Fluconazole and caspofungin resistance of invasive isolates of Candida glabrata and other Candida spp.

The HUP Clinical Microbiology Laboratory determines the fluconazole MIC for blood and invasive isolates of Candida spp., using a FDA-cleared commercial microtiter panel. Other invasive isolates are tested on request. The methodology adheres to CLSI guidelines for antifungal susceptibility testing of yeasts. Results for July 2011 through June 2012, and May 2010 through June 2011 are shown below. Starting in May 2012 caspofungin susceptibility testing was begun.

CLSI issued new interpretive guidelines for yeast susceptibility data in December 2012. These are Candida species specific, based on wild type distributions and newer scientific and clinical findings. The July 2011 to June 2012 data are shown below using the old and new interpretive guidelines.

 


Fluconazole

 

Comparison of new and old CLSI guidelines for fluconazole
Candida spp Old CLSI New CLSI
S SDD R S SDD R
albicans, tropicalis, parapsilosis

≤8

16-32 ≥64 ≤2 4 ≥8
glabrata ≤8 16-32 ≥64 --- ≤32 ≥64
others ≤8 16-32 ≥64 no breakpoints

 

Fluconazole susceptibility according to newDecember 2012 CLSI guidelines

 

Summary of Susceptibility Data New/Old Breakpoints
N %S %S-DD %R
C albicans blood 41 95/98 2/0 2/2
other 28 86/93 4/0 10/7
C glabrata blood 30 NA/50 83/33 17/17
other 24 NA/50 88/38 12/12
C parapsilosis all 16 100/100 0/0 0/0
C tropicalis all 10 60/80 10/10 30/10

 

 

 

 

 

 

 

 

Fluconazole susceptibility according to old, pre-December 2012 CLSI guidelines

Summary of Susceptibility Data
N %S %S-DD %R
C albicans blood 41 98 0 2
other 28 93 0 7
C glabrata blood 30 50 33 17
other 24 50 38 12
C parapsilosis all 16 100 0 0
C tropicalis all 10 80 10 10

 

 

 

 

 

 

 

Summary of Susceptibility Data
N %S %S-DD %R
C albicans blood 28 100 0 0
other 29 100 0 0
C glabrata blood 44 50 41 9
other 24 17 62 21
C parapsilosis all 9 100 0 0
C tropicalis blood 8 50 25 25
other 7 86 14 0

 

 

 

 

 

 

 

These data show little change in fluconazole susceptibility from 2010 to 2011. For the period July 2011 to June 2012, about 10-17% of C. glabrata and C. tropicalis isolates would not be expected to respond to fluconazole therapy regardless of dosage. About half of C. glabrata isolates would require would require dosage higher than the usually recommended dosage of 200 mg/day for those with normal renal function ("SDD", or "sensitive, dose dependent"). Three C. albicans isolates were highly resistant to fluconazole, an unusual finding.

 

There is a reasonable correlation between MIC and clinical outcome, one reasonable predictor being the AUC/MIC ratio. AUC/MIC >10 to 20 seem predictive of better outcome than AUC/MIC<10-20. The AUC for a 400 mg dose is around 300, and around 600 for a 800 mg dose in patients with normal renal function. This study suggests that the outcome of patients with "R" isolates would be unlikely to respond to dosages up to 800 mg/d, but that isolates with lower MICs would be likely to respond to dosages of 800 mg/d or lower.Note that these relationships does not hold for urine isolates, which may respond to therapy regardless of MIC, because of high drug urine concentrations (~64-128 ug/mL after 400 mg dose), assuming normal renal function.

 


Caspofungin

Caspofungin Susceptibilities of Candida species from May 2012 through June 2013

 

 

Caspofungin breakpoints - CLSI 2012
Candida spp. S I R
albicans, tropicalis ≤0.25 0.5 ≥1
glabrata ≤0.125 0.25 ≥0.5
parapsilosis ≤2 4 ≥8

 

 

Summary of Caspofungin Susceptibility Data
N %S %I %R
C albicans blood 44 100 0 0
other 38 100 0 0
C glabrata blood 35 80 17 3
other 23 78 17 5
C parapsilosis all 15 100 0 0
C tropicalis all 15 93 0 6

 

 

 

 

 

 

 

 

Caspofungin resistance is still rare at HUP and PPMC, but based on historical controls, seems to be increasing for C. glabrata and C. tropicalis, pari passu with fluconazole resistance. The clinical meaning of caspofungin intermediate susceptibility is unclear and whether the drug can be used to successfully treat infections caused by organisms with intermediate susceptibility is not known. The clinical implications of caspofungin intermediate or resistant susceptibility of non-blood isolates is unknown. Recent published findings show a similar trend.

 

8/15/2012, updated 6/26/2013 P. Edelstein

Archived data on Candida susceptibility from prior years can be found here