US Pharm. 2008;33(5):HS14-HS19.

Candida is a genus of opportunistic pathogens that affect high-risk patients who are immunosuppressed or critically ill. Candidemia affects approximately one in 5,000 patients, with about 60,000 cases of candidemia occurring annually in the United States.1,2 Candida is the fourth-leading cause of nosocomial bloodstream infection today.3 The literature indicates that 8% to 15% of all nosocomial bloodstream infections are caused by Candida species.4 Candidemia carries with it a crude mortality of 40%, which is one of the highest of all nosocomial bloodstream infections. 5 Depending on the population being evaluated, mortality rates range from 57% in surgical patients to 78% in oncology patients.5

The literature suggests that 25% to 50% of nosocomial candidemia occurs in the critical care setting or intensive care unit.3 Symptoms can range from low-grade temperature to systemic inflammatory response with multiorgan failure. The lack of reliable diagnostic tests also makes early detection difficult. Candidemia is associated with higher rates of mortality and morbidity, as well as increased costs, underscoring the need for safer and more effective therapies.2,4 Patients should be evaluated for their risk of developing invasive candidiasis or candidemia, with empiric therapy initiated as quickly as possible (Table 1).6

Candida species are the most common cause of fungal infections, with Candida albicans being the most frequently isolated species.1,3,7 There has been a shift, with non-albicans Candida being responsible for invasive candidiasis in hospitalized patients caused by Candida tropicalis , Candida glabrata, Candida parapsilosis, and Candida krusei . These non-albicans species are becoming an increasing problem, especially in patients with acute life-threatening candidal infections. 1,3,7

Patients developing candidemia, on average, add 10 days to the length of their hospital stay, at a cost of approximately $39,000 per patient.8 The estimated cost (in 1997 U.S. dollars) to treat an episode of candidemia was $34,123 per Medicare patient and $44,536 per private insurance patient. The major cost associated with candidemia is that of increased length of stay.8

A retrospective study by Zaoutis et al estimated the incidence of candidemia in hospitalized children and adults in the U.S. in 2000.9 In adult patients, candidemia was associated with a mean 10.1-day increase in length of stay and a mean increase of hospital charges of $39,331 (ranging from $33,604 to $45,602).

The Infectious Diseases Society of America (IDSA) recommends fluconazole (Diflucan) as an option for initial treatment of presumed Candida infections.7 Other therapies include amphotericin B (Ambisome, Amphocin, Fungizone), caspofungin (Cancidas), flucytosine (Ancobon), itraconazole (Sporanox), and voriconazole (VFEND). The decision of which agent to choose should depend on the local epidemiology of the specific institution, the patient's clinical status, prior exposure to azole compounds, and the potential for drug-induced toxicities that compromise the outcome.7 This review will focus on fluconazole.

Fluconazole is a member of the azole family, which inhibits the synthesis of ergosterol of the fungal cell membrane.10 In vitro, the azoles are fungistatic against Candida species. Fluconazole is available as IV and oral formulations. Oral fluconazole is very well absorbed, and the bioavailability is greater than 90%. 11 Studies have shown that fluconazole 400 mg daily and amphotericin B deoxycholate showed similar efficacy as empirical treatment for candidemia in neutropenic and nonneutropenic patients, with fluconazole being associated with fewer side effects (Table 2).10,12-14

Most of the adverse effects associated with fluconazole are mild to moderate in severity. The most common treatment-related adverse events reported were headache, nausea, vomiting, diarrhea, and abdominal pain. Fluconazole has been associated with rare cases of serious hepatic toxicity, which has usually been reversible on discontinuation of therapy.11

In patients with impaired renal function, the dose of fluconazole may need to be reduced because the drug is primarily cleared by renal excretion. It may be useful to monitor renal function, especially in elderly patients.11

Major Studies
Zerr et al conducted a meta-analysis comparing amphotericin B deoxycholate and fluconazole.15 The meta-analysis attempted to summarize the efficacies of fluconazole and amphotericin B deoxycholate in treating invasive candidiasis. They found no statistically significant differences with respect to mortality. The authors found a statistical trend favoring amphotericin B deoxycholate with respect to clinical failure. Unfortunately, the individual trials included in the analysis and the meta-analysis were not powered to detect a difference of clinical failure.

The National Committee for Clinical Laboratory Standards developed standardized reproducible and clinically relevant susceptibility testing methods for fungi.16 Data-driven interpretive breakpoints using this method are available for testing the susceptibility of Candida species to fluconazole, itraconazole, and flucytosine (Table 3).17-20 The interpretive breakpoints place a strong emphasis on interpretation in the context of the delivered dose of the azole antifungal agent. The category susceptibility-dose/delivery dependent (S-DD) indicates that maximization of the dose and bioavailability are critical to a successful outcome (minimum inhibitory concentration [MIC] 16-32 mcg/mL). For fluconazole, data for both humans and animals suggest that S-DD isolates may be treated successfully with a dose of 12-mg/kg daily (800 mg daily for a 70-kg patient).19,21

Animal studies have demonstrated that the ratio of the area under the concentration-time curve (AUC) to the MIC best predicts the response to fluconazole therapy.22,23 This observation has potential clinical relevance since the AUC of fluconazole in healthy adults is virtually identical to the daily dose in milligrams.23 Rex et al demonstrated that a fluconazole dose to 48-hour MIC ratio of less than 25 correlated with an increased likelihood of therapeutic failure.17,18,24

A study by Clancy et al tested 32 Candida isolates from blood cultures of patients with candidemia for in vitro susceptibility to fluconazole and determined if the MIC and/or the daily dose of fluconazole to MIC ratio correlated with the response to therapy. Eighty-seven percent of patients were treated with 200 mg or less of fluconazole daily, which contributed to a therapeutic failure in 53% of the cases (17/32).25 Clancy's study revealed that a dose to MIC ratio greater than 50 was associated with a success rate of 74% (14/19) compared to 8% (1/13) for a dose to MIC ratio less than or equal to 50. The therapeutic success rate among patients infected with susceptible isolates (MIC ?8 mcg/mL) was 67% (14/21), susceptible-dose dependent (MIC 16-32 mcg/mL) was 20% (1/5), and resistant (MIC ?64 mcg/mL) was 0% (0/6).25

In another study, 20 solid-tumor transplant patients with candidemia were treated with 600 or 800 mg of fluconazole daily. Three of the patients had isolates with an MIC of 32 mcg/mL (one patient) and an MIC of 64 mcg/mL (two patients). The only patient in the study who failed therapy was receiving 600 mg daily and had an isolate with an MIC of 64 mcg/mL.26

Munoz et al showed that three patients with candidemia and infected with sensitive dose-dependent isolates with an MIC of 16 mcg/mL were treated with 200 to 400 mg of fluconazole and failed to respond.27 This would suggest that to achieve a dose to MIC ratio of greater than 50, the minimum dose of fluconazole should be 6 mg/kg (400 mg for a 70-kg patient) and preferably 12 mg/kg (800 mg for a 70-kg patient) for isolates with S-DD (MIC 16-32 mcg/mL).

Mortality has been shown to increase in patients with candidemia who receive inappropriate fluconazole therapy. Garey et al performed a retrospective cohort study of patients with candidemia who were prescribed fluconazole at the onset of candidemia or later. 28 Total cost was lowest for patients receiving an adequate dose of fluconazole on the day of fungal cultures. After controlling for covariates, each one-day delay in fluconazole therapy was associated with increased total hospital costs, and an adequate fluconazole dose was associated with decreased total hospital costs.28 A delay or an inadequate dose in patients with candidemia was associated with increased hospital costs. Inappropriate antimicrobial therapy has been shown to be an important independent risk factor for mortality among hospitalized patients with serious infection, including bloodstream infections.29,30 Changing empiric antimicrobial therapy to an appropriate regimen after identification of a microorganism and its susceptibility does not improve clinical outcomes. 31,32 A study by Morrell et al demonstrated that the administration of appropriate antifungal therapy more than 12 hours after the first positive culture is drawn is associated with hospital mortality.33

These studies suggest that administration of appropriate empiric therapy (drug and dose) to patients with serious infections including candidemia should be initiated as soon as possible.

The IDSA recommends fluconazole as an option for initial therapy of presumed candidemia. It also recommends a dose of at least 6-mg/kg daily (12-mg/kg daily for S-DD isolates). Clancy's data suggest that both fluconazole MIC and dose to MIC ratio correlate with the therapeutic response to fluconazole in patients with candidemia. Since candidemia is associated with increased cost and mortality, the dose of fluconazole in patients at risk for developing candidemia should be 6- to 12-mg/kg daily (400-800 mg daily). Patients unable to receive high-dose fluconazole (e.g., patients with renal insufficiency) should receive an alternate antifungal agent.

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