species, Eikenella corrodens, and Kingella species—Information and Interpretive Criteria for Broth Microdilution Susceptibility Testing ....................................................................................................22

Table 8. Lactobacillus species—Information and Interpretive Criteria for Broth Microdilution Susceptibility Testing............................................................................................................................24

Table 9. Leuconostoc species—Information and Interpretive Criteria for Broth Microdilution Susceptibility Testing............................................................................................................................26

Table 10. Listeria monocytogenes—Information and Interpretive Criteria for Broth Microdilution Susceptibility Testing............................................................................................................................27

Table 11. Moraxella catarrhalis—Information and Interpretive Criteria for Broth Microdilution Susceptibility Testing............................................................................................................................28

Table 12. Pasteurella species—Information and Interpretive Criteria for Broth Microdilution and Disk Diffusion Susceptibility Testing...................................................................................................30

Table 13. Pediococcus species—Information and Interpretive Criteria for Broth Microdilution Susceptibility Testing............................................................................................................................32

Table 14. Vibrio species (Not V. cholerae)—Information and Interpretive Criteria for Broth Microdilution and Disk Diffusion Susceptibility Testing.....................................................................34

Table 15. Summary of Testing Conditions and QC Recommendations for Infrequently Isolated or Fastidious Bacteria................................................................................................................................36

Table 16. Acceptable Limits for Quality Control Strains Used to Monitor Accuracy of Minimal Inhibitory Concentrations (MICs) (µg/mL) of Nonfastidious Organisms (Using Cation-Adjusted Mueller-Hinton Medium Without Blood or Other Supplements).........................................................37

Table 16A. Acceptable Limits for Streptococcus pneumoniae ATCC® 49619 Used to Monitor Accuracy of Minimal Inhibitory Concentrations (MICs) (µg/mL) (Using Cation-Adjusted Mueller-Hinton Broth With Lysed Horse Blood [2.5 to 5% v/v]) ......................................................................38

Table 16B. Acceptable Limits for Quality Control Strains Used to Monitor Accuracy of Broth Microdilution Minimal Inhibitory Concentrations (MICs) (µg/mL) of Campylobacter jejuni ATCC® 33560 (Using Cation-Adjusted Mueller-Hinton Broth With Lysed Horse Blood [2.5 to 5% v/v])......39

Table 17. Acceptable Limits for Quality Control Strains Used to Monitor Accuracy of Disk Diffusion Testing of Nonfastidious Organisms (Using Mueller-Hinton Medium Without Blood or Other Supplements) ..............................................................................................................................40

Table 17A. Acceptable Limits for Streptococcus pneumoniae ATCC® 49619 Used to Monitor Accuracy of Disk Diffusion Testing .....................................................................................................41

Glossary I (Part 1). β-lactams: Class and Subclass Designation and Generic Name............................42

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Contents (Continued)

Glossary I (Part 2). Non-β-lactams: Class and Subclass Designation and Generic Name ...................43

Glossary II. Abbreviations/Routes of Administration/Drug Class for Antimicrobial Agents Listed in CLSI Document M100......................................................................................................................44

Additional References...........................................................................................................................47

Summary of Consensus Comments and Committee Responses ...........................................................57

The Quality System Approach..............................................................................................................60

Related CLSI/NCCLS Publications ......................................................................................................61

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Foreword This document was developed for the purpose of providing guidance to clinical microbiology laboratories regarding the performance of standardized susceptibility testing, when needed, of infrequently isolated or fastidious bacteria that are not presently included in the most current editions of CLSI/NCCLS documents M2—Performance Standards for Antimicrobial Disk Susceptibility Tests, M7—Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically, or M11—Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria. Some of the organisms included herein are aerobic gram-negative bacilli that are not members of the family Enterobacteriaceae, but may be tested by the standard CLSI broth microdilution or disk diffusion methods in the same manner as the much more common Enterobacteriaceae isolates. Some aerobic gram-positive cocci and bacilli that are encountered periodically by clinical laboratories can likewise be tested reliably by the standard CLSI MIC or disk diffusion test methods in a manner analogous to Staphylococcus or Enterococcus spp. In addition, several genera of fastidious gram-positive and gram-negative bacteria can be tested in the same manner as the streptococci, using blood-supplemented Mueller-Hinton media. For the purpose of this document, the term fastidious is used to describe bacteria that require media supplemented with blood or blood components and that possibly need an atmosphere other than ambient air (e.g., with 5% CO2) for acceptable growth. Because the standard CLSI media, reagents, and procedures can be used to test the organisms included in this guideline, the quality control procedures, strains, and acceptable zone diameter and MIC limits that have been established through previous rigorous studies can be utilized for tests with the less common organisms that are included in this document. The working group used a thorough search of the published literature in conjunction with the clinical experience of the members to apply or adapt interpretive criteria or breakpoints from other organisms that could best be applied to the interpretation of tests of the less common organisms in this document. Users of the guideline should be aware that the very extensive microbiological, clinical, and pharmacodynamic databases normally employed for setting breakpoints by CLSI did not exist for the collection of “orphan” organisms described in this document.

It is important for users of M45-A to recognize that commercial susceptibility testing devices are not addressed in this guideline. The methods described herein are generic reference procedures that can be used for routine susceptibility testing by clinical laboratories, or that can be used by clinical laboratories to evaluate commercial devices for possible routine use. Results generated by the CLSI reference methods are used by the United States Food and Drug Administration to evaluate the performance of commercial systems before clearance is given for marketing in the United States. Clearance by the FDA indicates that the agency concludes that commercial devices provide susceptibility results that are substantially equivalent to results generated using the CLSI reference methods for the organisms and antimicrobial agents described in the manufacturer’s approved package insert. Some laboratories could find that a commercial dilution, antibiotic gradient, colorimetric, turbidimetric, fluorometric, or other method is suitable for selective or routine use. Key Words Agar dilution, antimicrobial agent, antimicrobial susceptibility, broth dilution, disk diffusion, microdilution, minimal inhibitory concentration (MIC), susceptibility testing

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CLSI Subcommittee on Antimicrobial Susceptibility Testing Mission Statement The CLSI Subcommittee on Antimicrobial Susceptibility Testing is composed of representatives from the professions, government, and industry, including microbiology laboratories, government agencies, healthcare 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 CLSI Subcommittee on Antimicrobial Susceptibility Testing is to: • develop standard reference methods for antimicrobial susceptibility tests; • provide quality control 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 cost-effective; • continually refine standards and optimize the detection of emerging resistance mechanisms through

the development of new or revised methods, interpretive criteria, and quality control parameters; • educate users through multimedia communication of standards and guidelines; and • foster a dialogue 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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©Clinical and Laboratory Standards Institute. All rights reserved. 1

Methods for Antimicrobial Dilution and Disk Susceptibility Testing of Infrequently Isolated or Fastidious Bacteria; Approved Guideline

1 Scope CLSI documents M2—Performance Standards for Antimicrobial Disk Susceptibility Tests and M7—Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically describe standardized methods for antimicrobial susceptibility testing of common aerobic bacteria, including some fastidious organisms or potential agents of bioterrorism. However, there are a number of less frequently encountered or fastidious bacteria that are not addressed in M2, M7, and M100—Performance Standards for Antimicrobial Susceptibility Testing. Some of these are organisms that may cause serious infections (e.g., infective endocarditis), infections associated with trauma and environmental contamination, or device-associated infections in immunocompromised or postsurgical patients (e.g., intravascular catheters, implanted devices, central nervous system shunts). Key gram-positive organisms include Corynebacterium spp., Bacillus spp. (not B. anthracis), and several genera that have intrinsic vancomycin resistance. Nonfastidious gram-negative bacteria include Aeromonas spp., Plesiomonas spp., Vibrio spp., and Moraxella catarrhalis. The fastidious gram-negative bacilli include the HACEK group, Campylobacter, and Pasteurella spp. Organisms considered to be members of the HACEK group are the Aphrophilus cluster of the genus Haemophilus (i.e., H. aphrophilus, H. paraphrophilus, H. segnis), Actinobacillus actinomycetemcomitans, Cardiobacterium spp., Eikenella corrodens, and Kingella spp. Capnocytophaga spp. are outside the scope of this document because of the lack of suitable methods for broth dilution or disk diffusion susceptibility testing. The Capnocytophaga spp. frequently produce β-lactamase, but they are generally susceptible to β-lactam/β-lactamase inhibitor combinations, clindamycin, imipenem, and linezolid. Fastidious gram-positive bacteria that may cause endocarditis include Abiotrophia spp. and Granulicatella spp. Acquired antimicrobial resistance mechanisms have been reported in many of these organisms, and the medical literature includes descriptions of susceptibility results derived from use of standard CLSI methods or certain nonstandard procedures. Because infections due to organisms addressed in M45 occur less frequently than many of the organisms presently covered in CLSI documents M2 and M7, and the fact that many of the antimicrobial agents of interest have been marketed for a number of years, it is not reasonable to expect the intensive CLSI/NCCLS document M23-specified studies (Development of In Vitro Susceptibility Testing Criteria and Quality Control Parameters) to be conducted on this special group of organisms. Instead, the goal of this document is to propose test conditions and interpretive criteria based upon a careful review of published microbiological data (distributions of MICs), and the extant clinical literature regarding therapy for these organisms, and in a few instances, a review of existing pharmacokinetic data on the drugs of interest. In some cases, limited in vitro testing was performed. It is hoped that this CLSI guideline will assist clinical microbiology laboratories in determining an approach for testing these unusual organisms that is relevant to their individual practice settings. 2 Introduction CLSI documents M2 and M7 describe reference and standardized methods for antimicrobial susceptibility testing of common, rapidly growing aerobic bacteria, including staphylococci, enterococci, members of the Enterobacteriaceae, Pseudomonas spp., and Acinetobacter spp., Burkholderia cepacia, and Stenotrophomonas maltophilia (in addition to a few other nonglucose-fermentative gram-negative bacilli). These documents also include standard susceptibility testing methods, quality control values, and specific breakpoints for several fastidious bacterial species, including Haemophilus influenzae, Neisseria

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gonorrhoeae, Neisseria meningitidis, and Streptococcus spp. In addition, the standards include a limited amount of information regarding the testing of Helicobacter pylori, Vibrio cholerae, and several potential agents of bioterrorism (i.e., Bacillus anthracis, Yersinia pestis, Burkholderia mallei, B. pseudomallei, Francisella tularensis, and Brucella spp.). Despite this extensive list of organisms included in CLSI documents M2 and M7, there are a number of genera of bacteria isolated periodically by clinical microbiology laboratories from human diagnostic specimens for which there are no current CLSI standards. Organisms that presently lack defined methods for susceptibility testing and interpretive criteria include various Coryneform bacteria, Bacillus spp. (other than B. anthracis), Abiotrophia and Granulicatella spp., several genera of gram-positive bacteria with intrinsic glycopeptide resistance (e.g., Erysipelothrix spp., Lactobacillus spp., Leuconostoc spp., Pediococcus spp.), as well as several species of fastidious gram-negative bacteria (e.g., HACEK group organisms, and Pasteurella spp.). In addition, more detailed guidance for test performance and interpretation are needed, especially breakpoints for Listeria spp., Aeromonas spp., Plesiomonas spp., Vibrio spp., Moraxella catarrhalis and Campylobacter spp. The lack of test methods or interpretive criteria has made it difficult to assess the frequency of acquired resistance in these less frequently isolated or fastidious organisms, and has discouraged the testing of individual patient isolates by clinical laboratories. However, concerns have been raised that resistance exists in certain of these organisms, and that laboratories should be prepared to test them when appropriate.1,2

Resistance Mechanisms in Gram-Positive Rods Bacillus cereus and B. thuringiensis have long been noted as producers of a potent broad-spectrum β-lactamase that affects penicillins and cephalosporins.3 However, these related species are often susceptible to several other drug classes including vancomycin, aminoglycosides, macrolides, and quinolones that might be used to treat ocular or wound infections. Among the Corynebacterium spp., C. jeikeium and C. urealyticum are often multidrug resistant, including resistance to β-lactams, macrolides, and aminoglycosides.4 Even C. diphtheriae may be macrolide and rifampin-resistant, while C. pseudodiphtheriticum and C. striatum may possess erm genes and be resistant to macrolides and lincosamides.4 Further, some strains of C. striatum are said to be resistant to tetracyclines and quinolones.4 The related bacilli, Arcanobacterium and Arthrobacter, have been reported to be resistant to aminoglycosides and quinolones,4 and Brevibacterium spp. may demonstrate reduced β-lactam susceptibility. Turicella spp. may be macrolide- and clindamycin-resistant.4 Erysipelothrix rhusiopathiae and most Lactobacillus spp. isolates are intrinsically resistant to vancomycin; and the uncommon species, Microbacterium resistans and Leifsonia aquatica, have been reported to have diminished vancomycin susceptibility.5,6 Resistance in Infrequently Isolated or Fastidious Gram-Positive Cocci Leuconostoc and Pediococcus are intrinsically resistant to vancomycin, but are usually susceptible to β-lactams, chloramphenicol, tetracyclines, and aminoglycosides, although Leuconostoc can be resistant to carbapenems and cephalosporins.7 Abiotrophia and Granulicatella (formerly nutritionally deficient streptococci) may demonstrate diminished susceptibility to penicillin, resulting in greater difficulty in treatment of patients with endocarditis, and in one case, fluoroquinolone resistance was reported in an isolate from an immunosuppressed patient.8 Infrequently Isolated Nonfastidious Gram-Negative Rods There are a few nonfastidious gram-negative rods that are not addressed in M2, M7, and M100 but that are capable of being grown using unsupplemented Mueller-Hinton medium. Aeromonas spp. may produce as many as three different β-lactamases, including a carbapenemase, that result in resistance to ampicillin, but variable susceptibility to cephalosporins.9 The significance of the carbapenemase produced

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by some strains is not fully understood.10 While Plesiomonas shigelloides is now regarded as a member of the Enterobacteriaceae,11 the genus has not been included in most prior studies to derive interpretive criteria for CLSI dilution and disk diffusion procedures as described in the most current editions of CLSI documents M2, M7, and M100. Most of the clinically significant noncholera Vibrio spp. can be grown in standard Mueller-Hinton medium. Susceptibilities of Vibrio spp. have been shown to vary by species, particularly with regard to the older penicillins, cephalosporins, and sulfonamides.12 Fastidious Gram-Negative Rods The HACEK (i.e., Haemophilus, Actinobacillus, Cardiobacterium, Eikenella, and Kingella) group of fastidious gram-negative bacilli has long been recognized as causative agents of infective endocarditis.13 Haemophilus aphrophilus or H. paraphrophilus are the species most often associated with endocarditis or brain abscess. Actinobacillus actinomycetemcomitans may be resistant to penicillins, macrolides, and aminoglycosides.14 Cardiobacterium hominis, Eikenella corrodens, Kingella spp., Capnocytophaga spp., and Pasteurella spp. may also produce β-lactamases that may be inhibited by clavulanic acid.15-18 The susceptibility testing conditions for Campylobacter spp. have been defined in the most current edition of CLSI document M100—Performance Standards for Antimicrobial Susceptibility Testing, although breakpoints have yet to be derived. Despite this, both fluoroquinolone and macrolide resistance have been reported in C. jejuni, C. coli, and C. fetus.19 Moraxella catarrhalis Moraxellae are intrinsically resistant to trimethoprim alone. The majority of M. catarrhalis strains produce one of two β-lactamases (BRO-1, or less commonly, BRO-2), rendering them resistant to penicillin and ampicillin.20 Acquired resistance in M. catarrhalis to tetracyclines and trimethoprim-sulfamethoxazole has been reported in some isolates; resistance to macrolides is very rare. The Development of Interpretive Criteria or Breakpoints In order to establish MIC interpretive criteria or breakpoints for new antimicrobial agents, to modify existing breakpoints, or to establish breakpoints for organisms that have not previously existed in the standards, the Antimicrobial Susceptibility Testing Subcommittee has employed an intensive analysis of MIC ranges of a particular drug with isolates that lack known resistance mechanisms, as well as with strains that contain known resistance mechanisms that affect the activity of the particular drug class. In addition, clinical and bacteriological response data collected during large clinical trials of new agents, as well as pharmacokinetic and pharmacodynamic simulations, are considered. The process of integrating these four types of data has been outlined in detail in CLSI/NCCLS document M23—Development of In Vitro Susceptibility Testing Criteria and Quality Control Parameters. Notably, however, when establishing or reestablishing breakpoints for older drugs or for organisms that have previously lacked breakpoints, large prospectively collected clinical data are often not available. This guideline has been developed to assist clinical microbiology laboratories in developing a strategy for susceptibility testing of infrequently encountered or fastidious organisms when circumstances indicate that testing of individual isolates would be helpful for clinical management, or for surveys of resistance for public health or research purposes. The testing methods and interpretive breakpoints included in this guideline have been proposed based upon an exhaustive search of the medical literature, and based upon the experience of the working group members. Breakpoints have been adapted from those for other, related organisms with approved CLSI breakpoints (see the most current edition of CLSI document M100—Performance Standards for Antimicrobial Susceptibility Testing) because of the similarities between MIC distributions and types of infections caused by the organisms. The derivation of the breakpoint is noted in the table for each organism. As stated, the large databases requested in CLSI/NCCLS document M23 have not been available for assessment with the “orphan” organisms included in this guideline.

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3 Standard Precautions Because it is often impossible to know what isolates or specimens might be infectious, all patient and laboratory specimens are treated as infectious and handled according to “standard precautions.” Standard precautions are guidelines that combine the major features of “universal precautions and body substance isolation” practices. Standard precautions cover the transmission of all infectious agents and thus are more comprehensive than universal precautions, which are intended to apply only to transmission of blood-borne pathogens. Standard and universal precaution guidelines are available from the U.S. Centers for Disease Control and Prevention (Garner JS. Hospital Infection Control Practices Advisory Committee. Guideline for isolation precautions in hospitals. Infect Control Hosp Epidemiol. 1996;17:53-80). For specific precautions for preventing the laboratory transmission of all infectious agents from laboratory instruments and materials and for recommendations for the management of exposure to all infectious disease, refer to the most current edition of CLSI document M29—Protection of Laboratory Workers From Occupationally Acquired Infections. 4 Definitions antimicrobial susceptibility test interpretive category – 1) a classification based on an in vitro response of an organism to an antimicrobial agent at levels corresponding to blood or tissue levels attainable with usually prescribed doses of that agent; 2) susceptible antimicrobial susceptibility test interpretive category – a category that implies that isolates are inhibited by the usually achievable concentrations of antimicrobial agent when the recommended dosage is used for the site of infection; 3) intermediate antimicrobial susceptibility test interpretive category – 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 (e.g., quinolones and β-lactams in urine) or when a higher than normal dosage of a drug can be used (e.g., 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; 4) resistant antimicrobial susceptibility test interpretive category – a category that 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 (e.g., β-lactamases) are likely, and clinical efficacy of the agent against the isolate has not been reliably shown in treatment studies. minimal inhibitory concentration (MIC) – the lowest concentration of an antimicrobial agent that prevents visible growth of a microorganism in an agar or broth dilution susceptibility test. quality control – in Microbiology, the operational techniques that are used to ensure accuracy and reproducibility. 5 Indications for Performing Susceptibility Tests Susceptibility testing is indicated for an organism that contributes to an infectious process warranting antimicrobial chemotherapy, if its susceptibility cannot be reliably predicted from knowledge of the organism’s identity. Susceptibility tests are most often indicated when the causative organism is thought to belong to a species capable of exhibiting resistance to commonly used antimicrobial agents. Certain organisms included in this guideline comprise part of the normal microbiota of human skin and mucous membranes (e.g., Corynebacterium spp., Abiotrophia and Granulicatella spp., Lactobacillus spp., Pediococcus spp., Leuconostoc spp.) or represent environmental organisms (Bacillus spp.). Susceptibility testing of these organisms should not be performed on isolates from nonsterile or superficial sources. The need for susceptibility testing of Aeromonas and Vibrio spp. isolates recovered from feces is

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controversial. Testing should only be undertaken in consultation with infectious diseases or other expert clinicians that can assist in determining if susceptibility testing is needed in the management of a specific patient, and in interpretation of any results generated. Generally, testing of these organisms should be limited to isolates recovered from normally sterile sites (e.g., blood, CSF, joint or bone specimens, prosthetic devices, or long-term indwelling catheters), serious wound infections (Aeromonas and Vibrio spp.), and refractory or persistent diarrhea due to Campylobacter jejuni/coli. When the nature of the infection is not clear and the specimen contains mixed growth of normal flora in which the organisms probably bear little relationship to the infectious process, susceptibility tests are often unnecessary, and the results may be misleading. Many times, therapy of individual patients infected with the organisms included in this guideline will be empiric, based upon the fact that a genus or species is very likely susceptible to a highly effective drug such that susceptibility testing would not be required. 6 Methods for Dilution Antimicrobial Susceptibility Testing of Infrequently Isolated or Fastidious Bacteria This document employs the standard broth microdilution technique. This technique is taken from CLSI document M7—Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically, based largely on information gathered from the International Collaborative Study on Antibiotic Sensitivity Testing.21 Although this method is primarily a standard reference method, it may be sufficiently practical to warrant its use both in clinical and research laboratories. The details of performing the broth microdilution procedure are not repeated in this document. Instead, readers should refer directly to the most current edition of M7 for procedural details. However, key elements of the recommended methods are highlighted in each organism table for easy reference. 6.1 Selection of Antimicrobial Agents To make routine susceptibility testing relevant and practical, the number of agents tested should be limited. In each organism table in this document, the consensus primary antimicrobial agents for testing are highlighted in a box labeled “Agents to Consider for Primary Testing.” Interpretive criteria are provided for the primary agents and several potentially useful alternatives for each organism (see Tables 1 to 14). This does not imply that testing of every agent in each table should be undertaken. In consultation with the clinicians caring for the patient, a priority list of critical drugs for a specific patient’s isolate can be developed. 6.2 Antimicrobial Agents A comprehensive review of antimicrobial agent classes, including those in this document, can be found in CLSI document M7—Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically, and will not be repeated here. 6.2.1 Broth Microdilution Procedure The broth microdilution procedure employing either cation-adjusted Mueller-Hinton broth or cation-adjusted Mueller-Hinton broth supplemented with lysed horse blood (2.5 to 5% v/v) is described in detail in CLSI document M7. The latest edition of M7 should be consulted for the details of medium preparation, drug dilutions, inoculum preparation, incubation, and reading of MIC end points. 6.3 Interpretive Categories In addition to the MICs generated with one or more antimicrobial agents on a particular isolate, an interpretive category of susceptible, intermediate, or resistant can be assigned based upon the tables

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included in this document. Definitions of those categories can be found in CLSI document M7 and in Section 4 above.

If only “S” criteria are specified: For some organism/antimicrobial 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. Subsequently, the isolates should be saved and submitted to a reference laboratory that will confirm results using a CLSI reference dilution method.

7 Methods for Antimicrobial Disk Diffusion Susceptibility Testing of Infrequently Isolated or Fastidious Bacteria In many clinical microbiology laboratories, the agar disk diffusion method is used for testing the common, rapidly growing bacterial pathogens and sometimes for fastidious species as indicated above. In laboratories that routinely perform dilution testing or use an automated susceptibility testing device, the disk diffusion test may represent a convenient method for testing the infrequently isolated organisms described in this guideline. The standardized disk diffusion testing method recommended by the CLSI Subcommittee on Antimicrobial Susceptibility Testing is described in CLSI document M2—Performance Standards for Antimicrobial Disk Susceptibility Tests. Disk diffusion testing interpretive criteria are provided where possible in M45. It is best suited to testing the rapidly growing pathogens (including Aeromonas spp. and Vibrio spp.) and modified for testing some fastidious organisms, such as Campylobacter jejuni/coli and Pasteurella spp. Adequate studies have not been conducted to recommend reproducible disk diffusion breakpoints for many of the organisms in this guideline. For those organisms, only the broth microdilution test should be performed. Such organisms should not be tested by the disk diffusion method, because the results cannot be interpreted reliably. The preparation of Mueller-Hinton agar including supplementation with 5% defibrinated sheep blood for fastidious organisms is described in the most current edition of CLSI document M2. 8 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 modification thereof) on the patient report. An example would be inclusion of a comment that “Rifampin should not be used alone for chemotherapy.” 9 Quality Control An effective quality control program is designed to monitor the accuracy of a susceptibility test procedure, the performance of reagents and equipment, and the performance of persons who conduct the tests. These goals are best realized with the use of standard reference strains selected for their genetic stability and for their usefulness in the particular method. A detailed approach to performance of routine quality control testing and maintenance of quality control strains is outlined in both CLSI documents M2 and M7. The latest edition of those documents should be consulted for the recommended quality control procedures. The standard control strains recommended in those documents are applicable to quality control of the media and procedures recommended in this document for infrequently isolated or fastidious bacteria. For that reason, an abbreviated list of acceptable limits of MICs and zone diameters has been extracted from CLSI documents M2 and M7 (and the accompanying M100 supplement) for inclusion in Tables 16, 16A, 16B, 17, and 17A of this document. Other control values may be extracted from M100, if needed to provide on-scale MICs for individual test panels.

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9.1 Minimum Laboratory Requirements for Testing Infrequently Isolated or Fastidious Bacteria Most MIC and disk diffusion tests described in M45-A should only be performed in select situations by qualified laboratorians experienced with the recommended procedures. Criteria that can be used to determine qualifications include: • performs antimicrobial susceptibility testing at least once per week using a CLSI broth microdilution

reference method or an FDA-cleared commercial microdilution method with visual interpretations of MICs, and that may be adapted and validated for the testing conditions described in this guideline;

• performs antimicrobial susceptibility testing at least once per week using a CLSI disk diffusion

reference method, if Aeromonas spp., Plesiomonas spp., Vibrio spp., Campylobacter jejuni/coli or Pasteurella spp. will be tested by disk diffusion;

• possesses the most current editions of CLSI documents M2, M7, and M100; • is part of a clinical microbiology laboratory coordinated by a doctoral-level clinical microbiologist,

infectious diseases physician, or pathologist with expertise in antimicrobial susceptibility testing.

10 Detection of Resistance to Some β-Lactams by a Direct β-Lactamase Test Testing for β-lactamase activity using a chromogenic, cephalosporin-based method such as nitrocefin may yield clinically relevant information earlier than the results of an MIC test. A positive β-lactamase test result predicts resistance to penicillin, ampicillin, and amoxicillin among Haemophilus spp., M. catarrhalis, Cardiobacterium hominis, Eikenella corrodens, Kingella spp., and Pasteurella spp. A negative β-lactamase test result does not rule out resistance due to other mechanisms. Do not test organisms other than those listed above, because the results may not be predictive of susceptibility or resistance to the β-lactams most often used for therapy.

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References 1 Hindler JF, Swenson JM. Susceptibility test methods: fastidious bacteria. In: Murray PR, Baron EJ, Jorgensen JH, Pfaller MA,

Yolken RH, eds. Manual of Clinical Microbiology. 8th ed. Washington, DC: ASM Press; 2003:1128-1140. 2 Jorgensen JH. The need for susceptibility testing guidelines for fastidious or less-frequently isolated bacteria. Minireview. J Clin

Microbiol. 2004;42:493-496. 3 Andrews JM, Wise R. Susceptibility testing of Bacillus species. J Antimicrob Chemother. 2002;49:1039-1046. 4 Funke G, Pünter V, von Graevenitz A. Antimicrobial susceptibility patterns of some recently established coryneform bacteria.

Antimicrob Agents Chemother. 1996;40:2874-2878. 5 Funke G, Bernard KA. Coryneform gram-positive rods. In: Murray PR, Baron EJ, Jorgensen JH, Pfaller MA, Yolken RH, eds.

Manual of Clinical Microbiology. 8th ed. Washington, DC: ASM Press; 2003:472-501. 6 Funke G, Lawson PA, Nolte FS, Weiss N, Collins MD. Aureobacterium resistens spp. Nov. exhibiting vancomycin resistance and

teicoplanin susceptibility. FEMS Microbiol Lett. 1998;158:89-93. 7 Deye G, Lewis J, Patterson J, Jorgensen J. A case of Leuconostoc ventriculitis with resistance to carbapenem antibiotics. Clin Infect

Dis. 2003;37:869-870. 8 Murray CK, Walter EA, Crawford S, McElmeel ML, Jorgensen JH. Abiotrophia bacteremia in a patient with neutropenic fever and

antimicrobial susceptibility testing of Abiotrophia isolates. Clin Infect Dis. 2001;32:e140-e142. 9 Rossolini GM, Walsh T, Amicosante G. The Aeromonas metallo-β-lactamases: genetics, enzymology, and contribution to drug

resistance. Microb Drug Resist. 1996;2:245-251. 10 Hayes MV, Thomson CJ, Amyes SGB. The “hidden” carbapenemase of Aeromonas hydrophila. J Antimicrob Chemother.

1996;37:33-44. 11 Abbott SL. Klebsiella, Enterobacter, Citrobacter, Serratia, Plesiomonas, and other Enterobacteriaceae. In: Murray PR, Baron EJ,

Jorgensen JH, Pfaller MA, Yolken RH, eds. Manual of Clinical Microbiology. 8th ed. Washington, DC: ASM Press; 2003:684-700. 12 Farmer JJ III, Janda JM, Birkhead K. Vibrio. In: Murray PR, Baron EJ, Jorgensen JH, Pfaller MA, Yolken RH, eds. Manual of

Clinical Microbiology. 8th ed. Washington, DC: ASM Press; 2003:706-718. 13 Das M, Bradley AD, Cockerill FR, Steckelberg JM, Wilson WR. Infective endocarditis caused by HACEK microorganisms. Ann

Rev Med. 1997;48:25-33. 14 Kugler KC, Biedenback DJ, Jones RN. Determination of the antimicrobial activity of 29 clinically important compounds tested

against fastidious HACEK group organisms. Diagn Microbiol Infect Dis. 1999;34:73-76. 15 Gomez-Garces JL, Alos JI, Sanchez J, Cogollos R. Bacteremia by multidrug-resistant Capnocytophaga sputigena. J Clin Microbiol.

1994;32:1067-1069. 16 Lu PL, Hsueh PR, Hung CC, Teng LJ, Jang TN, Luh KT. Infective endocarditis complicated with progressive heart failure due to

β-lactamase-producing Cardiobacterium hominis. J Clin Microbiol. 2000;38:2015-2017. 17 Paul K, Patel SS. Eikenella corrodens infections in children and adolescents: case reports and review of the literature. Clin Infect

Dis. 2001;33:54-61. 18 Sordillo EM, Rendel M, Sood R, Belinfanti J, Murray O, Brook D. Septicemia due to β-lactamase-positive Kingella kingae. Clin

Infect Dis. 1993;17:818-819. 19 Engberg J, Aarestrup FM, Taylor DE, Gerner-Schmidt P, Nachamkin I. Quinolone and macrolide resistance in Campylobacter

jejuni and C. coli resistance mechanisms and trends in human isolates. Emerg Infect Dis. 2001;7:24-34. 20 Wallace RJ, Steingrube VA, Nash DR, et al. BRO ß-lactamases of Branhamella catarrhalis and Moraxella subgenus Moraxella,

including evidence for chromosomal ß-lactamase transfer by conjugation in B. catarrhalis, M. nonliquefaciens, and M. lacunata. Antimicrob Agents Chemother. 1989;33:1845-1854.

21 Ericsson HM, Sherris JC. Antibiotic sensitivity testing: report of an international collaborative study. Acta Pathol Microbiol Scand.

1971;217(suppl. B):1-90.

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Table 1. Abiotrophia species and Granulicatella species (Formerly Known as Nutritionally Deficient or Nutritionally Variant Streptococci)—Information and Interpretive Criteria for Broth Microdilution Susceptibility Testing

General Comments (1) Growth characteristics on routine media: very fastidious; requires cysteine or pyridoxal for growth. Some strains may grow marginally on enriched

chocolate agar or anaerobe agar formulations supplemented with added cysteine; CO2; 20 to 24 hours. (2) For some organism/antimicrobial 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. Subsequently, the isolates should be saved and submitted to a reference laboratory for confirmation.

MIC (µg/mL) Interpretive Criteria

Antimicrobial

Class

Antimicrobial Agent

S I R

Comments

PENICILLINS Penicillin ≤0.12 0.25-2

≥4

Ampicillin ≤0.25 0.5-4 ≥8 CEPHEMS Cefepime ≤1 2 ≥4 Cefotaxime ≤1 2 ≥4 Ceftriaxone ≤1 2 ≥4 CARBAPENEMS Imipenem ≤0.5 1 ≥2 Meropenem ≤0.5 1 ≥2 GLYCOPEPTIDES

Vancomycin ≤1 - - See comment (2).

Testing Conditions Medium: Cation-adjusted Mueller-Hinton broth with lysed

horse blood (2.5 to 5% v/v) and 0.001% (i.e., 1 µg/mL) pyridoxal hydrochloride

Inoculum: Direct colony suspension, equivalent to a 0.5 McFarland standard Incubation: 35 °C; ambient air; 20 to 24 hours

Minimal QC Recommendations Streptococcus pneumoniae ATCC®a 49619

Agents to Consider for Primary Testing Penicillin Vancomycin Cefotaxime or ceftriaxone

10 ©Clinical and Laboratory Standards Institute. All rights reserved.

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Table 1. Abiotrophia species and Granulicatella species (Continued)

Footnote

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

Supplemental Information

Resistance: Abiotrophia spp. and Granulicatella spp. may demonstrate diminished susceptibility to penicillin, resulting in greater difficulty in treatment of patients with endocarditis; in one case, fluoroquinolone resistance was reported in an isolate from an immunosuppressed patient (see reference 7 under Additional References). Reasons for Testing/Not Testing: For isolates from respiratory sources or wounds, testing is usually not necessary. Testing of isolates from normally sterile sources (blood cultures, deep tissue, implanted prosthetic devices) may be warranted, especially in immunodeficient patients. Derivation of Interpretive Criteria: Interpretive criteria are adapted from those for Streptococcus spp. as published in the most current edition of CLSI document M100. Key citations used in derivation of interpretive breakpoints include references 2, 7, and 11 under Additional References. Testing Notes: Many laboratories cannot readily distinguish Abiotrophia spp. from Granulicatella spp. or determine species level identification. The requirement for cysteine or pyridoxal in the medium or satellite growth is characteristic for both Abiotrophia and Granulicatella. Many laboratories may not do additional tests to separate Abiotrophia from Granulicatella or to obtain a species identification.


Antimicrobial

Class

Antimicrobial Agent

S I R

Comments

MACROLIDES Erythromycin ≤0.25 0.5 ≥1

QUINOLONES Ciprofloxacin ≤1 2 ≥4 Gatifloxacin ≤1 2 ≥4 Levofloxacin ≤2 4 ≥8

PHENICOLS Chloramphenicol ≤4 - ≥8

LINCOSAMIDES Clindamycin ≤0.25 0.5 ≥1


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45-ATable 2. Aeromonas hydrophila Complex (Includes A. caviae, A. hydrophila, A. jandaei, A. schubertii, and A. veronii, Two Biotypes) and Plesiomonas shigelloides—Information and Interpretive Criteria for Broth Microdilution and Disk Diffusion Susceptibility Testing

General Comments (1) Growth characteristics on routine media: nonfastidious; grows well on BAP; ambient air; 16 to 20 hours.

Zone Diameter (mm) Interpretive Criteria


Comments Antimicrobial

Class

Antimicrobial Agent

Disk

Content S I R S I R

PENICILLINS AND β-LACTAM/β-LACTAMASE INHIBITOR COMBINATIONS Amoxicillin-clavulanic

acid 20/10 µg ≥18 14-17 ≤13 ≤8/4 16/8 ≥32/16

Ampicillin-sulbactam 10/10 µg ≥15 12-14 ≤11 ≤8/4 16/8 ≥32/16 Piperacillin-

tazobactam 100/10 µg ≥21 18-20 ≤17 ≤16/4 32/4-64/4 ≥128/4

CEPHEMS Cefazolin 30 µg ≥18 15-17 ≤14 ≤8 16 ≥32 Cefepime 30 µg ≥18 15-17 ≤14 ≤8 16 ≥32 Cefotaxime 30 µg ≥23 15-22 ≤14 ≤8 16-32 ≥64 Cefoxitin 30 µg ≥18 15-17 ≤14 ≤8 16 ≥32 Ceftazidime 30 µg ≥18 15-17 ≤14 ≤8 16 ≥32 Ceftriaxone 30 µg ≥21 14-20 ≤13 ≤8 16-32 ≥64 Cefuroxime sodium

(parenteral) 30 µg ≥18 15-17 ≤14 ≤8 16 ≥32

Cephalothin 30 µg ≥18 15-17 ≤14 ≤8 16 ≥32 CARBAPENEMS

Ertapenem 10 µg ≥19 16-18 ≤15 ≤2 4 ≥8 Imipenem 10 µg ≥16 14-15 ≤13 ≤4 8 ≥16 Meropenem 10 µg ≥16 14-15 ≤13 ≤4 8 ≥16

Testing Conditions Medium: Cation-adjusted Mueller-Hinton broth for microdilution, Mueller-Hinton agar for disk diffusion testing Inoculum: Direct colony suspension, equivalent to a 0.5 McFarland standard Incubation: 35 °C; ambient air; 16 to 20 hours

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

Agents to Consider for Primary Testing Amoxicillin-clavulanic acid Fluoroquinolones Trimethoprim-sulfamethoxazole 3rd- or 4th-generation cephalosporins


Table 2. Aeromonas hydrophila Complex and Plesiomonas shigelloides (Continued)


Aeromonas spp. There are currently 14 valid species in the genus Aeromonas; however, only five (A. caviae, A. hydrophila, A. jandaei, A. schubertii, and A. veronii) are currently recognized as human pathogens causing a variety of clinical infections including gastroenteritis, cellulitis, and bacteremia. New syndromes attributed to this genus include hemolytic uremic syndrome, burn-associated sepsis, and a variety of respiratory tract infections, including epiglottitis. The three Aeromonas spp. predominantly recovered from clinical material are A. hydrophila, A. caviae, and A. veronii biotype sobria. Therefore, most of the published data on susceptibility testing are limited to these three species. Plesiomonas spp. The genus Plesiomonas with its only species, P. shigelloides, has recently been placed in the family Enterobacteriaceae. However, because of its phenotypic similarity to Aeromonas spp., as well as its similar disease spectrum, it is included with Aeromonas in these susceptibility testing guidelines. Resistance: Aeromonas spp. are uniformly resistant to ampicillin; however, susceptibility to amoxicillin-clavulanic acid and cefazolin differs among species. Aeromonas strains may possess multiple, distinct, inducible β-lactamases and like other genera with inducible β-lactamases, resistance may emerge during therapy with a β-lactam. Plesiomonas spp. are resistant to penicillins due to the production of penicillinases. There are conflicting data regarding resistance of P. shigelloides to ampicillin and other penicillin drugs, and this may be related to test medium and inoculum effect. As a result, testing of P. shigelloides to ampicillin is not recommended in this guideline. Reasons for Testing/Not Testing: Testing is most often limited to isolates from extraintestinal sites. Derivation of Interpretive Criteria: Interpretive criteria are adapted from those for Enterobacteriaceae as published in the most current edition of CLSI document M100. Key citations used in derivation of interpretive breakpoints for Aeromonas spp. include references 13, and 17 to 22; and for Plesiomonas shigelloides include references 25 to 29 under Additional References.




Class

Antimicrobial

Agent

Disk Content

S I R S I R MONOBACTAMS

Aztreonam 30 µg ≥22 16-21 ≤15 ≤8 16 ≥32 AMINOGLYCOSIDES

Amikacin 30 µg ≥17 15-16 ≤14 ≤16 32 ≥64 Gentamicin 10 µg ≥15 13-14 ≤12 ≤4 8 ≥16

TETRACYCLINES Tetracycline 30 µg ≥19 15-18 ≤14 ≤4 8 ≥16

QUINOLONES Ciprofloxacin 5 µg ≥21 16-20 ≤15 ≤1 2 ≥4 Levofloxacin 5 µg ≥17 14-16 ≤13 ≤2 4 ≥8

FOLATE PATHWAY INHIBITORS Trimethoprim-

sulfamethoxazole 1.25/23.75 µg ≥16 11-15 ≤10 ≤2/38 - ≥4/76

PHENICOLS Chloramphenicol 30 µg ≥18 13-17 ≤12 ≤8 16 ≥32


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Table 3. Bacillus species (Not B. anthracis)—Information and Interpretive Criteria for Broth Microdilution Susceptibility Testing

General Comments

(1) Growth characteristics on routine media: nonfastidious; grows well on BAP; ambient air; 16 to 20 hours. (2) For some organism/antimicrobial combinations, the absence or rare occurrence of resistant strains precludes defining any results categories other than



Antimicrobial

Class

Antimicrobial Agent

S I R

Comments

PENICILLINS Penicillin ≤0.12 - ≥0.25 Ampicillin ≤0.25 - ≥0.5

CEPHEMS Cefazolin ≤8 16 ≥32 Cefotaxime ≤8 16-32 ≥64 Ceftazidime ≤8 16 ≥32 Ceftriaxone ≤8 16-32 ≥64

CARBAPENEMS Imipenem ≤4 8 ≥16

GLYCOPEPTIDES Vancomycin ≤4 - - See comment (2).

AMINOGLYCOSIDES Amikacin ≤16 32 ≥64 Gentamicin ≤4 8 ≥16

MACROLIDES Erythromycin ≤0.5 1-4 ≥8

Testing Conditions Medium: Cation-adjusted Mueller-Hinton broth Inoculum: Direct colony suspension, equivalent to a 0.5 McFarland

standard Incubation: 35 °C; ambient air; 16 to 20 hours

Minimal QC Recommendations Staphylococcus aureus ATCC® 29213

Agents to Consider for Primary Testing Vancomycin Clindamycin Gentamicin (for combined therapy)

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Table 3. Bacillus species (Continued)


Antimicrobial

Class

Antimicrobial Agent

S I R

Comments

TETRACYCLINES Tetracycline ≤4 8 ≥16

QUINOLONES Ciprofloxacin ≤1 2 ≥4 Levofloxacin ≤2 4 ≥8

LINCOSAMIDES Clindamycin ≤0.5 1-2 ≥4

FOLATE PATHWAY INHIBITORS Trimethoprim-sulfamethoxazole ≤2/38 - ≥4/76

PHENICOLS Chloramphenicol ≤8 16 ≥32

ANSAMYCINS Rifampin ≤1 2 ≥4 (3) Rx: Rifampin should not be used alone for chemotherapy.


Resistance: Bacillus cereus isolates are generally resistant to penicillins and cephalosporins. Reasons for Testing/Not Testing: Bacillus spp. are frequently encountered as contaminating bacteria in cultures. Testing of isolates from normally sterile sources (blood cultures, deep tissue, implanted prosthetic devices) may be warranted, especially in immunodeficient patients. Derivation of Interpretive Criteria: Interpretive criteria are adapted from those for Staphylococcus spp. as published in the most current edition of CLSI document M100. Key citations used in derivation of interpretive breakpoints include references 30 to 32 under Additional References. Testing Notes: Although many Bacillus spp. produce β-lactamase, β-lactamase testing of this genus is unreliable. Recommendations for disk diffusion of Bacillus spp. cannot be made at this time, as limited data exist for disk diffusion testing of this genus.


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Table 4. Campylobacter jejuni/coli—Information and Interpretive Criteria for Broth Microdilution and Disk Diffusion Susceptibility Testing

General Comments (1) Growth characteristics on routine media: fastidious; grows on media such as Mueller-Hinton agar supplemented with 5% sheep blood; requires a microaerobic atmosphere (10% CO2, 5% O2, and 85% N2); 36 to 37 °C for 48 hours or 42 °C for 24 hours.



Antimicrobial

Class

Antimicrobial

Agent

Disk

Content S I R S I R

Comments

MACROLIDE Erythromycin 15 µg - - 6 ≤8 16 ≥32 (2) A disk diffusion zone of 6 mm (growth up to the edge

of a 6-mm disk) indicates macrolide (e.g., erythromycin) resistance. Appearance of any zone of inhibition would require MIC determination for accurate categorization of susceptibility.

QUINOLONE Ciprofloxacin 5 µg - - 6 ≤1 2 ≥4 (3) A disk diffusion zone of 6 mm (growth up to the edge

of a 6-mm disk) indicates ciprofloxacin resistance. Appearance of any zone of inhibition would require MIC determination for accurate categorization of susceptibility.

TETRACYCLINES Tetracycline - - - - ≤4 8 ≥16 Doxycycline - - - - ≤2 4 ≥8

Testing Conditions Medium: Cation-adjusted Mueller-Hinton broth with lysed horse blood (2.5 to 5% v/v) for microdilution, Mueller-Hinton agar with 5% sheep blood (BMHA) for disk diffusion testing. Inoculum: Direct colony suspension, equivalent to a 0.5 McFarland standard Incubation: 36 to 37 °C for 48 hours or 42 °C for 24 hours (incubation at less than

36 °C or greater than 42 °C may not yield satisfactory growth). Microaerobic atmosphere equivalent to 10% CO2, 5% O2, and 85% N2. Use of a compressed gas incubator is preferable; however, acceptable performance may be achieved using microaerobic gas-generating sachets. Sealed plastic bags or pouches do not result in reproducible data, and are not recommended.

Minimal QC Recommendations Microdilution: Campylobacter jejuni ATCC® 33560, 36 to 37 °C for 48 hours or 42 °C for 24 hours Disk Diffusion: Staphylococcus aureus ATCC® 25923, MHA, 35 to 37 °C for 16 to 18 hours in ambient air

Agents to Consider for Primary Testing Erythromycin Ciprofloxacin


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Table 4. Campylobacter jejuni/coli (Continued)

Supplemental Information Resistance: Resistance among Campylobacter jejuni/coli is known to occur with erythromycin (0 to11%), but is more problematic with fluoroquinolones and is highly variable from country to country, with rates of 10% to as high as 40% being reported. Emergence of resistance to ciprofloxacin may occur while on therapy. Strains resistant to both macrolides and fluoroquinolones have been reported. Reasons for Testing/Not Testing: Testing may be useful for epidemiological purposes or for management of patients with prolonged or severe symptoms. Derivation of Interpretive Criteria: Interpretive criteria are adapted from those for Enterobacteriaceae (ciprofloxacin and tetracycline) as published in the most current edition of CLSI document M100. Interpretive criteria for erythromycin and doxycycline are based on population distributions following testing of 150 strains of wild-type Campylobacter jejuni/coli at 36 to 37 °C, using a microaerobic atmosphere for 48 hours. The erythromycin and ciprofloxacin disk diffusion screening breakpoints were developed by testing a group of 417 susceptible or resistant Campylobacter jejuni/coli isolates. These studies were conducted by two members of the CLSI M45 working group. Key citations used in derivation of interpretive breakpoints include references 36, 39, and 43 under Additional References.

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Table 5. Corynebacterium species (Including C. diphtheriae)—Information and Interpretive Criteria for Broth Microdilution Susceptibility Testing

General Comments

(1) Growth characteristics on routine media: often fastidious; requires blood supplemented media for adequate growth; ambient air; 20 to 24 hours. (2) For some organism/antimicrobial combinations, the absence or rare occurrence of resistant strains precludes defining any results categories other than



Antimicrobial

Class

Antimicrobial Agent

S I R

Comments

PENICILLINS (3) Interpretive criteria may not apply to meningitis. Penicillin ≤1 2 ≥4

CEPHEMS See comment (3). Cefepime ≤1 2 ≥4 Cefotaxime ≤1 2 ≥4 Ceftriaxone ≤1 2 ≥4

CARBAPENEMS See comment (3). Imipenem ≤4 8 ≥16 Meropenem ≤4 8 ≥16

GLYCOPEPTIDES Vancomycin ≤4 - - See comment (2).

LIPOPEPTIDES Daptomycin ≤1 - - See comment (2).

Testing Conditions Medium Cation-adjusted Mueller-Hinton broth with lysed horse blood (2.5 to 5% v/v). If testing daptomycin, the medium should contain 50 µg/mL calcium. Inoculum Direct colony suspension, equivalent to a 0.5 McFarland standard Incubation 35 °C; ambient air; 24 to 48 hours (see Testing Notes)

Minimal QC Recommendations Streptococcus pneumoniae ATCC® 49619 Escherichia coli ATCC® 25922 for gentamicin

Agents to Consider for Primary Testing Penicillin Vancomycin Erythromycin Gentamicin


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Table 5. Corynebacterium species (Continued)


Antimicrobial

Class

Antimicrobial Agent

S I R

Comments

AMINOGLYCOSIDES Gentamicin ≤4 8 ≥16

MACROLIDES Erythromycin ≤0.5 1 ≥2

QUINOLONES Ciprofloxacin ≤1 2 ≥4

TETRACYCLINES Doxycycline ≤4 8 ≥16 Tetracycline ≤4 8 ≥16


FOLATE PATHWAY INHIBITORS Trimethoprim-sulfamethoxazole ≤2/38 - ≥4/76


STREPTOGRAMINS Quinupristin-dalfopristin ≤1 2 ≥4

OXAZOLIDINONES Linezolid ≤2 - - See comment (2).


Resistance: Some species of Corynebacterium may exhibit resistance to multiple drug classes. Reasons for Testing/Not Testing: Testing of isolates from normally sterile sources (blood cultures, deep tissue, implanted prosthetic devices) may be warranted, especially in immunodeficient patients. Derivation of Interpretive Criteria: Interpretive criteria for penicillin and erythromycin are based primarily on MIC distributions following testing of a large number of isolates. Cephalosporin interpretive criteria are adapted from those for Streptococcus spp.; linezolid interpretive criteria are adapted from those for Enterococcus spp.; and remaining interpretive criteria are adapted from those for Staphylococcus spp. as published in the most current edition of CLSI document M100. In addition to the citations listed at the end of this document, data from three large organism collections tested by two of the working group members were used to derive the interpretive breakpoints. Testing Notes: Resistant results can be reported at 24 hours. Isolates demonstrating susceptible results for β-lactams should be reincubated and results reported at 48 hours.


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Table 6. Erysipelothrix rhusiopathiae—Information and Interpretive Criteria for Broth Microdilution Susceptibility Testing

General Comments (1) Growth characteristics on routine media: fastidious; may take one to three days for colonies to grow on BAP or chocolate agar; ambient air. At 24 hours,

growth may be pinpoint colonies. (2) For some organism/antimicrobial combinations, the absence or rare occurrence of resistant strains precludes defining any results categories other than



Antimicrobial

Class

Antimicrobial Agent

S I R

Comments

PENICILLINS Penicillin ≤0.12 - - See comment (2). Ampicillin ≤0.25 - - See comment (2).

CEPHEMS Cefepime ≤1 - - See comment (2). Cefotaxime ≤1 - - See comment (2). Ceftriaxone ≤1 - - See comment (2).

CARBAPENEMS Imipenem ≤0.5 - - See comment (2). Meropenem ≤0.5 - - See comment (2).

MACROLIDES Erythromycin ≤0.25 0.5 ≥1

QUINOLONES Ciprofloxacin ≤1 - - See comment (2). Gatifloxacin ≤1 - - See comment (2). Levofloxacin ≤2 - - See comment (2).

LINCOSAMIDES Clindamycin ≤0.25 0.5 ≥1

Testing Conditions Medium: Cation-adjusted Mueller-Hinton broth with lysed horse

blood (2.5 to 5% v/v) Inoculum: Direct colony suspension, equivalent to a 0.5 McFarland


Minimal QC Recommendations Streptococcus pneumoniae ATCC® 49619

Agents to Consider for Primary Testing Penicillin or ampicillin


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Table 6. Erysipelothrix rhusiopathiae (Continued)

Supplemental Information Resistance: Erysipelothrix rhusiopathiae is considered intrinsically resistant to vancomycin; routine testing of vancomycin is not necessary. No resistance has been described for β-lactams and fluoroquinolones. Reasons for Testing/Not Testing: Although antimicrobial susceptibility testing is not required, it is important to promptly identify this organism because of its potentially fulminant nature when causing endocarditis, and the fact that it is intrinsically resistant to vancomycin, the therapy often used empirically for gram-positive organisms. For patients with penicillin allergy, testing of erythromycin and clindamycin may be warranted. Derivation of Interpretive Criteria: Interpretive criteria for ciprofloxacin are adapted from those for Staphylococcus spp. as published in the most current edition of CLSI document M100. Interpretive criteria for all other antimicrobial agents are adapted from those for Streptococcus spp. as published in CLSI document M100. Key citations used in derivation of interpretive breakpoints include references 68, and 70 to 72 under Additional References.


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Table 7. HACEK Group: the Aphrophilus Cluster of the Genus Haemophilus (i.e., H. aphrophilus, H. paraphrophilus, H. segnis), Actinobacillus actinomycetemcomitans, Cardiobacterium species, Eikenella corrodens, and Kingella species—Information and Interpretive Criteria for Broth Microdilution Susceptibility Testing

General Comments (1) Growth characteristics on routine media: very fastidious; most will grow on BAP or chocolate agar in CO2; 24 to 48 hours; some strains may not grow well

in supplemented broths (CAMHB + 2.5 to 5% LHB). See Testing Notes.

(2) For some organism/antimicrobial 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. Subsequently, the isolates should be saved and submitted to a reference laboratory for confirmation.


Antimicrobial

Class

Antimicrobial Agent

S I R

Comments

PENICILLINS AND β-LACTAM/β-LACTAMASE INHIBITOR COMBINATIONS Ampicillin ≤1 2 ≥4 Ampicillin-sulbactam ≤2/1 - ≥4/2 Amoxicillin-clavulanic acid ≤4/2 - ≥8/4 Penicillin ≤1 2 ≥4

CEPHEMS Ceftriaxone ≤2 - - See comment (2). Cefotaxime ≤2 - - See comment (2).

CARBAPENEMS Imipenem (Haemophilus spp.) ≤4 8 ≥16 Meropenem (Haemophilus spp.) ≤4 8 ≥16 Imipenem (Other organisms) ≤0.5 1 ≥2 Meropenem (Other organisms) ≤0.5 1 ≥2


blood (2.5 to 5% v/v) Inoculum: Direct colony suspension, equivalent to a 0.5

McFarland standard Incubation: 35 °C; 5% CO2; 24 to 48 hours

Minimal QC Recommendations Streptococcus pneumoniae ATCC® 49619 Escherichia coli ATCC® 35218 (for β-lactam/β-lactamase inhibitor combinations)

Agents to Consider for Primary Testing Ceftriaxone or cefotaxime Ampicillin Amoxicillin-clavulanic acid Imipenem Ciprofloxacin or levofloxacin Trimethoprim-sulfamethoxazole


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Table 7. HACEK Group: the Aphrophilus Cluster of the Genus Haemophilus (Continued)


Antimicrobial

Class

Antimicrobial Agent

S I R

Comments

MACROLIDES Azithromycin ≤4 - - See comment (2). Clarithromycin ≤8 16 ≥32

QUINOLONES Ciprofloxacin ≤1 2 ≥4 Levofloxacin ≤2 4 ≥8




FOLATE PATHWAY INHIBITORS Trimethoprim-sulfamethoxazole ≤0.5/9.5 1/19-2/38 ≥4/76

Supplemental Information Resistance: β-lactamase production among members of the HACEK group is well-documented, and β-lactamase-producing isolates are ampicillin resistant. Some isolates of Haemophilus spp. and Actinobacillus spp. may be resistant to ampicillin due to mechanisms other than β-lactamase production. Reasons for Testing/Not Testing: Testing of isolates from normally sterile sources (blood cultures, deep tissue, implanted prosthetic devices) may be warranted, especially in immunodeficient patients or those patients unable to tolerate empiric β-lactam therapy. For isolates of Eikenella from bite wound infections, testing may not be necessary when using amoxicillin-clavulanate, considering the high probability of susceptibility to amoxicillin-clavulanic acid. Derivation of Interpretive Criteria: Interpretive criteria for penicillin are based primarily on MIC distributions. Chloramphenicol interpretive criteria are adapted from those for Streptococcus spp.; all others are adapted from those for Haemophilus influenzae. Key citations used in derivation of interpretive breakpoints include references 79, 85, 88 to 90, and 94 under Additional References. Testing Notes: Routine performance of a β-lactamase test is recommended for all HACEK isolates. Antimicrobial susceptibility testing may be difficult, given the slow growth and fastidiousness of some members in the HACEK group. Do not attempt to interpret results of testing for isolates that produce insufficient growth in growth-control wells.


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Table 8. Lactobacillus species—Information and Interpretive Criteria for Broth Microdilution Susceptibility Testing

General Comments (1) Growth characteristics on routine media: often fastidious; requires blood supplemented media for adequate growth; ambient air; 20 to 24 hours.

(2) For some organism/antimicrobial combinations, the absence or rare occurrence of resistant strains precludes defining any results categories other than


MIC (µg/mL)

Interpretive Criteria

Antimicrobial Class

Antimicrobial Agent

S I R

Comments

PENICILLINS Penicillin ≤8 - - See comment (2). Ampicillin ≤8 - - See comment (2).

CARBAPENEMS Imipenem ≤0.5 - - See comment (2).


GLYCOPEPTIDES Vancomycin ≤4 8-16 ≥32

MACROLIDES Erythromycin ≤0.5 1-4 ≥8






Agents to Consider for Primary Testing Penicillin or ampicillin Gentamicin (for combined therapy)

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Table 8. Lactobacillus species (Continued)

Supplemental Information Resistance: Many species of Lactobacillus spp. that grow well in ambient air are intrinsically resistant to vancomycin. Reasons for Testing/Not Testing: Testing of isolates from normally sterile body sources (blood cultures, deep tissue) may be warranted. Derivation of Interpretive Criteria: Interpretive criteria for gentamicin are adapted from those for Staphylococcus spp. as published in the most current edition of CLSI document M100. Interpretive criteria for all other antimicrobial agents are adapted from those for Enterococcus spp. as published in CLSI document M100. Key citations used in derivation of interpretive breakpoints include references 96 to 99 under Additional References.


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Table 9. Leuconostoc species—Information and Interpretive Criteria for Broth Microdilution Susceptibility Testing

General Comments (1) Growth characteristics on routine media: often fastidious; requires blood supplemented media for adequate growth; ambient air; 20 to 24 hours. (2) For some organism/antimicrobial combinations, the absence or rare occurrence of resistant strains precludes defining any results categories other than



Antimicrobial

Class

Antimicrobial Agent

S I R

Comments



TETRACYCLINES Minocycline ≤4 8 ≥16



Resistance: Leuconostoc spp. are considered intrinsically resistant to vancomycin; routine testing of vancomycin is not necessary. Reasons for Testing/Not Testing: Testing of isolates from normally sterile body sources (blood cultures, deep tissue) may be warranted. Derivation of Interpretive Criteria: Interpretive criteria for gentamicin are adapted from those for Staphylococcus spp. as published in the most current edition of CLSI document M100. Interpretive criteria for all other antimicrobial agents are adapted from those for Enterococcus spp. as published in CLSI document M100. Key citations used in derivation of interpretive breakpoints include references 101, 102, and 104 under Additional References.





Agents to Consider for Primary Testing Penicillin or ampicillin

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Table 10. Listeria monocytogenes—Information and Interpretive Criteria for Broth Microdilution Susceptibility Testing

General Comments




Antimicrobial

Class

Antimicrobial Agent

S I R

Comments




Resistance: Listeria monocytogenes is intrinsically resistant to cephalosporins. Reasons for Testing/Not Testing: Resistance to ampicillin or penicillin has not been described. Testing may be limited to suspected treatment failures or for patients with a penicillin allergy. Derivation of Interpretive Criteria: Interpretive criteria for penicillin and ampicillin were previously published in the most current edition of CLSI document M100. Interpretive criteria for trimethoprim-sulfamethoxazole are adapted from those for Streptococcus spp. as published in CLSI document M100. Key citations used in derivation of interpretive breakpoints include references 108 and 110 under Additional References.

Testing Conditions Medium: Cation-adjusted Mueller-Hinton broth with lysed horse blood (2.5 to 5% v/v) Inoculum: Direct colony suspension, equivalent to a 0.5 McFarland standard Incubation: 35 °C; ambient air; 20 to 24 hours

Minimal QC Recommendations Streptococcus pneumoniae ATCC® 49619

Agents to Consider for Primary Testing Penicillin or ampicillin Trimethoprim-sulfamethoxazole

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Table 11. Moraxella catarrhalis—Information and Interpretive Criteria for Broth Microdilution Susceptibility Testing

General Comments (1) Growth characteristics on routine media: nonfastidious; grows well on BAP; ambient air; 16 to 20 hours. (2) For some organism/antimicrobial combinations, the absence or rare occurrence of resistant strains precludes defining any results categories other than



Antimicrobial

Class

Antimicrobial Agent

S I R

Comments

PENICILLINS AND β-LACTAM/β-LACTAMASE INHIBITOR COMBINATIONS Amoxicillin-clavulanic acid ≤4/2 - ≥8/4

CEPHEMS Cefaclor ≤8 16 ≥32 Cefuroxime ≤4 8 ≥16 Cefotaxime ≤2 - - See comment (2). Ceftazidime ≤2 - - See comment (2). Ceftriaxone ≤2 - - See comment (2).

MACROLIDES Azithromycin ≤2 4 ≥8 Clarithromycin ≤2 4 ≥8 Erythromycin ≤0.5 1-4 ≥8

QUINOLONES Ciprofloxacin ≤1 - - See comment (2). Levofloxacin ≤2 - - See comment (2).

Testing Conditions Medium: Cation-adjusted Mueller-Hinton broth Inoculum: Direct colony suspension, equivalent to a 0.5 McFarland


Minimal QC Recommendations Staphylococcus aureus ATCC® 29213 Escherichia coli ATCC® 35218 (for β-lactam/β-lactamase inhibitor combinations)

Agents to Consider for Primary Testing Amoxicillin-clavulanic acid Cefaclor or cefuroxime Trimethoprim-sulfamethoxazole

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Table 11. Moraxella catarrhalis (Continued) MIC (µg/mL)

Interpretive Criteria

Antimicrobial Class

Antimicrobial Agent

S I R

Comments


LINCOSAMIDE Clindamycin ≤0.5 1-2 ≥4





Resistance: Most strains of Moraxella catarrhalis produce β-lactamase and are resistant to ampicillin and amoxicillin. Reasons for Testing/Not Testing: Testing is not recommended routinely. However, testing may be useful for epidemiological purposes or for management of patients with prolonged or severe infections. Derivation of Interpretive Criteria: Interpretive criteria are adapted from those for Haemophilus spp. as published in the most current edition of CLSI document M100. Testing Notes: If desired, β-lactamase testing can be performed using chromogenic cephalosporin methods such as nitrocefin.

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Table 12. Pasteurella species—Information and Interpretive Criteria for Broth Microdilution and Disk Diffusion Susceptibility Testing

General Comments (1) Growth characteristics on routine media: often fastidious; requires blood supplemented media for adequate growth; ambient air; 20 to 24 hours. (2) For some organism/antimicrobial combinations, the absence or rare occurrence of resistant strains precludes defining any results categories other than





Class

Antimicrobial

Agent

Disk Content

S I R S I R PENICILLINS AND β-LACTAM/β-LACTAMASE INHIBITOR COMBINATIONS

Amoxicillin - - - - ≤0.5 - -a See comment (2). Ampicillin 10 µg ≥27 - - ≤0.5 - -a See comment (2). Penicillin 10 units ≥25 - - ≤0.5 - -a See comment (2). Amoxicillin-

clavulanic acid 20/10 µg ≥27 - - ≤0.5/0.25 - -a See comment (2).

CEPHALOSPORINS Ceftriaxone 30 µg ≥34 - - ≤0.12 - - See comment (2).

QUINOLONES Moxifloxacin 5 µg ≥28 - - ≤0.06 - - See comment (2). Levofloxacin 5 µg ≥28 - - ≤0.06 - - See comment (2).

TETRACYCLINES Tetracycline 30 µg ≥23 - - ≤1 - - See comment (2). Doxycycline 30 µg ≥23 - - ≤0.5 - - See comment (2).


blood (2.5 to 5%) for broth microdilution; Mueller-Hinton agar with 5% sheep blood (BMHA) for

disk diffusion (see Testing Notes) Inoculum: Direct colony suspension, equivalent to a 0.5 McFarland

standard Incubation: 35 °C; ambient air for 18 to 24 hours

Minimal QC Recommendations Streptococcus pneumoniae ATCC® 49619 Escherichia coli ATCC® 35218 (for β-lactam/β-lactamase inhibitor combinations) Staphylococcus aureus ATCC® 25923 for disk diffusion (amoxicillin-clavulanic acid and doxycycline)

Agents to Consider for Primary Testing Penicillins β-lactam/β-lactamase inhibitor combinations Cephalosporins Fluoroquinolones Tetracyclines Macrolides Trimethoprim-sulfamethoxazole


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Table 12. Pasteurella species (Continued)




Class

Antimicrobial

Agent

Disk

Content S I R S I R

MACROLIDES Erythromycin 15 µg ≥27 25-26 ≤24 ≤0.5 1 ≥2 Azithromycin 15 µg ≥20 - - ≤1 - - See comment (2).

OTHERS Chloramphenicol 30 µg ≥28 - - ≤2 - - See comment (2). Trimethoprim-

sulfamethoxazole 1.25/23.75 µg ≥24 - - ≤0.5/9.5 - - See comment (2).


Resistance: a Rare isolates of Pasteurella spp. have been encountered that produce β-lactamase and have ampicillin, amoxicillin, and penicillin MICs >0.5 µg/mL. Reasons for Testing/Not Testing: For isolates from bite wounds, routine testing is usually not necessary. Multiple organisms are often present in these specimens; therefore, empiric therapy directed towards these organisms is generally effective for P. multocida, as well. Testing of isolates from normally sterile sources (blood cultures, deep tissue, implanted prosthetic devices) and also respiratory specimens may be warranted, especially in immunodeficient patients. Derivation of Interpretive Criteria: Interpretive criteria are based primarily on MIC distributions obtained by testing large numbers of isolates recovered from human animal-bite infections. Key citations used in derivation of interpretive breakpoints include references 129 and 134 under Additional References. Testing Notes: Testing for β-lactamase production using a chromogenic cephalosporin test is recommended for isolates recovered from respiratory or normally sterile sources. β-lactamase-positive isolates are resistant to ampicillin, amoxicillin, and penicillin. For β-lactamase-producing strains, ampicillin MIC may be >4 µg/mL and the MIC is reduced with addition of a β-lactamase inhibitor. Some isolates may require incubation in 5% CO2 for disk diffusion tests, and these should only be tested by broth microdilution. Testing of S. aureus ATCC® 25923 using BMHA has been shown to produce zones within the acceptable limits noted in the most current edition of CLSI document M100, Table 3, for the antimicrobial agents listed in this table.


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Table 13. Pediococcus species—Information and Interpretive Criteria for Broth Microdilution Susceptibility Testing

General Comments




Antimicrobial

Class

Antimicrobial Agent

S I R

Comments


CARBAPENEMS Imipenem ≤0.5 - - See comment (2).




Resistance: Pediococcus spp. are considered intrinsically resistant to vancomycin; routine testing of vancomycin is not necessary. Reasons for Testing/Not Testing: Testing of isolates from normally sterile sources (blood cultures, deep tissue, implanted prosthetic devices) may be warranted, especially in immunodeficient patients. Derivation of Interpretive Criteria: Interpretive criteria for gentamicin are adapted from those for Staphylococcus spp. as published in the most current edition of CLSI document M100. Interpretive criteria for all other antimicrobial agents are adapted from those for Enterococcus spp. as published in CLSI document M100. Key citations used in derivation of interpretive breakpoints include references 137, 138, 140, and 141 under Additional References.





Agents to Consider for Primary Testing Penicillin or ampicillin Gentamicin (for combined therapy)

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Table 14. Vibrio species (Not V. cholerae)—Information and Interpretive Criteria for Broth Microdilution and Disk Diffusion Susceptibility Testing

General Comments (1) Growth characteristics on routine media: halophilic; grows well on BAP; ambient air; 20 to 24 hours.

Zone diameter (mm) Interpretive Criteria


Comments

Antimicrobial

Class

Antimicrobial Agent

Disk

Diffusion S I R S I R

PENICILLINS AND β-LACTAM/β-LACTAMASE INHIBITOR COMBINATIONS Ampicillin 10 µg ≥17 14-16 ≤13 ≤8 16 ≥32 Amoxicillin-clavulanic

acid 20/10 µg ≥18 14-17 ≤13 ≤8/4 16/8 ≥32/16

Ampicillin-sulbactam 10/10 µg ≥15 12-14 ≤11 ≤8/4 16/8 ≥32/16 Piperacillin 100 µg ≥21 18-20 ≤17 ≤16 32-64 ≥128 Piperacillin-

tazobactam 100/10 µg ≥21 18-20 ≤17 ≤16/4 32/4-64/4 ≥128/4

CEPHEMS Cefazolin 30 µg ≥18 15-17 ≤14 ≤8 16 ≥32 Cefepime 30 µg ≥18 15-17 ≤14 ≤8 16 ≥32 Cefotaxime 30 µg ≥23 15-22 ≤14 ≤8 16-32 ≥64 Cefoxitin 30 µg ≥18 15-17 ≤14 ≤8 16 ≥32 Ceftazidime 30 µg ≥18 15-17 ≤14 ≤8 16 ≥32 Cefuroxime sodium

(parenteral) 30 µg ≥18 15-17 ≤14 ≤8 16 ≥32

Cephalothin 30 µg ≥18 15-17 ≤14 ≤8 16 ≥32 CARBAPENEMS

Imipenem 10 µg ≥16 14-15 ≤13 ≤4 8 ≥16 Meropenem 10 µg ≥16 14-15 ≤13 ≤4 8 ≥16

Testing Conditions Medium: Cation-adjusted Mueller-Hinton broth for microdilution;

Mueller-Hinton agar for disk diffusion Inoculum: Direct colony suspension, equivalent to a 0.5 McFarland

standard. Prepare inoculum in 0.85% NaCl (normal saline). Incubation: 35 °C; ambient air; 16 to 20 hours

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

Agents to Consider for Primary Testing Tetracycline Cefotaxime Ceftazidime Fluoroquinolones

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Table 14. Vibrio species (Continued)

Zone diameter (mm) Interpretive Criteria


Comments

Antimicrobial

Class

Antimicrobial Agent

Disk Content

S I R S I R AMINOGLYCOSIDES

Amikacin 30 µg ≥17 15-16 ≤14 ≤16 32 ≥64 Gentamicin 10 µg ≥15 13-14 ≤12 ≤4 8 ≥16

TETRACYCLINES Tetracycline 30 µg ≥19 15-18 ≤14 ≤4 8 ≥16

QUINOLONES Ciprofloxacin 5 µg ≥21 16-20 ≤15 ≤1 2 ≥4 Levofloxacin 5 µg ≥17 14-16 ≤13 ≤2 4 ≥8 Ofloxacin 5 µg ≥16 13-15 ≤12 ≤2 4 ≥8

OTHERS Chloramphenicol 30 µg ≥18 13-17 ≤12 ≤8 16 ≥32

FOLATE PATHWAY INHIBITORS Trimethoprim-

sulfamethoxazole 1.25/23.75 µg ≥16 11-15 ≤10 ≤2/38 - ≥4/76


Resistance: Halophilic Vibrio spp. are usually resistant to sulfonamides, penicillins, and older cephalosporins (cephalothin, cefuroxime). Reasons for Testing/Not Testing: Testing is most often limited to isolates from extraintestinal sites. Derivation of Interpretive Criteria: Interpretive criteria are adapted from those for Enterobacteriaceae as published in the most current edition of CLSI document M100. Key citations used in derivation of interpretive breakpoints include references 145, and 147 to 151 under Additional References. Testing Notes: Inoculum suspension should be prepared in 0.85% NaCl (normal saline). This will allow most isolates of Vibrio spp. to grow satisfactorily on MHA and CAMHB without adding supplemental NaCl to these test media.


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Table 15. Summary of Testing Conditions and QC Recommendations for Infrequently Isolated or Fastidious Bacteria Table No.

Organism/Organism Group

Broth Microdilution MIC Test Medium

Broth Microdilution MIC Incubation Conditions

Disk Diffusion Test Medium/Incubation

Conditions

QC

1 Abiotrophia spp., Granulicatella spp.

CAMHB-LHB (2.5-5% v/v) + 0.001% pyridoxal HCL

35 °C; ambient air; 20-24 h NAa S. pneumoniae ATCC® 49619

2 Aeromonas hydrophila complex, Plesiomonas shigelloides

CAMHB

35 °C; ambient air; 16-20 h MHA (unsupplemented)/35 °C; ambient air 16-18 h

E. coli ATCC® 25922 E. coli ATCC® 35218b

3 Bacillus spp. (not B. anthracis)

CAMHB

35 °C; ambient air; 16-20 h

NA S. aureus ATCC® 29213

4 Campylobacter jejuni/coli

CAMHB-LHB (2.5-5% v/v) 36 °C/48 h or 42 °C/24 h; 10% CO2, 5% O2, 85% N2 (microaerobic)

MHA with 5% sheep blood/36-37 °C; 48 h or 42 °C 24 h; 10% CO2, 5% O2, 85% N2

C. jejuni ATCC® 33560 for microdilution S. aureus ATCC® 25923, MHA/35-37 °C for 16-18 h in ambient air for disk diffusion

5 Corynebacterium spp. CAMHB-LHB (2.5-5% v/v) 35 °C; ambient air; 24-48 h NA S. pneumoniae ATCC® 49619 E. coli ATCC® 25922 for gentamicin

6 Erysipelothrix rhusiopathiae

CAMHB-LHB (2.5-5% v/v) 35 °C; ambient air; 20-24 h NA S. pneumoniae ATCC® 49619

7 HACEK group CAMHB-LHB (2.5-5% v/v) 35 °C; 5% CO2; 24-48 h NA S. pneumoniae ATCC® 49619 E. coli ATCC® 35218 b

8 Lactobacillus spp. CAMHB-LHB (2.5-5% v/v) 35 °C; ambient air; 20-24 h NA S. pneumoniae ATCC® 49619 E. coli ATCC® 25922 for gentamicin

9 Leuconostoc spp. CAMHB-LHB (2.5-5% v/v) 35 °C; ambient air; 20-24 h NA S. pneumoniae ATCC® 49619 E. coli ATCC® 25922 for gentamicin

10 Listeria monocytogenes CAMHB-LHB (2.5-5% v/v) 35 °C; ambient air; 20-24 h NA S. pneumoniae ATCC® 49619

11 Moraxella catarrhalis CAMHB

35 °C; ambient air; 20-24 h

NA S. aureus ATCC® 29213 E. coli ATCC® 35218 b

12 Pasteurella spp.

CAMHB-LHB (2.5-5% v/v) 35 °C; ambient air; 18-24 h MHA with 5% sheep blood/35 °C; ambient air; 18-24 h

S. pneumoniae ATCC® 49619 E. coli ATCC® 35218 b S. aureus ATCC® 25923 (for disk diffusion with selected drugs)

13 Pediococcus spp. CAMHB-LHB (2.5-5% v/v) 35 °C; ambient air; 20-24 h NA S. pneumoniae ATCC® 49619 E. coli ATCC® 25922 for gentamicin

14 Vibrio spp. (not V. cholerae)

CAMHB c 35 °C; ambient air; 16-20 h MHA (unsupplemented)/35 °C; ambient air 16-18 h c

E. coli ATCC® 25922 E. coli ATCC® 35218 b

Footnotes

a NA, not applicable b E. coli ATCC® 35218 is used for quality control when testing β-lactam/β-lactamase inhibitor combination drugs. c Prepare inoculum in 0.85% NaCl (normal saline).

Abbreviations: CAMHB (cation-adjusted Mueller-Hinton broth); LHB (lysed horse blood); MHA (Mueller-Hinton agar)

Volume 26 M45-A


Table 16. Acceptable Limits for Quality Control Strains Used to Monitor Accuracy of Minimal Inhibitory Concentrations (MICs) (µg/mL) of Nonfastidious Organisms (Using Cation-Adjusted Mueller-Hinton Medium Without Blood or Other Supplements)

Antimicrobial Agent

Staphylococcus aureus

ATCC® 29213a

Escherichia coli

ATCC® 25922

Escherichia coli

ATCC® 35218b

Amikacin 1–4 0.5–4 – Amoxicillin-clavulanic acid 0.12/0.06–0.5/0.25 2/1–8/4 4/2–16/8 Ampicillin 0.5–2 2–8 – Ampicillin-sulbactam – 2/1–8/4 8/4–32/16 Azithromycin 0.5–2 – – Aztreonam – 0.06–0.25 – Cefaclor 1–4 1–4 – Cefazolin 0.25–1 1–4 – Cefepime 1–4 0.015–0.12 – Cefotaxime 1–4 0.03–0.12 – Cefoxitin 1–4 2–8 – Cefpodoxime 1–8 0.25–1 – Cefprozil 0.25–1 1–4 – Ceftazidime 4–16 0.06–0.5 – Ceftriaxone 1–8 0.03–0.12 – Cefuroxime 0.5–2 2–8 – Cephalothin 0.12–0.5 4–16 – Chloramphenicol 2–16 2–8 – Ciprofloxacin 0.12–0.5 0.004–0.015 – Clarithromycin 0.12–0.5 – – Clindamycin 0.06–0.25 – – Ertapenem 0.06–0.25 0.004–0.015 – Erythromycin 0.25–1 – – Gentamicin 0.12–1 0.25–1 – Imipenem 0.015–0.06 0.06–0.25 – Levofloxacin 0.06–0.5 0.008–0.06 – Meropenem 0.03–0.12 0.008–0.06 – Ofloxacin 0.12–1 0.015–0.12 –

Penicillin 0.25–2 – – Piperacillin 1–4 1–4 – Piperacillin-tazobactam 0.25/4–2/4 1/4–4/4 0.5/4–2/4 Rifampin 0.004–0.015 4–16 – Tetracycline 0.12–1 0.5–2 – Trimethoprim-sulfamethoxazole ≤ 0.5/9.5 ≤ 0.5/9.5 – Vancomycin 0.5–2 – –

Footnotes


b. Because this strain may lose its plasmid, careful organism maintenance is required; refer to M7-A7, Section 16.3.

Number 19 M45-A


Table 16A. Acceptable Limits for Streptococcus pneumoniae ATCC®a 49619 Used to Monitor Accuracy of Minimal Inhibitory Concentrations (MICs) (µg/mL) (Using Cation-Adjusted Mueller-Hinton Broth With Lysed Horse Blood [2.5 to 5% v/v])

Antimicrobial Agent

Streptococcus pneumoniae ATCC® 49619

Escherichia coli ATCC®

25922

Escherichia coli ATCC®

35218

Amoxicillin 0.03–0.12 – – Amoxicillin-clavulanic acid 0.03/0.015–0.12/0.06 – 4–16b

Ampicillin 0.06–0.25 – – Ampicillin-sulbactam – – 8–32b

Azithromycin 0.06–0.25 – – Cefepime 0.03–0.25 – – Cefotaxime 0.03–0.12 – – Ceftriaxone 0.03–0.12 – – Chloramphenicol 2-8 – – Ciprofloxacin 0.25–1b – – Clarithromycin 0.03–0.12 – – Clindamycin 0.03–0.12 – – Daptomycinc 0.06–0.5 – – Doxycycline 0.015-0.12 – – Erythromycin 0.03–0.12 – – Gatifloxacin 0.12–0.5 – – Gentamicin – 0.25–1b – Imipenem 0.03–0.12 – – Levofloxacin 0.5–2 – – Linezolid 0.5–2 – – Meropenem 0.06–0.25 – – Minocycline – 0.25–1b – Moxifloxacin 0.06–0.25 – – Penicillin 0.25–1 – – Quinupristin-dalfopristin 0.25–1 – – Rifampin 0.015–0.06 – – Tetracycline 0.12–0.5 – – Trimethoprim-sulfamethoxazole 0.12/2.4–1/19 – – Vancomycin 0.12–0.5 – –

Footnotes

a. ATCC is a registered trademark of American Type Culture Collection. b. These quality control ranges were validated for tests performed in cation-adjusted Mueller-Hinton

broth with lysed horse blood and were not established by the studies outlined in the most current edition of CLSI/NCCLS document M23—Development of In Vitro Susceptibility Testing Criteria and Quality Control Parameters. The validation studies were conducted in at least three laboratories using multiple lots of media.

c. QC ranges reflect MICs obtained when Mueller-Hinton broth is supplemented with calcium to a final

concentration of 50 µg/mL. Agar dilution has not been validated for daptomycin.

Volume 26 M45-A


Table 16B. Acceptable Limits for Quality Control Strains Used to Monitor Accuracy of Broth Microdilution Minimal Inhibitory Concentrations (MICs) (µg/mL) of Campylobacter jejuni ATCC®a 33560 (Using Cation-Adjusted Mueller-Hinton Broth With Lysed Horse Blood [2.5 to 5% v/v])

Antimicrobial Agent

Campylobacter jejuni ATCC® 33560

36 °C/48 hours

Campylobacter jejuni ATCC® 33560

42 °C/24 hours Azithromycin 0.03-0.25 0.03-0.12 Ciprofloxacin 0.06-0.25 0.03-0.12 Doxycycline 0.12-0.5 0.12-0.5 Erythromycin 0.5-2 0.25-2 Gentamicin 0.5-2 0.25-2 Levofloxacin 0.06-0.25 0.03-0.25 Meropenem 0.008-0.03 0.008-0.03 Tetracycline 0.25-2 0.25-1

NOTE 1: These MICs were obtained in several reference laboratories by broth microdilution. If four or

fewer concentrations are tested, quality control may be more difficult. NOTE 2: For four-dilution ranges, results at the extremes of the acceptable range(s) should be

suspect. Verify control validity with data from other control strains.

MIC Testing Conditions for Clinical Isolates and Performance of Quality Control

Organism

Campylobacter spp.

Medium Broth dilution: Mueller-Hinton broth with 2.5 to 5% lysed horse blood

Inoculum

Direct colony suspension

Incubation Characteristics

36 °C/48 h or 42 °C/24 h; 10% CO2, 5% O2, 85% N2 (microaerobic)

Footnote


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Table 17. Acceptable Limits for Quality Control Strains Used to Monitor Accuracy of Disk Diffusion Testing of Nonfastidious Organisms (Using Mueller-Hinton Medium Without Blood or Other Supplements)

Antimicrobial Agent

Disk Content

Escherichia

coli ATCC® 25922a

Staphylococcus

aureus ATCC® 25923

Escherichia

coli ATCC® 35218b

Amikacin 30 µg 19-26 20-26 - Amoxicillin-clavulanic acid

20/10 µg 18-24 28-36 17-22

Ampicillin 10 µg 16-22 27-35 6 Ampicillin-sulbactam 10/10 µg 19-24 29-37 13-19 Aztreonam 30 µg 28-36 - - Cefazolin 30 µg 21-27 29-35 - Cefepime 30 µg 31-37 23-29 - Cefotaxime 30 µg 29-35 25-31 - Cefoxitin 30 µg 23-29 23-29 - Ceftazidime 30 µg 25-32 16-20 - Ceftriaxone 30 µg 29-35 22-28 - Cefuroxime 30 µg 20-26 27-35 - Cephalothin 30 µg 15-21 29-37 - Chloramphenicol 30 µg 21-27 19-26 - Ciprofloxacin 5 µg 30-40 22-30 - Doxycycline 30 µg 18-24 23-29 - Ertapenem 10 µg 29-36 24-31 - Gentamicin 10 µg 19-26 19-27 - Imipenem 10 µg 26-32 - - Levofloxacin 5 µg 29-37 25-30 - Meropenem 10 µg 28-34 29-37 - Ofloxacin 5 µg 29-33 24-28 - Piperacillin 100 µg 24-30 - 12-18 Piperacillin-tazobactam 100/10 µg 24-30 27-36 24-30 Tetracycline 30 µg 18-25 24-30 - Trimethoprim- sulfamethoxazolec

1.25/23.75 µg 23-29 24-32 -

.

Footnotes a. ATCC is a registered trademark of the American Type Culture Collection. b. Careful organism maintenance is required; refer to the most current edition of CLSI document M2,

Section 15.3. c. These agents can be affected by excess levels of thymidine and thymine. See the most current

edition of CLSI document M2, Section 7.1.4 for guidance, should a problem with quality control occur.

Volume 26 M45-A


Table 17A. Acceptable Limits for Streptococcus pneumoniae ATCC® 49619 Used to Monitor Accuracy of Disk Diffusion Testing

Antimicrobial Agent

Disk Content

Streptococcus pneumoniae

ATCC® 49619a

Ampicillin 10 µg 30-36 Azithromycin 15 µg 19-25 Ceftriaxone 30 µg 30-35 Chloramphenicol 30 µg 23-27 Erythromycin 15 µg 25-30 Levofloxacin 5 µg 20-25 Moxifloxacin 5 µg 25-31 Penicillin 10 units 24-30 Tetracycline 30 µg 27-31 Trimethoprim- sulfamethoxazole

1.25/23.75 µg 20-28

Disk Diffusion Testing Conditions for Clinical Isolates and Performance of Quality Control

Organism

Streptococcus pneumoniae

Medium MHA supplemented with 5% defibrinated sheep blood

Inoculum

Direct colony suspension

Incubation Characteristics

5% CO2; 20 to 24 hours; 35 °C

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

Number 19 M45-A


Glossary I (Part 1). β-lactams: Class and Subclass Designation and Generic Name Antimicrobial Class Antimicrobial Subclass Agents Included; Generic Names

penicillina penicillin aminopenicillina amoxicillin

ampicillin ureidopenicillina azlocillin

mezlocillin piperacillin

carboxypenicillina carbenicillin ticarcillin

penicillinase-stable penicillinsb

cloxacillin dicloxacillin methicillin nafcillin oxacillin

penicillins

amidinopenicillin mecillinam β-lactam/β-lactamase inhibitor combinations

amoxicillin-clavulanic acid ampicillin-sulbactam piperacillin-tazobactam ticarcillin-clavulanic acid

cephalosporin Ic,e cefazolin cephalothin cephapirin cephradine

cephalosporin IIc,e cefamandole cefonicid cefuroxime (sodium)

cephalosporin IIIc,e cefoperazone cefotaxime ceftazidime ceftizoxime ceftriaxone

cephalosporin IVc,e cefepime cephamycind cefmetazole

cefotetan cefoxitin

cephems (parenteral)

oxacephem moxalactam cephalosporine cefaclor

cefadroxil cefdinir cefditoren cefetamet cefixime cefpodoxime cefprozil ceftibuten cefuroxime (axetil) cephalexin cephradine

cephems (oral)

carbacephem loracarbef monobactams aztreonam

carbapenem doripenem ertapenem imipenem meropenem

penems

penem faropenem

Footnotes

a Penicillinase-labile; hydrolyzed by staphylococcal penicillinase. b 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 ESBL-producing 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.

Volume 26 M45-A


Glossary I (Part 2). Non-β-lactams: Class and Subclass Designation and Generic Name Antimicrobial Class Antimicrobial Subclass Agents Included; Generic Names aminocyclitols spectinomycin

trospectinomycin aminoglycosides amikacin

gentamicin kanamycin netilmicin streptomycin tobramycin

ansamycins rifampin quinolone cinoxacin

garenoxacin nalidixic acid

quinolones

fluoroquinolone ciprofloxacin clinafloxacin enoxacin fleroxacin gatifloxacin gemifloxacin grepafloxacin levofloxacin lomefloxacin moxifloxacin norfloxacin ofloxacin sparfloxacin trovafloxacin

folate pathway inhibitors sulfonamides trimethoprim trimethoprim-sulfamethoxazole

fosfomycins fosfomycin ketolides telithromycin lincosamides clindamycin

daptomycin lipopeptides polymyxins colistin

polymyxin B macrolides azithromycin

clarithromycin dirithromycin erythromycin

nitrofurans nitrofurantoin nitroimidazoles metronidazole oxazolidinones linezolid

glycopeptide oritavancin vancomycin

glycopeptides

lipoglycopeptide dalbavancin teicoplanin telavancin

phenicols chloramphenicol streptogramins quinupristin-dalfopristin tetracyclines doxycycline

minocycline tetracycline

glycylcyclines tigecycline

Number 19 M45-A


Glossary II. Abbreviations/Routes of Administration/Drug Class for Antimicrobial Agents Listed in CLSI Document M100 Antimicrobial Agent Agent Abbreviationa Routes of

Administrationb Drug Class

PO IM IV Amikacin AN, AK, Ak,

AMI, AMK X X aminoglycoside

Amoxicillin AMX, Amx, AMOX, AC

X penicillin

Amoxicillin-clavulanic acid AMC, Amc, A/C, AUG, Aug, XL, AML

X β-lactam/β- lactamase inhibitor

Ampicillin AM, Am, AMP X X X penicillin Ampicillin-sulbactam SAM, A/S,

AMS, AB X β-lactam/β-

lactamase inhibitor

Azithromycin AZM, Azi, AZI, AZ X X macrolide Azlocillin AZ, Az, AZL X X penicillin Aztreonam ATM, AZT, Azt, AT, AZM X monobactam Carbenicillin (indanyl salt) Carbenicillin

CB, Cb, BAR X

X

X

penicillin

Cefaclor CEC, CCL, Cfr, FAC, CF X cephem Cefadroxil CFR, FAD X cephem Cefamandole MA, CM, Cfm, FAM X X cephem Cefazolin CZ, CFZ, Cfz, FAZ, KZ X X cephem Cefdinir CDR, Cdn, DIN, CD,

CFD X cephem

Cefditoren CDN X cephem Cefepime FEP, Cpe, PM, CPM X X cephem Cefetamet CAT, FET X cephem Cefixime CFM, FIX, Cfe, IX X cephem Cefmetazole CMZ, CMZS, CMT X X cephem Cefonicid CID, Cfc, FON, CPO X X cephem Cefoperazone CFP, Cfp, CPZ, PER,

FOP, CP X X cephem

Cefotaxime CTX, TAX, Cft, FOT, CT X X cephem Cefotetan CTT, CTN, Ctn, CTE,

TANS, CN X X cephem

Cefoxitin FOX, CX, Cfx, FX X X cephem Cefpodoxime CPD, Cpd, POD, PX X cephem Cefprozil CPR, CPZ, FP X cephem Ceftazidime CAZ, Caz, TAZ, TZ X X cephem Ceftibuten CTB, TIB, CB X cephem Ceftizoxime ZOX, CZX, CZ, Cz, CTZ,

TIZ X X cephem

Ceftobiprole BPR X cephem Ceftriaxone CRO, CTR, FRX, Cax,

AXO, TX X X cephem

Cefuroxime (axetil) Cefuroxime (sodium)

CXM, CFX, ROX, Crm, FUR, XM

X

X

X

cephem

Cephalexin CN, LEX, CFL X cephem Cephalothin CF, Cf, CR, CL, CEP,

CE, KF X cephem

Volume 26 M45-A


Glossary II. (Continued) Antimicrobial Agent Agent Abbreviationa Routes of


PO IM IV Cephapirin CP, HAP X X cephem Cephradine RAD, CH X cephem Chloramphenicol C, CHL, CL X X phenicol Cinoxacin CIN, Cn X quinolone Ciprofloxacin CIP, Cp, CI X X fluoroquinolone Clarithromycin CLR, CLM,

CLA, Cla, CH X macrolide

Clinafloxacin CFN, CLX, LF X X fluoroquinolone Clindamycin CC, CM, CD, Cd, CLI,

DA X X X lincosamide

Colistin CL, CS, CT X lipopeptide Dalbavancin DAL X glycopeptide Daptomycin DAP X lipopeptide Dicloxacillin DX, DIC X penicillin Dirithromycin DTM, DT X macrolide Doripenem DOR X carbapenem Ertapenem ETP X X carbapenem Erythromycin E, ERY, EM X X macrolide Faropenem FAR, FARO X penem Fleroxacin FLE, Fle, FLX, FO X X fluoroquinolone Fosfomycin FOS, FF, FO, FM X fosfomycin Garenoxacin GRN X X quinolone Gatifloxacin GAT X X fluoroquinolone Gemifloxacin GEM X fluoroquinolone Gentamicin Gentamicin synergy

GM, Gm, CN, GEN GM500, HLG, Gms

X X aminoglycoside

Grepafloxacin GRX, Grx, GRE, GP X fluoroquinolone Imipenem IPM, IMI, Imp, IP X carbapenem Kanamycin K, KAN, HLK, KM X X aminoglycoside Levofloxacin LVX, Lvx,

LEV, LEVO, LE X X fluoroquinolone

Linezolid LNZ, LZ, LZD X X oxazolidinone Lomefloxacin LOM, Lmf X fluoroquinolone Loracarbef LOR, Lor, LO X cephem Mecillinam MEC X penicillin Meropenem MEM, Mer, MERO, MRP,

MP X carbapenem

Methicillin DP, MET, ME, SC X X penicillin Mezlocillin MZ, Mz, MEZ X X penicillin Minocycline MI, MIN, Min, MN, MNO,

MC, MH X X tetracycline

Moxalactam MOX X X cephem Moxifloxacin MXF X X fluoroquinolone Nafcillin NF, NAF, Naf X X penicillin Nalidixic acid NA, NAL X quinolone Netilmicin NET, Nt, NC X X aminoglycoside Nitrofurantoin F/M, FD, Fd, FT,

NIT, NI, F X nitrofurantoin

Norfloxacin NOR, Nxn, NX X fluoroquinolone Ofloxacin OFX, OFL, Ofl, OF X X X fluoroquinolone Oritavancin ORI X glycopeptide Oxacillin OX, Ox, OXS, OXA X X X penicillin

Number 19 M45-A


Glossary II. (Continued) Antimicrobial Agent Agent Abbreviationa Routes of


PO IM IV Penicillin P, PEN, PV X X X penicillin Piperacillin PIP, PI, PP, Pi X X penicillin Piperacillin-tazobactam TZP, PTZ, P/T, PTc X β-lactam/β-

lactamase inhibitor combination

Polymyxin B PB X lipopeptide Quinupristin-dalfopristin SYN, Syn, QDA, RP X streptogramin Rifampin RA, RIF, Rif, RI, RD X X ansamycin Sparfloxacin SPX, Sfx, SPA, SO X fluoroquinolone Spectinomycin SPT, SPE, SC X X aminocyclitol Streptomycin Streptomycin synergy

S, STR, StS, SM,

ST2000, HLS

X X aminoglycoside

Sulfonamides SSS, S3 X X folate pathway antagonist (some PO only)

Teicoplanin TEC, TPN, Tei, TEI, TP, TPL

X X glycopeptide

Telavancin TLV X glycopeptide Telithromycin TEL X ketolide Tetracycline TE, Te, TET, TC X X tetracycline Ticarcillin TIC, TC, TI, Ti X X penicillin Ticarcillin-clavulanic acid TIM, Tim, T/C, TCC, TLc X β-lactam/β-

lactamase inhibitor Tigecycline TGC X glycylcycline Tobramycin NN, TM, TO, To, TOB X X aminoglycoside Trimethoprim TMP, T, TR, W X folate pathway

inhibitor Trimethoprim- sulfamethoxazole

SXT, SxT, T/S, TS, COT X X folate pathway inhibitor

Trospectinomycin X X aminocyclitol Trovafloxacin TVA, Tva, TRV, TV X X fluoroquinolone Vancomycin VA, Va, VAN X X glycopeptide

Footnotes a Abbreviations assigned to one or more diagnostic products in the U.S. If no diagnostic product is

available, abbreviation is that of the manufacturer. b As available in the U.S. PO per OS (oral) IM intramuscular IV intravenous

Volume 26 M45-A


Additional References General Abramowicz M, ed. Treatment guidelines from The Medical Letter, choice of antibacterial drugs. The Medical Letter, Inc. 2004;2(19):13-26. Baddour LM, Wilson WR, Bayer AS, et al. Infective endocarditis: diagnosis, antimicrobial therapy, and management of complications: a statement for healthcare professionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, and the Councils on Clinical Cardiology, Stroke, and Cardiovascular Surgery and Anesthesia, American Heart Association (endorsed by the Infectious Diseases Society of America). Circulation. 2005;111:e394-e434. Gilbert DN, Moellering RC, Eliopoulos GM, Sande MA. The Sanford Guide to Antimicrobial Therapy. Hyde Park, VT: Antimicrobial Therapy, Inc; 2005. Mandell GL, Douglas RG, Dolin R, Bennett JE. Mandell, Douglas and Bennett’s Principles and Practice of Infectious Diseases. 6th ed. Philadelphia, PA: Churchill Livingstone; 2005. Table 1. Abiotrophia species and Granulicatella species 1. Biermann C, Fries G, Jehnichen P, et al. Isolation of Abiotrophia adjacens from a brain abscess which

developed in a patient after neurosurgery. J Clin Microbiol. 1999;37:769-771. 2. Bouvet A, Cremieux AC, Contrepois A, et al. Comparison of penicillin and vancomycin, individually and in

combination with gentamicin and amikacin, in the treatment of experimental endocarditis induced by nutritionally variant streptococci. Antimicrob Agents Chemother. 1985;28:607-611.

3. Chang HH, Lu CY, Hsueh PR, Wu MH, Wang JK, Huang LM. Endocarditis caused by Abiotrophia defectiva

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Microbiol. 2001;39:3520-3523. 5. Heath CH, Bowen SF, McCarthy JS, Dwyer B. Vertebral osteomyelitis and discitis associated with

Abiotrophia adiacens (nutritionally variant streptococcus) infection. Aust NZ J Med. 1998;28:663. 6. Michelow IC, McCracken GH Jr., Luckett PM, Krisher K. Abiotrophia spp. brain abscess in a child with

Down’s Syndrome. Ped Infect Dis J. 2000;19:760. 7. Murray CK, Walter EA, Crawford S, McElmeel ML, Jorgensen JH. Abiotrophia bacteremia in a patient with

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cataract extraction. J Clin Microbiol. 1999;37:1564-1566. 9. Poyart C, Quesne G, Acar P, Berche P, Trieu-Cuot P. Characterization of the Tn916-like transposon TN3872

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Abiotrophia defectiva. Diagn Microbiol Infect Dis. 2000;38:189-191.

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Table 2. Aeromonas hydrophila complex 12. Bakken JS, Sanders CC, Clark RB, Hori M. β-Lactam resistance in Aeromonas spp. caused by inducible β-

lactamases active against penicillins, cephalosporins, and carbapenems. Antimicrob Agents Chemother. 1988; 32:1314-1319.

13. Burgos A, Quindos G, Martinez R, Rojo P, Cisterna R. In vitro susceptibility of Aeromonas caviae,

Aeromonas hydrophilia, and Aeromonas sobria to fifteen antibacterial agents. Eur J Clin Microbiol Infect Dis. 1990;9:413-417.

14. Clark NM, Chenoweth CE. Aeromonas infection of the hepatobiliary system: report of 15 cases and review of

the literature. Clin Infect Dis. 2003;37:506-313. 15. Janda JM, Abbott SL. Evolving concepts regarding the genus Aeromonas: an expanding panorama of species,

disease presentations, and unanswered questions. Clin Infect Dis. 1998;27:332-344. 16. Jones BL, Wilcox MH. Aeromonas infections and their treatment. J Antimicrob Chemother. 1995;35:453-

461. 17. Kampfer P, Christmann C, Swings J, Huys G. In vitro susceptibilities of Aeromonas genomic species to 69

antimicrobial agents. Syst Appl Microbiol. 1999;22:662-669. 18. Ko WC, Yu KW, Liu CY, Huang CT, Leu HS, Chuang YC. Increasing antibiotic resistance in clinical

isolates of Aeromonas strains in Taiwan. Antimicrob Agents Chemother. 1996;40:1260-1262. 19. Koehler JM, Ashdown LR. In vitro susceptibilities of tropical strains of Aeromonas species from Queensland,

Australia, to 22 antimicrobial agents. Antimicrob Agents Chemother. 1993;37:905-907. 20. Overman TL, Janda JM. Antimicrobial susceptibility patterns of Aeromonas jandaei, A. schubertii, A. trota,

and A. veronii biotype veronii. J Clin Microbiol. 1999;37:706-708. 21. Vila J, Marco F, Soler L, Chacon M, Figueras MJ. In vitro antimicrobial susceptibility of clinical isolates of

Aeromonas caviae, Aeromonas hydrophila, and Aeromonas veronii biotype sobria. J Antimicrob Chemother. 2002;49:697-702.

22. Vila J, Ruiz J, Gallardo F, et al. Aeromonas spp. and traveler’s diarrhea: clinical features and antimicrobial

resistance. Emerg Infect Dis. 2003;9:552-555. Plesiomonas shigelloides 23. Avison MB, Bennett PM, Walsh TR. β-lactamase expression in Plesiomonas shigelloides. J Antimicrob

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Plesiomonas shigelloides infections in humans. Rev Infect Dis. 1988;10:303-316. 25. Clark RB, Lister PD, Arneson-Rotert L, Janda JM. In vitro susceptibilities to Plesiomonas shigelloides to 24

antibiotics and antibiotic-β-lactamase-inhibitor combinations. Antimicrob Agents Chemother. 1990;34:159-160.

26. Gonzalez-Rey C, Svenson SB, Bravo L, et al. Serotypes and antimicrobial susceptibility of Plesiomonas

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27. Kain KC, Kelly MT. Antimicrobial susceptibility of Plesiomonas shigelloides from patients with diarrhea.

Antimicrob Agents Chemother. 1989;33:1609-1610. 28. Stock I, Wiedemann B. Natural antimicrobial susceptibilities of Plesiomonas shigelloides strains. J

Antimicrob Chemother. 2001;48:803-811.

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29. Stock I, Wiedemann B. β-lactam-susceptibility patterns of Plesiomonas shigelloides strains: importance of inoculum and medium. Scand J Infect Dis. 2001;33:692-696.

Table 3. Bacillus species 30. Andrews JM, Wise R. Susceptibility testing of Bacillus species. J Antimicrob Chemother. 2002;49:1039-

1041. 31. Coonrod JD. Antibiotic susceptibility of Bacillus spp. J Infect Dis. 1971;123:102-105. 32. Weber DJ, Saviteer SM, Rutala WA, Thomann CA. In vitro susceptibility of Bacillus spp. to selected

antimicrobial agents. Antimicrob Agents Chemother. 1988;32:642-645. Table 4. Campylobacter jejuni/coli 33. Allos BM. Campylobacter jejuni infections: update on emerging issues and trends. Clin Infect Dis.

2001;32:1201-1206. 34. Drydon MS, Gabb RJE, Wright SK. Empirical treatment of severe acute community-acquired gastroenteritis

with ciprofloxacin. Clin Infect Dis. 1996;22:1019-1025. 35. Engberg J, Aarestrup FM, Taylor DE, Gerner-Smidt, Nachamkin I. Quinolone and macrolide resistance in

Campylobacter jejuni and C. coli: resistance mechanisms and trends in human isolates. Emerg Infect Dis. 2001;7:24-34.

36. Ge B, Bodeis S, Walker RD, et al. Comparison of Etest and agar dilution for in vitro antimicrobial

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diarrhea in urban adults. Arch Intern Med. 1990;150:541-546. 38. Jerris RC, Fields PI, Nicholson MA. Fecal culture for Campylobacter and related organisms. In: Isenberg H,

ed. Clinical Microbiology Procedure Handbook. 2nd ed. Washington, DC: ASM Press; 2004. 39. McDermott PF, Bodeis SM, Aarestrup FM, et al. Development of a standardized susceptibility test for

campylobacter with quality-control ranges for ciprofloxacin, doxycycline, erythromycin, gentamicin, and meropenem. Microb Drug Resist. 2004;10:124-131.

40. McDermott PF, Bodeis-Jones SM, Fritsche TR, Jones RN, Walker RD. Broth microdilution susceptibility

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41. Murphy GS Jr, Echeverria P, Jackson LR, Arness MK, LeBron C, Pitarangsi C. Ciprofloxacin- and

azithromycin-resistant Campylobacter causing traveler’s diarrhea in U.S. troops deployed to Thailand in 1994. Clin Infect Dis. 1996;22:868-869.

42. Nachamkin I. Curved and spiral-shaped gram-negative rods: Campylobacter and Arcobacter. In: Murray P,

Baron EJ, Jorgensen JH, Pfaller MA, Yolken RH, eds. Manual of Clinical Microbiology, 8th ed. Washington, DC: ASM Press; 2003:902-914.

43. Nachamkin I, Ung H, Li M. Increasing fluoroquinolone resistance in Campylobacter jejuni, Pennsylvania,

USA, 1982-2001. Emerg Infect Dis. 2002;8:1501-1503. 44. Spach DH, Liles WC. Antimicrobial therapy for bacterial diseases. In: Root RK, ed. Clinical Infectious

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from three patients infected with human immunodeficiency virus. Clin Infect Dis. 1995;21:634-638.

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Table 5. Corynebacterium species 46. Carlson P, Kontiainen S, Renkonen OV. Antimicrobial susceptibility of Arcanobacterium haemolyticum.

Antimicrob Agents Chemother. 1994;38:142-143. 47. Engler KH, Warner M, George RC. In vitro activity of ketolides HMR 3004 and HMR 3647 and seven other

antimicrobial agents against Corynebacterium diphtheriae. J Antimicrob Chemother. 2001;47:27-31. 48. Funke G, Alvarez N, Pascual C, et al. Actinomyces europaeus sp. nov., isolated from human clinical

specimens. Int J Syst Bacteriol. 1997;47:687-692. 49. Funke G, Bernard KA. Coryneform gram-positive rods. In: Murray PR, Baron EJ, Jorgensen JH, Pfaller MA,

Yolken RH, eds. Manual of Clinical Microbiology. 8th ed. Washington, DC: ASM Press; 2003:472-501. 50. Funke G, Nietznik C. Minimal inhibitory concentrations of linezolid against clinical isolates of coryneform

bacteria. Eur J Clin Microbiol Infect Dis. 2005;24:612-614. 51. Funke G, Pagano-Niederer M, Bernauer W. Corynebacterium macginleyi has to date been isolated

exclusively from conjunctival swabs. J Clin Microbiol. 1998;36:3670-3673. 52. Funke G, Pagano-Niederer M, Sjöden B, Falsen E. Characteristics of Arthrobacter cumminsii, the most

frequently encountered Arthrobacter species in human clinical specimens. J Clin Microbiol. 1998;36:1539-1543.

53. Funke G, Pünter V, von Graevenitz A. Antimicrobial susceptibility patterns of some recently established

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1995;23:73-75. 56. García-Rodriguez JA, García Sánchez JE, Muñoz Bellido JL, Nebreda Mayoral T, García Sánchez E, García

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57. Judson R, Songer JG. Corynebacterium pseudotuberculosis: in vitro susceptibility to 39 antimicrobial agents.

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twelve antibiotics. Eur J Clin Microbiol Infect Dis. 1990;9:892-895. 60. Riegel P, de Briel D, Prévost G, Jehl F, Monteil H. Genomic diversity among Corynebacterium jeikeium

strains and comparison with biochemical characteristics and antimicrobial susceptibilities. J Clin Microbiol. 1994;32:1860-1865.

61. Riegel P, Ruimy R, Christen R, Monteil H. Species identities and antimicrobial susceptibilities of

corynebacteria isolated from various clinical sources. Eur J Clin Microbiol Infect Dis. 1996;15:657-662. 62. Santamaría M, Ponte C, Wilhelmi I, Soriano F. Antimicrobial susceptibility of Corynebacterium group D2.

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64. Soriano F, Zapardiel J, Nieto E. Antimicrobial susceptibilities of Corynebacterium species and other non-spore-forming gram-positive bacilli to 18 antimicrobial agents. Antimicrob Agents Chemother. 1995;39:208-214.

65. Troxler R, Funke G, von Graevenitz A, Stock I. Natural antibiotic susceptibility of recently established

coryneform bacteria. Eur J Clin Microbiol Infect Dis. 2001;20:315-323. 66. Weiss K, Laverdière M, Rivest R. Comparison of antimicrobial susceptibilities of Corynebacterium species

by broth microdilution and disk diffusion methods. Antimicrob Agents Chemother. 1996;40:930-933. 67. Williams DY, Selepak ST, Gill VJ. Identification of clinical isolates of nondiphtherial Corynebacterium

species and their antibiotic susceptibility patterns. Diagn Microbiol Infect Dis. 1993;17:23-28. Table 6. Erysipelothrix rhusiopathiae 68. Fidalgo SG, Longbottom CJ, Riley TV. Susceptibility of Erysipelothrix rhusiopathiae to antimicrobial agents

and home disinfectants. Pathology. 2002;34:462-465. 69. Gorby GL, Peacock JE. Erysipelothrix rhusiopathiae endocarditis: microbiologic, epidemiologic, and clinical

features of an occupational disease. Rev Infect Dis. 1988;10:317-325. 70. Takahashi T, Sawada T, Muramatsu M, et al. Serotype, antimicrobial susceptibility, and pathogenicity of

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71. Venditti M, Gelfusa V, Tarasi A, Brandimarte C, Serra P. Antimicrobial susceptibilities of Erysipelothrix

rhusiopathiae. Antimicrob Agents Chemother. 1990;34:2038-2040. 72. Yamamoto K, Kijima M, Yoshimura H, Takahashi T. Antimicrobial susceptibilities of Erysipelothrix

rhusiopathiae isolated from pigs with swine erysipelas in Japan, 1988-1998. J Vet Med Series. B2001;48:115-126.

Table 7. HACEK Group 73. Alcala L, Garcia-Garrote F, Cercenado E, Pelaez T, Ramos G, Bouza E. Comparison of broth microdilution

method using Haemophilus test medium and agar dilution method for susceptibility testing of Eikenella corrodens. J Clin Microbiol. 1998;36:2386-2388.

74. Almeda FQ, Tenorio AR, Barkatullah S, Parrillo JE, Simon DM. Infective endocarditis due to Haemophilus

aphrophilus. Am J Med. 2002;113:702-704. 75. Cormican MG, Jones RN. Antimicrobial activity of cefotaxime tested against infrequently isolated pathogenic

species unusual pathogens. Diagn Microbiol Infect Dis. 1995;22:43-48. 76. Das M, Badley AD, Cockerill FR, Steckelberg JM, Wilson WR. Infective endocarditis caused by HACEK

microorganisms. Annu Rev Med. 1997;48:25-33. 77. el Khizzi N, Kasab SA, Osoba AO. HACEK group endocarditis at the Riyadh Armed Forces Hospital. J

Infect. 1997;34:69-74. 78. Goldstein EJ, Cherubin CE, Shulman M. Comparison of microtiter broth dilution and agar dilution methods

for susceptibility testing of Eikenella corrodens. Antimicrob Agents Chemother. 1983;23:42-45. 79. Goldstein EJC, Citron DM, Merriam CV, Warren Y, Tyrrell K, Fernandez H. In vitro activities of a new des-

fluoroquinolone, BMS 284756, and seven other antimicrobial agents against 151 isolates of Eikenella corrodens. Antimicrob Agents Chemother. 2002;46:1141-1143.

80. Goldstein EJC, Citron DM, Vagvolgyi AE, Gombert ME. Susceptibility of Eikenella corrodens to newer and

older quinolones. Antimicrob Agents Chemother. 1986;30:172-173.

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81. Han XY, Meltzer MC, Woods JT, Fainstein V. Endocarditis with ruptured cerebral aneurysm caused by Cardiobacterium valvarum sp. nov. J Clin Microbiol. 2004:1590-1595.

82. Jenny DB, Letendre PW, Iverson G. Endocarditis caused by Kingella indologenes. Rev Infect Dis.

1987;9:787-789. 83. Jorgensen JH, Howell AW, Maher LA. Antimicrobial susceptibility testing of less commonly isolated

Haemophilus species using Haemophilus Test Medium. J Clin Microbiol. 1990;28:985-988. 84. Khan JA, Sharp S, Mann KR, Brewer J. Kingella denitrificans prosthetic endocarditis. Am J Med Sci.

1986;291:187-189. 85. Kugler KC, Biedenback DJ, Jones RN. Determination of the antimicrobial activity of 29 clinically important

compounds tested against fastidious HACEK group organisms. Diagn Microbiol Infect Dis. 1999;34:73-76. 86. Le Quellec AD, Bessis D, Perez C, Ciurana AJ. Endocarditis due to beta-lactamase-producing

Cardiobacterium hominis. Clin Infect Dis. 1994;19:994-995. 87. Lu PL, Hsueh PR, Hung CC, Teng LJ, Jang TN, Luh KT. Infective endocarditis complicated with progressive

heart failure due to β-lactamase-producing Cardiobacterium hominis. J Clin Microbiol. 2000;38:2015-2017. 88. Madinier IM, Fosse TB, Hitzig C, Charbit Y, Hannoun LR. Resistance profile survey of 50 periodontal

strains of Actinobacillus actinomyectomcomitans. J Periodontol. 1999;70:888-892. 89. Paju S, Carlson P, Jousimies-Somer H, Asikainen S. Actinobacillus actinomycetemcomitans and

Haemophilus aphrophilus in systemic and nonoral infections in Finland. APMIS. 2003;111:653-657. 90. Prior RB, Spagna VA, Perkins RL. Endocarditis due to strain of Cardiobacterium hominis resistant to

erythromycin and vancomycin. Chest. 1979;75:85-86. 91. Roe DE, Braham PH, Weinberg A, Roberts MC. Characterization of tetracycline resistance in Actinobacillus

actinomycetemcomitans. Oral Microbiol Immunol. 1995;10:227-232. 92. Sordillo EM, Rendel M, Sood R, Belinfanti J, Murray O, Brook D. Septicemia due to β-lactamase-positive

Kingella kingae. Clin Infect Dis. 1993;17:818-819. 93. Vogt K, Klefisch F, Hahn H, Schmutzler H. Antibacterial efficacy of ciprofloxacin in a case of endocarditis

due to Cardiobacterium hominis. Zentralbl Bakteriol. 1994;281:80-84. 94. Yagupsky P, Katz O, Peled N. Antibiotic susceptibility of Kingella kingae isolates from respiratory carriers

and patients with invasive infections. J Antimicrob Chemother. 2001;47:191-193. Table 8. Lactobacillus species 95. Barrett MS, Jones RN. In vitro activity of quinupristin/dalfopristin (RP 59500) against a large collection of

infrequently isolated or tested species. Diagn Microbiol Infect Dis. 1996;25:147-149. 96. Collins LA, Malanoski GJ, Eliopoulos GM, Wennersten CB, Ferraro MJ, Moellering RC Jr. In vitro activity

of RP59500, an injectable streptogramin antibiotic, against vancomycin-resistant gram-positive organisms. Antimicrob Agents Chemother. 1993;37:598-601.

97. de la Maza L, Ruoff KL, Ferraro MJ. In vitro activities of daptomycin and other antimicrobial agents against

vancomycin-resistant gram-positive bacteria. Antimicrob Agents Chemother. 1989;33:1383-1384. 98. Goldstein EJ, Citron DM, Merriam CV, Warren YA, Tyrrell KL, Fernandez HT. In vitro activities of

daptomycin, vancomycin, quinupristin-dalfopristin, linezolid, and five other antimicrobials against 307 gram-positive anaerobic and 31 Corynebacterium clinical isolates. Antimicrob Agents Chemother. 2003;47:337-341.

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99. Swenson JM, Facklam RR, Thornsberry C. Antimicrobial susceptibility of vancomycin-resistant Leuconostoc, Pediococcus, and Lactobacillus species. Antimicrob Agents Chemother. 1990;34:543-549.

Table 9. Leuconostoc species 100. Barrett MS, Jones RN. In vitro activity of quinupristin/dalfopristin (RP 59500) against a large collection of




vancomycin-resistant gram-positive bacteria. Antimicrob Agents Chemother. 1989;33:1383-1384. 103. Deye G, Lewis J, Patterson J, Jorgensen J. A case of Leuconostoc ventriculitis with resistance to carbapenem

antibiotics. Clin Infect Dis. 2003;37:869-870. 104. Swenson JM, Facklam RR, Thornsberry C. Antimicrobial susceptibility of vancomycin-resistant

Leuconostoc, Pediococcus, and Lactobacillus species. Antimicrob Agents Chemother. 1990;34:543-549. 105. Yamane N, Jones RN. In vitro activity of 43 antimicrobial agents tested against ampicillin-resistant

enterococci and gram-positive species resistant to vancomycin. Diagn Microbiol Infect Dis. 1991;14:337-345. Table 10. Listeria monocytogenes 106. Charpentier E, Courvalin P. Antibiotic resistance in Listeria spp. Antimicrob Agents Chemother. 1999;

43(9):2103-2108. 107. Fernandez Guerrero ML, Rivas P, Rabago R, Nunez A, de Gorgolas M, Martinell J. Prosthetic valve

endocarditis due to Listeria monocytogenes. Report of two cases and reviews. Int J Infect Dis. 2004;8(2):97-102.

108. Hansen JM, Gerner-Smidt P, Bruun B. Antibiotic susceptibility of Listeria monocytogenes in Denmark 1958-

2001. APMIS. 2005;113:31-36. 109. Jones EM, MacGowan AP. Antimicrobial chemotherapy of human infection due to Listeria monocytogenes.

Eur J Clin Microbiol Infect Dis. 1995;14:165-175. 110. Marco F, Almela M, Nolla-Salas J, et al. In vitro activities of 22 antimicrobial agents against Listeria

monocytogenes strains isolated in Barcelona, Spain. Diagn Microbiol Infect Dis. 2000;38(4):259-261. 111. Safdar A, Armstrong D. Antimicrobial activities against 84 Listeria monocytogenes isolates from patients

with systemic listeriosis at a comprehensive cancer center (1955-1997). J Clin Microbiol. 2003;41(1):483-485.

112. Spyrou N, Anderson M, Foale R. Listeria endocarditis: current management and patient outcome—world

literature review. Heart. 1997;77(4):380-383. 113. Wing EJ, Gregory SH. Listeria monocytogenes: clinical and experimental update. J Infect Dis.

2002;185(Suppl 1):S18-24. Table 11. Moraxella catarrhalis 114. Catlin BW. Branhamella catarrhalis: an organism gaining respect as a pathogen. Clin Microbiol Rev. 1990;

3:293-320. 115. De Baere T, Muylaert A, Everaert E, et al. Bacteremia due to Moraxella atlantae in a cancer patient. J Clin

Microbiol. 2002;40:2693-2695.

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116. Doern GV, Tubert TA. Disk diffusion susceptibility testing of Branhamella catarrhalis with ampicillin and seven other antimicrobial agents. Antimicrob Agents Chemother. 1987;31:1519-1523.

117. Doern GV, Tubert TA. In vitro activities of 39 antimicrobial agents for Branhamella catarrhalis and

comparison of results with different quantitative susceptibility test methods. Antimicrob Agents Chemother. 1988;32:259-261.

118. Felmingham D, Gruneberg RN, and the Alexander Project Group. A multicentre collaborative study of the

antimicrobial susceptibility of community-acquired, lower respiratory tract pathogens, 1992-1993: the Alexander Project. J Antimicrob Chemother. 1996;38(Suppl A):1-57.

119. Graham DR, Band JD, Thornsberry C, Hollis DG, Weaver RE. Infections caused by Moraxella, Moraxella

urethralis, Moraxella-like groups M-5 and M-6, Kingella kingae in the United States, 1953-1980. Rev Infect Dis. 1990;12:423-431.

120. Hansen W, Butzler JP, Fuglesang JE, Henriksen SD. Isolation of penicillin and streptomycin resistant strains

of Moraxella osloensis. Acta Pathol Microbiol Scand. 1974;82(Suppl B):318-322. 121. Jones RN, Sommers HM. Identification and antimicrobial susceptibility testing of Branhamella catarrhalis in

United States laboratories, 1983-1985. Drugs. 1986;31(Suppl 3):34-37. 122. Kibsey PC, Rennie RP, Rushton JE. Disk diffusion versus broth microdilution susceptibility testing of

Haemophilus species and Moraxella catarrhalis using seven oral antimicrobial agents: application of updated susceptibility guidelines of the National Committee for Clinical Laboratory Standards. J Clin Microbiol. 1994;32:2786-2790.

123. Meza A, Verghese A, Berk SL. Moraxella catarrhalis. In: Yu V, Weber R, Raoult D, eds. Antimicrobial

Therapy and Vaccines. 2nd ed. New York, NY: Apple Tree Productions; 2002. 124. Reynolds R, Shackcloth J, Felmingham D, McGowan A, on behalf of the BSAC Extended Working Party on

Respiratory Resistance Surveillance. Comparison of BSAC agar dilution and NCCLS broth microdilution MIC methods for the in vitro susceptibility testing of Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis: the BSAC Respiratory Resistance Surveillance Programme. J Antimicrob Chemother. 2003;52:925-930.

125. Shah SS, Ruth A, Coffin SE. Infection due to Moraxella osloensis: case report and review of the literature.

Clin Infect Dis. 2000;30:179-181. 126. Verduin CM, Hol C, Fleer A, van Dijk H, van Belkum A. Moraxella catarrhalis: from emerging to

established pathogen. Clin Microbiol Rev. 2002;15:125-144. 127. Wallace RJ, Steingrube VA, Nash DR, et al. BRO ß-lactamases of Branhamella catarrhalis and Moraxella

subgenus Moraxella, including evidence for chromosomal ß-lactamase transfer by conjugation in B. catarrhalis, M. nonliquefaciens, and M. lacunata. Antimicrob Agents Chemother. 1989;33:1845-1854.

Table 12. Pasteurella species 128. Andrews JM, Jevons G, Brenwald N, Fraise A. BSAC Working Party on Sensitivity Testing. Susceptibility

testing Pasteurella multocida by BSAC standardized methodology. J Antimicrob Chemother. 2004;54:962-964.

129. Citron DM, Warren YA, Fernandez HT, Goldstein MA, Tyrrell KL, Goldstein EJC. Broth microdilution and

disk diffusion tests for susceptibility testing of Pasteurella species from human clinical specimens. J Clin Microbiol. 2005;43:2485-2488.

130. Goldstein EJ, Citron DM, Merriam CV, Warren YA, Tyrrell KL, Fernandez HT. In vitro activities of

garenoxacin (BMS-284756) against 170 clinical isolates of nine Pasteurella species. Antimicrob Agents Chemother. 2002;46:3068-3070.

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131. Goldstein EJC, Citron DM, Richwald GA. Lack of in vitro activity of oral forms of certain cephalosporins, erythromycin, and oxacillin against Pasteurella multocida. J Clin Microbiol. 1988;32:213-215.

132. Johnson LB, Busuito MJ, Khatib R. Breast implant infection in a cat owner due to Pasteurella multocida. J

Infect. 2000;41:110-111. 133. Lion C, Lozniewski A, Rosner V, Weber M. Lung abscess due to beta-lactamase-producing Pasteurella

multocida. Clin Infect Dis. 1999;29:1345-1346. 134. Mortensen JE, Giger O, Rodgers GL. In vitro activity of oral antimicrobial agents against clinical isolates of

Pasteurella multocida. Diagn Microbiol Infect Dis. 1998;30:99-102. 135. Van Langenhove G, Daelemans R, Zachee P, Lins RL. Pasteurella multocida as a rare cause of peritonitis in

peritoneal dialysis. Nephron. 2000;85:283-284. Table 13. Pediococcus species 136. Barrett MS, Jones RN. In vitro activity of quinupristin/dalfopristin (RP 59500) against a large collection of




vancomycin-resistant gram-positive bacteria. Antimicrob Agents Chemother. 1989;33:1383-1384. 139. Long SS, Pickering LK, Prober CG, eds. Principles and Practice of Pediatric Infectious Diseases.

Philadelphia, PA: Churchill Livingstone; 2002. 140. Swenson JM, Facklam RR, Thornsberry C. Antimicrobial susceptibility of vancomycin-resistant

Leuconostoc, Pediococcus, and Lactobacillus species. Antimicrob Agents Chemother. 1990;34:543-549. 141. Yamane N, Jones RN. In vitro activity of 43 antimicrobial agents tested against ampicillin-resistant

enterococci and gram-positive species resistant to vancomycin. Diagn Microbiol Infect Dis. 1991;14:337-345. Table 14. Vibrio species 142. Asenjo CW, Ramirez-Rhonda CH. Halophilic Vibrio infections: a review. Bol Asoc Med PR. 1991;83:154-

156. 143. Chiang SR, Chuang YC. Vibrio vulnificus infection: clinical manifestations, pathogenesis, and antimicrobial

therapy. J Microbiol Immunol Infect. 2003;36:81-88. 144. Chien JY, Shih JT, Hsueh PR, Yang PC, Luh KT. Vibrio alginolyticus as the cause of pleural empyema and

bacteremia in an immunocompromised patient. Eur J Clin Microbiol Infect Dis. 2002;21:401-403. 145. Chuang YC, Liu JW, Ko WC, Lin KY, Wu JJ, Huang KY. In vitro synergism between cefotaxime and

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Chemother. 1989;24:183-194. 147. Gomez JM, Fajardo R, Patino JF, Arias CA. Necrotizing fasciitis due to Vibrio alginolyticus in an

immunocompetent patient. J Clin Microbiol. 2003;41:3427-3429. 148. Hsueh PR, Chang JC, Chang SC, Ho SW, Hsieh WC. In vitro antimicrobial susceptibility of Vibrio vulnificus

isolated in Taiwan. Eur J Clin Microbiol Infect Dis. 1995;14:151-153.

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149. Morris JG Jr, Tenney JH, Drusano GL. In vitro susceptibility of pathogenic Vibrio species to norfloxacin and six other antimicrobial agents. Antimicrob Agents Chemother. 1985;28:442-445.

150. Ottaviani D, Bacchiocchi I, Masini L, et al. Antimicrobial susceptibility of potentially pathogenic halophilic

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fluoroquinolones against Vibrio vulnificus. Antimicrob Agents Chemother. 2002;46:3580-3584. 152. Zanetti S, Spanu T, Deriu A, Romano L, Sechi LA, Fadda G. In vitro susceptibility of Vibrio spp. isolated

from the environment. Int J Antimicrob Agents. 2001;17:407-409.

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Summary of Consensus/Delegate Comments and Committee Responses M45-P: Methods for Antimicrobial Dilution and Disk Susceptibility Testing of Infrequently Isolated or Fastidious Bacteria; Proposed Guideline General 1. Since Erysipelothrix is very much like Lactobacillus, Pediococcus, and Leuconostoc in biochemical profile,

resistance patterns, and colony appearance, I just want to be sure that we had a reason to use the streptococcus breakpoints (≤ 0.12 and 0.25) for the former and the Enterococcus breakpoints (≤ 8) for the three other genera. A concern is that none of these are known to have any penicillin resistance, so we truly have no idea what the MIC of resistance is. Also, the MIC of 8 for Enterococcus is based on using an aminoglycoside with penicillin. Since data showed that 8 is not an achievable blood level, I think the wrong message is being given. Personally I like the pneumococcal breakpoint for all, since that is the best example of non-β-lactamase resistance.

• Based upon studies performed primarily at the CDC, it was determined that the MIC distributions of the

antimicrobial agents recommended for testing with Lactobacillus, Pediococcus, and Leuconostoc were very consistent with MIC distributions of those agents with Enterococcus spp., but were not consistent with MIC distributions of streptococci. In contrast, MIC distributions observed with Erysipelothrix were quite similar to those of streptococci.

2. The publishing of breakpoint tables, while helpful for laboratories, may present problems clinically, as PK/PD

principles were not applied, and in most cases clinical outcome information is anecdotal or completely lacking. The sources of data (citations) are not always clear, and the use of M100 existing breakpoints for many groups without further explanations may not always be appropriate. In such cases, providing MIC values using the established methods may be preferable, without attempts at interpretation. At a minimum, where published information is available, references should be footnoted to the tables to provide the authority for the given breakpoints. In several cases, epidemiologically derived breakpoints are given based upon MIC population distributions, which at least provides some existing experimental data on frequency distributions and resistance population detection. Overall, the document is a good advance in providing direction to clinical laboratories that are often asked to test these organisms by clinical staff, and bringing together the methods in one place is especially helpful. Further collection of data can now be performed with laboratorians at least using similar methodologies.

• As stated in the Scope and Introduction of the document, data from large clinical trials were not available

for review with these infrequently isolated organisms. Where possible, clinical case reports or small series that support the proposed breakpoints have been cited. The working group felt that it would be more appropriate to adapt breakpoints whenever possible from more commonly isolated organisms that may cause similar infections and whose interpretive breakpoints have been developed using more extensive data sets, including in many instances PK/PD principles, as well as clinical outcomes data.

3. Is it recommended to do a β-lactamase routinely for Moraxella catarrhalis, because greater than 95% of strains

are positive? I would reword to state that “it is not necessary to test routinely, since practically all strains are resistant to penicillin and susceptible to recommended therapies.”

• The working group agrees with the comment and has changed the footnotes of this table. 4. Pasteurella is included in the “fastidious” group. Since it doesn’t require special supplements or CO2 for

growth, in the table it is described as nonfastidious. Should the committee define what is meant by fastidious? Does just a requirement for blood supplementation make an organism fastidious? (Also on page 3, paragraph 1; page 6, paragraph 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.

Number 19 M45-A


• The term “fastidious” is commonly used to describe bacteria that require media supplemented with animal blood or blood components, and that possibly need a CO2-enriched atmosphere for acceptable growth. In that regard, the addition of horse or sheep blood has been recommended in this document for testing Pasteurella spp.

Section 1, Scope 5. The second sentence of paragraph 2 does not make sense; Table 7 describes methods for HACEK organisms—

all except Capnocytophaga. I suggest that the parenthesis ends at Kingella spp. and a new sentence starts with Capnocytophaga spp. are outside the scope…

• This has been corrected. Section 2, Introduction 6. Second paragraph under “Resistance Mechanisms in Gram-Positive Rods”: misspelling of C.

pseudodiphtheriticum. • This has been corrected. 7. Second paragraph under “Resistance Mechanisms in Gram-Positive Rods”: Not all clinical isolates of

Lactobacillus are intrinsically vancomycin-resistant. The “acidophilus group” (L. gasseri, L. jensenii, L. crispatus) are all vancomycin-susceptible and are also occasionally isolated from blood cultures and other specimens. When speaking of intrinsically vancomycin-resistant Lactobacillus, I suggest the statement be modified and say “many” Lactobacillus spp.

• The word “most” has been added. 8. Second paragraph under “Resistance Mechanisms in Gram-Positive Rods”: C. jeikeium and C. urealyticum are

also often resistant to carbapenems. • The broad category “β-lactams” is correctly applied in that sentence and includes carbapenems. In the

most current editions of CLSI documents M2 and M7, β-lactams are defined as including penicillins, cephems, carbapenems, and monobactams.

Section 8, Therapy-Related Comments 9. Should “therapy-related comments be eliminated”? • The only therapy-related comment in the tables is the caution not to use rifampin as monotherapy. Tables 10. Tables have “Note: Information in boldface is considered tentative for one year.” There is nothing bolded in any

of the tables. Should this statement be deleted at this time? • This has been standard language in CLSI susceptibility testing tables, but is not specifically needed in this

totally new document. Table 3. Bacillus species (Not B. anthracis)—Information and Interpretive Criteria for Broth Microdilution Susceptibility Testing 11. Under testing notes for Bacillus: I suggest adding the line “However, the lack of a zone of inhibition around a

penicillin disk would indicate resistance to penicillin.” • This may be a true statement, but has not been critically assessed by the working group. Moreover, the

presence of a zone of inhibition might be misconstrued as representing susceptibility to penicillin if such a statement were added.

Volume 26 M45-A


12. Why is it necessary to incubate Bacillus for a full 24 hours? They are rapid growers and reach stationary phase after 16 to 18 hours. Table 15 has 16 to 20 hours.

• It is recommended that Bacillus spp. be incubated for 16 to 20 hours. The text has been revised to reflect

this. Table 5. Corynebacterium species (Including C. diphtheriae)—Information and Interpretive Criteria for Broth Microdilution Susceptibility Testing 13. There is an Rx comment for rifampin—should this be deleted? • The only therapy-related comment in the tables is the caution not to use rifampin as monotherapy, and

should be retained for the sake of patient safety. Table 7. HACEK Group: the Aphrophilus Cluster of the Genus Haemophilus (i.e., H. aphrophilus, H. paraphrophilus, H. segnis), Actinobacillus actinomycetemcomitans, Cardiobacterium species, Eikenella corrodens, and Kingella species—Information and Interpretive Criteria for Broth Microdilution Susceptibility Testing 14. Incubation condition should be CO2 instead of ambient air. • This error has been corrected. Table 8. Lactobacillus species—Information and Interpretive Criteria for Broth Microdilution Susceptibility Testing 15. While vancomycin is a last choice for treating Lactobacillus infection, to say that routine testing with

vancomycin is not necessary is misleading. The acidophilus group are all vancomycin-susceptible and do cause infection. I suggest deleting “routine testing with vancomycin is not necessary” and not make any suggestion at all.

• This has been deleted as suggested. Table 12. Pasteurella species—Information and Interpretive Criteria for Broth Microdilution and Disk Diffusion Susceptibility Testing 16. Pasteurella is described as nonfastidious—again, this is inconsistent with the text in the introductory pages.

Since the β-lactamase-producing strains described in the literature were isolated from respiratory specimens, I recommend adding respiratory specimens to the list for “Reasons for testing/not testing.”

• The working group agrees that “nonfastidious” should be removed. Respiratory specimens has been

added to the list. Table 15. Summary of Testing Conditions and QC Recommendations for Infrequently Isolated or Fastidious Bacteria 17. Since this document is for organisms associated with endocarditis, or infections from trauma, or device-

associated infections—I think that many of these infections would involve biofilms and persister bacterial growth in vivo. I have been questioned by some whether in vitro susceptibility testing in cystic fibrosis patients with Pseudomonas aeruginosa biofilm infections, for example, correlate well to patient treatment results. (1) Is not that a concern here as well with these biofilm infections? Although Pseudomonas aeruginosa is covered in another document—should any comment be included in this document related to the need for further research to continuously improve methods in order to improve the correlation of in vitro susceptibility to in vivo outcomes?

• The possibility does exist that organisms causing endocarditis or device-associated infections exist in

biofilms. However, the MIC of an antimicrobial agent determined as described in this document has proven useful in guiding therapy in a number of case reports and case series. Testing modifications that would take into account biofilm-associated bacteria go beyond the scope of this document.

Number 19 M45-A


The Quality 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/NCCLS document HS1—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 healthcare service’s path of workflow (i.e., 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 quality system essentials (QSEs) are: Documents & Records Equipment Information Management Process Improvement Organization Purchasing & Inventory Occurrence Management Service & Satisfaction Personnel Process Control Assessment Facilities & Safety M45-A addresses the quality system essentials (QSEs) indicated by an “X.” For a description of the other documents listed in the grid, please refer to the Related CLSI/NCCLS Publications section on the following page.

Doc

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& R

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Pers

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Equi

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Purc

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X M2 M7 M23

M100

Adapted from CLSI/NCCLS document HS1—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/NCCLS 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. M45-A 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/NCCLS Publications section on the following page.

Preexamination Examination Postexamination

Exam

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orde

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Sam

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colle

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Adapted from CLSI/NCCLS document HS1—A Quality Management System Model for Health Care.

Volume 26 M45-A


Related CLSI/NCCLS Publications∗ M2-A9 Performance Standards for Antimicrobial Disk Susceptibility Tests; Approved Standard—Ninth

Edition (2006). This document contains the current CLSI-recommended methods for disk susceptibility testing, criteria for quality control testing, and updated tables for interpretive zone diameters.

M7-A7 Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved

Standard—Seventh Edition (2006). This document addresses reference methods for the determination of minimal inhibitory concentrations (MICs) of aerobic bacteria by broth macrodilution, broth microdilution, and agar dilution.

M23-A2 Development of In Vitro Susceptibility Testing Criteria and Quality Control Parameters; Approved

Guideline—Second Edition (2001). This document addresses the required and recommended data needed for the selection of appropriate interpretive standards and quality control guidelines for antimicrobial agents.

M100-S16 Performance Standards for Antimicrobial Susceptibility Testing; Sixteenth Informational Supplement

(2006). This document provides updated tables for the Clinical and Laboratory Standards Institute (CLSI) antimicrobial susceptibility testing standards M2-A9 and M7-A7.

∗ Proposed-level documents are being advanced through the Clinical and Laboratory Standards Institute consensus process; therefore, readers should refer to the most current editions.

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OFFICERS

BOARD OF DIRECTORS

Robert L. Habig, PhD, President Abbott Laboratories Gerald A. Hoeltge, MD, President-Elect The Cleveland Clinic Foundation Wayne Brinster, Secretary BD W. Gregory Miller, PhD, Treasurer Virginia Commonwealth University Thomas L. Hearn, PhD, Immediate Past President Centers for Disease Control and Prevention Glen Fine, MS, MBA, Executive Vice President

Susan Blonshine, RRT, RPFT, FAARC TechEd Maria Carballo Health Canada Russel K. Enns, PhD Cepheid Mary Lou Gantzer, PhD Dade Behring Inc. Lillian J. Gill, DPA FDA Center for Devices and Radiological Health Jeannie Miller, RN, MPH Centers for Medicare & Medicaid Services

Gary L. Myers, PhD Centers for Disease Control and Prevention Valerie Ng, PhD, MD Alameda County Medical Center/ Highland General Hospital Klaus E. Stinshoff, Dr.rer.nat. Digene (Switzerland) Sàrl James A. Thomas ASTM International Kiyoaki Watanabe, MD Keio University School of Medicine

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