Voriconazole With Surgery Benefits Patients With CNS Fungal Infections

Barbara Boughton

September 22, 2009

September 22, 2009 (San Francisco, California) — The use of voriconazole (VFEND, Pfizer) combined with central nervous system (CNS) surgery appears to improve response rates and survival in patients with CNS fungal infections, which have been associated with a greater than 90% mortality rate, according to research presented here at the 49th Interscience Conference on Antimicrobial Agents and Chemotherapy.

"Voriconazole results in improved response rates and survival in these high-risk patients. In our study, a relevant number of patients experienced long-term survival, which suggests that some of these patients might be cured of their CNS fungal disease," said lead researcher Stefan Schwartz, MD, a specialist in internal medicine, hematology, oncology, and infectious disease at Charité Campus Benjamin Franklin in Berlin, Germany.

"Neurosurgical interventions might further improve these patients' survival," Dr. Schwartz noted.

In the retrospective study, 192 patients with proven or probable CNS infections treated with voriconazole were identified from the Pfizer clinical trials database or during a Medline literature search, which identified published studies from 2002 through 2008. Most of the patients were infected with Aspergillus; the remaining were infected with Aspergillus fumigatus, Scedosporium species, or other yeasts or rare or emerging fungi.

A previous study by Dr. Schwartz's team (Blood. 2005;106:2641-2645) found that 35% of patients with CNS aspergillosis achieved a partial or complete response to voriconazole.

"In this study, we wanted to evaluate the effects of voriconazole in CNS fungal infections caused by Aspergillus as well as other fungi," Dr. Schwarz said in an interview with Medscape Infectious Diseases.

Most patients were salvage therapy cases, and 61% of patients in the study received treatment in addition to voriconazole, either sequentially or in combination. Patients included those who had undergone stem-cell or organ transplant and those with hematologic malignancy or chronic immunosuppression. Of the group, 57 patients had other underlying conditions, such as diabetes mellitus, prematurity, multiple sclerosis, renal failure, or cerebrovascular disease.

Results indicated that 48% of patients had a partial or complete response to the medication. Median survival was 297 days, and 28% of patients survived for a median of 638 days.

Results varied according to diagnosis and underlying condition. Those who had undergone stem-cell transplant had the poorest outcomes (14% response rate), compared with those who were not immunosuppressed or who had underlying conditions such as diabetes, prematurity, or multiple sclerosis (71% response rate). Patients treated with combination therapy fared better than those who received voriconazole monotherapy (62% vs 45% response rate; P = .09). A striking number of patients who underwent neurosurgical interventions also had improved outcomes, compared with those who had not undergone neurosurgeries, such as ventricular drainage or shunts, or abscess biopsy or drainage (62% vs 42%; P = .017).

"It's clear that removal of avital tissue with areas of attenuated drug penetration and treatment or prevention of CNS complications has potential clinical benefits," Dr. Schwartz said. Yet it remains unclear which surgeries are most appropriate for patients with different diagnoses, he added.

Dr. Schwartz noted that voriconazole has been proven as the drug of choice for first-line treatment of invasive aspergillosis. In the treatment of CNS aspergillosis, voriconazole has the benefit of broad antifungal activity and the ability to penetrate the CNS, he said. Because of the drug's efficacy when used in combination with other agents, Dr. Schwartz is currently testing voriconazole in combination with anidulafungin in patients with invasive aspergillosis in a large randomized clinical trial.

"There are a couple of useful take-home messages from this study," explained Luke Chen, MBBS, FRACP, assistant professor of medicine in the Division of Infectious Diseases at Duke University Medical Center in Durham, North Carolina. "The study reasserted the observation that the outcome of patients with fungal infections in the central nervous system is directly related to their underlying illness and the cause of their reduced immunological function. For instance, patients with fungal CNS infections following hematopoietic stem-cell transplantation were high-risk patients with poor outcomes, regardless of the type of pathogen or the antifungal therapy. But patients with fungal CNS infections and immunosuppression due to medical therapy or nontransplant conditions had statistically better outcomes and response rates to therapy."

The study adds to an increasing body of evidence that supports the use of voriconazole, either alone or in combination with other antifungal agents, for salvage therapy of susceptible fungal CNS infections in immunocompromised patients, Dr. Chen said. "Voriconazole-based therapy makes sense because there are increasing amounts of pharmacokinetic data showing voriconazole can achieve potentially therapeutic levels in the cerebrospinal fluid and cerebral tissue," he said.

There were several questions that were not well answered by the study, Dr. Chen said. One is whether voriconazole should be given as monotherapy or in combination with another antifungal agent. Another is whether voriconazole should be used as first-line therapy or as salvage therapy.

"Unfortunately, this study was not able to answer this question since most of the patients in this study received voriconazole as part of salvage therapy," he added.

Dr. Schwartz and Dr. Chen have disclosed no relevant financial relationships.

49th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC): Abstract M-1056. Presented September 13, 2009.