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Why there is an increase in fungal infections in hospitals and what drugs are in the pipeline
The advent of new drugs and technologies has enabled practitioners to treat critically ill patients more aggressively, thereby prolonging their lives, said Donald Alexander, Pharm.D., clinical coordinator for oncology and bone marrow transplantation at the University of Utah Hospitals and Clinics in Salt Lake City. Their tools include parenteral nutrition, invasive procedures such as surgery and catheterization, broad-spectrum antimicrobials, chemotherapy, and immunosuppression following bone marrow or solid organ transplantation. But, paradoxically, all these factorsalong with HIVimpair the body's natural defenses, putting patients at risk for what has become a growing threat to life: opportunistic fungal infections.
The increase in fungal infections over the past 20 yearsmost commonly caused by Candida species and Aspergillushas led to an expansion in the arsenal of drugs to combat them. But despite the use of available antifungals, the mortality rate for fungal infections remains high, reported Alpa Patel, Pharm.D., clinical specialist in infectious diseases at Johns Hopkins Hospital in Baltimore.
Ongoing efforts are focused on developing new agents and determining how to best use existing agents. "Pharmacists are in a unique position to understand a compound's pharmacokinetic and pharmacodynamic parameters," said John Papadopoulos, Pharm.D., critical care pharmacist at New York University Medical Center and assistant professor of pharmacy practice at the Arnold & Marie Schwartz College of Pharmacy in Brooklyn, N.Y. They can assist physicians in appropriately choosing and dosing antifungal agents, as well as monitoring for efficacy, toxicity, and drug interactions.
Amphotericin B, a polyene antifungal, is the gold standard for the treatment of aspergillosis. The original Fungizone Intravenous (amphotericin B desoxycholate, Apothecon), which carries a high risk of nephrotoxicity, has been joined by lipid formulationsprimarily Abelcet (amphotericin B lipid complex, Liposome Co.) and AmBisome (amphotericin B liposomal, Fujisawa)which have "less toxicity" and an "improved ability to deliver consistent therapy," Alexander said.
Because these products carry a high price tag, they are usually reserved for patients at risk for nephrotoxicity, such as those with baseline renal impairment. Amphotericin's nephrotoxicity "is often associated with total cumulative dose," Patel said, so a lipid formulation may be considered when a prolonged course of therapy is expected. Patients who experience a rise in creatinine clearance during standard amphotericin therapy may be switched to a lipid formulation. And, Alexander noted, institutions that are heavy users of other nephrotoxic drugs, such as cisplatin, vancomycin, and aminoglycosides, often advocate using lipid amphotericin up front.
Although Alexander acknowledged that there are pharmacokinetic differences between the lipid-based products, he said there have been no good comparative studies. So when a lipid amphotericin is indicated, product selection is usually driven by formulary and cost considerations. All amphotericin B products are associated with infusion-related reactions, which can be lessened by premedication with aspirin, antipyretics, antihistamines, and antiemetics.
Early members of the azole (imidazole and triazole) class, while less toxic than amphotericin, had their own set of disadvantages, Alexander said, including absorption problems, a limited spectrum of activity, and poor side-effect and drug-interaction profiles. Some of these problems were solved by the newer triazoles.
Diflucan (fluconazole, Roerig) is commonly used for candidal infections, Patel said, because it is "relatively well tolerated" and "very well absorbed," and it can be used for both initial IV therapy and subsequent oral therapy. Fluconazole is active against C. albicans and, to a lesser degree, some other Candida species. But with the emergence of resistance, Patel reported, there has been "an increase in the number of candidal infections due to non-albicans species ... for which fluconazole often does not have activity."
Sporanox (itraconazole, Janssen-Ortho), available in both intravenous and oral forms, is active against Aspergillus and other systemic mycoses as well as Candida. Itraconazole solution is often used as step-down oral therapy following IV treatment for aspergillosis, Patel said; use of the capsule is limited by its poor bioavailability. Itraconazole labeling carries a black box warning about congestive heart failure.
Leading a group of new, broad-spectrum triazoles having Aspergillus coverage as well as improved activity against Candida species is Vfend (voriconazole, Pfizer); the drug is awaiting final Food & Drug Administration approval. In clinical studies, voriconazole demonstrated equivalent or superior efficacy to amphotericin B for the treatment of febrile neutropenia and invasive aspergillosis. Patel anticipates that voriconazole, which will be available in both oral and injectable forms, will be "a potentially less toxic alternative to amphotericin" for Aspergillus and may replace itraconazole as an oral switch-off after IV therapy because it is absorbed better. Papadopoulos predicted that voriconazole would be used in transplant patients and hematology/oncology patients, who are at risk for both candidiasis and aspergillosis. In clinical trials, Alexander reported, voriconazole was associated with a reversible visual disturbance.
All the triazoles are potent inhibitors of cytochrome P450 3A4 and are associated with many drug interactions, some of which can be serious. Patel's strategy for managing interactions is to "predict them"by knowing which isoenzymes are involved in the metabolism of other drugs"avoid them if possible, and, if not, adjust the dose of either the antifungal agent or the other drug."
A promising development was the early 2001 approval of IV Cancidas (caspofungin acetate, Merck), the first member of the echinocandin class, which inhibits the synthesis of beta-glucan, a fungal cell wall component. Caspofungin is indicated for aspergillosis in patients unresponsive to or intolerant of amphotericin B, but it has also demonstrated activity against most Candidas, Alexander reported. The drug is now experiencing limited distribution due to "manufacturing issues and unexpectedly high market demand relative to current manufacturing capacity," according the FDA's drug-shortages Web site. Because caspofungin "binds differently from amphotericin and the triazoles," Alexander said, it "may potentially have some synergy" when used in combination. This theory is being investigated.
Antifungal therapy is largely empiric. Fungi "may take from many days to several weeks to grow" from a culture or tissue biopsy, Alexander said, thereby precluding an early definitive diagnosis. Keeping in mind a patient's risk factors for fungal infection, practitioners must rely on clinical presentation (which may include signs of infection unresponsive to broad-spectrum antimicrobial therapy, shortness of breath, and/or central nervous system symptoms) to diagnose a fungal infection and deduce the probable pathogen. An educated guess as to which Candida species is the culprit should be based on an "institution's specific prevalence patterns," Papadopoulos said. While C. albicans is the No. 1 Candida isolate nationwide, he noted, C. tropicalis and C. glabrata are also on the rise.
Antifungals are selected based on coverage of the suspected pathogen and the seriousness of the patient's illness. For example, Papadopoulos said, hematogenous candidiasis in a hemodynamically unstable patient requires fungicidal therapy with amphotericin B, whereas the same disease in a hemodynamically stable patient can be effectively treated with the fungi-static fluconazole. Drug choice for disseminated candidiasis, Papadopoulos explained, requires "a very thorough knowledge of a compound's pharmacokinetic parameters" to determine whether the antifungal distributes sufficiently into the affected organ.
Appropriate dosing of antifungals is key to maximizing their efficacy, Papadopoulos added. "Because of nationwide patterns of resistance, we're finding that the MICs [minimum inhibitory concentrations] for C. glabrata or C. cruzii for ampho B are increasing." While doses of 0.4 to 0.6 mg/kg of amphotericin B are sufficient to cover C. albicans or C. tropicalis, other isolates might require doses as high 0.6 to 1.0 mg/kg. "Fluconazole's dose should be tailored to the pathogen" as well, he said. Depending on the Candida species, doses may range from 200 mg to 800 mg/day or more.
Duration of antifungal therapy varies based on clinical response; months of treatment are not uncommon. But, Alexander stressed, "until you get an immune system that works again, you're only buying time temporarily with many of these agents." Some patients, such as those with neutropenia caused by chemotherapy, he explained, may need a short course of antifungals following each round of chemotherapy, until blood counts recover and fever drops. Others, such as those chronically immunosuppressed with steroids, he added, "may never recover their immune system and probably will have intermittent, if not prolonged, treatment with an antifungal agent, maybe [for] the rest of their lives."
|Ravuconazole||Bristol-Myers Squibb||Phase II|
|Micafungin||Fujisawa Healthcare||Phase II|
|Liposomal nystatin (Nyotran)||Antigenics||Phase III completed|
Tzipora Lieder. Pharmacists help fight upsurge in fungal infections.