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17th European Congress of Clinical Microbiology and Infectious Diseases

Munich, Germany / March 31-April 3, 2007

The epidemiology of candidemia is complex and varies among the different patient care units. The increase in non-albicans Candida (NAC) species in hospitalized patients over the last decade is a major challenge for clinicians largely because of differences in the susceptibility of these species to antifungal agents. Increased awareness of risk factors for NAC is important to guide adequate initial antifungal therapy and to select the most effective treatment for persistent and recurrent infection.

Changing Epidemiological Trends

Candidemia is one of the most common nosocomial bloodstream infections and the incidence due to NAC is increasing in all age groups, especially in the elderly. It is associated with a high mortality rate (30 to 40%), extends the length of hospital stay and increases the costs of medical care. Patients in intensive care units (ICUs) with severe underlying illness are at highest risk due to mechanical ventilation, indwelling central catheters, total parenteral nutrition and urinary catheters. In surgical ICU patients, triple-lumen catheters, complicated abdominal wounds and the need for renal replacement therapy facilitate the emergence of candidemia. “The challenge is to carefully distinguish between mortality solely attributable to candidiasis and mortality predominantly attributed to the severe underlying disease,” stated Dr. Georg Maschmeyer, Professor of Internal Medicine, Klinikum Ernst von Bergmann, Potsdam, Germany. “The distribution pattern of Candida isolates from patients with invasive candidiasis must be critically examined at each institution before conclusions for antifungal algorithms can be drawn.” As the increase in these NAC organisms may be due to the widespread use of fluconazole for prophylaxis or early empirical treatment of candidiasis, newer agents such as voriconazole and the promising class of echinocandins (anidulafungin, caspofungin, micafungin) have become the preferred treatment option either in monotherapy or in combination regimens.

Echinocandins

Echinocandins are large lipopeptide molecules that inhibit beta-glucan synthesis, thereby damaging the fungal cell wall, which is rapidly lethal in most Candida species. Echinocandins also appear to be active against biofilm-embedded organisms that are resistant to triazoles and could be important in the treatment of chronic recurrent mucocutaneous or device-associated Candida infections. “Studies have shown that 0.5 µg/mL of echinocandins completely kill device-associated infections,” indicated Russell Lewis, PharmD, Assistant Professor, University of Texas M.D. Anderson Cancer Center, Houston.

All three echinocandins are widely distributed after intravenous administration. Caspofungin and micafungin are eliminated through hepatic metabolism, and anidulafungin by chemical degradation. The relatively long elimination half-life allows for once-daily dosing. In animal models, echinocandin activity is maximized when the plasma drug Cmax:minimum inhibitory concentration (MIC) ratio approaches 10 or when the plasma or tissue 24-hour area under the curve concentration: MIC is greater than 250. The persistent tissue retention resulting in continuous decline in the fungal burden suggests that echinocandins could be administered less frequently and also that a higher dose may be as effective as daily dosing regimens. “Further investigation is required to evaluate the effects of extended-interval, high-dose echinocandin regimens on both the fungus and the host, in light of observations from animal studies suggesting that high doses may be associated with major bleeding and a paradoxical increase in fungal burden,” added Dr. Lewis.

Candida Infections in ICU Patients

“Invasive candidiasis is the third leading infection in ICU patients and is associated with considerable morbidity, mortality and healthcare expenditure due to the potential of Candida bloodstream infection to produce more acute respiratory failure, ventilatory dependence and prolonged ICU stay,” stated Dr. Coleman Rotstein, Professor of Medicine, McMaster University, Hamilton, Ontario. Guidelines from the Infectious Diseases Society of America state that the mainstays of therapy are fluconazole and amphotericin B. Fluconazole can be administered either intravenously or orally and therefore it can be useful as a step-down agent. However, it is inactive against C. krusei and less active against C. glabrata and would likely require higher doses. The nephrotoxicity associated with amphotericin B limits its use and efficacy.

A study of outcomes using different treatment strategies has shown that amphotericin B alone, fluconazole alone and amphotericin B combined with fluconazole were associated with 40% mortality, and amphotericin B combined with caspofungin with 32% mortality. Voriconazole, a triazole, has shown enhanced activity against Candida species, including those resistant to fluconazole.

Dr. Mamie Hui, Department of Microbiology, Chinese University, Hong Kong, presented a study of the in vitro activities of fluconazole and voriconazole against invasive Candida species. Among the total of 84 isolates, 27 were C. parapsilosis, 32 were C. tropicalis, and 25 were C. glabrata. All C. parapsilosis were susceptible to fluconazole and voriconazole. Only 10 isolates (40%) of C. glabrata were susceptible to fluconazole, 12 (48%) showed decreased susceptibility, and three (12%) were resistant, whereas 24 (96%) were susceptible to voriconazole, which was significantly more active (P<0.05). Both agents had similar activity against C. tropicalis. These findings show that activity between antifungals differs and susceptibility testing is warranted to guide the choice of antifungal agents and to closely monitor resistance trends.

The new echinocandins anidulafungin and micafungin have become established in the treatment of candidemia/invasive candidiasis following the results of recent randomized clinical trials demonstrating that this therapeutic class is effective and safe with a very low potential for drug interactions.

The clinical status of the patient is also very important when making treatment decisions. “If a patient is stable, the Candida species is known and the strain is susceptible to fluconazole, then fluconazole, an echinocandin, or voriconazole should be used as first-line therapy. In patients with hemodynamic instability, infection due to C. glabrata, C. krusei or an unknown Candida species, and/or prior azole therapy, an echinocandin is the treatment of choice for initial therapy, with amphotericin B or voriconazole as second choice,” recommended Dr. Rotstein.

Findings from Clinical Studies on Candidemia

The expanding choice of antifungals currently available is reflected in the large number of studies that have been published comparing the efficacy and safety of the different treatments for candidemia/invasive candidiasis. However, randomized trials of antifungal agents have used a variety of study designs and end points which make direct comparison of outcomes between studies difficult. “Pitfalls include the choice of comparator and whether the study is reporting equivalent efficacy or treatment superiority and is adequately powered to demonstrate equivalence,” enumerated Dr. Bart-Jan Kullberg, Professor of Medicine and Infectious Diseases, Radboud University, Nijmegen, The Netherlands. Studies using amphotericin B as the comparator are only significantly different due to adverse events related to toxicity which drives the reported difference between treatments. Indeed, the agents have the same efficacy but differ in toxicity. “Also, in a study comparing anidulafungin and fluconazole, the difference was driven by C. albicans,” observed Dr. Kullberg.

Summary

An increasing number of patients are at high risk of invasive candidiasis, which is an important cause of morbidity and mortality. Although several treatment options for candidemia are currently available, activity of these agents differs and selection of the most appropriate treatment regimen is challenging. Amphotericin B is associated with significant dose-limiting nephrotoxicity and infusion-related reactions. Fluconazole has increasingly limited activity against Candida species other than C. albicans. Voriconazole has a wider antifungal spectrum and is better tolerated. Echinocandins are a promising choice in the management of serious and difficult-to-treat invasive fungal infections due to rapid onset of activity, predictable pharmacokinetics, and greater tissue penetration which prolongs activity. Susceptibility testing is warranted to guide the choice of antifungal agents and resistance trends should be closely monitored.