Trends in Antifungal Drug Susceptibility of Cryptococcus neoformans Isolates Obtained through Population-Based Surveillance in South Africa in 2002-2003 and 2007-2008

Govender, Nelesh P.; Patel, Jaymati; Wyk, Marelize Van; Chiller, Tom; Lockhart, Shawn R.

doi:10.1128/aac.00048-11

Cited by 65 publications

(43 citation statements)

References 33 publications

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“…Based on the distribution of MICs to FLZ among wild-type and clinical isolates, epidemiologic cutoff values (ECV) have been determined for nontyped isolates of C. neoformans (16 g/ml FLZ) and isolates of the most prevalent molecular type VNI and for molecular type VNIII (8 g/ml and 16 g/ml, respectively) (24). MICs to amphotericin B (AMB) were not assessed because no resistance was observed in our recent analysis of nearly 500 isolates (23).…”

Section: Methodsmentioning

confidence: 99%

“…grubii with identical MLST genotypes that were isolated from the same patient were tested for antifungal susceptibility. MICs to fluconazole (FLZ) were determined using the Clinical and Laboratory Standards Institute M27-A3 microdilution broth method; microtiter plates were prepared at the NICD (23). As clinical breakpoints are not available for FLZ, we compared the MICs of incident and serial isolates and defined resistance as a 4-fold increase in the MIC.…”

Section: Methodsmentioning

confidence: 99%

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Multilocus Sequence Typing of Serially Collected Isolates of Cryptococcus from HIV-Infected Patients in South Africa

Wyk¹,

Govender

Mitchell

et al. 2014

J Clin Microbiol

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cPatients with cryptococcal meningitis in sub-Saharan Africa frequently relapse following treatment. The natural history and etiology of these recurrent episodes warrant investigation. Here, we used multilocus sequence typing (MLST) to compare the molecular genotypes of strains of Cryptococcus neoformans and Cryptococcus gattii isolated from serial episodes of cryptococcal meningitis that were separated by at least 110 days. The most common MLST genotypes among the isolates were the dominant global clinical genotypes (M5 and M4) of molecular type VNI, as well as the VNI genotypes apparently restricted to southern Africa. In addition, there was considerable genetic diversity among these South African isolates, as 15% of the patients had unique genotypes. Eleven percent of the patients were reinfected with a genetically different strain following their initial diagnosis and treatment. However, the majority of serial episodes (89%) were caused by strains with the same genotype as the original strain. These results indicate that serial episodes of cryptococcosis in South Africa are frequently associated with persistence or relapse of the original infection. Using a reference broth microdilution method, we found that the serial isolates of 11% of the patients infected with strains of C. neoformans var. grubii with identical genotypes exhibited >4-fold increases in the MICs to fluconazole. Therefore, these recurrent episodes may have been precipitated by inadequate induction or consolidation of antifungal treatment and occasionally may have been due to increased resistance to fluconazole, which may have developed during the chronic infection.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Multilocus Sequence Typing of Serially Collected Isolates of Cryptococcus from HIV-Infected Patients in South Africa

Wyk¹,

Govender

Mitchell

et al. 2014

J Clin Microbiol

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“…CBPs are based on MIC distributions, pharmacokinetic and pharmacodynamic (PK/PD) parameters, animal studies, and clinical outcomes to therapy, while the ECV is based mostly on MIC distributions. Numerous surveys indicate that CLSI MICs are Յ16 g/ml (fluconazole) and Յ0.5 g/ml (the other three triazoles) for most C. neoformans and C. gattii isolates (5,9,10,16,24,43,50). In the last few years, azole (mostly fluconazole) antifungal susceptibility differences have been reported for these two species and for their molecular types and serotypes (10,11,25,33,50,51).…”

mentioning

confidence: 99%

“…In addition to the different amphotericin B formulations, fluconazole and itraconazole are recommended as primary alternative induction treatments for infections caused by C. neoformans and C. gattii and voriconazole and posaconazole as salvage consolidation therapies (35,38); fluconazole is also the drug of choice for lifelong suppressive (maintenance) therapy or primary therapy in some areas (24). The azoles block the pathway of ergosterol biosynthesis by inhibiting the 14-␣-lanosterol demethylase enzyme, which is coded by the CYP51 gene in C. neoformans (CnCYP51; also called ERG11) (46).…”

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confidence: 99%

Cryptococcus neoformans-Cryptococcus gattii Species Complex: an International Study of Wild-Type Susceptibility Endpoint Distributions and Epidemiological Cutoff Values for Fluconazole, Itraconazole, Posaconazole, and Voriconazole

Espinel-Ingroff

Aller

Cantón

et al. 2012

Antimicrob Agents Chemother

221

214

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MICs measured using CLSI yeast nitrogen base (YNB) medium instead of CLSI RPMI medium for C. neoformans were evaluated. CLSI RPMI medium ECVs for distributions originating from at least three laboratories, which included >95% of the modeled WT population, were as follows: fluconazole, 8 g/ml (VNI, C. gattii nontyped, VGI, VGIIa, and VGIII), 16 g/ml (C. neoformans nontyped, VNIII, and VGIV), and 32 g/ml (VGII); itraconazole, 0.25 g/ml (VNI), 0.5 g/ml (C. neoformans and C. gattii nontyped and VGI to VGIII), and 1 g/ml (VGIV); posaconazole, 0.25 g/ml (C. neoformans nontyped and VNI) and 0.5 g/ml (C. gattii nontyped and VGI); and voriconazole, 0.12 g/ml (VNIV), 0.25 g/ml (C. neoformans and C. gattii nontyped, VNI, VNIII, VGII, and VGIIa,), and 0.5 g/ml (VGI). The number of laboratories contributing data for other molecular types was too low to ascertain that the differences were due to factors other than assay variation. In the absence of clinical breakpoints, our ECVs may aid in the detection of isolates with acquired resistance mechanisms and should be listed in the revised CLSI M27-A3 and CLSI M27-S3 documents.

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“…However, in the northwest United States, Cryptococcus gattii is the primary causative agent of cryptococcosis and can also affect immunocompetent people; it has been classified endemic in some regions of the eastern United States, and several cases of cryptococcosis outside that area where the disease is endemic have been reported recently (34)(35)(36). This infection can produce both meningitis and pulmonary complications in these patients (37,38). Routine clinical diagnosis of cryptococcosis is based on culture and detection of a capsular antigen, with varied sensitivity and specificity (39,40).…”

mentioning

confidence: 99%

A Multiplex Real-Time PCR Assay for Identification of Pneumocystis jirovecii, Histoplasma capsulatum, and Cryptococcus neoformans/Cryptococcus gattii in Samples from AIDS Patients with Opportunistic Pneumonia

et al. 2014

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A molecular diagnostic technique based on real-time PCR was developed for the simultaneous detection of three of the most frequent causative agents of fungal opportunistic pneumonia in AIDS patients: Pneumocystis jirovecii, Histoplasma capsulatum, and Cryptococcus neoformans/Cryptococcus gattii. This technique was tested in cultured strains and in clinical samples from HIV-positive patients. The methodology used involved species-specific molecular beacon probes targeted to the internal transcribed spacer regions of the rDNA. An internal control was also included in each assay. The multiplex real-time PCR assay was tested in 24 clinical strains and 43 clinical samples from AIDS patients with proven fungal infection. The technique developed showed high reproducibility (r 2 of >0.98) and specificity (100%). For H. capsulatum and Cryptococcus spp., the detection limits of the method were 20 and 2 fg of genomic DNA/20 l reaction mixture, respectively, while for P. jirovecii the detection limit was 2.92 log 10 copies/20 l reaction mixture. The sensitivity in vitro was 100% for clinical strains and 90.7% for clinical samples. The assay was positive for 92.5% of the patients. For one of the patients with proven histoplasmosis, P. jirovecii was also detected in a bronchoalveolar lavage sample. No PCR inhibition was detected. This multiplex real-time PCR technique is fast, sensitive, and specific and may have clinical applications.

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Trends in Antifungal Drug Susceptibility of Cryptococcus neoformans Isolates Obtained through Population-Based Surveillance in South Africa in 2002-2003 and 2007-2008

Cited by 65 publications

References 33 publications

Multilocus Sequence Typing of Serially Collected Isolates of Cryptococcus from HIV-Infected Patients in South Africa

Multilocus Sequence Typing of Serially Collected Isolates of Cryptococcus from HIV-Infected Patients in South Africa

Cryptococcus neoformans-Cryptococcus gattii Species Complex: an International Study of Wild-Type Susceptibility Endpoint Distributions and Epidemiological Cutoff Values for Fluconazole, Itraconazole, Posaconazole, and Voriconazole

A Multiplex Real-Time PCR Assay for Identification of Pneumocystis jirovecii, Histoplasma capsulatum, and Cryptococcus neoformans/Cryptococcus gattii in Samples from AIDS Patients with Opportunistic Pneumonia

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