Reports

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.

Association of Medical Microbiology and Infectious Disease (AMMI) Canada—Canadian Association for Clinical Microbiology and Infectious Diseases (CACMID) 2006 Annual Conference

Victoria, British Columbia / March 15-19, 2006

Among presentations discussed here this week during the scientific sessions were novel directions for the treatment of neutropenia and invasive fungal infections. Though febrile neutropenia is a relatively rare condition in the general population, it has a much higher incidence among certain patient populations, such as those undergoing chemotherapy or those who are otherwise immunocompromised.

Tracking Febrile Neutropenia

The first step to addressing a disease is to assess and understand disease prevalence. Regarding the incidence of febrile neutropenia, there are some observable trends across Canada. One study presented here sought to determine the prevalence of hospital-based fungal infections associated with febrile neutropenia by province in Canada. The study made use of 2001 data from the Canadian Institute for Health Information hospital discharge statistics to examine diagnoses of neutropenia, invasive candidiasis and invasive aspergillosis, according to their related international classification of disease (ICD-9 and ICD-10) codes. Since febrile neutropenia is not reported under a single ICD code, the study examined literature-based figures to identify the proportion of febrile cases in the entire neutropenic population.

The results of the study indicated that in 2001, 0.055% of the entire Canadian population, or 17,129 cases, was diagnosed with neutropenia. A regional analysis demonstrated that there was a wide range of incidence among provinces, from 0.013% (four cases) in the Yukon Territory to 0.084% (6189 cases) in Quebec (the latter possibly due to provincial differences in oncology therapy or diagnostic coding). The study also documented invasive candidiasis and invasive aspergillosis rates: for invasive candidiasis, there were a total of 5535 cases representing 0.018% of the Canadian population and for invasive aspergillosis, there were a total of 892 cases representing 0.003% of the entire Canadian population. Researchers also found that among patients with neutropenia as the diagnosis most often resulting in hospitalization, the incidence of invasive candidiasis and invasive aspergillosis is several-fold higher (68-fold and 50-fold, respectively) than that found in the general population.

The data were then extrapolated to forecast the incidence of neutropenia and febrile neutropenia for the years 2005-2007. Based on the 2001 data, it is estimated that over 17,000 Canadians will be diagnosed annually with neutropenia; over 7000 of these cases are estimated to be febrile neutropenia.

Given these current figures and future projections, investigators suggested that safe and effective antifungal therapy options adequate to handle the projected growing demand should be made available in all provinces. A better understanding of incidence can help estimate costs associated with the disease, as well as potentially better control future outbreaks by ensuring that adequate resources are directed toward its treatment.

Assessing Cost of Treatment

Another presentation here took into account the broad pharmacoeconomic impact of antifungal treatment, including long-term costs of care associated with nephrotoxicity. Researchers suggested that indirect costs should also be included in the total costs to the health care system as well as their eventual impact on patient outcomes. They examined clinical outcomes data for all antifungal agents with indication for the empirical treatment of febrile neutropenia in Canada. By taking into account therapy costs, the estimated burden of treatment-induced nephrotoxicity, as well as the mean cost of treating one case of neutropenia, researchers assessed mean cost for each available therapeutic option. “Cost is a key factor when considering treatment options,” according to Dr. Coleman Rotstein, Professor of Medicine, Director, Division of Infectious Diseases, McMaster University and Chief, Infectious Disease Service, Hamilton Health Sciences, Henderson Site, Ontario.

The Role of Echinocandins

Conventional antifungal therapies have included the use of amphotericin B, although there are known nephrotoxic effects of this type of therapy, limiting its use over extended periods. Newer therapies make use of a new class of antifungal agents known as echinocandins. These compounds have shown promise against both Aspergillus and Candida species, including a wide range of indications, such as invasive candidiasis (Mora-Duarte et al. N Engl J Med 2002; 347(25):2020-9), associated febrile neutropenia (Walsh et al. N Engl J Med 2004;351(14):1391-402) and salvage treatment of invasive aspergillosis (Maertens et al. Clin Infect Dis 2004;39(11):1563-71). Echinocandins work by disrupting cell wall formation of fungal pathogens. Since human and other types of mammalian cells do not engage in cell wall formation, they are not direct targets of the echinocandin therapy, suggesting a potentially safer toxicity profile or fewer side effects than the more conventional therapeutic approaches.

Dr. Rotstein, along with his colleagues, Dr. Gary Garber, Professor of Medicine, University of Ottawa and Head, Division of Infectious Diseases, The Ottawa Hospital, Ontario, and Daniel Thirion, PharmD, Clinical Assistant Professor, Faculté de pharmacie de l’Université de Montréal, and Pharmacist, Hôpital du Sacré-Coeur de Montréal, Quebec, indicated to delegates that there are some advantages to using caspofungin therapy. It is effective because of its intravenous delivery and has a reduced toxicity profile when compared to more traditional amphotericin B treatment. In addition, it has fewer deleterious drug interactions and is potentially indicated for all candidemias, febrile neutropenia and in salvage invasive aspergillosis. The use of caspofungin is indicated in use against a range of candidiasis species, including C. galbrata and C. krusei. In the case of invasive aspergillosis, caspofungin can potentially be used in combination therapy with voriconazole.

Researchers found that when assessing only direct costs, caspofungin acetate is the most costly agent, estimated at $5847 annually (all figures estimated for 2003 and given in Canadian dollars). However, using a more comprehensive measurement of total treatment costs, defined as the sum of drug costs plus renal toxicity costs (Bates et al. Clin Infect Dis 2001;32(5):686-93), caspofungin acetate is found to be the least expensive agent. It has a total cost of $7092, including a reduced indirect cost of nephrotoxicity of $1245 when compared to a total cost of $16,589 for conventional amphotericin B therapy ($454 in direct drug costs and $16,135 in indirect renal toxicity costs). Investigators found that therapy with conventional amphotericin B can cost up to 134% more than with caspofungin. By further comparison, the estimated annual cost for the liposomal amphotericin B was estimated to be between $15,032 and $19,978 (includes between $9526 and $11,025 for direct drug costs and $5506 to $8953 in indirect costs associated with nephrotoxicity). Because it is estimated that 7425 Canadians will experience febrile neutropenia annually, the costs to the system become significant in scale. If all costs, both direct and indirect, are taken into account, including patient outcomes, newer therapies, such as caspofungin that result in reduced nephrotoxicity, may represent a savings in the long term.

In his presentation, Dr. Rotstein, along with his colleagues, Dr. Garber and Mr. Thirion, concluded that the use of caspofungin as primary therapy was indicated when compared with amphotericin B for candidemia patients. This was due to an estimated average savings of over $700 per patient attributable to savings associated with reduced risk of renal failure.

Summary

As fungal strains grow resistant to more conventional therapies, there is a need for a broader range of effective therapeutic options. Newer therapies, such as caspofungin, can be used as single or combination therapy to potentially target these resistant strains while also reducing the risk of nephrotoxicity, particularly when compared to more traditional amphotericin B therapy.