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This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

PRIORITY PRESS - 48th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy/The Infectious Diseases Society of America 46th Annual Meeting

Washington, DC / October 25-28, 2008

Candida isolates are the third most commonly identified bloodstream pathogens (Wisplinghoff et al; Clin Infect Dis 2004;39:309-17). Antifungal resistance is becoming a major problem, as reflected in the literature of the past 10 to 15 years. Primary (intrinsic) resistance is exacerbated by secondary (acquired) resistance and thus is mediated by secondary resistance factors such as previous use and compliance, as well as disease burden.

Molecular mechanisms of resistance have been described for the azole class of drugs. The reported rate of refractory disease to fluconazole treatment for C. albicans starts in the range of 5% (Sobel JD, Vasquez JA. Contemporary Diagnosis and Management of Fungal Infections. 2nd ed. In: Handbook in Health Care, 2007:76) and is higher for less common Candida organisms. There is emerging evidence of some cross-resistance by class.

In light of these findings reported by centres in Europe and North America, the Infectious Diseases Society of America (IDSA) last year modified its guidelines to recommend echinocandins as the first-line therapy against invasive and septic Candida infections among non-neutropenic patients who are severely ill or who have received azole prophylaxis when the Candida species is unknown. Treatment can be stepped down from the echinocandin to fluconazole in clinically stable patients once a pathogen likely to be susceptible to fluconazole, such as C. albicans or C. parapsilosis, has been isolated. Fluconazole remains a first-line antifungal defense for patients who are less ill and without recent azole exposure.

The mechanism of action is noncompetitive inhibition of glucan synthase, an enzyme responsible for producing (1,3)²-D-glucan, which is a key component of the cell wall in susceptible fungi. Importantly, mammalian cells do not exhibit (1,3)²-D-glucan.

As the newest of the three echinocandin agents, anidulafungin is the only one approved on the basis of a direct comparison with fluconazole on treatment efficacy whereas both caspofungin and micafungin were approved on the basis of comparisons with amphotericin B. The results of a multicentre randomized trial published last year showed anidulafungin to be as effective as fluconazole against invasive candidiasis (Reboli et al. N Engl J Med 2007;356:2472-82).

Microbiologic success was observed for 88.1% of baseline pathogen in the experimental group receiving anidulafungin vs. 76.2% of controls (P=0.02) and global response was 77% vs. 61%, respectively (P=0.01).

Of 47 participating centres, one site achieved a striking disparity in treatment effect (i.e. 93.35% global treatment success with anidulafungin vs. 50% with fluconazole). Although the primary analysis did not show evidence of a centre effect, the investigators, in keeping with the study design, corrected for that possibility by removing this subset (n=25) from the reported results, which led to the representation of anidulafungin as “non-inferior” rather than “superior” to fluconazole.

Dr. Coleman Rotstein, Professor of Medicine, Division of Infectious Disease, University of Toronto and Co-director, UHN-Transplant/Infectious Diseases Centre, Ontario, was second author on the published trial and lead investigator at that site. Here at ICAAC, he discussed the echinocandins now available in Canada and the US.

“Anidulafungin is a very safe agent and comparable to caspofungin and micafungin for Candida infections, both candidemia and invasive candidiasis,” he told the audience. Its longer half-life makes it attractive from a pharmacokinetic standpoint, and “of the three, it has probably the best safety profile,” he added. It is unique from the other two drugs in the class in that it is broken down in the blood stream as opposed to the liver, thus obviating concerns about hepatic function. Study data showed that it posed no risk of drug interactions. “It’s the cleanest of the three,” Dr. Rotstein indicated.

He characterized anidulafungin as “not only safe, but efficacious.” Referring back to the pivotal study, he noted that the analysis of results, as published under the efficacy section of the article, did show superiority in a statistical sense.

“Our primary end point included everybody,” he explained. “We demonstrated quite clearly that anidulafungin was superior to flucanozole and [that] our analysis showed no centre effect. But we removed those 25 patients and still found the drug to be non-inferior— it still worked,” he mentioned. “It was a hoop we had to jump through. The most important thing was to get the data out.”

The Reboli trial showed anidulafungin to be effective against a broad range of Candida pathogens. Anidulafungin recipients exhibited a higher rate of successful global response for every pathogen except C. parapsilosis. The difference in global response rate was most striking for C. albicans, where there was 81.1% treatment success with anidulafungin vs. 62.3 % with the fluconazole group (P=0.02). Global response rates for C. glabrata infections were similar (56.3% with anidulafungin vs. 50.0% with flucanazole) and treatment groups were too small to show significance.

New Research Helps Differentiate Candida Infections

The literature reflects attempts to guide initial empiric therapy by distinguishing among clinical characteristics of infection with C. albicans vs. non-albicans species, with the latter types presumed to be at risk for fluconazole resistance.

At ICAAC, Carver et al. reported on a retrospective cohort study reviewing all MICs, therapy and outcomes for C. glabrata fungemias treated at the University of Michigan Medical Center from January 2003 to June 2007. Of 477 infections involving Candida species organisms, 244 stemmed from C. albicans (51%) and 100 from C. glabrata (21%).

MICs and susceptibility data were not available to clinicians at the time of therapy but were later used to assess appropriateness of therapy. For fluconazole and voriconazole, resistance was 14.7% and 12%, respectively. Prior fluconazole use (within 30 days) was associated with increased azole MICs.

Despite high resistance rates to fluconazole, 56 patients (29.5%) were treated initially with fluconazole (32 inappropriately). In 28 cases, treatment was changed to an echinocandin within five days. Thirteen patients remained on their initial therapy. The overall mortality rate in this study was 46.9%.

Global Variations in Candida Species Prevalence

Other findings reinforced the efficacy of echinocandins as a class and anidulafungin, in particular, against specific Candida pathogens worldwide. An international surveillance study reported by Moet et al., North Liberty, Iowa, analyzed a total of 1448 Candida specimens from infected sterile-site sources in patients from North America, Europe, Latin America, and the Asia Pacific region, and susceptibility tested. MICs for anidulafungin, caspofungin, 5-fluorocytosine, fluconazole, itraconazole, posaconazole, voriconazole and amphotericin B were determined using CLSI reference methods.

The rank order of CSP occurrence was: C. albicans (53.4%), C. parapsilosis (16.4%) C. glabrata (13.9%), C. tropicalis (10.8%), C krusei (2.0%) and other (3.5%). C. albicans accounted for 46% of Candida infections in North America, 60.8% in Europe, 42.1% in Latin America, and 50.0% in the Asia-Pacific region (Abstract M-2200). The results showed that anidulafungin was more active when compared with fluconazole, itraconazole and posaconazole against C. albicans, C. glabrata, C. tropicalis and C krusei, and was less active against C. parapsilosis. There was no difference in results by geographic region. Findings were largely unchanged from an earlier surveillance study undertaken by the same researchers and showed no evidence of emerging anidulafungin resistance among more recent clinical isolates.

Dr. Oluwadamilola Adeyemi and colleagues, Northwestern University Feinberg School of Medicine, Chicago, Illinois, showed a significant increase in the proportion of patients infected with C. albicans vs. other Candida infections (P=0.008) over a 10-year period from January 1998 through December 2007 (Abstract K-1390). The retrospective study used microbiologic data from all 648 adult patients hospitalized with candidemia from a single Candida species during that period. Patients infected with multiple Candida species or who had recurrent episodes of candidemia over the study period were excluded. The study pointed to a high all-cause mortality rate of 38% from single-source candidemia; however, the proportion of patients who died decreased over time (P=0.051). Their analysis provided no information about treatment approaches.