Successful treatment of cerebral aspergillosis with a novel triazole (voriconazole) in a patient with acute leukaemia

Abstract

Summary.Invasive aspergillosis is an increasing problem in patients with acute leukaemia, bone marrow transplantation, immunosuppression after solid organ transplantation, or acquired immunodeficiency syndrome. Despite available antifungal treatment, the mortality approaches 100% in patients with dissemination of the infection into the central nervous system (CNS). Using a novel triazole, voriconazole, we successfully treated an Aspergillus brain abscess in a patient with acute leukaemia. Drug levels above the minimal fungicidal concentration for Aspergillus species were detected in cerebrospinal fluid (CSF) specimens, and the treatment achieved an objective response.Keywords: Aspergillus, azoles, brain abscess, immunosuppression, voriconazole.Invasive aspergillosis causes considerable morbidity and mortality in growing numbers of patients treated with intensive chemotherapy, immunosuppressive therapy after solid organ or bone marrow transplantation, or those with acquired immunodeficiency syndrome (Denning & Stevens, 1990). Mortality approaches 100% after dissemination of aspergilli into the central nervous system (CNS), and there have been very few reports of patients surviving this condition (Coleman et al, 1995).A novel triazole, voriconazole, exhibits in vitro activity against various fungi, including Aspergillus species, and has been successfully used in immunocompromised patients with invasive aspergillosis (Denning et al, 1995). We treated a patient with refractory acute leukaemia and an Aspergillus brain abscess with voriconazole after conventional amphotericin B, liposomal amphotericin B and itraconazole had failed. CASE REPORTIn June 1994 an 18-year-old male with acute lymphoblastic leukaemia was admitted for standard induction polychemotherapy (day 1). Because of resistant leukaemia after 9 weeks, he was switched to a more intensive protocol including cytarabine and mitoxantrone (day 63). Fever, despite broad-spectrum antibiotics on day 81, sudden onset of pleural chest pain and a pulmonary infiltrate prompted antifungal treatment with intravenous (i.v.) amphotericin B (Bristol-Myers Squibb, Munich, Germany), which was rapidly escalated to 1·1 mg/kg/d. Because of renal toxicity, antifungal treatment was changed on day 86 to liposomal amphotericin B (AmBisome, Vestar, Braunschweig, Germany) at a maximum dosage of 2·1 mg/kg/d. Meningism developed on day 92 when the cerebrospinal fluid (CSF) contained 1056 cells/ml (96% neutrophils, 2% lymphocytes, 2% monocytes) with negative cultures for bacteria and fungi. A magnetic resonance scan (MR) on day 93 disclosed a hypointense paraventricular lesion suggestive of a fungal brain abscess on T1-weighted images. Defervescence occurred with recovery from neutropenia on day 101, and antifungal therapy was continued with itraconazole (Sempera, Janssen, Neuss, Germany) at a dose of 200 mg three times daily, starting the same day. Progression of the paraventricular lesion and an additional lesion in the cerebellum were documented by a follow-up MR on day 111. Broncho...

Central nervous system aspergillosis in allogeneic stem cell transplant recipients

“…In our series the median survival was only 7 days after the first symptoms, which is comparable to other reports. 14,21 However, some promising case reports have been published suggesting that the therapy may be effective in some patients with acute leukaemia 27,28 or even in allogeneic SCT recipients. 29,30 Amphotericin B, the standard therapy for aspergillosis, as well as itraconazole both have poor penetrance into the CNS.…”

“…29,30 Amphotericin B, the standard therapy for aspergillosis, as well as itraconazole both have poor penetrance into the CNS. [31][32][33] Voriconazole has better penetrance 28 and may thus become the therapy of choice in patients with CNS aspergillosis. Recently, voriconazole has been found superior to amphotericin B in the primary treatment of invasive aspergillosis.…”

Effects of Voriconazole on Cryptococcus neoformans

“…Voriconazole demonstrates excellent in vitro activity against C. neoformans (17,31) and achieves good levels in cerebrospinal fluid (35). Voriconazole is not currently licensed for use in cryptococcosis and no clinical trials have evaluated its efficacy for cryptococcal disease.…”

Treatment of Refractory Cerebral Aspergillosis in a Liver Transplant Recipient With Voriconazole: Case Report and Review of the Literature

“…Voriconazole was continued for an additional 6 months, and he In comparison, many reports since 1997 have noted the efficacy of voriconazole in invasive aspergillosis. 17,23 Two convincing studies were published in 2002 (including a randomized trial that compared amphotericin with voriconazole), which collectively showed improved survival rates and a lower frequency of adverse events with voriconazole compared with amphotericin B, establishing voriconazole as the treatment of choice for invasive aspergillosis. 11,24 Voriconazole is a second-generation triazole, which targets ergosterol biosynthesis, altering cell membrane integrity.…”