Transcript Resistance trends in clinical antifungals

Identification, Susceptibility &
Resistance
Dr Caroline B. Moore
Mycology Reference Centre
University Hospital of South Manchester
The University of Manchester
Yeasts
Why bother with identification
& susceptibility testing?
• Significant number of invasive fungal
infections
• Increase in ‘at-risk’ patient population
Why bother with identification
& susceptibility testing?
• Significant number of invasive fungal
infections
• Increase in ‘at-risk’ patient population
• Increase in non-C. albicans species
• Increase in ‘rarer’ species
Proportion of nosocomial Candida
infections caused by different species in a
teaching hospital
C.albicans
50
C.tropicalis
45
C.parapsilosis
40
C.glabrata
Percentage
35
C.krusei
30
25
20
15
10
5
0
87-88
88-89
89-90
90-91
Year
Berrouane et al. J Clin Micro 1999; 37:531
91-92
92-93
93-94
Why bother with identification
& susceptibility testing?
• Significant number of invasive fungal
infections
• Increase in ‘at-risk’ patient population
• Increase in non-C. albicans species
• Increase in ‘rarer’ species
• Increase in drug resistance
Increasing fluconazole resistance in
Intensive Care Unit
600
100
90
500
80
70
400
DDD
300
50
40
200
30
20
100
10
1996
1995
1994
1993
0
1992
0
% FCZ Res
Fluconazole
60
Moore et al. ECMM 1998
Amphotericin
C. tropicalis
C. glabrata
C. albicans
C. krusei
Why bother with identification
& susceptibility testing?
• Significant number of invasive fungal
infections
• Increase in ‘at-risk’ patient population
• Increase in non-C. albicans species
• Increase in ‘rarer’ species
• Increase in drug resistance
• More drug choices available
• Informed therapeutic choice
How do we identify yeasts?
• Culture morphology
Chromagar
How do we identify yeasts?
• Germ tube test
• Microscopic
morphology
• Other tests
Terminal
chlamydospores
Arthrospores
How do we identify yeasts?
• Traditional methods
– Wickerham tests
Auxacolor
• Commercial kits
– numerous!
Vitek-2
API ID 32C
• Molecular methods
MICs
He uses statistics
like a drunken man
uses lamp-posts ...
For support
rather than
illumination
Do we have a good test of
susceptibility for yeasts?
• CLSI (NCCLS) M27-A3 method
– USA standard
• EUCAST Document E-Def 7.1 method
– European standard
Extensive clinical
correlation work
Do we have a good test of
susceptibility for yeasts?
• Disc diffusion
– no MIC obtained
– screening method
• E-test strips
– MIC value obtained
– problematic endpoints
Do we have a good test of
susceptibility for yeasts?
• An array of commercial formats
– Vitek-2
– YeastOne
– Fungitest
– Others…
Some are more
equal than
others!
• Molecular methods
Candida albicans
•
•
•
•
•
Most common cause of candidosis (50-70%)
Can cause a wide range of diseases
May cause vaginal and oral/oesophageal thrush
Produces germ tubes
Attributable mortality (18-25%)
– differences in patient age and underlying illness
Candida albicans
• Azole susceptibility can depend on HIV status
C.albicans
C.albicans FLU-resistant
FLU ITR VOR POS AMB
5FC CASP
++
++
++
++
++
++
++
-
+
++
+
++
++
++
Rates of resistance seen in our
laboratory 1992-2006
flucytosine 6%
fluconazole 1.2%
5% of C. albicans with
reduced susceptibility
Candida parapsilosis
complex
• Candida parapsilosis, Candida orthopsilosis,
Candida metapsilosis
• 2nd most common species in blood, related to
catheters and glucose solutions including
TPN
• Often seen in neonates
• Generally do not cause thrush
• Less pathogenic than C. albicans
Candida parapsilosis
complex
FLU ITR VOR POS AMB
C.parapsilosis ++
++ ++
++
++
Rates of resistance seen in our
laboratory 1992-2006
fluconazole 0.4%
5FC CASP
+
-
Candida glabrata
•
•
•
•
3rd or 4th most common species in blood
Increasing in many institutions
Common cause of thrush, particularly vaginal
Generally thought as unable to produce
pseudohyphae in vitro
• Evidence of ability to grow as filamentous
organism
Candida glabrata
• Usually reduced susceptibility to fluconazole
• Responds poorly to amphotericin B
C.glabrata
FLU ITR VOR POS AMB
+
+
+
+
+
5FC CASP
++
++
Rates of resistance seen in our
laboratory 1992-2006
fluconazole 53%
Candida tropicalis
• Usually 4th most common species in blood, much
commoner in some institutions
• Generally does not cause thrush
• More invasive than other Candida species
• High attributable mortality (33-50%)
• High frequency (~80-100%) of infection if coloniser
during neutropenia
Candida tropicalis
• Usually fluconazole susceptible, but may develop
resistance quickly
C.tropicalis
FLU ITR VOR POS AMB
+
++
++
++
++
5FC CASP
++
++
Rates of resistance seen in our
laboratory 1992-2006
flucytosine 20%
fluconazole 46%
Candida krusei
• 5th most common species in blood
• Does not cause thrush, except in late-stage
AIDS
• High mortality in leukaemic patients
Candida krusei
• May be a breakthrough species
• Always fluconazole resistant and
amphotericin intermediate
C.krusei
FLU ITR VOR POS AMB
- +
+
+
+
5FC CASP
+
++
Cryptococcus
neoformans
• Neurotropic fungus
• Most common predisposing factor is AIDS
• Also organ transplant recipients or cancer patients
receiving chemotherapeutics
• Produces a polysaccharide capsule - major
virulence factor
Cryptococcus
neoformans
• Combination therapy generally used
Crypto.
neoformans
FLU ITR VOR POS AMB
+
+
++
++
++
5FC CASP
+
-
Image Courtesy of Carsten Kettner
Rhodotorula
mucilaginosa
Saccharomyces species
Malassezia species
High degree of
mortality
Species of….
Trichosporon
Geotrichum
Blastoschizomyces
Can be intrinsically
resistant to some
antifungal drugs
Moulds - the Aspergilli
Increasing incidence of invasive
aspergillosis in hematopoietic stem
cell transplant recipients
14
12
Incidence (%)
10
Allograft recipients
8
Autograft recipients
6
4
2
0
1990 1991 1992 1993 1994 1995 1996 1997 1998
Year
Marr et al. Clin Infect Dis 2002; 34:909
What tests do we have
to identify moulds?
• morphology
• microscopy
Experience!
• additional tests
• molecular methods
Aspergillus
Wide spectrum of disease – dependent on
immune status
• Allergic bronchopulmonary
aspergillosis
• Pulmonary aspergilloma
• Invasive aspergillosis
Can be a secondary pathogen
in cases of carcinoma or TB
Aspergillus fumigatus complex
most common cause of aspergillosis
~90% of cases
Aspergillus niger complex
Common cause of ear
infections
Aspergillus terreus complex
Cause of superficial,
eye, ear and systemic
infections
Aspergillus flavus complex
Cause of pulmonary and
sinus infections
In vitro susceptibility of filamentous fungi
ITR VOR POS AMB
5FC CASP FLU
Asp. fumigatus ++
++
++
++
+/-
++
-
Asp. niger
++
++
++
++
-
++
-
Asp. terreus
++
++
++
-
-
++
-
Asp. flavus
++
++
++
++
-
++
-
Azole resistance in A. fumigatus
complex
Itraconazole
• recent literature 0 - 5%
• 7% RMLM 1992 – 2007 (n = 519)
• significant increase in resistance since 2004
– now 13%
Itraconazole resistant isolates
• 58% cross-resistant to voriconazole
• 66% cross-resistant to posaconazole
Data from Dr Susan Howard
MIC mg/L
Azole cross resistance of Asp. fumigatus complex
Mosquera & Denning.
Antimicrob Agents Chemother
2002; 46:556
Other Aspergilli
Klich MA. Identification of common Aspergillus species (2002). CBS.
Non-Aspergillus moulds
Increasing frequency of non-Aspergillus
mould infections in hematopoietic stem
cell transplant recipients
16
14
Infections (no.)
12
10
Fusarium spp
8
Zygomycetes
Scedosporium
spp
6
4
2
0
1985-1989
1990-1994
1995-1999
Time period
Marr et al. Clin Infect Dis 2002; 34:909
Fusarium spp.
Range of disease from
cutaneous through to
disseminated infection
Scedosporium spp.
Can cause subcutaneous infections but
dissemination may occur in
immunocompromised host
Mucorales
Cunninghamella
Rhizomucor
Rhizopus
Absidia
Mucor
etc…
In vitro susceptibility of filamentous fungi
ITR VOR POS AMB
5FC CASP FLU
Asp. fumigatus ++
++
++
++
+/-
++
-
Asp. niger
++
++
++
++
-
++
-
Asp. terreus
++
++
++
-
-
++
-
Asp. flavus
++
++
++
++
-
++
-
Fusarium
-
+
+/-
+/-
-
-
-
+/-
+
+/-
-
-
+/-
-
-
-
+
+
-
-
-
Scedosporium
Mucorales
Others…
Acremonium
Wangiella
Penicillium
Paecilomyces
Phialophora
Cladophialophora
Alternaria
Plus many more…
Take time to ‘know’ the fungus in
your hospital….
Better the devil….