Susceptibility and Resistance: What
Does it Mean and Why Should it
Matter?
Michael A. Pfaller, M.D.
JMI Laboratories and the University of Iowa College of
Medicine
Disclosures: Research support from Astellas, Merck and Pfizer
Susceptibility and Resistance: What Does it
Mean and Why Should it Matter?
• Definitions
• Microbiological
• Clinical
• Composite
Susceptibility and Resistance: What Does it
Mean and Why Should it Matter?
• Definitions
• Microbiological
- Susceptible: Growth of the organism is inhibited by an
antimicrobial agent concentration in the range found for wild-type
(WT) strains ( harbor no acquired or intrinsic resistance
mechanisms).
- Resistant: Growth of the organism is inhibited by an antimicrobial
agent concentration higher than the range seen for WT strains.
Turnidge and Paterson Clin Microbiol Rev 2007; 20:391-408
Susceptibility and Resistance: What Does it
Mean and Why Should it Matter?
• Definitions
• Clinical
- Susceptible: The infecting organism is inhibited by a concentration
of an antimicrobial agent that is associated with a high likelihood
of therapeutic success.
- Resistant: The infecting organism is inhibited by a concentration of
an antimicrobial agent that is associated with a high likelihood of
therapeutic failure.
Turnidge and Paterson Clin Microbiol Rev 2007; 20:391-408
Factors that Contribute to
Antifungal Drug Resistance
• Host factors
- Immune status
- Site of infection
- Presence of foreign materials
- Patient noncompliance
• Drug factors
- Static vs cidal
- Dosing (timing, quantity, cumulative amt)
- PK ( absorption, distribution, metabolism)
- PD ( static, cidal, exposure, PAFE )
- Drug-drug interactions
• Fungal factors
- Cell type (morphology, metabolic state, biofilm)
- Genome stability
- Organism burden
- Resistance mechanisms
- MIC
Susceptibility and Resistance: What Does it
Mean and Why Should it Matter?
• Definitions
• Composite as applied to in vitro susceptibility testing (CLSI &
EUCAST)
- Susceptible: Isolates are inhibited by the usually achievable concentrations
of an antimicrobial agent when the recommended dosage is used for that
site of infection.
- Resistant: Isolates are not inhibited by the usually achievable
concentrations of the agent with normal dosage schedules and/or
demonstrate MICs that fall in the range where specific microbial
resistance mechanisms are likely and that clinical efficacy against the
isolate has not been shown reliably in treatment studies.
Turnidge and Paterson Clin Microbiol Rev 2007; 20:391-408
Successful Outcome
The 90/60 Rule
Breakpoint concentrations that are associated with
100
90
80
70
60
50
40
30
20
10
0
clinically-relevant outcomes
Susceptible Resistant
Bacteria (12 studies, 5447 pts) Candida (13 studies, 1197 pts)
Rex and Pfaller. Clin Infect Dis 2002;35:982-989.
CLSI / EUCAST Approach to the
Development of Clinical Breakpoints
• Standardized method
• Quality control
• MIC frequency distribution (for each species)
• Epidemiological cutoff values (for each species)
• Mechanisms of resistance and cross-resistance
• PK/PD parameters
• Clinical outcome vs MICs according to species
• Alternative methods
• Post market surveillance
Susceptibility and Resistance: What Does it
Mean and Why Should it Matter?
• Although in vitro susceptibility testing is often
used to select antimicrobial agents that are
most likely to be active clinically, perhaps the
most important role of such testing is in
detecting resistance ( e.g. determining those
agents that will not work).
• Turnidge and Paterson Clin Microbiol Rev
2007; 20:391-408.
Why Discuss Antifungal Resistance?
• IFIs are increasing in incidence
– 10 th to 7 th leading cause of infxn related death in U.S.
– Healthcare associated IFI cause most mortality
• McNeil MM, et al. Clin Infect Dis 2001;33:641-647.
– Fungal sepsis increased by 207% from 1979-2000
• Martin GS et al. N Engl J Med. 2003;348:1546–1554.
• High associated mortality for HA-IFI
– Crude mortality rates of 40-85%
– Attributable mortality as high as 20-50%
• Options for therapy have been limited
Systemic Antifungal Timeline
Amphotericin B
Flucytosine
Fluconazole
Itraconazole
Ketoconazole Caspofungin
Voriconazole
1950 1960 1970 1980 1990 2000
Lipid
amphotericin B
formulations
Micafungin
Anidulafungin
Posaconazole
Fungal Cell Wall and Membrane
Site of action of relevant systemic agents
Azoles: inhibit ergosterol synthesis, component of fungal cell membrane
Polyenes: bind to ergosterol, produce pores, disrupt fungal cell membrane
Echinocandins: inhibits glucan synthase, interferes with fungal cell wall synthesis
Antifungal Resistance:Major Areas of
Concern
• Bugs: Candida and Aspergillus
• Drugs: Azoles and Echinocandins
Limited information regarding…
• Polyenes (amphotericin)
– Testing issues, ? Clinical correlation
• Endemic mycoses, dermatophytes, assorted
opportunists (Fusarium, Zygomycetes,
Scedosporium)
Candida and Echinocandins
• Most recently introduced anti-Candida agents
– Target glucan synthase complex
– Resistance associated with mutations in 2 highly
conserved regions of fks1/fks2
– Mutants have reduced sensitivity of glucan
synthase, and poor response in murine candidiasis
models
Garcia Effron, et al. Antimicrob Agents Chemother 2009;53:112.
Perlin DS. Drug Resist Update 2007;10:121.
Baixench MT, et al. J Antimicrob Chemother 2007;59:1076.
Candida and Echinocandins
• 2009 IDSA guidelines emphasize
echinocandins for severely ill patients
with invasive candidiasis, or for those
with prior azole exposure
• CLSI established initial clinical
breakpoint of
1400
1200
1000
800
600
400
200
0
2800
2600
2400
2200
2000
1800
1600
1400
1200
1000
800
600
400
200
Anidulafungin
2
Micafungin
0
2
2200
2000
1800
1600
1400
1200
1000
800
600
400
200
0
Caspofungin
2
MIC distributions of the
echinocandins against 5,346
invasive Candida spp. isolates
Pfaller et al. JCM 2008;46:150.
Clinical and In Vitro Resistance:
Caspofungin in Candidiasis Patients
Species
Infection
Type
No.
Isolates
MIC Range,
μg/mL Reference
C albicans Esophagitis 3 0.25->64 Hernandez a
C parapsilosis Endocarditis 6 2->16 Moudgal b
C glabrata Candidemia 4 0.5->8 Krogh-Madsen c
C albicans Esophagitis 1 8 Miller d
C glabrata Candidemia 3 0.06->4 Cleary e
C krusei Candidemia 2 2-8 Hakki f
a Hernandez et al. Antimicrob Agents Chemother. 2004;48:1382-1383; b Moudgal et al. Antimicrob
Agents Chemother. 2005;49:767-769; c Krogh-Madsen et al. Clin Infect Dis. 2006;42:938-944;
d Miller et al. Pharmacotherapy. 2006;26:877-880; e Cleary et al. Antimicrob. Agents Chemother.
2008;52:2263-5; f Hakki et al. Antimicrob Agents Chemother. 2006;50:2522-2524.
N
3000
2000
1000
0
N=4266
MIC distribution of the Echinocandins
against C. albicans
=8
MIC (micrograms/ml)
Anidulafungin Caspofungin Micafungin
Epidemiological Cutoff Values
(ECVs)
• Define upper limit of “wild type” MIC distribution
for each species
– no acquired resistance mechanisms
• Establishes cutoffs to help detect emergence of
reduced susceptibility (acquired resistance) in
the absence of clinical breakpoints
– or “in addition to” clinical breakpoints
• Helps identify organisms requiring further
characterization
2200
2000
1800
1600
1400
1200
1000
800
600
400
200
0
Caspofungin MIC distribution
ECV for most Candida species
Clinical breakpoint
2
MIC (micrograms/mL)
N= 5346 Pfaller et al. JCM 2010;48:52-56.
Epidemiological Cutoff Values (ECVs) for
Candida and Echinocandins
Pfaller et al JCM 2010; 48:52-56
No. ECV (mcg/ml)
Species tested ANF CSF MCF
CA 4,283 0.12 0.12 0.03
CG 1,236 0.25 0.12 0.03
CT
CK
996
270
0.12
0.12
0.12
0.25
0.12
0.12
Epidemiological Cutoff Values (ECVs) for
Candida and Echinocandins
Pfaller et al JCM 2010; 48:52-56
No. ECV (mcg/ml)
Species tested ANF CSF MCF
CL 276 2 1 0.5
CP 1,238 4 1 4
CGu 176 4 2 4
CLSI Approach to the Development of
Clinical Breakpoints (CBPs)
• ECVs are not always the same as CBPs
• Whereas the CBPs are used to indicate those
isolates that are likely to respond to treatment
with a given antimicrobial agent administered
at the approved dosing regimen for that agent,
the ECV may serve as the most sensitive
measure for the emergence of strains with
reduced susceptibility (acquired resistance
mechanisms) to that agent
• Turnidge & Paterson, Clin Microbiol Rev 2007;20:391-408
Mutations in FKS Help Define
Resistance to the Echinocandins
• Relatively narrow spectrum of FKS1/ FKS2 (C. glabrata)
mutations in strains of C.albicans, C. glabrata, C. tropicalis and C.
krusei confer reduced susceptibility to echinocandins
• Mutations that decrease enzyme sensitivity (IC50 and Ki) to drug
by at least 50X do so across entire class
• Amino acid changes at Ser645 have highest MIC values, changes
at C-terminal portion of hsp1 (Asp648 and Pro649) and in hsp2
have less pronounced effects
Garcia-Effron et al AAC 2009;53:112-22
Garcia-Effron et al AAC 2009;53:3690-99
Garcia-Effron et al 2010; 54:2225-7
Not all elevated MICs are the same
MIC FKS1 Glucan Synthase P successful
Genotype Clinical Outcome
Low WT Sensitive Good
High WT Sensitive Good
High mutant weakly resistant Good
High mutant moderately resistant Mixed
High mutant strongly resistant Poor
FKS1 genotype matters
S645, F641 > L642, T643, L644, A645, L646, R647, D648 > P649
MIC Distributions of Three Echinocandins
vs Candida spp. Strains Tested for the
Presence of fks1/fks2 Mutations
Species Antifungal No. of isolates at MIC (no. showing mutation)
(no. tested) agent 8
C. albicans
(52)
C. glabrata
(53)
C. tropicalis
(31)
Arendrup et al
AAC
2010;54:426-39
Pfaller et al, JCM
2010; 48:1592-9
ANF
CSF
MCF
ANF
CSF
MCF
ANF
CSF
MCF
31
15
31
12
1
25
18
8
9
7
23
7
15
20
9(1)
6
12
6
4(1)
3
3
7(1)
7
5(2)
1(1)
3
7
-
-
2(2)
3
3(1)
5(3)
1
3(1)
3(1)
2(2)
2(2)
1(1)
-
1
3(2)
1(1)
-
3(2)
6(6)
1(1)
2(2)
6(3)
8(3)
1(1)
4(4)
1(1)
3(3)
2(2)
3(3)
5(5)
5(5)
5(4)
3(3)
-
2(2)
-
-
2(2)
1(1)
5(5)
2
2(2)
-
2(2)
-
-
3(3)
-
6(6)
-
-
-
-
CLSI Approach to the Development of
Clinical Breakpoints
• Primarily rely on data from clinical trials
• 90/60 Rule
• Problem with clinical trials data for
echinocandins and Candida
- Almost all isolates are WT
- No resistance
- May not represent “real world” situation
- Pts are not as sick or complicated
- Need post market surveillance data
Interpretive Breakpoints for
Caspofungin
• Esophageal candidiasis
- No relationship seen
- Isolates from patients treated with caspofungin,
291/292 (99.7%) MICs
CLSI Approach to the Development of
Clinical Breakpoints
• Post market surveillance
• Provide evidence for resistant BP
- Case reports and case series
- Longitudinal surveillance
Case reports of echinocandin failures
Species Infection MICs (A/C/M) Mutation
C. albicans Esoph ---/2/1 Yes
C. glabrata BSI 0.5/2/0.25 Yes
C. tropicalis BSI 2/4/2 Yes
C. tropicalis BSI 1/4/2 Yes
C. tropicalis BSI 0.5/1/0.5 Yes
C. albicans Esoph 1/2/2 Yes
Baixench et al. J Antimicrob Chemother 2007;59:1076.
Garcia-Effron et al. Antimicrob Agents Chemother 2008;52:4181.
Laverdiere et al. J Antimicrob Chemother 2006;57:705.
Thompson et al. Antimicrob Agents Chemother 2008;52:3783.
MIC Distributions of Three Echinocandins
vs Candida spp. Strains Tested for the
Presence of fks1/fks2 Mutations
Species Antifungal No. of isolates at MIC (no. showing mutation)
(no. tested) agent 8
C. albicans
(52)
C. glabrata
(53)
C. tropicalis
(31)
Arendrup et al
AAC
2010;54:426-39
Pfaller et al, JCM
2010; 48:1592-9
ANF
CSF
MCF
ANF
CSF
MCF
ANF
CSF
MCF
31
15
31
12
1
25
18
8
9
7
23
7
15
20
9(1)
6
12
6
4(1)
3
3
7(1)
7
5(2)
1(1)
3
7
-
-
2(2)
3
3(1)
5(3)
1
3(1)
3(1)
2(2)
2(2)
1(1)
-
1
3(2)
1(1)
-
3(2)
6(6)
1(1)
2(2)
6(3)
8(3)
1(1)
4(4)
1(1)
3(3)
2(2)
3(3)
5(5)
5(5)
5(4)
3(3)
-
2(2)
-
-
2(2)
1(1)
5(5)
2
2(2)
-
2(2)
-
-
3(3)
-
6(6)
-
-
-
-
MIC Distributions of Three Echinocandins versus
C. glabrata Strains Tested for the presence of FKS
Mutations *
MIC
(mcg/ml)
ANF CSF MCF
N # mut N # mut N # mut
=8
* Pfaller et al JCM 2010; 48:1592-99;
Zimbeck et al AAC 2010; 54:5042-7.
12
7
12
7
7
3
12
6
1
12
7
7
7
7
A Possible Solution to Optimize Separation
of WT Strains of C. glabrata from FKS
Mutants
• For ANF and CSF use < 0.12mcg/ml (S),
0.25 mcg/ml (I) and > 0.5 mcg/ml (R)
• For MCF use < 0.06 mcg/ml (S), 0.12
mcg/ml (I) and > 0.25 mcg/ml (R)
Species-Specific Echinocandin
Breakpoints
Pfaller et al Drug Resist Updates 2011; in press
1. ANF, CSF, MCF and C.albicans, C. tropicalis and C.
krusei
- S, < 0.25 mcg/ml; I, 0.5 mcg/ml; R, > 1 mcg/ml
2. ANF, CSF, MCF and C. parapsilosis
- S, < 2 mcg/ml; I, 4 mcg/ml; R, > 8 mcg/ml
3. ANF, CSF and C. glabrata
- S, < 0.12 mcg/ml; I, 0.25 mcg/ml; R, >0.5 mcg/ml
4. MCF and C. glabrata
- S, < 0.06 mcg/ml; I, 0.12 mcg/ml; R, > 0.25 mcg/ml
CBPs for Echinocandins vs Candida Using
CLSI BMD
Pfaller et al Drug Resist. Updates 2011; in press
Species
C.albicans
C.glabrata
C.tropicalis
Antifungal
agent
ANF
CSF
MCF
ANF
CSF
MCF
ANF
CSF
MCF
No.
tested S
52
52
52
169
169
169
31
31
31
42(1)
41
43(2)
135(2)
129(1)
134(1)
27(2)
26(1)
25(1)
Category
I R
2(2)
2(2)
1(1)
4(1)
5(3)
6(3)
1(1)
-
3(2)
8(8)
9(9)
8(8)
30(27)
35(26)
29(26)
4(4)
5(5)
3(3)
C. parapsilosis and Echinocandins
• C. parapsilosis isolated in 53% of cancer pts who developed
candidemia while receiving caspofungin therapy (Cancer
2009;115:4745-52)
• Strong correlation between caspofungin usage and a 400%
increase in C. parapsilosis BSI (J Infect 2008;56:126-129)
• Species-specific incidence of C. parapsilosis BSI has doubled in US
between 1993 and 2009 (CDC, 2009).
• Pre exposure to CSF associated with a decreased prevalence of C.
albicans in favor of C. parapsilosis (AAC 2011; 55:532-8).
• Improved response in treating pts with C.parapsilosis BSI with
high-dose caspofungin (150 mg/d) vs standard dose (70 mg load/50
mg daily): 81% vs 61% ; not statistically significant. ( CID 2009;
48:1676-84)
Invasive Aspergillosis
• Invasive aspergillosis (IA) is a devastating
opportunistic infection, with crude mortality
rates of 40-90%
• Voriconazole and posaconazole use is
increasing, both for treatment and prevention
of IA and other systemic mycoses
• Echinocandins are used for salvage and as
part of combination regimens for invasive
aspergillosis
Lin, et al. Clin Infect Dis 2001;32:358.
Herbrecht, et al. N Engl J Med 2002;347:408-415.
Patterson, et al. Clin Infect Dis 2008;46:327-360.
de With, et al. BMC Clin Pharmacol 2005;1-6.
Aspergillus spp. and Azoles
• In vitro “reduced susceptibility” remains 0-5% in
most large surveys, often using itraconazole
– Most data for A. fumigatus complex
• Case reports and case series suggest that
multiply-azole resistant Aspergillus could emerge
– ? association with agricultural azole use
Rodriguez-Tudela, et al. Antimicrob Agents Chemother 2008;52:2468.
Verweij, et al. N Engl J Med 2007;356:1481-83.
Arendrup, et al. Antimicrob Agents Chemother 2008;52:3504-11.
Howard, et al. Int J Antimicrob Agents Chemother 2006;28:450-53.
Snelders et al. PLoS Medicine 2008;5:e219.
Azole Resistance Mechanisms in
Aspergillus fumigatus
• Mutations involving cyp51A gene (target)
- G54 mutation
Cross resistance between ITR and PSC
VRC, RVC MICs < 1 mcg/mL
- M220 mutation
Complete cross resistance ITR, PSC, VRC, RVC
- Tandem repeat – L98H (TR)
Complete cross resistance
• Decreased accumulation (slowed uptake/efflux)
also described
Rodriguez-Tudela et al AAC 2008;52:2468-72.
Nascimento et al. AAC 2003;47:1719-26.
N
Emergence of itraconazole resistance in
The Netherlands
L98H (TR) was the dominant resistance mechanism
Isolates genetically distinct but clustered.
% R
Year
Snelders et al. PLoS Medicine 2008;5:e219.
MIC Distribution and CLSI Epidemiological
Cutoff Values (ECVs) for Azoles and A.fumigatus
Antifungal
agent (N)
ITR
(2,591)
PSC
(1,684)
VRC
(2,851)
MIC (mcg/ml)
Range Mode ECV %
< ECV
0.03->4 0.5 1 98.8
4 0.06 0.5 97.8
0.03->4 0.25 1 98.2
Espinel-Ingroff et al, JCM 2010;48:3251-7
Resistance Mechanisms and Azole
Cross Resistance in A. fumigatus
Strain type
(N)
GM MIC (µg/mL)
ITR VRC RVC PSC
WT (361) 0.32 0.53 0.60 0.08
G54 (9) 16 0.42 0.32 1.6
M220 (6)
TR (17)
16
16
1.0
3.7
1.85
6.8
Rodriguez-Tudela et al AAC 2008;52:2468-72
0.65
0.68
Resistance and Susceptibility:
Why Does it Matter?
• Outcomes
-Clinical trials
- Case series
- Post market surveillance
• Spread of resistance
- Longitudinal surveillance
- Documentation of acquired resistance
mechanisms
- Multidrug resistance (MDR)
Treatment related risk factors for
hospital mortality with candidemia
Mortality by number of risk factors
[retained CVC, inadequate initial FLU dose, treatment delayed >48 h]
Labelle et al. Crit Care Med 2008;36:2967.
Adequacy of Initial Empirical Antifungal
Therapy: Relationship to Outcome in
Patients with Candidemia
• Parkins et al JAC 2007;60:613-18
• Only 30% of 199 pts received empirical therapy
• Empirical therapy was adequate in only 26% of pts
• Adequate empirical therapy associated with reduction
in mortality from 46% to 27%
• Empirical therapy with fluconazole most likely to be
inadequate
- wrong dose (23%)
- resistant organism (77%)
• Accurate and timely ID and AST is important
Epidemiology of Azole and Echinocandin
Resistance in Candida and Aspergillus
• Application of ECVs and new CBPs
• Determination of resistance mechanisms
Use of ECVs to Examine Annual Trends in
Susceptibility of Candida spp. to
Echinocandins: 2001-2009
Mean % of non-WT isolates per year
Species (N) ANF CSF MCF
C. albicans
(8378)
C. glabrata
(2352)
C. tropicalis
(1841)
C. parapsilosis
(2195)
Pfaller et al. JCM 2011; 49: 624-9
0.3 0.1 2.1
0.8 1.3 1.6
0.9 0.7 0.9
0.0 1.5 0.5
Frequency of Antifungal Resistance Among C.
glabrata BSI Isolates by Patient Age Group;
SENTRY Program, 2008-2009
Pfaller et al DMID 2010; 68: 278-83.
Antifungal
% of isolates by pt age group (no. tested)
0-19 20-39 40-59 60-79 80-99 Total
agent (5) (18) (71) (91) (30) (215)
Anidulafungin 0.0 16.7 7.0 2.2 0.0 4.7
Caspofungin 0.0 16.7 7.0 2.2 0.0 4.7
Micafungin 0.0 16.7 4.2 0.0 0.0 2.8
Fluconazole 0.0 16.7 11.3 3.3 0.0 6.5
Posaconazole 0.0 5.6 4.2 2.2 3.3 3.3
Voriconazole 0.0 11.1 5.6 2.2 0.0 3.7
Frequency of Antifungal Resistance Among Community-Onset
(CO) and Nosocomial (NOS) BSI Isolates of Candida glabrata:
SENTRY Program, 2008-2009
Antifungal
agent
% R to each agent
CO NOS
N % R N % R
ANF 91 1.1 156 3.8
CSF 91 2.2 156 5.1
MCF 91 0.0 156 3.2
FLC 91 3.3 156 7.7
PSC 91 3.3 156 5.1
VRC 91 3.3 156 6.4
Pfaller et al AAC
2011;55: 561-6.
Resistance to Anidulafungin and Micafungin
among Isolates of C. glabrata from Four
Geographic Regions, SENTRY 2008-2009
Antifungal No.
Region agent tested % resistant
Asia-Pacific Anidulafungin 7 0.0
Micafungin 7 0.0
Latin America Anidulafungin 18 0.0
Micafungin 18 0.0
Europe Anidulafungin 131 1.5
Micafungin 131 0.8
North America Anidulafungin 220 3.2
Pfaller et al, JCM 2011; 49:396-9.
Micafungin 220 2.7
% with MIC > 1 ug/mL
5
4
3
2
1
0
5-year trend in % A. fumigatus clinical
isolates with ITR MIC of > 1 ug/mL
0
0.9
0.5
3.6
2.5
2005 2006 2007 2008 2009
N = 1031 (by year from 2005-2009): 107, 317, 197, 250, 160
% with MIC > 1 ug/mL
9-year trend in % Aspergillus spp. clinical
isolates with VOR MIC of > 1 ug/mL
30
20
10
0
2000
2.5
2001
1.7 0
2002
2003
1
2004
5.2
2005
1
2006
3.8
2007
1.1
2008
N = 1970 (by year from 2000-2008): 203, 233, 76, 105, 116, 191, 422, 280, 344
Pfaller et al JCM 2010, submitted
4.9
MIC Distributions of Three Azoles vs
A.fumigatus Strains Tested for the
Presence of cyp51A Mutations
Antifungal No. No. isolates at MIC (no. showing mutation)
agent tested 0.007 0.015 0.03 0.06 0.12 0.25 0.5 1 2 4 >8
ITR 28 3 13 1 1 10(8)
PSC 28 16 3(2) 8(6) 1
VRC 28 2 13 4(1) 7(6) 1(1) 1
Lockhart et al AAC 2011; submitted
Note: All mutant strains were from China and contained the TR/L98H
mutation in cyp51A (as well as S297T and F495I): all had unique
microsatellite genotypes.
In vitro resistance confirmed by the sterol quantification method.
Summary and Conclusions
• Susceptibility and resistance remain useful concepts in guiding the use of
antifungal therapy.
• Antifungal resistance is now documented by qualitative and quantitative
in vitro data, clinical outcomes and molecular characterization of
resistance determinants.
• Recent data re resistance mutations encompasses both Candida and
Aspergillus and documents spread of antifungal resistance within
hospitals and possibly the environment.
• MDR in both Candida and Aspergillus is an emerging concern.
• Antifungal susceptibility testing is now becoming essential in patient
management and resistance surveillance.
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