Molecular Subtypes and Antifungal Susceptibilities of Serial Cryptococcus neoformans Isolates in Human Immunodeficiency Virus-Associated Cryptococcosis

Brandt, Mary E.; Pfaller, Michael A.; Hajjeh, Rana; Graviss, Edward A.; Rees, J. W.; Spitzer, Eric D.; Pinner, Robert W.; Mayer, Leonard W.

doi:10.1093/infdis/174.4.812

Cited by 72 publications

(72 citation statements)

References 22 publications

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“…In 1995, Haynes et al reported that paired isolates were genetically distinct in three of five individuals with HIV and cryptococcosis and suggested that this represented dual infection (14). Subsequently, a larger study of serial isolates from 33 individuals with HIV documented the persistence of a single C. neoformans isolate and failed to find evidence for dual infection or reinfection with a second strain (2). Nevertheless, additional instances of dual infections and acquisition of a second strain of C. neoformans have been described (16,21,37,38).…”

Section: Discussionmentioning

confidence: 99%

Dual Infections with Pigmented and Albino Strains ofCryptococcus neoformansin Patients with or without Human Immunodeficiency Virus Infection in India

et al. 2005

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Cryptococcus neoformans is an encapsulated yeast-like fungus of worldwide distribution. Melanin production is an important virulence factor of C. neoformans. We report the identification of distinct cryptococcal isolates with either pigmented or white colony phenotypes on L-dihydroxyphenylalanine agar plates in three patients who presented with meningitis to the All India Institute of Medical Sciences in India. Two of the patients were also infected with human immunodeficiency virus. Biochemical studies, India ink analysis, immunofluorescence with antibodies specific to capsular antigen, and serotyping confirmed that the melanotic and albino strains were C. neoformans serotypes A and D, respectively. Genotyping with M13 and [GACA]4 primers revealed that all the C. neoformans isolates were genetically different. The CNLAC1 gene associated with melanin production was identified in all the strains by PCR. Standard MIC testing revealed that the strains had similar susceptibilities to amphotericin B, but time-kill assays with the antifungal showed reduced susceptibility in melanin-producing strains. Infection studies with A/Jcr mice showed that the melanin-lacking yeast were less virulent than melanin-producing isolates. These findings indicate that these patients had dual infections with pigmented and albino strains of C. neoformans that were phenotypically and biologically different. Continued surveillance of primary isolates from patients with cryptococcosis by analyzing phenotypic differences and by molecular methods may reveal that mixed infections occur more commonly than is currently realized.

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Section: Discussionmentioning

confidence: 99%

Dual Infections with Pigmented and Albino Strains ofCryptococcus neoformansin Patients with or without Human Immunodeficiency Virus Infection in India

et al. 2005

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“…neoformans, where mixed results have been seen. Multilocus enzyme electrophoresis (MLEE), electrophoretic karyotyping, and DNA sequence analysis all demonstrated few genotypes over a wide geographic region (3,15,42); the explanation for this was extensive clonal propagation of C. neoformans var. neoformans on pigeon guano and the worldwide expansion of the pigeon population.…”

Section: Discussionmentioning

confidence: 99%

Clonal Reproduction and Limited Dispersal in an Environmental Population of Cryptococcus neoformans var. gattii Isolates from Australia

Halliday

Carter

2003

J Clin Microbiol

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Cryptococcus neoformans var. gattii is a causative agent of cryptococcosis and is thought to have a specific ecological association with a number of Eucalyptus species in Australia. However, the role that the tree plays in the life cycle of the fungus and the nature of the infectious propagule are not well understood. This study set out to examine whether sexual recombination is occurring in a natural population of C. neoformans var. gattii and whether the fungus disseminates between colonized trees. Thirty C. neoformans var. gattii isolates, consisting of both the ␣ and a mating types, were collected from 13 Eucalyptus camaldulensis trees growing along a riverbank in Renmark, South Australia. The genetic diversity within the population was studied by using amplified fragment length polymorphism fingerprinting, and each isolate was assigned a unique multilocus genotype. Population genetic analyses of the multilocus data found no evidence of genetic exchange between members of the population, indicating a clonal population structure. Canonical variate analysis was then used to study the relationship between isolates from different colonized trees. Isolates from individual trees were strongly correlated, and it appeared that dispersal between trees was not occurring to any appreciable extent. These results suggest that the eucalypt may not be the primary niche for C. neoformans var. gattii but that the decaying wood present in hollows on these trees may provide a favorable substrate for extensive clonal propagation of the yeast cells.

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“…Current regimens for treatment of the disease remain focused on amphotericin B, with or without flucytosine, for induction treatment, while fluconazole remains the agent of choice for long-term maintenance treatment (6,17,23). Previous studies have demonstrated that most recurrences of cryptococcal meningitis during maintenance therapy were due to the persistence of the original infecting strains rather than reinfection with a new cryptococcal strain (5,8,21). The MICs for serial isolates from patients with persistent cryptococcosis generally did not change significantly, and strains resistant to fluconazole were infrequently isolated from these patients during episodes of recurrent cryptococcal meningitis (5,6,8).…”

mentioning

confidence: 94%

“…Previous studies have demonstrated that most recurrences of cryptococcal meningitis during maintenance therapy were due to the persistence of the original infecting strains rather than reinfection with a new cryptococcal strain (5,8,21). The MICs for serial isolates from patients with persistent cryptococcosis generally did not change significantly, and strains resistant to fluconazole were infrequently isolated from these patients during episodes of recurrent cryptococcal meningitis (5,6,8). However, concerns regarding fluconazole-resistant strains of C. neoformans have been expressed by several investigators (1, 4, 5, 6, 24; J. P. Viard, C. Hennequin, N. Fortineau, N. Pertuiset, C. Rothschild, and H. Zylberberg, Letter, Lancet 346:118, 1995).…”

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confidence: 99%

Characterization of Heteroresistance to Fluconazole among Clinical Isolates of Cryptococcus neoformans

et al. 2003

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Strains of Cryptococcus neoformans expressing heteroresistance to fluconazole have been described previously. The present study was conducted to investigate the prevalence of heteroresistance among clinical isolates of C. neoformans and to characterize the heteroresistant phenotypes. A total of 107 clinical isolates of C. neoformans for which the MICs of fluconazole ranged from 0.25 to 32 g/ml were selected. The isolates were chosen to represent a broad geographic distribution. Of the 107 C. neoformans isolates tested, 4 grew on medium containing fluconazole at concentrations that were four to eight times higher than the MICs for each strain. A fifth isolate, for which the fluconazole MIC was 32 g/ml, grew on agar with 64 g of fluconazole per ml. These five isolates (4.7% of the total number) were confirmed to exhibit heteroresistant compositions by population analysis. The degree and frequency of resistance varied among the isolates. Stepwise selection by exposure to fluconazole resulted in subclones of all five strains for which the fluconazole MIC was >64 g/ml. Subclones of three strains demonstrated a homogenous population of resistant cells on medium containing 64 g of fluconazole/ml. The resistance was sensitive to incubation temperature, that is, heteroresistance was demonstrable only at 30°C by agar-based tests, and was reversible through serial transfers on fluconazole-free medium over a period of 8 days. These results suggest that the fluconazole-heteroresistant phenotype of C. neoformans exists in a significant proportion of clinical isolates and that fluconazole resistance can be developed by selection from heteroresistant clones and induction by exposure to fluconazole.

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Molecular Subtypes and Antifungal Susceptibilities of Serial Cryptococcus neoformans Isolates in Human Immunodeficiency Virus-Associated Cryptococcosis

Cited by 72 publications

References 22 publications

Dual Infections with Pigmented and Albino Strains ofCryptococcus neoformansin Patients with or without Human Immunodeficiency Virus Infection in India

Dual Infections with Pigmented and Albino Strains ofCryptococcus neoformansin Patients with or without Human Immunodeficiency Virus Infection in India

Clonal Reproduction and Limited Dispersal in an Environmental Population of Cryptococcus neoformans var. gattii Isolates from Australia

Characterization of Heteroresistance to Fluconazole among Clinical Isolates of Cryptococcus neoformans

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