3rd Edition

M27M44S
Performance Standards for Antifungal
Susceptibility Testing of Yeasts

This document includes updated minimal inhibitory

concentration, zone diameter, and quality control tables for
the Clinical and Laboratory Standards Institute antifungal
susceptibility testing documents M27 and M44.

A CLSI supplement for global application.

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 Clinical and Laboratory Standards Institute
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 M27M44S-Ed3
August 2022
Replaces M60-Ed2
Performance Standards for Antifungal Susceptibility Testing of
Yeasts
Gary W. Procop, MD, MS
Philippe J. Dufresne, PhD, RMCCM
Elizabeth Berkow, PhD
Sharon K. Cullen, BS, RAC
Tanis Dingle, PhD, D(ABMM), FCCM
Jeff Fuller, PhD, FCCM, D(ABMM)
Kimberly E. Hanson, MD, MHS
Nicole M. Holliday, BA
Audrey N. Schuetz, MD, MPH, D(ABMM)
Paul E. Verweij, MD, FECMM
Nathan P. Wiederhold, PharmD
Adrian M. Zelazny, PhD, D(ABMM)

Abstract
Clinical and Laboratory Standards Institute document M27M44SPerformance Standards for Antifungal
Susceptibility Testing of Yeasts includes minimal inhibitory concentration, zone diameter, and quality control
tables developed following the guidance in CLSI documents M271 and M44.2 The data in the tables are valid only
when the methodologies in CLSI documents M271 and M442 are followed. Users should replace previously published
tables with these new tables. Changes in the tables since the previous edition was published appear in boldface
type.

Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antifungal Susceptibility Testing of
Yeasts. 3rd ed. CLSI supplement M27M44S (ISBN 978-1-68440-162-8 [Print]; ISBN 978-1-68440-163-5 [Electronic]).
Clinical and Laboratory Standards Institute, USA, 2022.

The Clinical and Laboratory Standards Institute consensus process, which is the mechanism for moving a
document through two or more levels of review by the health care community, is an ongoing process. Users
should expect revised editions of any given document. Because rapid changes in technology may affect the
procedures, methods, and protocols in a standard or guideline, users should replace outdated editions with the
current editions of CLSI documents. Current editions are listed in the CLSI catalog and posted on our website at
www.clsi.org.

If you or your organization is not a member and would like to become one,
The Clinical and Laboratory Standards Institute aconsensus
or to request process,
copy of the whichcontact
catalog, is the mechanism
us at: for moving a document through two
or more levels of review by the health care community, is an ongoing process. Users should expect revised editions of any given
P: +1.610.688.0100;
document. Because rapid changes in +1.610.688.0700;
F:technology may affect customerservice@clsi.org;
E: the W:
procedures, methods, and www.clsi.org
protocols in a standard or guideline,
users should replace outdated editions with the current editions of CLSI documents. Current editions are listed in the CLSI catalog
and posted on our website at www.clsi.org.

If you or your organization is not a member and would like to become one, or to request a copy of the catalog, contact us at:

P: +1.610.688.0100 F: +1.610.688.0700 E: customerservice@clsi.org W: www.clsi.org

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Copyright ©2022 Clinical and Laboratory Standards Institute. Except as stated below, any
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Suggested Citation
CLSI. Performance Standards for Antifungal Susceptibility Testing of Yeasts. 3rd ed. CLSI
supplement M27M44S. Clinical and Laboratory Standards Institute; 2022.

Previous Editions:
M27-S4: May 2004, April 2005, April 2008, December 2012
M44-S3: January 2006, August 2007, August 2009
M60: November 2017, June 2020

M27-Ed4-M44-Ed3-S-Ed3
ISBN 978-1-68440-162-8 (Print)
ISBN 978-1-68440-163-5 (Electronic)
ISSN 1558-6502 (Print)
ISSN 2162-2914 (Electronic) Volume 42, Number 20

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Committee Membership
Subcommittee on Antifungal Susceptibility Tests

Gary W. Procop, MD, MS Sharon K. Cullen, BS, RAC Audrey N. Schuetz, MD, MPH,
Chairholder Beckman Coulter, Inc. D(ABMM)
American Board of Pathology Microbiology Business Mayo Clinic
USA USA USA

Philippe J. Dufresne, PhD, RMCCM Jeff Fuller, PhD, FCCM, D(ABMM) Paul E. Verweij, MD, FECMM
Vice-Chairholder London Health Sciences Centre Radboud University Medical Center
Institut national de santé publique Canada the Netherlands
du Québec
Canada Kimberly E. Hanson, MD, MHS Nathan P. Wiederhold, PharmD
University of Utah and University of Texas Health Science
Camille Hamula, PhD, D(ABMM) ARUP Laboratories Center at San Antonio
Committee Secretary USA USA
Saskatoon Health Region/
University of Saskatchewan Nicole M. Holliday, BA Adrian M. Zelazny, PhD, D(ABMM)
Canada Thermo Fisher Scientific National Institutes of Health
USA Department of Laboratory Medicine
Elizabeth Berkow, PhD USA
Centers for Disease Control and
Prevention
USA

Working Group on Antifungal Breakpoints

David Andes, MD Mariana Castanheira, PhD Shawn R. Lockhart, PhD, D(ABMM),

Co-Chairholder JMI Laboratories F(AAM)
University of Wisconsin– USA Centers for Disease Control and
Madison Medical School Prevention
USA Philippe J. Dufresne, PhD, RMCCM USA
Institut national de santé publique
Andrew M. Borman, BSc, PhD du Québec Gary W. Procop, MD, MS
Co-Chairholder Canada American Board of Pathology
Public Health England USA
United Kingdom Kimberly E. Hanson, MD, MHS
University of Utah and
Nathan P. Wiederhold, PharmD ARUP Laboratories
Committee Secretary USA
University of Texas Health Science
Center at San Antonio
USA

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Working Group on Antifungal Epidemiological Cutoff Values

Shawn R. Lockhart, PhD, D(ABMM), Elizabeth Berkow, PhD Kimberly E. Hanson, MD, MHS
F(AAM) Centers for Disease Control and University of Utah and
Chairholder Prevention ARUP Laboratories
Centers for Disease Control and USA USA
Prevention
USA Jeff Fuller, PhD, FCCM, D(ABMM) John D. Turnidge, MD, BS, FRACP,
London Health Sciences Centre FASM, FRCPA
Philippe J. Dufresne, PhD, RMCCM Canada The University of Adelaide
Vice-Chairholder Australia
Institut national de santé publique Mahmoud A. Ghannoum, PhD,
du Québec FIDSA, MBA Thomas J. Walsh, MD, FIDSA, FAAM,
Canada Case Western Reserve University FECMM
USA Weill Cornell Medicine of Cornell
Nathan P. Wiederhold, PharmD University and New York
Committee Secretary Kerian K. Grande Roche, PhD Presbyterian Hospital
University of Texas Health Science FDA Center for Drug Evaluation and USA
Center at San Antonio Research
USA USA

Barbara D. Alexander, MD, MHS

Duke University Medical Center
USA

Working Group on Antifungal Reporting

Audrey N. Schuetz, MD, MPH, Stephanie L. Mitchell, PhD, Matthew A. Wikler, MD, FIDSA, MBA
D(ABMM) D(ABMM) IDTD Consulting
Co-Chairholder Cepheid USA
Mayo Clinic USA
USA Yanan (Nancy) Zhao, PhD
Natasha N. Pettit, PharmD, Center for Discovery and
Vera Tesic, MD, MS, D(ABMM) BCPS (AQ-ID) Innovation, Hackensack Meridian
Co-Chairholder University of Chicago Medicine Health
University of Chicago USA USA
USA
Thomas J. Walsh, MD, PhD(hon),
Tanis Dingle, PhD, D(ABMM), FCCM FIDSA, FAAM, FECMM
Alberta Precision Laboratories– Weill Cornell Medicine of Cornell
Public Health Laboratory University and New York
Canada Presbyterian Hospital
USA
Kimberly E. Hanson, MD, MHS
University of Utah and Nathan P. Wiederhold, PharmD
ARUP Laboratories University of Texas Health Science
USA Center at San Antonio
USA

Staff

Clinical and Laboratory Standards Laura Martin Kristy L. Leirer, MS

Institute Editorial Manager Editor
USA
Catherine E.M. Jenkins, ELS Lisa M.W. Walker, MS, ELS
Christine M. Lam, MT(ASCP) Editor Editor
Project Manager

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 M27M44S-Ed3

Acknowledgment

CLSI and the Subcommittee on Antifungal Susceptibility Tests gratefully acknowledge the following volunteer for
her important contributions to the revision of this document:

Tanis Dingle, PhD, D(ABMM), FCCM

Alberta Precision Laboratories–
Public Health Laboratory
Canada

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Contents
Abstract .................................................................................................... i

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

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

Overview of Changes ................................................................................... xi

Abbreviations and Acronyms ......................................................................... xiv

References ............................................................................................... xv

Table 1. Minimal Inhibitory Concentration Breakpoints for In Vitro Broth Dilution

Susceptibility Testing of Candida spp. and Select Antifungal Agents After 24-Hour
Incubation ................................................................................................. 1

Table 2. Solvents and Diluents for Preparing Stock Antifungal Agent Solutions for Broth
Dilution Testing .......................................................................................... 5

Table 3. Recommended 24-Hour Minimal Inhibitory Concentration Limits for Quality

Control Strains for Broth Microdilution Procedures ................................................ 6

Table 4. Recommended 48-Hour Minimal Inhibitory Concentration Limits for Two

Quality Control and Four Reference Strains for Broth Macrodilution Procedures ............. 8

Table 5. Zone Diameter and Equivalent Minimal Inhibitory Concentration Breakpoints for
Select Antifungal Agents Against Candida spp. After 24-Hour Incubation ...................... 9

Table 6. Recommended Quality Control Zone Diameter (mm) Ranges After 24-Hour
Incubation ............................................................................................... 11

Appendix A. Body Site Reporting for Candida spp. ............................................... 12

Appendix B. Intrinsic Resistance for Yeasts ....................................................... 15

Glossary. Antifungal Agent Abbreviations, Routes of Administration, and Drug Class ...... 18

The Quality Management System Approach ....................................................... 19

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Foreword
The breakpoints and interpretive categories provided in this document are generated using
the reference methods for antifungal susceptibility testing of yeasts described in CLSI
documents M271 and M44.2 These reference methods may be used for:

 Routine antifungal testing of patient isolates to guide therapy

 Evaluation of commercial devices that will be used in medical laboratories
 Testing of new agents or systems by drug or device manufacturers

Results generated by reference methods, such as those described in CLSI documents, may be
used by regulatory authorities to evaluate commercial susceptibility testing device
performance as part of the commercial device approval process. Regulatory clearance
indicates that the commercial susceptibility testing device provides results that are
substantially equivalent to those generated using reference methods for the organisms and
antimicrobial agents described in the device manufacturer’s approved package insert.

However, CLSI breakpoints may differ from breakpoints approved by various regulatory
organizations for many reasons, including:

 Database differences
 Data interpretation
 Dosage amounts used in different parts of the world
 Public health policies

Differences also exist because CLSI proactively evaluates the need for changing breakpoints.
The reasons that breakpoints may change, as well as the manner in which CLSI evaluates data
and determines breakpoints, are described in CLSI document M23. 3

When CLSI decides to change an existing breakpoint, regulatory organizations may review
data to determine how the changes may affect antimicrobial agent safety and effectiveness
for the approved indications. When a regulatory authority changes breakpoints, commercial
device manufacturers may have to conduct a clinical trial, submit the data to the regulatory
organization, and await review and approval. For these reasons, there might be a delay of
one or more years if a device manufacturer decides to implement a breakpoint change. Some
regulatory and accreditation requirements permit laboratories using cleared or approved
testing devices to use existing regulatory organization breakpoints. Either the regulatory
approved breakpoints or CLSI breakpoints may be acceptable to laboratory accreditation
organizations, depending on the method used for susceptibility testing. Other regulatory
and accreditation requirements vary. Each laboratory should consult its susceptibility test
system manufacturer for additional information on the breakpoints used in its system
software. Laboratories should be aware of their specific regulatory and accreditation
requirements for using CLSI breakpoints.

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Following discussions with appropriate stakeholders (eg, infectious diseases practitioners and
pharmacy practitioners, the hospital’s pharmacy and therapeutics and infection prevention
committees), laboratories may verify and implement newly approved or revised CLSI
breakpoints as soon as they are published. Some devices might specify antimicrobial test
concentrations that are sufficient to interpret susceptibility and resistance to an agent using
the CLSI breakpoints. In such cases, after appropriate validation as outlined in CLSI document
M52,4 a laboratory could choose to interpret and report results from that device using CLSI
breakpoints.

NOTE: Current fungal taxonomy is under revision. Many genera have both a teleomorph
(sexual state) and an anamorph (asexual state) name. In this document, the traditional
Candida anamorph names are used to provide continuity with both past procedures and
associated documents such as CLSI document M271 and others.5-7

NOTE: When serial twofold dilution MICs are being prepared and tested, the actual
dilution scheme is, eg, 64, 32, 16, 8, 4, 2, 1, 0.5, 0.25, 0.125, 0.0625, 0.03125,
0.015625, 0.0078125, 0.0039063, 0.0019531 µg/mL, etc. For convenience only, and not
because these are the actual concentrations tested, it was decided to use the following
values in M27M44S: 64, 32, 16, 8, 4, 2, 1, 0.5, 0.25, 0.12, 0.06, 0.03, 0.016, 0.008,
0.004, 0.002 µg/mL, etc. The values that appear in the tables are equivalent to the actual
values tested, eg, 0.12 µg/mL = 0.125 µg/mL, and laboratories should report an MIC of
≤ 0.125 μg/mL as ≤ 0.12 μg/mL.

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Overview of Changes
This document replaces the previous edition of the approved document, M60-Ed2, published
in 2020. Several changes were made in this edition, including:

Section/Table Action Change to: Reason/Specific Change

General Revised Document code Align with parent documents
(M27 and M44)
Foreword Revised Foreword  Clarifying that breakpoints used
depend on which test method is
used
 Clarifying that laboratories
verify data validated by
manufacturers
Added Foreword Text regarding MIC reporting
concentrations
Table 1. Minimal Revised General NOTEs and some footnotes were
Inhibitory reorganized as general comments
Concentration and footnotes
Breakpoints for In Footnotes  Regarding breakpoints and ECVs
Vitro Broth Dilution for cryptic species
Susceptibility Testing  Regarding reference to
of Candida spp. and Appendix B defining IR for
Select Antifungal Candida krusei
Agents After 24-Hour Added MIC susceptible  Candida albicans
Incubation breakpoints for  Candida auris
rezafungin  Candida dubliniensis
 Candida glabrata
 C. krusei
 Candida parapsilosis
 Candida tropicalis
Footnotes  Regarding newly accepted
teleomorph names for some
Candida spp. to inform user of
recently adopted official
alternate taxonomic names
 Regarding tentative rezafungin
MICs
 Regarding tentative,
susceptible-only breakpoints for
rezafungin
Table 2. Solvents and Added Oteseconazole New antifungal agent
Diluents for Preparing
Stock Antifungal Agent
Solutions for Broth
Dilution Testing

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Overview of Changes (Continued)

Section/Table Action Change to: Reason/Specific Change
Table 3. Revised General NOTEs and some footnotes were
Recommended 24-Hour reorganized as general comments
Minimal Inhibitory and footnotes
Concentration Limits MIC QC range for C. krusei ATCC®a 6258
for Quality Control micafungin
Strains for Broth MIC QC mode for  C. krusei ATCC® 6258
Microdilution micafungin  C. parapsilosis ATCC® 22019
Procedures MIC QC mode for  C. krusei ATCC® 6258
voriconazole  C. parapsilosis ATCC® 22019
Added General comment Regarding yeast MICs for antifungal
agents
MIC QC ranges and  C. albicans ATCC® 90028
modes for  C. parapsilosis ATCC® 22019
oteseconazole  C. parapsilosis ATCC® 90018
Footnote Regarding strains that can be used
for QC with oteseconazole
Table 5. Zone Revised Footnote Regarding reference to Appendix B
Diameter and defining IR for C. krusei
Equivalent Minimal
Inhibitory
Concentration
Breakpoints for Select
Antifungal Agents
Against Candida spp.
After 24-Hour
Incubation

Appendix A. Body Site Added Entire appendix For reporting on specific body sites
Reporting for
Candida spp. (New)

Appendix B. Intrinsic Added Entire appendix Intrinsic resistance designations for

Resistance for Yeasts various antifungal agents and yeast
(New) species

Glossary. Antifungal Added Entire glossary Table of antifungal agents, routes

Agent Abbreviations, of administration, and drug classes
Routes of
Administration, and
Drug Class (New)
Abbreviations: ATCC, American Type Culture Collection; ECV, epidemiological cutoff value; IR, intrinsic
resistance; MIC, minimal inhibitory concentration; QC, quality control.

Footnote

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

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NOTE: The content of this document is supported by the CLSI consensus process and does not
necessarily reflect the views of any single individual or organization.

Key Words

antifungal agent, azole, breakpoint, broth dilution, echinocandin, interpretive category,

minimal inhibitory concentration, quality control, susceptibility testing, yeasts, zone
diameter

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Abbreviations and Acronyms

ATCC®a American Type Culture Collection
CNS central nervous system
CSF cerebrospinal fluid
DMSO dimethyl sulfoxide
DNA deoxyribonucleic acid
ECV epidemiological cutoff value
5-FC flucytosine
I intermediate
IR intrinsic resistance
IV intravenous
MIC minimal inhibitory concentration
PO oral
QC quality control
QMS quality management system
QSE quality system essential
R resistant
S susceptible
SDD susceptible-dose dependent
UTI urinary tract infection

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

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References
1 CLSI. Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts. 4th ed. CLSI
standard M27. Clinical and Laboratory Standards Institute; 2017.
2 CLSI. Method for Antifungal Disk Diffusion Susceptibility Testing of Yeasts. 3rd ed. CLSI guideline M44.
Clinical and Laboratory Standards Institute; 2018.
3 CLSI. Development of In Vitro Susceptibility Testing Criteria and Quality Control Parameters. 5th ed. CLSI
guideline M23. Clinical and Laboratory Standards Institute; 2018.
4 CLSI. Verification of Commercial Microbial Identification and Antimicrobial Susceptibility Testing
Systems. 1st ed. CLSI guideline M52. Clinical and Laboratory Standards Institute; 2015.
5 Borman AM, Johnson EM. Name changes for fungi of medical importance, 2018 to 2019. J Clin Microbiol.
2021;59(2). doi:10.1128/jcm.01811-20
6 Warnock DW. Name changes for fungi of medical importance, 2012 to 2015. J Clin Microbiol.
2017;55(1):53-59. doi:10.1128/jcm.00829-16
7 Warnock DW. Name changes for fungi of medical importance, 2016-2017. J Clin Microbiol. 2019;57(2).
doi:10.1128/jcm.01183-18

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Table 1. Minimal Inhibitory Concentration Breakpoints for In Vitro Broth

Dilution Susceptibility Testing of Candida spp. and Select Antifungal Agents
After 24-Hour Incubation
General Comments

(1) If the 24-hour growth control is insufficient, breakpoints may also be used for 48-hour
readings.

(2) The intermediate category provides a buffer zone for antifungal susceptibility testing that
is necessary to avoid major and very major errors that may occur, given the inherent
variability of the in vitro testing method. Available data do not permit isolates with MIC
results in the intermediate range to be clearly categorized as either “susceptible” or
“resistant.” Strains with intermediate MICs might respond clinically to a higher-than-
standard dose of a drug or in situations in which drug penetration is maximized.

(3) The MIC breakpoints (µg/mL) for Candida spp. are shown against the indicated agents. If
MICs are measured using a scale yielding results that fall between the categories, the next
highest category is implied. Thus, an isolate for which the fluconazole MIC equals 3 µg/mL
would be placed in the susceptible-dose dependent category.

(4) Per CLSI document M38M51S,1 previous breakpoints for itraconazole and flucytosine were
established with minimal clinical data. Emerging data now suggest that the previous
breakpoints were not correct and should not be used. For Candida spp. and itraconazole,
ECVs that define the limit of the wild-type distribution are established and may be useful
for distinguishing between wild-type and non-wild-type isolates (those with acquired
known resistance mechanisms) (see CLSI documents M572 and M57S3).

NOTE: Information in boldface type is new or modified since the previous edition.

MIC Breakpoints and Interpretive Categories,

µg/mL
Antifungal Agent Species S I SDD R
Anidulafungin4,a C. albicans ≤ 0.25 0.5 – ≥1
C. glabratab ≤ 0.12 0.25 – ≥ 0.5
C. guilliermondiib ≤2 4 – ≥8
C. kruseib ≤ 0.25 0.5 – ≥1
C. parapsilosisc ≤2 4 – ≥8
C. tropicalis ≤ 0.25 0.5 – ≥1
Caspofungin4,a,d C. albicans ≤ 0.25 0.5 – ≥1
C. glabrata ≤ 0.12 0.25 – ≥ 0.5
C. guilliermondiib ≤2 4 – ≥8
C. kruseib ≤ 0.25 0.5 – ≥1
C. parapsilosisc ≤2 4 – ≥8
C. tropicalis ≤ 0.25 0.5 – ≥1

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Table 1. (Continued)
MIC Breakpoints and Interpretive Categories,
µg/mL
Antifungal Agent Species S I SDD R
Fluconazole5,e,f C. albicans ≤2 – 4 ≥8
C. glabratab – – ≤ 32 ≥ 64
C. kruseib,g – – – –
C. parapsilosisc ≤2 – 4 ≥8
C. tropicalis ≤2 – 4 ≥8
Micafungin4,a C. albicans ≤ 0.25 0.5 – ≥1
C. glabratab,h ≤ 0.06 0.12 – ≥ 0.25
C. guilliermondiib ≤2 4 – ≥8
C. kruseib ≤ 0.25 0.5 – ≥1
C. parapsilosisc ≤2 4 – ≥8
C. tropicalis ≤ 0.25 0.5 – ≥1
Rezafungini,j C. albicans ≤ 0.25 – – –
C. auris ≤ 0.5 – – –
C. dubliniensis ≤ 0.12 – – –
C. glabrata ≤ 0.5 – – –
C. kruseib ≤ 0.25 – – –
C. parapsilosisc ≤2 – – –
C. tropicalis ≤ 0.25 – – –
Voriconazole6,a C. albicans ≤ 0.12 0.25–0.5 – ≥1
C. glabratab,k – – – –
C. kruseib ≤ 0.5 1 – ≥2
C. parapsilosisc ≤ 0.12 0.25–0.5 – ≥1
C. tropicalis ≤ 0.12 0.25–0.5 – ≥1
Abbreviations: ECV, epidemiological cutoff value; I, intermediate; MIC, minimal inhibitory concentration;
R, resistant; S, susceptible; SDD, susceptible-dose dependent.

Footnotes

a. For these antifungal agents, the data are based largely on experience with non-neutropenic patients with
candidemia. The clinical relevance of the antifungal agents in other settings is uncertain.

b. These Candida spp. are also recognized under the following alternate taxonomic names:
 C. glabrata: Nakaseomyces glabrata
 C. guilliermondii: Meyerozyma guilliermondii
 C. krusei: Pichia kudriavzevii

c. When no further species determination has been performed, C. parapsilosis breakpoints may be applied in
areas where the prevalence of the cryptic species (C. orthopsilosis or C. metapsilosis) is low (eg, North
America).7-11 However, if further species determination identifies one of the cryptic species within the
complex, C. parapsilosis breakpoints should not be applied. Instead, it should be indicated on the laboratory
report that no breakpoints exist for interpretation and that use of ECVs should be considered (see CLSI
document M57S3).

d. Caspofungin susceptibility testing in vitro has been associated with significant interlaboratory variability,
contributing to reports of false resistance when the reference method described in CLSI document M2712 is
used.13 The cause of the variability is unclear. When caspofungin is tested, susceptible results may be
reported as “susceptible.” However, laboratories should confirm “intermediate” or “resistant” results with
one of the following options:

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Table 1. (Continued)

 Additional susceptibility testing with micafungin14 or anidulafungin15

 DNA sequence analysis of FKS genes to identify resistance hot-spot mutations in FKS1 (all Candida spp.)
and FKS2 (C. glabrata only)16,17

 Sending the isolate to a reference laboratory for confirmation

Candida spp. that are resistant to anidulafungin or micafungin or that possess characteristic FKS hot-spot
mutations are considered resistant to all echinocandins, including caspofungin, and should be reported as
such.14,15

e. Susceptibility depends on achieving the maximum possible blood level. For fluconazole, doses higher than the
standard dosing amount (6 mg/kg/day) may be needed in adults with normal renal function and body habitus.

f. For fluconazole, these breakpoints are based on extensive experience with mucosal and invasive infections
due to Candida spp. When an isolate is identified as C. glabrata and the MIC is ≤ 32 µg/mL, the clinician should
determine whether fluconazole is appropriate in the specific clinical context. If so, patients should receive
the maximum dosage regimen of fluconazole. Expert consultation on selecting a maximum dosage regimen
may be useful.

g. Isolates of C. krusei are intrinsically resistant to fluconazole, so their MICs should not be interpreted using this
scale (see Appendix B).

h. The selected breakpoints have been established to distinguish resistant variants from susceptible isolates.
Differences in breakpoints reflect methodological issues. Due to in vitro methodological issues, the breakpoint
for micafungin against C. glabrata is lower than that of other echinocandins, which does not reflect any
inherent clinical differences in efficacy. True differences in antifungal activity among the echinocandins are
rare.18

i. MIC interpretive categories for rezafungin were adopted during a meeting with the Subcommittee on
Antifungal Tests held in June 2021. The MICs are considered tentative for one year from the publication
of M27M44S and are open for comment.

j. At this time, only susceptible breakpoints have been set for rezafungin. Once more data are available,
intermediate and resistant breakpoints will be added.

k. For C. glabrata and voriconazole, current data are insufficient to demonstrate a correlation between in vitro
susceptibility testing and clinical outcome.

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 M27M44S-Ed3

Table 1. (Continued)

References for Table 1

1 CLSI. Performance Standards for Antifungal Susceptibility Testing of Filamentous Fungi. 3rd ed. CLSI
supplement M38M51S. Clinical and Laboratory Standards Institute; 2022.
2 CLSI. Principles and Procedures for the Development of Epidemiological Cutoff Values for Antifungal
Susceptibility Testing. 1st ed. CLSI guideline M57. Clinical and Laboratory Standards Institute; 2016.
3 CLSI. Epidemiological Cutoff Values for Antifungal Susceptibility Testing. 4th ed. CLSI supplement M57S.
Clinical and Laboratory Standards Institute; 2022.
4 Pfaller MA, Diekema DJ, Andes D, et al. Clinical breakpoints for the echinocandins and Candida revisited:
integration of molecular, clinical, and microbiological data to arrive at species-specific interpretive
criteria. Drug Resist Updat. 2011;14(3):164-176. doi:10.1016/j.drup.2011.01.004
5 Pfaller MA, Diekema DJ. Wild-type MIC distributions and epidemiologic cutoff values for fluconazole and
Candida: time for new clinical breakpoints? Current Fungal Infection Reports. 2010;4(3):168-174.
doi:10.1007/s12281-010-0022-x
6 Pfaller MA, Andes D, Arendrup MC, et al. Clinical breakpoints for voriconazole and Candida spp. revisited:
review of microbiologic, molecular, pharmacodynamic, and clinical data as they pertain to the
development of species-specific interpretive criteria. Diagn Microbiol Infect Dis. 2011;70(3):330-343.
doi:10.1016/j.diagmicrobio.2011.03.002
7 Borman AM, Muller J, Walsh-Quantick J, et al. Fluconazole resistance in isolates of uncommon pathogenic
yeast species from the United Kingdom. Antimicrob Agents Chemother. 2019;63(8).
doi:10.1128/aac.00211-19
8 Castanheira M, Deshpande LM, Messer SA, Rhomberg PR, Pfaller MA. Analysis of global antifungal
surveillance results reveals predominance of Erg11 Y132F alteration among azole-resistant Candida
parapsilosis and Candida tropicalis and country-specific isolate dissemination. Int J Antimicrob Agents.
2020;55(1):105799. doi:10.1016/j.ijantimicag.2019.09.003
9 Maria S, Barnwal G, Kumar A, et al. Species distribution and antifungal susceptibility among clinical
isolates of Candida parapsilosis complex from India. Rev Iberoam Micol. 2018;35(3):147-150.
doi:10.1016/j.riam.2018.01.004
10 Pfaller MA, Diekema DJ, Turnidge JD, Castanheira M, Jones RN. Twenty years of the SENTRY antifungal
surveillance program: results for Candida species from 1997-2016. Open Forum Infect Dis. 2019;6(suppl
1):S79-S94. doi:10.1093/ofid/ofy358
11 Vigezzi C, Icely PA, Dudiuk C, et al. Frequency, virulence factors and antifungal susceptibility of Candida
parapsilosis species complex isolated from patients with candidemia in the central region of Argentina. J
Mycol Med. 2019;29(4):285-291. doi:10.1016/j.mycmed.2019.100907
12 CLSI. Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts. 4th ed. CLSI
standard M27. Clinical and Laboratory Standards Institute; 2017.
13 Espinel-Ingroff A, Arendrup MC, Pfaller MA, et al. Interlaboratory variability of caspofungin MICs for
Candida spp. using CLSI and EUCAST methods: should the clinical laboratory be testing this agent?
Antimicrob Agents Chemother. 2013;57(12):5836-5842. doi:10.1128/aac.01519-13
14 Pfaller MA, Messer SA, Diekema DJ, Jones RN, Castanheira M. Use of micafungin as a surrogate marker to
predict susceptibility and resistance to caspofungin among 3,764 clinical isolates of Candida by use of CLSI
methods and interpretive criteria. J Clin Microbiol. 2014;52(1):108-114. doi:10.1128/jcm.02481-13
15 Pfaller MA, Diekema DJ, Jones RN, Castanheira M. Use of anidulafungin as a surrogate marker to predict
susceptibility and resistance to caspofungin among 4,290 clinical isolates of Candida by using CLSI
methods and interpretive criteria. J Clin Microbiol. 2014;52(9):3223-3229. doi:10.1128/jcm.00782-14
16 Arendrup MC, Perlin DS. Echinocandin resistance: an emerging clinical problem? Curr Opin Infect Dis.
2014;27(6):484-492. doi:10.1097/qco.0000000000000111
17 Garcia-Effron G, Lee S, Park S, Cleary JD, Perlin DS. Effect of Candida glabrata FKS1 and FKS2 mutations
on echinocandin sensitivity and kinetics of 1,3-beta-D-glucan synthase: implication for the existing
susceptibility breakpoint. Antimicrob Agents Chemother. 2009;53(9):3690-3699. doi:10.1128/aac.00443-
09
18 Arendrup MC, Perlin DS, Jensen RH, Howard SJ, Goodwin J, Hope W. Differential in vivo activities of
anidulafungin, caspofungin, and micafungin against Candida glabrata isolates with and without FKS
resistance mutations. Antimicrob Agents Chemother. 2012;56(5):2435-2442. doi:10.1128/aac.06369-11

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 M27M44S-Ed3

Table 2. Solvents and Diluents for Preparing Stock Antifungal Agent

Solutions for Broth Dilution Testing
Solventa,b
(full-strength and Diluent
Antifungal Agent intermediate solutions) (final concentration)
Amphotericin B DMSO Medium
Anidulafungin DMSO Medium
Caspofungin DMSO Medium
Fluconazole DMSO Medium
Flucytosine DMSO Medium
Ibrexafungerp DMSO Medium
Isavuconazole DMSO Medium
Itraconazole DMSO Medium
Ketoconazole DMSO Medium
Manogepix DMSO Medium
Micafungin DMSO Medium
Oteseconazole DMSO Medium
Posaconazole DMSO Medium
Rezafungin DMSO Medium
Voriconazole DMSO Medium
Abbreviation: DMSO, dimethyl sulfoxide.

Footnotes

a. DMSO can be toxic and also enables other drugs to be absorbed through the skin. Before DMSO is used, the DMSO
safety data sheet should be consulted.

b. The laboratory should follow the manufacturer’s recommendations when selecting a solvent.

NOTE: Information in boldface type is new or modified since the previous edition.

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 M27M44S-Ed3

Table 3. Recommended 24-Hour Minimal Inhibitory Concentration Limits for

Quality Control Strains for Broth Microdilution Procedures1,2
General Comments

(1) When a commercial test system is used for susceptibility testing, the users should refer to
the manufacturer’s instructions for QC test recommendations and QC ranges.

(2) For yeasts, the MICs for the antifungal agents listed are read at 50% or a score of 2 as
observed after 24 hours of incubation (prominent decrease in turbidity or > 50%
inhibition of growth compared with the growth control), except for amphotericin B,
which is read at 100% (see CLSI document M273).

NOTE: Information in boldface type is new or modified since the previous edition.

MIC QC Range, MIC QC MICs

Organism Antifungal Agent µg/mL Mode, μg/mL Within Range, %
Candida albicans Manogepix 0.004–0.016 0.008 100
ATCC®a 90028 Oteseconazoleb 0.002–0.016 0.004 95.3
Candida krusei Amphotericin B 0.5–2 1 100
ATCC® 6258 Anidulafungin 0.03–0.12 0.06 97.9
Caspofunginc 0.12–1 0.5 98.8
Fluconazole 8–64 16 100
Flucytosine 4–16 8 97.5
Ibrexafungerpd 0.25–1 0.5 100
Isavuconazole 0.06–0.5 0.25 95.2
Itraconazole 0.12–1 0.5 95.8
Ketoconazole 0.12–1 0.5 95.4
Micafungin 0.06–0.25 0.12–0.25 99.6
Posaconazole 0.06–0.5 0.25 100
Rezafungin 0.016–0.12 0.03 99.5
Voriconazole 0.06–0.5 0.12 98.3
Candida parapsilosis Amphotericin B 0.25–2 0.5 97.1
ATCC® 22019 Anidulafungin 0.25–2 1 95
Caspofungin 0.25–1 0.5 96.7
Fluconazole 0.5–4 2 98.2
Flucytosine 0.06–0.25 0.12 99.2
Ibrexafungerpd 0.06–0.25 0.12 99.0
Isavuconazole 0.016–0.06 0.06 90.5
Itraconazole 0.06–0.5 0.25 95.8
Ketoconazole 0.03–0.25 0.06/0.12 97.5
Manogepix 0.008–0.03 0.016 100
Micafungin 0.5–2 0.5–1 100
Oteseconazoleb 0.008–0.06 0.03–0.25 99.6
Posaconazole 0.03–0.25 0.12 96.7
Rezafungin 0.25–2 0.5 99.2
Voriconazole 0.016–0.12 0.016–0.03 100
C. parapsilosis Oteseconazoleb 0.001–0.008 0.004 99.2
ATCC® 90018
Abbreviations: ATCC®, American Type Culture Collection; MIC, minimal inhibitory concentration; QC, quality
control.

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 M27M44S-Ed3

Table 3. (Continued)

Footnotes

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

b. For oteseconazole, any of the QC strains are appropriate for routine QC testing.

c. The QC ranges were established using data generated in 2010 from 15 reference laboratories. Since then,
caspofungin susceptibility testing has been associated with significant variation. Therefore, misclassification
of susceptible isolates may occur despite acceptable performance of the QC strains according to the range in
this table4-6 (see CLSI document M273).

d. The 48-hour microdilution MIC QC range for ibrexafungerp is available for C. krusei ATCC® 6258: 0.25 to
1 µg/mL. No 48-hour MIC QC range for ibrexafungerp is currently available for C. parapsilosis ATCC® 22019.

References for Table 3

1 Barry AL, Pfaller MA, Brown SD, et al. Quality control limits for broth microdilution susceptibility tests of
ten antifungal agents. J Clin Microbiol. 2000;38(9):3457-3459. doi:10.1128/jcm.38.9.3457-3459.2000
2 Krisher K, Brown SD, Traczewski MM. Quality control parameters for broth microdilution tests of
anidulafungin. J Clin Microbiol. 2004;42(1):490. doi:10.1128/jcm.42.1.490.2004
3 CLSI. Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts. 4th ed. CLSI
standard M27. Clinical and Laboratory Standards Institute; 2017.
4 Shields RK, Nguyen MH, Press EG, et al. The presence of an FKS mutation rather than MIC is an
independent risk factor for failure of echinocandin therapy among patients with invasive candidiasis due
to Candida glabrata. Antimicrob Agents Chemother. 2012;56(9):4862-4869. doi:10.1128/aac.00027-12
5 Arendrup MC, Pfaller MA. Caspofungin Etest susceptibility testing of Candida species: risk of
misclassification of susceptible isolates of C. glabrata and C. krusei when adopting the revised CLSI
caspofungin breakpoints. Antimicrob Agents Chemother. 2012;56(7):3965-3968. doi:10.1128/aac.00355-12
6 Espinel-Ingroff A, Arendrup MC, Pfaller MA, et al. Interlaboratory variability of caspofungin MICs for
Candida spp. using CLSI and EUCAST methods: should the clinical laboratory be testing this agent?
Antimicrob Agents Chemother. 2013;57(12):5836-5842. doi:10.1128/aac.01519-13

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 M27M44S-Ed3

Table 4. Recommended 48-Hour Minimal Inhibitory Concentration Limits for

Two Quality Control and Four Reference Strains for Broth Macrodilution
Procedures1,2
MIC Range, MICs Within
Organism Purpose Antifungal Agent µg/mL Range, %
Candida krusei QC Amphotericin B 0.25–2 99.5
ATCC®a 6258 Fluconazole 16–64 99.1
Flucytosine 4–16 96.8
Itraconazole 0.12–0.5 94
Ketoconazole 0.12–0.5 100
Candida QC Amphotericin B 0.25–1 99.1
parapsilosis Fluconazole 2–8 99.1
ATCC® 22019 Flucytosine 0.12–0.5 98.6
Itraconazole 0.06–0.25 99
Ketoconazole 0.06–0.25 99
Candida albicans Reference Amphotericin B 0.5–2 91.9
ATCC® 90028 Fluconazole 0.25–1 97.3
Flucytosine 0.5–2 95
C. albicans Reference Amphotericin B 0.25–1 99.5
ATCC® 24433 Fluconazole 0.25–1 95.9
Flucytosine 1–4 91.9
C. parapsilosis Reference Amphotericin B 0.5–2 96.4
ATCC® 90018 Fluconazole 0.25–1 98.2
Flucytosine  0.12–0.25 99.5
Candida Reference Amphotericin B 0.5–2 93.7
tropicalis Fluconazole 1–4 95.5
ATCC® 750 Flucytosine  0.12–0.25 99.5
Abbreviations: ATCC®, American Type Culture Collection; MIC, minimal inhibitory concentration; QC, quality
control.

Footnote

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

References for Table 4

1 Pfaller MA, Bale M, Buschelman B, et al. Quality control guidelines for National Committee for Clinical
Laboratory Standards recommended broth macrodilution testing of amphotericin B, fluconazole, and
flucytosine. J Clin Microbiol. 1995;33(5):1104-1107. doi:10.1128/jcm.33.5.1104-1107.1995
2 Rex JH, Pfaller MA, Lancaster M, Odds FC, Bolmström A, Rinaldi MG. Quality control guidelines for
National Committee for Clinical Laboratory Standards-recommended broth macrodilution testing of
ketoconazole and itraconazole. J Clin Microbiol. 1996;34(4):816-817. doi:10.1128/jcm.34.4.816-817.1996

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

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 M27M44S-Ed3

Table 5. Zone Diameter and Equivalent Minimal Inhibitory Concentration

Breakpoints for Select Antifungal Agents Against Candida spp. After
24-Hour Incubation1-9
Zone Diameter Breakpoints Equivalent MIC Breakpoints
and Interpretive and Interpretive Categories,
Antifungal Categories, mm µg/mL
Agenta Species S I SDD R S I SDD R
Caspofungin C. albicans ≥ 17 15–16 – ≤ 14 ≤ 0.25 0.5 – ≥1
C. glabrata – – – – ≤ 0.12 0.25 – ≥ 0.5
C. ≥ 13 11–12 – ≤ 10 ≤2 4 – ≥8
guilliermondii
C. krusei ≥ 17 15–16 – ≤ 14 ≤ 0.25 0.5 – >1
C. parapsilosis ≥ 13 11–12 – ≤ 10 ≤2 4 – ≥8
C. tropicalis ≥ 17 15–16 – ≤ 14 ≤ 0.25 0.5 – >1
Fluconazole C. albicans ≥ 17 – 14–16 ≤ 13 ≤2 – 4 ≥8
C. glabrata – – ≥ 15 ≤ 14 – – ≤ 32 ≥ 64
C. kruseib – – – – – – – –
C. parapsilosis ≥ 17 – 14–16 ≤ 13 ≤2 – 4 ≥8
C. tropicalis ≥ 17 – 14–16 ≤ 13 ≤2 – 4 ≥8
Micafungin C. albicans ≥ 22 20–21 – ≤ 19 ≤ 0.25 0.5 – ≥1
C. glabrata ≥ 30 28–29 – ≤ 27 ≤ 0.06 0.12 – ≥ 0.25
C. ≥ 16 14–15 – ≤ 13 ≤2 4 – ≥8
guilliermondii
C. krusei ≥ 22 20–21 – ≤ 19 ≤ 0.25 0.5 – ≥1
C. parapsilosis ≥ 16 14–15 – ≤ 13 ≤2 4 – ≥8
C. tropicalis ≥ 22 20–21 – ≤ 19 ≤ 0.25 0.5 – ≥1
Voriconazole C. albicans ≥ 17 15–16 – ≤ 14 ≤ 0.12 0.25– – ≥1
0.5
C. glabratac – – – – – – – –
C. krusei ≥ 15 13–14 – ≤ 12 ≤ 0.5 1 – ≥2
C. parapsilosis ≥ 17 15–16 – ≤ 14 ≤ 0.12 0.25– – ≥1
0.5
C. tropicalis ≥ 17 15–16 – ≤ 14 ≤ 0.12 0.25– – ≥1
0.5
Abbreviations: I, intermediate; MIC, minimal inhibitory concentration; R, resistant; S, susceptible;
SDD, susceptible-dose dependent.

Footnotes

a. Breakpoints may also be used for 48-hour readings if the 24-hour growth control is insufficient.

b. Isolates of C. krusei are intrinsically resistant to fluconazole, so their MICs should not be interpreted using this
scale (see Appendix B).

c. For C. glabrata and voriconazole, current data are insufficient to demonstrate a correlation between in vitro
susceptibility testing and clinical outcome.

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 M27M44S-Ed3

Table 5. (Continued)

NOTE: Information in boldface type is new or modified since the previous edition.

References for Table 5

1 Arendrup MC, Park S, Brown S, Pfaller M, Perlin DS. Evaluation of CLSI M44-A2 disk diffusion and
associated breakpoint testing of caspofungin and micafungin using a well-characterized panel of wild-type
and fks hot spot mutant Candida isolates. Antimicrob Agents Chemother. 2011;55(5):1891-1895.
doi:10.1128/aac.01373-10
2 Barry AL, Pfaller MA, Rennie RP, Fuchs PC, Brown SD. Precision and accuracy of fluconazole susceptibility
testing by broth microdilution, Etest, and disk diffusion methods. Antimicrob Agents Chemother.
2002;46(6):1781-1784. doi:10.1128/aac.46.6.1781-1784.2002
3 Brown SD, Traczewski MM. Caspofungin disk diffusion breakpoints and quality control. J Clin Microbiol.
2008;46(6):1927-1929. doi:10.1128/jcm.00279-08
4 Pfaller MA, Andes D, Arendrup MC, et al. Clinical breakpoints for voriconazole and Candida spp. revisited:
review of microbiologic, molecular, pharmacodynamic, and clinical data as they pertain to the
development of species-specific interpretive criteria. Diagn Microbiol Infect Dis. 2011;70(3):330-343.
doi:10.1016/j.diagmicrobio.2011.03.002
5 Pfaller MA, Boyken L, Hollis RJ, et al. Comparison of results of fluconazole and voriconazole disk diffusion
testing for Candida spp. with results from a central reference laboratory in the ARTEMIS DISK Global
Antifungal Surveillance Program. Diagn Microbiol Infect Dis. 2009;65(1):27-34.
doi:10.1016/j.diagmicrobio.2009.05.007
6 Pfaller MA, Diekema DJ, Ostrosky-Zeichner L, et al. Correlation of MIC with outcome for Candida species
tested against caspofungin, anidulafungin, and micafungin: analysis and proposal for interpretive MIC
breakpoints. J Clin Microbiol. 2008;46(8):2620-2629. doi:10.1128/jcm.00566-08
7 Pfaller MA, Diekema DJ, Rex JH, et al. Correlation of MIC with outcome for Candida species tested against
voriconazole: analysis and proposal for interpretive breakpoints. J Clin Microbiol. 2006;44(3):819-826.
doi:10.1128/jcm.44.3.819-826.2006
8 Pfaller MA, Diekema DJ, Sheehan DJ. Interpretive breakpoints for fluconazole and Candida revisited: a
blueprint for the future of antifungal susceptibility testing. Clin Microbiol Rev. 2006;19(2):435-447.
doi:10.1128/cmr.19.2.435-447.2006
9 Rex JH, Pfaller MA, Galgiani JN, et al. Development of interpretive breakpoints for antifungal
susceptibility testing: conceptual framework and analysis of in vitro–in vivo correlation data for
fluconazole, itraconazole, and Candida infections. Subcommittee on Antifungal Susceptibility Testing of
the National Committee for Clinical Laboratory Standards. Clin Infect Dis. 1997;24(2):235-247.
doi:10.1093/clinids/24.2.235

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Table 6. Recommended Quality Control Zone Diameter (mm) Ranges After

24-Hour Incubation1-5
Disk Candida Candida Candida Candida
Antifungal Content, albicans krusei parapsilosis tropicalis
Agent µg ATCC®a 90028 ATCC® 6258 ATCC® 22019 ATCC® 750
Caspofungin 5 18–27 19–26 14–23 20–27
Fluconazole 25 28–39 –b 22–33 26–37
Manogepix 5 32–44 – 26–34 33–43
Micafungin 10 24–31 23–29 14–23 24–30
Posaconazole 5 24–34 23–31 25–36 23–33
Rezafunginc 5 13–20 14–20 9–16 14–20
Voriconazole 1 31–42 16–25 28–37 –b
Abbreviation: ATCC®, American Type Culture Collection.

Footnotes

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

b. QC ranges have not been established for these fungal strain–antifungal agent combinations, owing to their
extensive interlaboratory variation during initial QC studies.

c. QC ranges for rezafungin were established using data from only one disk manufacturer. Disks from other
manufacturers were not available at the time of testing.

References for Table 6

1 Arendrup MC, Park S, Brown S, Pfaller M, Perlin DS. Evaluation of CLSI M44-A2 disk diffusion and
associated breakpoint testing of caspofungin and micafungin using a well-characterized panel of wild-type
and fks hot spot mutant Candida isolates. Antimicrob Agents Chemother. 2011;55(5):1891-1895.
doi:10.1128/aac.01373-10
2 Barry A, Bille J, Brown S, et al. Quality control limits for fluconazole disk susceptibility tests on Mueller-
Hinton agar with glucose and methylene blue. J Clin Microbiol. 2003;41(7):3410-3412.
doi:10.1128/jcm.41.7.3410-3412.2003
3 Brown SD, Traczewski MM. Caspofungin disk diffusion breakpoints and quality control. J Clin Microbiol.
2008;46(6):1927-1929. doi:10.1128/jcm.00279-08
4 Brown S, Traczewski M. Quality control limits for posaconazole disk susceptibility tests on Mueller-Hinton
agar with glucose and methylene blue. J Clin Microbiol. 2007;45(1):222-223. doi:10.1128/jcm.01732-06
5
Pfaller MA, Barry A, Bille J, et al. Quality control limits for voriconazole disk susceptibility tests on
Mueller-Hinton agar with glucose and methylene blue. J Clin Microbiol. 2004;42(4):1716-1718.
doi:10.1128/jcm.42.4.1716-1718.2004

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 M27M44S-Ed3

Appendix A. Body Site Reporting for Candida spp.1,2

The table below provides guidelines for reporting antifungal agents and reporting options
when Candida spp. susceptibility is tested in specific body sites. Guidelines are also
provided for body sites from which certain antifungals would not be appropriate to
report.

Antifungal Agent Specimen Reporting Comment Rationale

Amphotericin B3 Urine4 No reporting Lipid Small percentages
restrictions formulations of of amphotericin B
amphotericin B lipid formulations
do not achieve are recovered in the
adequate urine urine after systemic
concentrations administration,
and should not compared with high
be used to treat recovery of
UTIs. amphotericin B
deoxycholate.
5-FC No reporting 5-FC should not
restrictions be used as
monotherapy for
severe Candida
infections
because
resistance can
develop rapidly.
It should be
used rarely in
neonates.5,6
Azoles CNS (brain Routinely report Report by request
tissue, only fluconazole and suppress results
abscess and voriconazole. for itraconazole,
material)7-11; Report posaconazole, and
CSF itraconazole, isavuconazole
posaconazole, and because clinical
isavuconazole data are limited.
only by request.
Ocular Routinely report Report by request
(cornea, only fluconazole and suppress results
aqueous, and voriconazole. for itraconazole,
vitreous)12-15 Report posaconazole, and
itraconazole, isavuconazole
posaconazole, and because clinical
isavuconazole data are limited.
only by request.
Urine4 If testing azoles, Other azoles could
report only be reported by
fluconazole. request because
these agents may
penetrate kidney
tissue.

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Appendix A. (Continued)
Antifungal Agent Specimen Reporting Comment Rationale
Echinocandins16-18 CNS (brain No reporting The The echinocandins
tissue, restrictions echinocandins have suboptimal
abscess have suboptimal penetration into CSF
material)7,19; penetration in and CNS tissues;
CSF CSF and CNS however, based on
tissues. Consult animal models, the
the pharmacy concentrations in
and/or the various CNS
infectious subcompartments
disease service may achieve a
for additional signicant
guidance. anti-Candida effect.
Ocular Should not be Systemic
(cornea, routinely administration
aqueous, reporteda of echinocandins
vitreous)20 is not
recommended
for ocular
infections
because it has
minimal tissue
penetration.
Consult
ophthalmology,
pharmacy, or
infectious
disease service
for guidance.
Urine4,a Should not be Echinocandins are
routinely reported generally not
recommended for
treating candiduria;
only 1% of the active
echinocandin agent is
excreted into the
urine.21

Echinocandins
(micafungin,
caspofungin, and
anidulafungin) are
expected to penetrate
kidney tissue and
could be tested and
reported by request.2
Abbreviations: CNS, central nervous system; CSF, cerebrospinal fluid; 5-FC, flucytosine; UTI, urinary tract
infection.

Footnote

a. Selective reporting may vary by institution.

NOTE: Information in boldface type is new or modified since the previous edition.

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 M27M44S-Ed3

Appendix A. (Continued)
References for Appendix A
1 Andes D. Optimizing antifungal choice and administration. Curr Med Res Opin. 2013;29(suppl 4):13-18.
doi:10.1185/03007995.2012.761135
2 Felton T, Troke PF, Hope WW. Tissue penetration of antifungal agents. Clin Microbiol Rev. 2014;27(1):68-
88. doi:10.1128/cmr.00046-13
3 Bekersky I, Fielding RM, Dressler DE, Lee JW, Buell DN, Walsh TJ. Pharmacokinetics, excretion, and mass
balance of liposomal amphotericin B (AmBisome) and amphotericin B deoxycholate in humans. Antimicrob
Agents Chemother. 2002;46(3):828-833. doi:10.1128/aac.46.3.828-833.2002
4 Fisher JF, Sobel JD, Kauffman CA, Newman CA. Candida urinary tract infections—treatment. Clin Infect
Dis. 2011;52(suppl 6):S457-466. doi:10.1093/cid/cir112
5 Lestner JM, Smith PB, Cohen-Wolkowiez M, Benjamin DK, Jr., Hope WW. Antifungal agents and therapy
for infants and children with invasive fungal infections: a pharmacological perspective. Br J Clin
Pharmacol. 2013;75(6):1381-1395. doi:10.1111/bcp.12025
6 Pasqualotto AC, Howard SJ, Moore CB, Denning DW. Flucytosine therapeutic monitoring: 15 years
experience from the UK. J Antimicrob Chemother. 2007;59(4):791-793. doi:10.1093/jac/dkl550
7 Nau R, Sörgel F, Eiffert H. Penetration of drugs through the blood-cerebrospinal fluid/blood-brain barrier
for treatment of central nervous system infections. Clin Microbiol Rev. 2010;23(4):858-883.
doi:10.1128/cmr.00007-10
8 Pitisuttithum P, Negroni R, Graybill JR, et al. Activity of posaconazole in the treatment of central nervous
system fungal infections. J Antimicrob Chemother. 2005;56(4):745-755. doi:10.1093/jac/dki288
9 Schmitt-Hoffmann AH, Kato K, Townsend R, et al. Tissue distribution and elimination of isavuconazole
following single and repeat oral-dose administration of isavuconazonium sulfate to rats. Antimicrob
Agents Chemother. 2017;61(12). doi:10.1128/aac.01292-17
10 Schwartz S, Cornely OA, Hamed K, et al. Isavuconazole for the treatment of patients with invasive fungal
diseases involving the central nervous system. Med Mycol. 2020;58(4):417-424. doi:10.1093/mmy/myz103
11 Tu EY, McCartney DL, Beatty RF, Springer KL, Levy J, Edward D. Successful treatment of resistant ocular
fusariosis with posaconazole (SCH-56592). Am J Ophthalmol. 2007;143(2):222-227.
doi:10.1016/j.ajo.2006.10.048
12 Almeida Oliveira M, Carmo A, Rosa A, Murta J. Posaconazole in the treatment of refractory
Purpureocillium lilacinum (former Paecilomyces lilacinus) keratitis: the salvation when nothing works.
BMJ Case Rep. 2019;12(4). doi:10.1136/bcr-2018-228645
13 Altun A, Kurna SA, Sengor T, et al. Effectiveness of posaconazole in recalcitrant fungal keratitis resistant
to conventional antifungal drugs. Case Rep Ophthalmol Med. 2014;2014:701653. doi:10.1155/2014/701653
14 Arnoldner MA, Kheirkhah A, Jakobiec FA, Durand ML, Hamrah P. Successful treatment of Paecilomyces
lilacinus keratitis with oral posaconazole. Cornea. 2014;33(7):747-749.
doi:10.1097/ico.0000000000000143
15 Guest JM, Singh PK, Revankar SG, Chandrasekar PH, Kumar A. Isavuconazole for treatment of
experimental fungal endophthalmitis caused by Aspergillus fumigatus. Antimicrob Agents Chemother.
2018;62(11). doi:10.1128/aac.01537-18
16 Aguilar-Zapata D, Petraitiene R, Petraitis V. Echinocandins: the expanding antifungal armamentarium.
Clin Infect Dis. 2015;61(suppl 6):S604-611. doi:10.1093/cid/civ814
17 Nicasio AM, Tessier PR, Nicolau DP, et al. Bronchopulmonary disposition of micafungin in healthy adult
volunteers. Antimicrob Agents Chemother. 2009;53(3):1218-1220. doi:10.1128/aac.01386-08
18 Zhao Y, Prideaux B, Nagasaki Y, et al. Unraveling drug penetration of echinocandin antifungals at the site
of infection in an intra-abdominal abscess model. Antimicrob Agents Chemother. 2017;61(10).
doi:10.1128/aac.01009-17
19 Lat A, Thompson GR, 3rd, Rinaldi MG, Dorsey SA, Pennick G, Lewis JS, 2nd. Micafungin concentrations
from brain tissue and pancreatic pseudocyst fluid. Antimicrob Agents Chemother. 2010;54(2):943-944.
doi:10.1128/aac.01294-09
20 Patil A, Majumdar S. Echinocandins in ocular therapeutics. J Ocul Pharmacol Ther. 2017;33(5):340-352.
doi:10.1089/jop.2016.0186
21 Pappas PG, Kauffman CA, Andes DR, et al. Clinical practice guideline for the management of candidiasis:
2016 update by the Infectious Diseases Society of America. Clin Infect Dis. 2016;62(4):e1-50.
doi:10.1093/cid/civ933

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 M27M44S-Ed3

Appendix B. Intrinsic Resistance for Yeasts

IR is defined as inherent or innate (not acquired) antimicrobial resistance, which is
reflected in wild-type antimicrobial patterns of all or almost all representatives of a
species. IR is so common that susceptibility testing is unnecessary. For example,
Cryptococcus spp. is intrinsically resistant to echinocandins.

IR tables can be helpful in at least three ways: 1) they provide a way to evaluate the
accuracy of testing methods, 2) they aid in the recognition of common phenotypes, and 3)
they can assist with verification of cumulative antimicrobial susceptibility test data. In the
table below, an “IR” occurring with an antifungal agent and organism combination means
that strains should test resistant. A small percentage (up to 3%) may appear susceptible
due to method variation, mutation, or low levels of resistance expression.

In consultation with institutional leaders representing infectious diseases practitioners,

the pharmacy and therapeutics and infection prevention committees of the medical staff,
and the antimicrobial stewardship team, each laboratory should decide which agents to
test and report. If an antifungal agent and organism combination is tested and listed as
having IR, it should be reported as “resistant” or “intrinsically resistant.” Consideration
may be given to adding comments regarding IR of agents not tested.

Antifungal Agent
Amphotericin B

Anidulafungin

Caspofungin

Fluconazole

Micafungin
Organism
Candida kruseia – – – IR1-12 –
Candida lusitaniae –b – – – –
Cryptococcus spp. – IR13-23 IR13-23 – IR13-23
Rhodotorula spp. – IR13-23 IR13-23 IR24-31 IR13-23
Trichosporon spp. – IR13-23 IR13-23 – IR13-23
Abbreviation: IR, intrinsic resistance.

Footnotes

a. C. krusei is also recognized under the taxonomic name Pichia kudriavzevii.

b. C. lusitaniae is not intrinsically resistant to amphotericin B. However, C. lusitaniae may develop

resistance to amphotericin B in vivo during therapy. When phenotypic resistance was noted in studies,
the phenotype was observed only when agar gradient strips were used and was not detected by broth
microdilution methods.32

NOTE: Information in boldface type is new or modified since the previous edition.

© Clinical and Laboratory Standards Institute. All rights reserved. 15

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 M27M44S-Ed3

Appendix B. (Continued)
References for Appendix B
1 Berkow EL, Lockhart SR. Fluconazole resistance in Candida species: a current perspective. Infect Drug
Resist. 2017;10:237-245. doi:10.2147/idr.S118892
2 Espinel-Ingroff A, Barchiesi F, Cuenca-Estrella M, et al. International and multicenter comparison of
EUCAST and CLSI M27-A2 broth microdilution methods for testing susceptibilities of Candida spp. to
fluconazole, itraconazole, posaconazole, and voriconazole. J Clin Microbiol. 2005;43(8):3884-3889.
doi:10.1128/jcm.43.8.3884-3889.2005
3 Espinel-Ingroff A, Pfaller MA, Bustamante B, et al. Multilaboratory study of epidemiological cutoff values
for detection of resistance in eight Candida species to fluconazole, posaconazole, and voriconazole.
Antimicrob Agents Chemother. 2014;58(4):2006-2012. doi:10.1128/aac.02615-13
4 Guinea J, Sánchez-Somolinos M, Cuevas O, Peláez T, Bouza E. Fluconazole resistance mechanisms in
Candida krusei: the contribution of efflux-pumps. Med Mycol. 2006;44(6):575-578.
doi:10.1080/13693780600561544
5 Marichal P, Gorrens J, Coene MC, Le Jeune L, Vanden Bossche H. Origin of differences in susceptibility of
Candida krusei to azole antifungal agents. Mycoses. 1995;38(3–4):111-117. doi:10.1111/j.1439-
0507.1995.tb00032.x
6 Orozco AS, Higginbotham LM, Hitchcock CA, et al. Mechanism of fluconazole resistance in Candida krusei.
Antimicrob Agents Chemother. 1998;42(10):2645-2649. doi:10.1128/aac.42.10.2645
7 Ostrosky-Zeichner L, Rex JH, Pappas PG, et al. Antifungal susceptibility survey of 2,000 bloodstream
Candida isolates in the United States. Antimicrob Agents Chemother. 2003;47(10):3149-3154.
doi:10.1128/aac.47.10.3149-3154.2003
8 Pfaller MA, Boyken LB, Hollis RJ, et al. Validation of 24-hour fluconazole MIC readings versus the CLSI 48-
hour broth microdilution reference method: results from a global Candida antifungal surveillance
program. J Clin Microbiol. 2008;46(11):3585-3590. doi:10.1128/jcm.01391-08
9 Pfaller MA, Diekema DJ, Sheehan DJ. Interpretive breakpoints for fluconazole and Candida revisited: a
blueprint for the future of antifungal susceptibility testing. Clin Microbiol Rev. 2006;19(2):435-447.
doi:10.1128/cmr.19.2.435-447.2006
10 Pfaller MA, Diekema DJ. Wild-type MIC distributions and epidemiologic cutoff values for fluconazole and
Candida: time for new clinical breakpoints? Current Fungal Infection Reports. 2010;4(3):168-174.
doi:10.1007/s12281-010-0022-x
11 Pfaller MA, Espinel-Ingroff A, Boyken L, et al. Comparison of the broth microdilution (BMD) method of the
European Committee on Antimicrobial Susceptibility Testing with the 24-hour CLSI BMD method for testing
susceptibility of Candida species to fluconazole, posaconazole, and voriconazole by use of epidemiological
cutoff values. J Clin Microbiol. 2011;49(3):845-850. doi:10.1128/jcm.02441-10
12 Whaley SG, Berkow EL, Rybak JM, Nishimoto AT, Barker KS, Rogers PD. Azole antifungal resistance in
Candida albicans and emerging non-albicans Candida species. Front Microbiol. 2016;7:2173.
doi:10.3389/fmicb.2016.02173
13 Bartizal K, Gill CJ, Abruzzo GK, et al. In vitro preclinical evaluation studies with the echinocandin
antifungal MK-0991 (L-743,872). Antimicrob Agents Chemother. 1997;41(11):2326-2332.
doi:10.1128/aac.41.11.2326
14 Diekema DJ, Petroelje B, Messer SA, Hollis RJ, Pfaller MA. Activities of available and investigational
antifungal agents against Rhodotorula species. J Clin Microbiol. 2005;43(1):476-478.
doi:10.1128/jcm.43.1.476-478.2005
15 Espinel-Ingroff A. Comparison of in vitro activities of the new triazole SCH56592 and the echinocandins
MK-0991 (L-743,872) and LY303366 against opportunistic filamentous and dimorphic fungi and yeasts. J
Clin Microbiol. 1998;36(10):2950-2956. doi:10.1128/jcm.36.10.2950-2956.1998
16 Espinel-Ingroff A. In vitro antifungal activities of anidulafungin and micafungin, licensed agents and the
investigational triazole posaconazole as determined by NCCLS methods for 12,052 fungal isolates: review
of the literature. Rev Iberoam Micol. 2003;20(4):121-136.
17 Hector RF. Compounds active against cell walls of medically important fungi. Clin Microbiol Rev.
1993;6(1):1-21. doi:10.1128/cmr.6.1.1
18 James PG, Cherniak R, Jones RG, Stortz CA, Reiss E. Cell-wall glucans of Cryptococcus neoformans Cap
67. Carbohydr Res. 1990;198(1):23-38. doi:10.1016/0008-6215(90)84273-w
19 Krishnarao TV, Galgiani JN. Comparison of the in vitro activities of the echinocandin LY303366, the
pneumocandin MK-0991, and fluconazole against Candida species and Cryptococcus neoformans.
Antimicrob Agents Chemother. 1997;41(9):1957-1960. doi:10.1128/aac.41.9.1957

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

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Appendix B. (Continued)
20 Serena C, Mariné M, Pastor FJ, Nolard N, Guarro J. In vitro interaction of micafungin with conventional
and new antifungals against clinical isolates of Trichosporon, Sporobolomyces and Rhodotorula. J
Antimicrob Chemother. 2005;55(6):1020-1023. doi:10.1093/jac/dki131
21 Tawara S, Ikeda F, Maki K, et al. In vitro activities of a new lipopeptide antifungal agent, FK463, against a
variety of clinically important fungi. Antimicrob Agents Chemother. 2000;44(1):57-62.
doi:10.1128/aac.44.1.57-62.2000
22 Uchida K, Nishiyama Y, Yokota N, Yamaguchi H. In vitro antifungal activity of a novel lipopeptide
antifungal agent, FK463, against various fungal pathogens. J Antibiot (Tokyo). 2000;53(10):1175-1181.
doi:10.7164/antibiotics.53.1175
23 Zhanel GG, Karlowsky JA, Harding GA, et al. In vitro activity of a new semisynthetic echinocandin, LY-
303366, against systemic isolates of Candida species, Cryptococcus neoformans, Blastomyces
dermatitidis, and Aspergillus species. Antimicrob Agents Chemother. 1997;41(4):863-865.
doi:10.1128/aac.41.4.863
24 Borman AM, Muller J, Walsh-Quantick J, et al. MIC distributions for amphotericin B, fluconazole,
itraconazole, voriconazole, flucytosine and anidulafungin and 35 uncommon pathogenic yeast species
from the UK determined using the CLSI broth microdilution method. J Antimicrob Chemother.
2020;75(5):1194-1205. doi:10.1093/jac/dkz568
25 Espinel-Ingroff A. In vitro activity of the new triazole voriconazole (UK-109,496) against opportunistic
filamentous and dimorphic fungi and common and emerging yeast pathogens. J Clin Microbiol.
1998;36(1):198-202. doi:10.1128/jcm.36.1.198-202.1998
26 Galán-Sánchez F, García-Martos P, Rodríguez-Ramos C, Marín-Casanova P, Mira-Gutiérrez J.
Microbiological characteristics and susceptibility patterns of strains of Rhodotorula isolated from clinical
samples. Mycopathologia. 1999;145(3):109-112. doi:10.1023/a:1007059005753
27 García-Martos P, Domínguez I, Marín P, García-Agudo R, Aoufi S, Mira J. [Antifungal susceptibility of
emerging yeast pathogens]. Enferm Infecc Microbiol Clin. 2001;19(6):249-256. doi:10.1016/s0213-
005x(01)72630-4
28 Gomez-Lopez A, Mellado E, Rodriguez-Tudela JL, Cuenca-Estrella M. Susceptibility profile of 29 clinical
isolates of Rhodotorula spp. and literature review. J Antimicrob Chemother. 2005;55(3):312-316.
doi:10.1093/jac/dki020
29 Nunes JM, Bizerra FC, Ferreira RC, Colombo AL. Molecular identification, antifungal susceptibility profile,
and biofilm formation of clinical and environmental Rhodotorula species isolates. Antimicrob Agents
Chemother. 2013;57(1):382-389. doi:10.1128/aac.01647-12
30 Serena C, Pastor FJ, Ortoneda M, Capilla J, Nolard N, Guarro J. In vitro antifungal susceptibilities of
uncommon basidiomycetous yeasts. Antimicrob Agents Chemother. 2004;48(7):2724-2726.
doi:10.1128/aac.48.7.2724-2726.2004
31 Zaas AK, Boyce M, Schell W, Lodge BA, Miller JL, Perfect JR. Risk of fungemia due to Rhodotorula and
antifungal susceptibility testing of Rhodotorula isolates. J Clin Microbiol. 2003;41(11):5233-5235.
doi:10.1128/jcm.41.11.5233-5235.2003
32 Peyron F, Favel A, Michel-Nguyen A, Gilly M, Regli P, Bolmström A. Improved detection of amphotericin B-
resistant isolates of Candida lusitaniae by Etest. J Clin Microbiol. 2001;39(1):339-342.
doi:10.1128/jcm.39.1.339-342.2001

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Glossary. Antifungal Agent Abbreviations, Routes of Administration, and

Drug Class
Routes of
Antifungal Administrationb
Agent Abbreviationsa PO IV Drug Class
Amphotericin B AMB X Polyene
Anidulafungin AND X Echinocandin
Caspofungin CAS, CFG X Echinocandin
Fluconazole FLC, FLU, FLS, FCA, FLZ, FZ X X Azole
Flucytosine 5-FC X Fluorinated
pyrimidine
Isavuconazole ISA X X Azole
Itraconazole ITR X Xc Azole
Manogepix MGPX X X Inhibitor of Gwt1
Micafungin MCF X Echinocandin
Oteseconazole OTE X Azole
Posaconazole POS, PCO, POC X X Azole
Rezafungin RZF X Echinocandin
Voriconazole VRC, VCO, VOC, VO X X Azole
Abbreviations: IV, intravenous; PO, oral.

Footnotes

a. These abbreviations are assigned to one or more diagnostic products in the United States. If no diagnostic
product is available, the abbreviation is that of the manufacturer.

b. As available in the United States.

c. Itraconazole is not available for IV administration in the United States.

NOTE: Information in boldface type is new or modified since the previous edition.

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