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44th Annual Meeting of the Infectious Diseases Society of America

Toronto, Ontario / October 12-15, 2006

Antifungal prophylaxis may be considered in a variety of patient populations but the key feature that characterizes those who should be considered is their level of risk. For example, not all patients who develop neutropenia need antifungal prophylaxis, the duration and severity of the neutropenic episode dictating whether a patient requires prophylactic therapy. As discussed by Dr. Jack Sobel, Professor of Infectious Disease, Wayne State University School of Medicine, Detroit, Michigan, in the short term, the target fungus is likely to be Candidiasis but over the long term, prophylactic measures should be targeting moulds.

The most widely used of the antifungals in the setting of neutropenia is fluconazole 100 to 400 mg/day, itraconazole being used less often due to a poorer tolerability profile. As Dr. Sobel indicated, voriconazole and posaconazole are not traditionally used for conventional prophylaxis because most patients do not benefit from the advantages of these broad-spectrum agents. Nevertheless, in high-risk patients who have prolonged neutropenia, voriconazole and posaconazole do offer greater protection against invasive fungal infections than standard azole therapy. In one randomized trial of high-risk neutropenic patients, for example, the development of Aspergillus during treatment, all invasive fungal infections within 100 days’ post-randomization, treatment failures and overall mortality were all significantly lower in the posaconazole arm than in the standard azole arm.

Targeting Moulds

Moulds are typically the target organism in febrile neutropenic patients refractory to broad-spectrum antibiotics. Here, as Dr. Sobel indicated, empirical agents may include either caspofungin or amphotericin B. Yet as results from a double-blind study involving close to 1100 patients with febrile neutropenia showed, caspofungin is generally better tolerated than liposomal amphotericin B (L-AmB) and is at least as effective. Another study suggested that caspofungin may be more effective than L-AmB in neutropenic patients colonized with Candida species, where response rates in this particular study were 66.7% for caspofungin compared with 41.7% for L-AmB (Walsh et al. N Engl J Med 2004;351(14):1391-402).

Moulds are also the target fungus in high-risk, non-neutropenic bone marrow transplant (BMT) recipients and recent evidence suggests these patients do benefit from antifungal prophylaxis, especially from an agent such as posaconazole. In one such study comparing prophylaxis in graft-vs.-host disease (GVHD) with either posaconazole or fluconazole, the incidence of Aspergillus over the 16-week study, as well as breakthrough Aspergillus, was significantly lower among posaconazole recipients.

Not all patients in the ICU are at the same risk for an invasive fungal infection, Dr. Sobel emphasized. Indeed, the overall risk of candidiasis in the ICU is low at approximately 2%. Antifungal prophylaxis may be justified in surgical or medical ICU patients who have at least a 10% risk of developing invasive candidiasis. Among the small number of candidates for antifungal prophylaxis in the ICU—likely no more than 10%—are patients who have had a prolonged length of stay and those with other risk factors, including diabetes, hemodialysis, central venous catheters and immunosuppressive therapy.

In order to guide his own decision-making, Dr. Sobel divides his ICU patients into those who are uncomplicated and those who are complicated. Uncomplicated patients are non-neutropenic, hemodynamically stable, have had no recent exposure to the azoles and no evidence they are colonized with either Candida glabrata or C. krusei. In these patients, Dr. Sobel initiates antifungal prophylaxis with fluconazole intravenously (i.v.).

Complicated patients are those who are neutropenic, hemodynamically unstable, have been recently exposed to an azole and who are colonized with C. glabrata or C. krusei. In these patients, Dr. Sobel starts with an echinocandin. “Certainly, the presence of renal failure dramatically forces your hand in the direction of an echinocandin as well,” he noted.

Although none of the echinocandins are currently approved as first-line therapy for Aspergillosis, caspofungin is approved in Canada and in the US for treatment of invasive Aspergillosis in patients who are refractory to or intolerant of other therapies. As such, the echinocandin class “is a valuable addition” to the antimicrobial armamentarium, Dr. Sobel concluded, because they are “ideally suited for infections caused by all Candida species, are remarkably easy to use, are safe and well tolerated.”

Further Evidence

As demonstrated by a large case series involving severely ill immunocompromised patients, caspofungin can produce encouraging response rates with little toxicity in patients with invasive fungal infections due to Aspergillus and Candida species. As recently reported, 81 out of 115 patients or 70% of those treated with caspofungin were alive 30 days after the end of therapy (Glasmacher et al. J Antimicrob Chemother 2006;57(1):127-34). Response rates at 63% for proven infections and 59% for probable infections were similar in neutropenic patients as well as those who were both refractory (63%) and not refractory (67%) to antifungal pre-treatment. The response rate to the echinocandin in mechanically ventilated patients in the same case series was 29%. As investigators concluded, “the results of this study clearly help to increase our confidence in caspofungin and its role in the management of systemic fungal infections.”

A recent single-centre study also tested the agent as first-line therapy for invasive pulmonary fungal disease in immunocompromised patients with hematological malignancies (Candoni et al. Eur J Haematol 2005; 75(3):227-33). After a median duration of 20 days, caspofungin given in combination with G-CSF support produced an overall response rate of 56%.

An ongoing multicentre trial is currently evaluating the compound as first-line treatment for aspergillosis in patients with hematological malignancy or those who have undergone stem cell transplantation.

Increased Antimicrobial Activity

An important question that has yet to be answered by clinical trials is whether the use of two different classes of antifungal agents increase antimicrobial activity. Dr. Carol Kauffman, Veterans Affairs Ann Arbor Healthcare System, University of Michigan, reviewed available data, including one comparison of caspofungin plus L-AmB to L-AmB alone. In this study—the CombiStrat European Trial—the complete response/partial response (CR/PR) at the end of therapy was 67% in the combination group vs. 27% for L-AmB alone. At week 12, this difference had narrowed to 80% (CR/PR) in the combination group vs. 67% in the monotherapy group.

A more robust study was a historically controlled trial involving 47 stem cell therapy patients with proven or probable invasive Aspergillosis. “All had AmB initially followed by salvage therapy,” Dr. Kauffman reported. Thirty-one patients received salvage with voriconazole while 16 received salvage with voriconazole plus caspofungin. At three months, more patients at 70% were alive in the combination arm compared with 35% in the voriconazole arm. The combination also decreased death from invasive Aspergillosis to 18% compared with 50% for the monotherapy arm, “The data is again suggestive,” Dr. Kauffman observed.