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18th European Congress of Clinical Microbiology and Infectious Diseases (ECCMID)

Barcelona, Spain / April 19-22, 2008

For many years, azoles have been the standard of care for patients with invasive and septic Candida infection. “But the epidemiology of candidiasis is changing, with a potential decrease in susceptibility to these drugs,” according to Prof. Bart-Jan Kullberg, Deputy Chair, Infectious Diseases, and Professor of Medicine, St. Radboud University Nijmegen Medical Centre, The Netherlands. This change has been recognized by the Infectious Diseases Society of America (IDSA), which recently modified the guidelines for first-line treatment of invasive fungal infections in non-neutropenic patients. Newer echinocandins that have demonstrated comparable efficacy against candidemia but superior cure rates against other invasive fungal infections have prompted the change in recommendations.

One of the major problems facing clinicians who manage Candida infections is that the right empiric choice of therapy may have a critical impact on outcome. As Prof. Peter Gaustad, Rikshospitalet University Hospital, Oslo, Norway, pointed out, “It is important to start treatment early because delays can lead to an increase in the mortality of the patients.” Early treatment, i.e. within 12 hours of taking the first blood sample, may significantly reduce mortality from around 40% to 10% to 15%.

While treatment must be given empirically (or even pre-emptively in some cases), the choice of agent must have as wide a spectrum of action as possible. In a review of data from Norway, where an excellent surveillance system is in place, Prof. Gaustad commented, “Twenty per cent of Candida infections are caused by species with potentially decreased susceptibility to fluconazole. This is important to bear in mind when choosing empirical therapy.”

Revised Guidelines to Reflect New Reality

Responding to this and similar data reported from other centres, including those in North America, the IDSA has modified its guidelines. In a review of these modifications, Prof. Georg Maschmeyer, Klinikum Ernst von Bergmann, Potsdam, Germany, reported that echinocandins are now preferred as first-line therapy among non-neutropenic patients who are severely ill or who have received azole prophylaxis when the species is unknown. He noted that treatment can be stepped down from the echinocandin to fluconazole once a pathogen has been isolated that is likely to be susceptible to fluconazole, such as C. albicans or C. parapsilosis, as long as patients are clinically stable. Fluconazole remains favoured for patients who are less clinically ill and who have had no recent azole exposure.

The changes in the guidelines were highly influenced by a multicentre randomized study that was published last year (Reboli et al. N Engl J Med 2007;356:2472-82) that demonstrated a new echinocandin is as effective as an azole against candidemia but is more effective against other forms of invasive fungal infections. In that study, 245 adults with invasive candidiasis were randomly assigned to intravenous (i.v.) formulations of anidulafungin or fluconazole. The primary end point was treatment success at the end of 10 days of i.v. treatment. Although neutropenic patients were not excluded from the study, 97% did not have neutropenia.

When compared for the primary end point, anidulafungin achieved treatment success in 75.6% of patients vs. 60.2% for fluconazole (Figure 1). Although the confidence intervals (CIs) for the 15.4% absolute advantage for anidulafungin over fluconazole also favoured anidulafungin (95% CI 3.9-27.0), the result was considered to be a demonstration of non-inferiority based on study design assumptions. However, outcomes consistently favoured the echinocandin, particularly when patients were stratified for pathogen. In particular, among those with an invasive fungal infection other than candidemia, the treatment success rates were 72.7% vs. 53.3%. Microbiologic success was achieved in 88.1% of those randomized to anidulafungin vs. 76.2%. Overall mortality from any cause was 31% in the fluconazole group and 23% in the anidulafungin group.

Figure 1. Estimates of Survival (modified ITT population)

The Challenges of Starting Empirical Therapy Early

The substantial rates of mortality encountered in this study underscore the need to detect fungal infections early and treat aggressively. In some case series, crude mortality from invasive fungal infections has been as high as 50%. Recurrence of Candida infection is another problem facing those who have to manage infected patients, particularly those who are critically ill and in an intensive care unit (ICU) setting. Risk markers may help guide decisions and one “burning question” is whether colonization by Candida species is useful, according to Dr. Paolo Manzoni, Sant’ Anna Hospital, Turin, Italy.

“The answer is yes,” Dr. Manzoni affirmed, citing a study conducted in his neonatal unit. In a multivariate regression analysis, colonization of central venous catheters (CVCs) and at multiple sites were significantly associated with progression to invasive disease whereas fluconazole prophylaxis provided a protective effect (Manzoni et al. Pediatrics 2006;118:2359-64).

Another question is whether surveillance cultures and knowledge of colonization status can guide the use of “pre-emptive” therapy. “This issue is controversial,” asserted Dr. Manzoni. A recent study did, however, illustrate what can be achieved by systematic surveillance. Acquired candidiasis in a surgical unit was 10% in the two years prior to adoption of pre-emptive therapy when the corrected colonization index was greater than 0.4, whereas after adoption of this strategy, no cases of candidiasis were reported. “Targeted surveillance… is efficacious in preventing acquisition of candidiasis in a surgical intensive care setting,” concluded Dr. Manzoni.

Defining Treatment Success and Choosing the Right Antifungal

Most clinical trials of antifungal agents for Candida infection use primary end points that combine favourable clinical response (resolution of the signs and symptoms secondary to fungal infection) and favourable biological response (eradication), and mortality has been a secondary end point. However, in the view of Dr. Daniel Kett, University of Miami/Jackson Memorial Hospital, Florida, “Our patients really care if they live or die.” In his opinion, “Live or die has to be put into the algorithm” when designing new clinical trials.

He stressed that treating physicians do have options when deciding which drugs to use. “In ICUs where I work, the echinocandins tend to be better drugs and I agree strongly with the new recommendations that in critically ill patients who are more severely ill, you may want to favour an echinocandin as first-line therapy.” Like others, Dr. Kett contended that there is strong evidence to support the new recommendations. In addition to the comparison of anidulafungin to fluconazole, there are comparisons of caspofungin to amphotericin B and micafungin to amphotericin B. In both cases, the echinocandin was favoured. In a randomized study that compared two doses of micafungin and caspofungin (Clin Infect Dis 2007;45:883-93), no differences were found between the two echinocandins. Although anidulafungin has not been compared with other echinocandins in a large clinical trial, one of its potential benefits relative to other agents in its class is that it is not metabolized in the liver and has no known drug interactions. This could make it preferable in patients with hepatic dysfunction or those taking other medications cleared by the liver.

Summary

The nature of Candida infections is changing, and potentially azole-resistant species are becoming more common. New treatment options in the form of echinocandins represent an important advance, although they should be combined with other measures such as early initiation of treatment, replacement of CVC, and possibly assessment of colonization.