Azole antifungal agents, and especially fluconazole, have been used widely to treat oropharyngeal candidiasis in patients with AIDS. An increasing number of cases of clinical resistance against fluconazole, often correlating with in vitro resistance, have been reported. To investigate the mechanisms of resistance toward azole antifungal agents at the molecular level in clinical C. albicans isolates, we focused on resistance mechanisms related to the cellular target of azoles, i.e., cytochrome P450 14DM (14DM) and those regulating the transport or accumulation of fluconazole. The analysis of sequential isogenic C. albicans isolates with increasing levels of resistance to fluconazole from five AIDS patients showed that overexpression of the gene encoding 14DM either by gene amplification or by gene deregulation was not the major cause of resistance among these clinical isolates. We found, however, that fluconazole-resistant C. albicans isolates failed to accumulate 3 H-labelled fluconazole. This phenomenon was reversed in resistant cells by inhibiting the cellular energy supply with azide, suggesting that resistance could be mediated by energy-requiring efflux pumps such as those described as ATP-binding cassette (ABC) multidrug transporters. In fact, some but not all fluconazole-resistant clinical C. albicans isolates exhibited up to a 10-fold relative increase in mRNA levels for a recently cloned ABC transporter gene called CDR1. In an azole-resistant C. albicans isolate not overexpressing CDR1, the gene for another efflux pump named BEN r was massively overexpressed. This gene was cloned from C. albicans for conferring benomyl resistance in Saccharomyces cerevisiae. Therefore, at least the overexpression or the deregulation of these two genes potentially mediates resistance to azoles in C. albicans clinical isolates from AIDS patients with oropharyngeal candidiasis. Involvement of ABC transporters in azole resistance was further evidenced with S. cerevisiae mutants lacking specific multidrug transporters which were rendered hypersusceptible to azole derivatives including fluconazole, itraconazole, and ketoconazole.
Background: Candidemia is an opportunistic infection associated with high morbidity and mortality in patients hospitalized both inside and outside intensive care units (ICUs). Identification of patients at risk is crucial to ensure prompt antifungal therapy. We sought to assess risk factors for candidemia and death, both outside and inside ICUs. Methods: This prospective multicenter matched case-control study involved six teaching hospitals in Switzerland and France. Cases were defined by positive blood cultures for Candida sp. Controls were matched to cases using the following criteria: age, hospitalization ward, hospitalization duration, and, when applicable, type of surgery. One to three controls were enrolled by case. Risk factors were analyzed by univariate and multivariate conditional regression models, as a basis for a new scoring system to predict candidemia. Results: One hundred ninety-two candidemic patients and 411 matched controls were included. Forty-four percent of included patients were hospitalized in ICUs, and 56% were hospitalized outside ICUs. Independent risk factors for candidemia in the ICU population included total parenteral nutrition, acute kidney injury, heart disease, prior septic shock, and exposure to aminoglycoside antibiotics. Independent risk factors for candidemia in the non-ICU population included central venous catheter, total parenteral nutrition, and exposure to glycopeptides and nitroimidazoles. The accuracy of the scores based on these risk factors is better in the ICU than in the non-ICU population. Independent risk factors for death in candidemic patients included septic shock, acute kidney injury, and the number of antibiotics to which patients were exposed before candidemia. Discussion: While this study shows a role for known and novel risk factors for candidemia, it specifically highlights important differences in their distribution according to the hospital setting (ICU versus non-ICU). Conclusion: This study provides novel risk scores for candidemia accounting for the hospital setting and recent progress in patients' management strategies and fungal epidemiology.
Twenty-one chlamydospore-forming and germ tube-positive Candida albicans clinical isolates from 15 human immunodeficiency virus (HIV)-positive and 3 HIV-negative patients were examined by two different genetic methods. Multilocus enzyme electrophoresis and hybridization with the C. albicans-specific Ca3 probe showed that such isolates can be split into two genetically distinct groups that can be clearly distinguished. One group mainly contained strains with atypical sugar assimilation patterns and could be distinguished from the other group by the absence of intracellular -glucosidase activity. All 13 strains belonging to this group were isolated from the oral cavities of asymptomatic HIV-positive drug users and may be less pathogenic than the eight strains from the other group isolated either from HIV-positive patients with oropharyngeal candidiasis or from HIV-negative patients with invasive candidiasis.
Invasive candidiasis is associated with high mortality rates, ranging from 35% to 60%, in the range reported for septic shock. The epidemiology and pathogenesis of invasive candidiasis differ according to the patient's immune status; the majority of cases in immunocompromised hosts are candidaemia, whereas non-candidaemic systemic candidiasis accounts for the majority of cases in critically ill patients. In contrast to candidaemia, non-candidaemic systemic candidiasis is difficult to prove, especially in critically ill patients. Up to 80% of these patients are colonized, but only 5-30% develop invasive infection. The differentiation of colonization and proven infection is challenging, and evolution from the former to the latter requires seven to 10 days. This continuum from colonization of mucosal surfaces to local invasion and then invasive infection makes it difficult to identify those critically ill patients likely to benefit most from antifungal prophylaxis or early empirical antifungal treatment. Early empirical treatment of non-candidaemic systemic candidiasis currently relies on the positive predictive value of risk assessment strategies, such as the colonization index, candida score, and predictive rules based on combinations of risk factors such as candida colonization, broad-spectrum antibiotics, and abdominal surgery. Although guidelines recently scored these strategies as being supported by limited evidence, they are widely used at bedside and have substantially decreased the incidence of invasive candidiasis.
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