In vitro susceptibilities of Malaysian clinical isolates of Cryptococcus neoformans var. grubii and Cryptococcus gattii to five antifungal drugs
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Abstract:
Summary The in vitro susceptibilities of Malaysian clinical isolates of Cryptococcus neoformans var. grubii and C . gattii to five antifungal drugs (amphotericin B, flucytosine, fluconazole, itraconazole and ketoconazole) were determined using the Etest method. None of the Malaysian isolates was resistant to amphotericin B and ketoconazole. Isolates resistant to flucytosine, fluconazole and itraconazole were observed in this study. Minimum inhibition concentrations (MICs) of ≥32 μ g ml −1 against flucytosine, ≥64 μ g ml −1 against fluconazole and ≥1 μ g ml −1 against itraconazole were noted in four (8.3%), two (4.2%) and one (2.1%) isolates respectively. There was no significant difference in the MICs for both Cryptococcus species ( P > 0.05), indicating that C. gattii was as susceptible as var. grubii to all the antifungal drugs tested. No significant difference in the MICs for both Cryptococcus species collected from 1980 to 1990 and 2002 to 2004 were observed ( P > 0.05).Keywords:
Flucytosine
Cryptococcus gattii
Etest
Cryptococcus spp is a major cause of opportunistic infections in immunocompromised patients, primarily due to Cryptococcus neoformans and Cryptococcus gattii. There are occasional reports of other Cryptococcus species causing invasive human disease. However, their epidemiology and clinical significance are not fully defined. We sought to describe cases with cultures positive for Cryptococcus species other than C neoformans and C gattii.A retrospective descriptive analysis of clinical and laboratory data of patients with cultures growing Cryptococcus species other than C neoformans and C gattii from November 2011 to February 2019 was performed. Three Mayo Clinic sites in Arizona, Florida, and Minnesota were included.From 176 cases with a culture growing Cryptococcus spp, 54 patients (30%) had a culture for Cryptococcus other than C neoformans and C gattii in the study time frame. The most common species were Cryptococcus magnus, Cryptococcus laurentii, and Cryptococcus ater. The organisms were isolated and identified in culture of bronchoalveolar lavage (11), skin (11), urine (7), oral (4), sinus (3), intraoperative soft tissue (3), sputum (2), synovial fluid (2), cerebrospinal fluid (2), and intravenous catheter (2), among others (7).Only 8 (15%) cases were considered to be potentially pathogenic, with 1 case of invasive disease. Antifungal treatment was fluconazole, itraconazole, and griseofulvin, for a mean systemic antifungal duration of 42 days.This large series of patients with Cryptococcus spp other than C neoformans and C gattii suggests that these species rarely cause clinically significant infection in humans. Only 1 case of invasive disease was found.
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Summary The in vitro susceptibilities of Malaysian clinical isolates of Cryptococcus neoformans var. grubii and C . gattii to five antifungal drugs (amphotericin B, flucytosine, fluconazole, itraconazole and ketoconazole) were determined using the Etest method. None of the Malaysian isolates was resistant to amphotericin B and ketoconazole. Isolates resistant to flucytosine, fluconazole and itraconazole were observed in this study. Minimum inhibition concentrations (MICs) of ≥32 μ g ml −1 against flucytosine, ≥64 μ g ml −1 against fluconazole and ≥1 μ g ml −1 against itraconazole were noted in four (8.3%), two (4.2%) and one (2.1%) isolates respectively. There was no significant difference in the MICs for both Cryptococcus species ( P > 0.05), indicating that C. gattii was as susceptible as var. grubii to all the antifungal drugs tested. No significant difference in the MICs for both Cryptococcus species collected from 1980 to 1990 and 2002 to 2004 were observed ( P > 0.05).
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ABSTRACT The in vitro susceptibilities of Cryptococcus neoformans isolates from consecutive human immunodeficiency virus-positive and -negative patients to the antifungal agents fluconazole, amphotericin B, and flucytosine were determined by different techniques, including the CLSI method, Etest, and broth microdilution in yeast nitrogen base (YNB) medium, during a multicenter prospective study in France. The relationship between the in vitro data and the clinical outcome 2 weeks after the initiation of antifungal therapy was assessed. In addition, the correlation between the strain serotype and the in vitro activities of the antifungals was determined, and the susceptibility results obtained with the different techniques were also compared. Thirty-seven patients received a combination of amphotericin B with flucytosine as first-line therapy, 22 were treated with amphotericin B alone, and 15 received fluconazole alone. Whatever the antifungal tested, there was no trend toward higher MICs for strains isolated from patients who failed to respond to a given therapy compared to those from patients who did not with either the CLSI method, Etest, or broth microdilution in YNB medium. The MICs obtained by the CLSI or Etest method were significantly lower for serotype D strains than for serotype A strains for both fluconazole and amphotericin B, while flucytosine MICs were not different according to serotype. These findings suggest that the in vitro antifungal susceptibility of C. neoformans , as determined with the techniques used, is not able to predict the early clinical outcome in patients with cryptococcosis.
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Emerging environmental pathogenic fungal infections, including cryptococcosis, continue to pose a significant threat to humans with compromised immunity and, to some extent, healthy ones. Cryptococcus neoformans was originally identified as the main etiological agent of human cryptococcosis, but recent studies have also identified the occurrence of opportunistic infections caused by Cryptococcus gattii . These two saprophytic facultative yeasts present a paradox as they can infect humans without requiring a host for replication or survival, a phenomenon termed readymade virulence. Many cryptococcal virulence traits appear to have dual effects that provide survival advantages in both animal hosts and the environment. Several molecular techniques have been developed to provide in-depth knowledge of these species complexes. This review will focus on the description of the Cryptococcus neoformans and Cryptococcus gattii ( CnCg ) species complexes and associated cryptococcal pathogenesis, ecological niches, and virulence factors employed by the pathogens to cause disease.
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Ketoconazole was used to treat an indolent case of cryptococcal meningitis that had not completely responded to a course of standard therapy with amphotericin B and flucytosine. Despite treatment with 600 mg/day of ketoconazole for seven months and adequate serum and CSF concentrations, the patient suffered a relapse while still receiving the drug. After the relapse, the condition responded to a higher-than-standard dose course of amphotericin B and flucytosine. (JAMA1982;247:3349-3351)
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Combination of Oral Flucytosine and Ketoconazole as Therapy for Experimental Cryptococcal Meningitis
Current therapy for cryptococcal meningitis often is ineffective, toxic, and inconvenient. Ketoconazole has been shown to penetrate into brain tissue of mice and cerebrospinal fluid of humans and to improve the course of human coccidioidal meningitis. Ketoconazole, flucytosine, and amphotericin B, alone and in two-drug combinations, were used to treat cryptococcal meningitis in mice injected intracranially with Cryptococcus neoformans. Mortality was assessed, and numbers of cryptococci in brain and liver were counted. By both of these parameters, the combination of flucytosine and ketoconazole produced results superior to those of either agent used alone. The standard combination of amphotericin Band flucytosine also showed an additive effect in this model. However, the combination of amphotericin Band ketoconazole consistently showed no additive effect. None of the combinations of drugs was antagonistic. Our results indicate a possible role for therapy with a combination of oral flucytosine and ketoconazole as part of the treatment for cryptococcal meningitis.
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Ketoconazole was used to treat an indolent case of cryptococcal meningitis that had not completely responded to a course of standard therapy with amphotericin B and flucytosine. Despite treatment with 600 mg/day of ketoconazole for seven months and adequate serum and CSF concentrations, the patient suffered a relapse while still receiving the drug. After the relapse, the condition responded to a higher-than-standard dose course of amphotericin B and flucytosine. (JAMA1982;247:3349-3351)
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Objective
To understand the in vitro growth characteristics of Cryptococcus gattii VGⅠ and VGⅡ isolated in China and the diversity in their virulence to Galleria mellonella.
Methods
Based on the results of multilocus sequence typing for eight strains of Cryptococcus gattii isolated in China, the strains were cultured in vitro to draw growth curves, observe the melanin production and measure the capsule thickness. The median lethal time (LT50) and median lethal dose (LC50) at 48 h of Cryptococcus gattii were calculated using Galleria mellonella infection test. Fourteen strains of Cryptococcus neoformans were studied for comparison.
Results
The eight Cryptococcus gattii strains were six VGⅠ and two VGⅡ. The growth curves of Cryptococcus gattii VGⅠ and VGⅡ were similar to that of Cryptococcus neoformans when culture at 30℃. The total number for each of them could reach 108 CFU/ml at 96 h under 30℃. However, the total number at any time point at 37℃ was less than that at 30℃. There was no significant difference in the amount of melanin produced by Cryptococcus neoformans under 30℃ and 37℃, but both VGⅠand VGⅡ types of Cryptococcus gattii could produce more amount of melanin under 37℃ than under 30℃. The ratio of capsule/cell wall diameter of Cryptococcus gattii VGⅠwas greater at 37℃ than that at 30℃ with statistical significance (P<0.001). Cryptococcus neoformans showed the longest LT50, followed by VGⅠand VGⅡ types of Cryptococcus gattii. The LT50 of Cryptococcus gattii VGⅡ at the concentration of 1×106 CFU/ml was 72 h, and its LC50 at 48 h was 1×108 CFU/ml.
Conclusions
Like Cryptococcus neoformans, Cryptococcus gattii VGⅠ and VGⅡ grew faster under 30℃ than under 37℃, but more melanin was produced and thicker capsule was formed under 37℃ than under 30℃. Among Cryptococcus neoformans and VGⅠ and VGⅡ types of Cryptococcus gattii, Cryptococcus gattii VGⅡ showed the shortest LT50 and the strongest virulence to Galleria mellonella.
Key words:
Cryptococcus gattii; Molecular type; Growth characteristics; Galleria mellonella; Virulence
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Galleria mellonella
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Flucytosine
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The in vitro susceptibility profile of 24 clinical isolates of non-Cryptococcus neoformans/non-Cryptococcus gattii Cryptococcus species was analysed. In addition, the susceptibility results of 98 other strains from seven different reports were reviewed. The latter included studies which used antifungal susceptibility testing reference procedures or commercial methods which exhibited high correlation rates with the reference procedures. A total of 122 isolates were analysed (57 Cryptococcus albidus, 39 Cryptococcus laurentii, ten Cryptococcus uniguttulatus, ten Cryptococcus humicola, four Cryptococcus curvatus, and two Cryptococcus luteolus). Amphotericin B was in vitro the most active compound against all species, while flucytosine and candins were inactive. Fluconazole exhibited a limited in vitro activity, particularly against C. albidus, C. uniguttulatus and C. laurentii. Voriconazole, itraconazole and posaconazole were active against most of isolates, but we found significant rates of decreased susceptibility. Identification and susceptibility testing of Cryptococcus spp. should be performed on a routine basis in view of their unpredictable susceptibility profiles.
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