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MEDICAL FRONTIERS - 48th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC)/Infectious Diseases Society of America 46th Annual Meeting (IDSA)

Washington, DC / October 25-28, 2008

Invasive fungal infections represent important causes of morbidity and mortality in multiple patient populations, including those with neutropenia who receive chemotherapy for cancer or who undergo hematopoietic stem-cell transplant (HSCT). Amphotericin B and its lipid formulations, the triazoles (fluconazole, itraconazole, voriconazole) and the echinocandins (caspofungin, micafungin, anidulafungin), are options for therapy of invasive fungal infections. As well, caspofungin has shown efficacy in patients with persistent fever and neutropenia. The echinocandins act by noncompetitively inhibiting the synthesis of fungal cell wall 1,3-beta-D-glucan and are generally better tolerated than amphotericin B and the triazoles. For example, amphotericin B is associated with renal and infusion-related toxicity.

Among the topics in mycology explored here during the scientific sessions were the use of echinocandins for the treatment of invasive candidiasis, the treatment of invasive aspergillosis, as empiric therapy, and for pediatric patients. In addition, the selection of appropriate candidates for antifungal prophylaxis and empiric therapy in critically ill patients was examined.

Approaches to Invasive Aspergillosis

Primary therapy for invasive aspergillosis has not yet included echinocandins because of the lack of studies conducted for this indication, stated Dr. Kieren Marr, Director, Transplant and Oncology Infectious Diseases, Johns Hopkins University, Baltimore, Maryland. Caspofungin has previously been proven successful as salvage therapy for invasive aspergillosis. A potentially important mechanism of caspofungin against Aspergillus fumigatus is modulation of inflammatory responses by alteration of the fungal beta-glucan surface content, she explained. It has been found to reduce secretion of inflammatory cytokines by murine bone marrow-derived macrophages.

Invasive pulmonary aspergillosis is present in up to 30% of HSCT recipients and is often fatal. The management in this patient population with standard doses of voriconazole is problematic because of the variability of voriconazole plasma levels and potential voriconazole toxicity, noted Dr. Marr. In HSCT recipients, she cited two approaches that are valid in cases of voriconazole failure: one approach is to increase the dose of voriconazole (depending on the original dose) and add an echinocandin: the other alternative is to use a lipid formulation of amphotericin B.

Prof. Raoul Herbrecht, Strasbourg University Hospital, France, presented data here showing that caspofungin is effective as primary monotherapy of mycologically documented invasive aspergillosis. The results were obtained in an open-label study of 24 patients undergoing allogeneic HSCT who were treated with caspofungin for a median duration of 24 days. At the end of treatment, 10 of 24 (42%) had a favourable outcome, defined as a complete or partial response. In follow-up out to 84 days after treatment onset, eight of 24 (33%) assessable patients had a complete or partial response. None of the patients experienced a drug-related serious adverse event or discontinued treatment because of toxicity.

“Caspofungin should be further assessed in the treatment of invasive aspergillosis in this setting of severe immunosuppression related to HSCT,” Prof. Herbrecht concluded.

Highly Active Against Candida spp

As explained by Dr. Coleman Rotstein, Professor of Medicine and Director, Division of Infectious Diseases, University of Toronto, Ontario, as a class, the echinocandins are highly active against Candida spp and are very active against C. parapsilosis and C. lusitaniae. “In particular, they are highly active against fluconazole-resistant strains of Candida,” he noted.

In the treatment of patients with invasive candidiasis and a subset with candidemia, there was a trend toward more successful clinical outcomes with caspofungin than with amphotericin B, with fewer drug-related adverse events in caspofungin-treated patients, Dr. Rotstein observed (Mora-Duarte et al. N Engl J Med 2002; 347(25):2020-9).

Anidulafungin has been shown more efficacious than fluconazole in the treatment of invasive candidiasis and may eradicate Candida from the bloodstream faster than fluconazole, he noted (Reboli et al. N Engl J Med 2007;356(24):2472-82). Clinical trials appear to show a difference in persistence of Candida between the echinocandins, with fewer episodes of persistence with micafungin and anidulafungin compared with caspofungin, he added.

Considerations for ICU Prophylaxis Against Candida

Delays in therapy for invasive candidiasis are associated with an increased risk of mortality, therefore prophylactic therapy has been proposed. A difficult question is the selection of appropriate patients in the intensive care unit (ICU) for prophylaxis against invasive candidiasis.

A broad-based algorithm for prophylaxis against invasive candidiasis in the ICU was suggested by Dr. Thierry F. Calandra, Professor of Medicine and Head, Infectious Disease Service, Department of Medicine, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland. He considers prophylaxis in patients who have been in the ICU for more than three days. “I am more concerned if they are colonized [with Candida] at one or more sites and if they remain with fever despite broad-spectrum antibiotics. If the patient is deteriorating, I consider adding an antifungal agent and then I wait for the results from the microbiology lab, and I may continue with the antifungal depending on the clinical situation.”

A clinical prediction rule for nosocomial invasive candidiasis had been created by investigators at the University of Texas Health Science Center at Houston. The prediction rule consists of any of the following: fever, hypothermia, hypotension or leukocytosis, plus the placement of a central venous catheter, mechanical ventilation and treatment with antibiotics on days 1 to 3 of ICU stay, and any of the following: parenteral nutrition on days 1 to 3, dialysis on days 1 to 3, major surgery the week prior to ICU admission, the development of pancreatitis the week prior to ICU stay, or treatment with systemic steroids or other immunosuppressants prior to ICU stay.

In applying this rule prospectively to 649 cases from sites in Switzerland, France, the US and Australia, they found that its predictive accuracy was 68%. Applying the rule found a rate of invasive candidiasis of 4.7% and would result in the use of prophylaxis in 32%, explained Dr. Luis Ostrosky-Zeichner, Mycosis Study Group and Professor of Medicine, University of Texas at Houston. By adding colonization of Candida spp identified from routine clinical cultures of nonsterile sites, the rule’s predictive accuracy could be improved to 87%. This addition identified a rate of invasive candidiasis of 9.3% and resulted in the treatment of only 13% of ICU patients.

Empiric Antifungal Therapy

When used as empiric antifungal therapy in patients with persistent fever and neutropenia, successful outcomes occurred with similar frequency between caspofungin and amphotericin B, but a significantly higher proportion of patients with baseline fungal infections had successful outcomes with caspofungin compared with amphotericin B (51.9% vs. 25.9%; P=0.04) and seven-day survival was significantly higher in the caspofungin group (92.6% vs. 89.2%; P=0.05), reported Dr. Rotstein (Walsh et al. N Engl J Med 2004; 351(14):1391-402). Further, nephrotoxic events were significantly fewer in the caspofungin arm.

In a trial that included both adults and pediatric patients, micafungin proved more efficacious than fluconazole for prophylaxis of invasive fungal infections during neutropenia in patients undergoing HSCT (van Burik et al. Clin Infect Dis 2004;39(10):1407-16). “There were fewer treatment failure with micafungin and a trend toward fewer aspergillosis infections with micafungin, which does not come as a surprise,” Dr. Rotstein told delegates. The overall efficacy in this study was 80% in micafungin-treated patients and 73% in fluconazole-treated patients (P=0.03).

High Activity Against Invasive Aspergillosis

According to Dr. Rotstein, the echinocandins are “very active” against Aspergillus spp. Caspofungin has demonstrated utility as salvage therapy for invasive aspergillosis. In a key study of patients who were refractory to or intolerant of amphotericin B, lipid formulations of amphotericin B or triazoles, 45% had a favourable response to caspofungin therapy and only two of 83 patients discontinued due to caspofungin-related toxicity (Maertens et al. Clin Infect Dis 2004;39(11):1563-71). He referred to the success of caspofungin in the treatment of invasive aspergillosis in HSCT recipients as evidence of efficacy as primary therapy as seen in Prof. Herbrecht’s presentation.

Among neutropenic patients with documented invasive candidiasis or invasive aspergillosis who were treated with caspofungin, 58% of patients with invasive candidiasis had a favourable response to caspofungin primary therapy and 100% to salvage therapy, and 42% of patients with invasive aspergillosis had a favourable response when caspofungin was used as primary therapy and 38% had a favourable response when used as salvage therapy (Betts et al. Cancer 2006;106(2):466-73).

Dr. Rotstein remarked that “micafungin is reasonably comparable to caspofungin” for the treatment of invasive aspergillosis, pointing to data demonstrating a 36% response rate with micafungin in an open-label trial of 331 patients with proven or probable Aspergillus spp infection (Denning et al. J Infect 2006;53(5):337-49).

Formulary Selection

In addition to activity against invasive fungal species and clinical efficacy, selecting an echinocandin for inclusion on drug formularies relies on pharmacokinetic/pharmacodynamic data, toxicity and the potential for drug interactions, stated Dr. Rotstein, who reviewed each of these parameters.

He noted that of the echinocandins, caspofungin has the most clinical indications: the primary treatment of invasive candidiasis/candidemia and other Candida infections (intra-abdominal abscesses, peritonitis and pleural-space infections), the primary treatment of esophageal candidiasis, the treatment of invasive aspergillosis that is refractory to or intolerant of other antifungal therapy, and as empiric antifungal therapy for episodes of febrile neutropenia. “The echinocandins are very safe agents,” confirmed Dr. Rotstein. “Hematologic abnormalities occur in less than 5% of patients treated with an echinocandin.” Elevations in liver enzymes are apparent in 11% to 24% of patients treated with caspofungin, he noted.

One caveat with the use of micafungin is the formation of hepatic tumours in rats after three months of therapy, and a warning of the possibility of liver tumours in patients with persistent elevations of transaminases, he added. All of the echinocandins demonstrate concentration-dependent killing, Dr. Rotstein continued. The unique elimination profile of anidulafungin (via the fecal route) means that no dose adjustment is necessary in patients with renal or hepatic impairment. In contrast, caspofungin is metabolized in the liver, “necessitating alteration of dose in the face of hepatic dysfunction,” he said. There are also no known drug interactions with anidulafungin, whereas caspofungin interacts with cyclosporine (and potentially tacrolimus) and micafungin can increase sirolimus concentrations. Overall, however, the few drug interactions with the echinocandins make combination treatment with other antifungals possible (i.e. salvage therapy).

None of the echinocandins interact in a significant manner with the cytochrome P450 enzyme system and therefore drug interactions are few. Dr. Rotstein did note that concomitant use of cyclosporine and caspofungin was associated with more frequent increases in liver enzymes compared with cyclosporine alone.

Pediatric Antifungal Therapy

Caspofungin is the only echinocandin approved for use in children, noted Dr. Theoklis Zaoutis, Assistant Professor of Pediatrics and Epidemiology, University of Pennsylvania, Philadelphia. Its pharmacokinetics and pharmacodynamics support a 50 mg/m² daily dosing regimen, investigators reported. They collected pharmacokinetic/pharmacodynamic and safety data from four studies of children and adolescents (three months to 17 years of age) who received empiric therapy for persistent fever and neutropenia. The analysis revealed that clinical adverse experiences and/or clinically significant laboratory abnormalities were not increased by higher caspofungin plasma concentrations over the various pharmacokinetic parameters examined. Drug interaction screening did not identify any medications that altered caspofungin pharmacokinetics in pediatric patients.

Dr. Zaoutis made mention of a study presented during the ICAAC 2007 sessions, in which caspofungin was compared with liposomal amphotericin B as empiric therapy in 82 children aged two to 17 years who had persistent fever and neutropenia. In a modified intention-to-treat analysis, the overall treatment success rate was 41% with caspofungin and 28% with liposomal amphotericin B, although the difference was not significant. Serious drug-related effects were more common with amphotericin (11%) than caspofungin (2%), although this difference was also not significant.

In an open-label noncomparative trial of caspofungin in pediatric patients with documented invasive fungal infection, favourable responses were obtained in 30 of 37 (81%) patients with invasive candidiasis, one of one patient with esophageal candidiasis and five of 10 (50%) patients with invasive aspergillosis, he reported. As noted previously, micafungin was more efficacious than fluconazole for prophylaxis of invasive fungal infections during neutropenia in a study that included both adults and pediatric patients undergoing HSCT. “The treatment success [in children] mirrored the pattern in adults,” noted Dr. Zaoutis.

Among children with invasive candidiasis or candidemia, success rates were similar between micafungin and liposomal amphotericin B, and discontinuation of study drug due to adverse events was less frequent in the micafungin group (3.8% vs. 16.7%; P=0.052) (data presented at ECCMID/ICC 2007). Despite the promising data with micafungin in pediatric patients, “it should only be used in children if other antifungals are inappropriate,” Dr. Zaoutis told delegates.