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PRIORITY PRESS - Critical Care Canada Forum

Toronto, Ontario / November 11-13, 2008

Invasive and septic Candida infections are associated with high levels of mortality and morbidity. However, the agents most commonly used to empirically treat these pathogens are associated with significant drawbacks: there are now high levels of resistance among Candida spp. to fluconazole, and amphotericin B causes significant toxicity.

That is why leading infectious-disease experts are encouraged by the efficacy and cost-effectiveness of the newest agents available to treat candidemia. This is epitomized by the enthusiasm with which Dr. Coleman Rotstein, Professor of Medicine, Division of Infectious Diseases, University of Toronto and Co-director, Transplant Infectious Diseases, Toronto General Hospital, Ontario, discussed the use of echinocandins in the intensive care unit (ICU), where physicians face an uphill battle saving the lives of severely ill individuals.

“Echinocandins are now recommended in the new IDSA (Infectious Diseases Society of America) guidelines for first-line therapy of candidemia in moderately severe to severely ill patients and those with prior azole exposure,” revealed Dr. Coleman. “So in the ICU population, it appears the echinocandins may be the way to go.”

The new IDSA guidelines are expected to be published in January 2009, he added (Pappas et al. Clin Infect Dis 2008;in press). The changes were prompted by the fact that the new echinocandins are associated with lower mortality rates and higher overall response rates than older agents.

Candida Infections a Rapidly Growing Problem in ICU

Candidemia/invasive candidiasis (C/IC) is the most common invasive fungal infection encountered in the hospital setting. The rate of sepsis with fungal infections has been rising “precipitously,” noted Dr. Rotstein, pointing to an article that demonstrates this (Martin et al. N Engl J Med 2003;348:1546-54). Furthermore, the increasingly common problem of C/IC is particularly evident in the ICU.

Candida colonization and infection are associated with prolonged stay in the ICU and in the hospital, and also with increased cost of care (Olaechea et al. Eur J Clin Microbiol Infect Dis 2004;3:323-30). C/IC also leads to significant mortality. Studies indicated that such infections were associated with mortality rates of approximately 40% in the 1990s, but later studies with echinocandins showed they were associated with mortality rates below 30% (Pappas et al. Clin Infect Dis 2007;45:883-93).

“Is this an advance?” asked Dr. Rotstein. “Let’s look at treatment of C/IC in the ICU—what are we going to use now, in 2008? … There are two key principles of treatment. The first concept is, we have to hit it early. If we do not start treatment early, we are going to get higher mortality rates. The second concept is that we have to use adequate therapy. This is particularly true with C/IC.”

One of the medications in the traditional armamentarium for C/IC is amphotericin B. However, this antifungal is associated with severe toxicity, including nephrotoxicity, infusion-related toxicity, hypokalemia, hypomagnesemia and liver-function abnormalities. Liposomal formulations have been developed but these are all substantially more expensive than plain amphotericin B. For their part, azoles have proven effective, particularly fluconazole. However, there are holes in the fluconazole spectrum. The Candida species that have demonstrated resistance to fluconazole include C. glabrata and C. parapsilosis.

Fortunately, echinocandins work against fluconazole-resistant strains. They are broad-spectrum, covering species including C. glabrata, C. tropicans, C. albicans, C. parapsilosis (although this species is slightly less susceptible than the others) and C. tropicalis. In an international trial Dr. Rotstein and his co-investigators randomized 191 patients with C/IC to micafungin 100 or 150 mg/day, and another 150 patients to caspofungin at the standard dose of 70 mg followed by 50 mg daily (Pappas et al. Clin Infect Dis 2007;45:883-93). After an average of two weeks, micafungin was non-inferior to caspofungin, with treatment success rates of 76.4% in the micafungin 100-mg group, 71.4% in the micafungin 150-mg group and 72.3% in the caspofungin group. Echinocandins are also safer, noted Dr. Rotstein. Furthermore, for its part, anidulafungin is not degraded in the liver but rather it is metabolized in the bloodstream. Micafungin has hepatic metabolism and caspofungin has some hepatic metabolism and some renal elimination.

Particularly in the ICU setting where patients are often poly-medicated, “this is a key advantage, because this means there are no known drug-drug interactions with anidulafungin, while there are with micafungin—including sirolimus and nifedipine—and caspofungin—including cyclosporine, tacrolimus, rifampin, efavirenz, nevirapine, phenytoin, dexamethasone and carbamazepine,” explained Dr. Rotstein. “There is also no dose adjustment necessary with anidulafungin in the face of renal failure.”

Key Trial Helps Guide Candida Therapy

A double-blind, randomized, controlled trial of anidulafungin vs. fluconazole in invasive candidiasis, and of which Dr. Rotstein was a co-investigator, has further clarified which therapies to use for these infections, he explained (Reboli et al. N Engl J Med 2007;356:2472-82).

Patients enrolled in the study were 16 years of age or older and had candidemia or another form of invasive candidiasis. Some had prior azole treatment, and most were not neutropenic. The subjects were typical of patients with such infections: they were extremely ill, with hepatic impairment, renal failure or insufficiency, diabetes, and other comorbidities. The modified intention-to-treat analysis involved all patients who received at least one dose of study medication and had a positive culture for Candida species within 96 hours before enrolment.

One hundred and twenty-seven patients were randomly assigned to receive intravenous anidulafungin at a dose of 200 mg on day 1 and then at a daily dose of 100 mg. The other 118 in the modified intention-to-treat analysis were randomized to intravenous fluconazole at 800 mg on the first day of treatment and then 400 mg/day. The medications were administered for 14 to 42 days, and for at least two weeks after a negative blood culture and improvement in signs and symptoms. All patients could take oral fluconazole at the investigators’ discretion after at least 10 days of intravenous therapy.

C. albicans was present in 61.6% of patients. C. glabrata was present in 15.7% of those who received anidulafungin and in 25.4% of those receiving fluconazole (P=0.08). The two groups had smaller but similar proportions of other Candida species.

The primary end point was global response at the end of intravenous therapy. This was achieved by 75.6% (96/127) of the anidulafungin group and by 60.2% (71/118) of the fluconazole subjects (P=0.01). This difference remained statistically significant (P=0.04), in a multivariate logistic-regression model of global response at the end of intravenous therapy that adjusted for parameters including presence of diabetes mellitus, prior azole therapy, catheter removal and infection with C. glabrata.

The echinocandin was also superior to fluconazole in patients with candidemia only, with response rates at the end of intravenous therapy of 75.9% and 61.2%, respectively (P=0.02). Furthermore, a higher proportion of patients with other forms of invasive candidiasis also responded to anidulafungin than to fluconazole, at 72.7% and 53.3%, respectively, as did more of those with an Acute Physiology and Chronic Health Evaluation (APACHE) II score of 20 or more, at 81.2% vs. 61.2%. Overall, it showed statistically significantly greater efficacy at the end of all therapy and at the two weeks follow-up, although at the six-week follow-up the difference met only non-inferiority criteria.

Unpublished data from the trial on subsets of patients on dialysis, with hepatic impairment or on mechanical ventilation also showed superiority of anidulafungin over fluconazole. Results from the 63 ICU subjects in the trial that were presented at the 18th European Congress of Clinical Microbiology and Infectious Diseases indicated that those receiving anidulafungin had a higher response rate, a lower all-cause-mortality rate and shorter ICU stays.

“Therefore, there was a significant difference overall between the two arms, favouring anidulafungin,” concluded Dr. Rotstein. “Overall, the echinocandins generally are efficacious and safe drugs, and anidulafungin appears to be the “cleanest” of this drug class.”