Resistant

conference.cast.com

Resistant

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.

More magazines by this user
Similar magazines