Medical Grand Rounds

Update in infectious disease treatment

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Reboli AC, Rotstein C, Pappas PG, et al; Anidulafungin Study Group. Anidulafungin versus fluconazole for invasive candidiasis. N Engl J Med 2007; 356:2472 2482.

In 2002, caspofungin (Cancidas) was the first of a new class of drugs, the echinocandins, to be approved by the FDA. The echinocandins have been shown to be as effective as amphotericin B for the treatment of invasive candidiasis, but how they compare with azoles is an ongoing debate. Currently approved treatments for candidiasis, an important cause of disease and death in hospitalized patients, include fluconazole, voriconazole, caspofungin, and amphotericin B. Anidulafungin is the newest echinocandin and has been shown in a phase 2 study to be effective against invasive candidiasis.

The study. Reboli et al18 performed a randomized, double-blind, noninferiority trial comparing anidulafungin and fluconazole to treat candidemia and other forms of candidiasis. The trial was conducted in multiple centers over 15 months and involved 245 patients at least 16 years old who had a single blood culture or culture from a normally sterile site that was positive for Candida species, and who also had one or more of the following: fever, hypothermia, hypotension, local signs and symptoms, or radiographic findings of candidiasis. Patients were excluded if they had had more than 48 hours of systemic therapy with either of these agents or another antifungal drug, if they had had prophylaxis with an azole for more than 7 of the previous 30 days, or if they had refractory candidal infection, elevated liver function test results, Candida krusei infection, meningitis, endocarditis, or osteomyelitis. Removal of central venous catheters was recommended for all patients with candidemia.

Patients were initially stratified by severity of illness based on the Acute Physiology and Chronic Health Evaluation (APACHE II) score (= 20 or > 20, with higher scores indicating more severe disease) and the presence or absence of neutropenia at enrollment. They were then randomly assigned to receive either intravenous anidulafungin (200 mg on day 1 and then 100 mg daily) or intravenous fluconazole (800 mg on day 1 and then 400 mg daily, with the dose adjusted according to creatinine clearance) for at least 14 days after a negative blood culture and improved clinical state and for up to 42 days in total. After 10 days of intravenous therapy, all patients could receive oral fluconazole 400 mg daily at the investigators’ discretion if clinical improvement criteria were met.

The primary end point was global response at the end of intravenous therapy, defined as clinical and microbiologic improvement. A number of secondary end points were also studied. Response failure was defined as no significant clinical improvement, death due to candidiasis, persistent or recurrent candidiasis or a new Candida infection, or an indeterminate response (eg, loss to follow-up or death not attributed to candidiasis).

Of the 245 patients in the primary analysis, 89% had candidemia alone, and nearly two-thirds of those cases were caused by Candida albicans. Only 3% of patients had neutropenia at baseline. Fluconazole resistance was monitored and was rare.

Findings. Intravenous therapy was successful in 76% of patients receiving anidulafungin and in 60% of fluconazole recipients, a difference of 15.4 percentage points (95% CI 3.9–27.0). Results were similar for other efficacy end points. The rate of death from all causes was 31% in the fluconazole group and 23% in the anidulafungin group (P = .13). The frequency and types of adverse events were similar in the two groups. The authors concluded that anidulafungin was not inferior to fluconazole in the treatment of invasive candidiasis.

Comments. Does this study prove that anidulafungin is the treatment of choice for invasive candidiasis? Although the study noted trends in favor of anidulafungin, the differences did not achieve statistical significance for superiority. In addition, the study included so few patients with neutropenia that the results are not applicable to those patients. Finally, anidulafungin is several times more expensive than fluconazole.

Fluconazole has stood the test of time and is probably still the treatment of choice in patients who have suspected or proven candidemia or invasive candidiasis, unless they have already been treated with azoles or are critically ill. In those settings, echinocandins may be the preferred treatment.

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