Despite advances in antifungal therapy, the mortality associated with invasive candidiasis remains as high as 40%. A new review article summarizes recent trends and current strategies, including early treatment and the emergence of resistance against triazoles and echinocandins.
Invasive candidiasis is the most common fungal disease among hospitalized patients in the developed world. Mortality among patients with invasive candidiasis is as high as 40%, even when patients receive antifungal therapy. In addition, the global shift in favor of nonalbicans candida species is troubling, as is the emerging resistance to antifungal drugs.
• What are the major risk factors for invasive candidiasis?
The incidence of candidemia is age-specific, with the maximum rates observed at the extremes of age. The presence of central vascular catheters, recent surgery (particularly abdominal surgery with anastomotic leakages), and the administration of broad-spectrum, antibiotic therapy constitute the major risk factors for invasive candidiasis.
Figure 1. Pathogenesis of Invasive Candidiasis.
• Does Candida albicans remain the dominant pathogen?
The species distribution has changed over the past decades. Whereas Candida albicans had previously been the dominating pathogen, this species today accounts for only half the isolates detected in many surveys. C. glabrata has emerged as an important pathogen in northern Europe, the United States, and Canada, whereas C. parapsilosis is more prominent in southern Europe, Asia, and South America. Changes in species distribution may drive treatment recommendations, given the differences in susceptibility to azoles and echinocandins among these species.
Morning Report Questions
Q: What diagnostic tests are available for invasive candidiasis?
A: The armamentarium available for diagnosing invasive candidiasis includes direct detection, in which specimens of blood or tissue from other normally sterile sites are cultured, and indirect detection, in which surrogate markers and polymerase-chain-reaction (PCR) assays are used. No test is perfect, and it is therefore necessary to perform several diagnostic tests to achieve maximal accuracy. Culture is currently the only diagnostic approach that allows subsequent susceptibility testing. The sensitivity of blood cultures is far from ideal, with sensitivity of 21 to 71% reported in autopsy studies. Candida mannan antigens and antimannan antibodies and beta-D-glucan are the primary surrogate markers for invasive candidiasis. The reported performance of assays for these markers varies somewhat according to case mix, the frequency of sampling, and the choice of comparator. Studies that include healthy controls or less severely ill patients may overestimate specificity, since there are many potential sources of contamination of beta-D-glucan testing that can produce false positive results, and these are found more frequently in patients at high risk for candidiasis. The major diagnostic benefit of beta-D-glucan is its negative predictive value for invasive candidiasis in environments in which the prevalence is low to moderate. A number of in-house PCR tests for the detection of invasive candidiasis have been evaluated. However, limited validation and standardization have hindered their acceptance and implementation.
Q: Are echinocandins superior to azoles for the treatment of invasive candidiasis?
A: A pivotal study compared the efficacy of anidulafungin with that of fluconazole. Although the study had been designed to assess the noninferiority of anidulafungin, overall response rates were significantly higher with anidulafungin than with fluconazole (76% vs. 60%; P=0.01). The apparent superiority of anidulafungin over fluconazole was most distinct in patients infected with C. albicans (global response, 81% vs. 62%; P=0.02), even though the C. albicans was almost uniformly susceptible to fluconazole. Inferior outcomes with fluconazole were also observed in patients with low scores (indicating less severe disease) on the Acute Physiology and Chronic Health Evaluation (APACHE II), which suggested that inferior outcomes with fluconazole were not related to severity of illness. Post hoc multivariate analyses have not indicated that the differences in outcome with each drug were related to other confounding factors. Nevertheless, the question of whether a single noninferiority trial can establish the superiority of echinocandins over azoles for the treatment of invasive candidiasis has remained controversial, and opinions among experts in mycology are divided. More recent studies have provided reasonable support, but no formal proof, for the superiority of echinocandins as treatment for the majority of patients with invasive candidiasis. Most notable is the pooled analysis of patient-level data from seven randomized trials that assessed antifungal treatments. With 30-day all-cause mortality used as an unequivocal end point, the most important finding was that randomization to an echinocandin was associated with better survival rates and greater clinical success than treatment with a triazole or amphotericin B. The improved outcomes were most evident among patients infected with C. albicans or C. glabrata. The benefit of echinocandin therapy was observed among patients with APACHE II scores in all but the highest quartiles, suggesting that the survival benefit associated with echinocandin treatment is not limited to the sickest patients.