Posaconazole—Treatment for Refractory Coccidioidomycosis
Abstract & Commentary
By Mary-Louise Scully, MD
Sansum-Santa Barbara Medical Foundation Clinic, Santa Barbara, CA
Dr. Scully reports no consultant, stockholder, speaker’s bureau, research, or other financial relationships with companies having ties to this field of study.
Synopsis: Posaconazole, an investigational extended spectrum triazole, shows promise as a treatment option for patients with disseminated coccidioidomycosis who have failed to improve with conventional antifungal medications.
Source: Anstead GM, et al. Refractory Coccidioidomycosis Treated with Posaconazole. Clin Infect Dis. 2005;40:1770-1776.
Six patients with culture documented disseminated coccidioidomycosis were treated with posaconazole at the University Hospital of San Antonio, Texas. These patients all had progressive disease despite receiving over 40 days of conventional antifungal treatment. Patients were given an oral posaconazole suspension of at least 800 mg/day in divided doses as part of an open label clinical trial.
All 6 patients had at least 1 risk factor for disseminated coccidioidomycosis. Three patients were African American and 3 were Hispanic—known risk factors for disseminated disease. In addition, 3 patients each had underlying diseases, such as systemic lupus erythematosus (SLE), HIV, or chronic bronchiectasis. The 3 patients without underlying disease were actually quite young, under age 25, and all were previously healthy. The 1 HIV-infected patient had AIDS, with a low CD4 count of 5 cells/mm and a viral load of 451,000 copies/mL.
Successful outcomes were observed in 5 of the 6 patients. Two patients were still receiving posaconazole at the time of publication. Overall, posaconazole was well tolerated despite long-term administration for 1 to 2 years. The patient who failed treatment, despite initial improvement with posaconazole, died of peritonitis from a ruptured intra-abdominal abscess that was infected with Coccidioides. This patient had also failed liposomal amphotericin B (5 mg/kg/day for 40 days), voriconazole (200-400mg/day and interferon for over a year), and fluconazole (1600 mg/day for 5 weeks). The patient with SLE had shown significant clinical and radiologic improvement, and was being maintained on posaconazole until day 342 of treatment when he died of a cerebrovascular event, felt to be unrelated to the posaconazole.
Of note, Anstead and colleagues used a modified version of the Mycosis Study Group global scoring system for assessing the burden of disease in coccidioidomycosis. In this scoring system, points are given for symptoms (1 point each), number of individual lesions (2 points each), positive cultures from respiratory, soft tissue, or osteoarticular sites (4 points each, for a maximum of 12 points), and serology results (up to 3 points, depending on the titer determined by immunodiffusion complement fixation). A successful response is defined as a score ≤ 50% of the pretreatment aggregate score.1 If no follow-up cultures or serology tests are done, pretreatment points are carried over, perhaps falsely elevating the score if these tests were not obtained. Anstead et al developed a modified scoring version that omitted culture and serologic data from the scoring, citing that 5 out of 6 of their patients lacked follow-up cultures, and that their serological testing techniques changed during the study period, making direct comparison difficult. Using this modified scoring system, an additional 2 of the 6 patients are classified as having a successful outcome. Anstead et al felt this was consistent with observed clinical improvements as well. In disseminated coccidioidomycosis, follow-up cultures may not be pursued if a patient improves clinically, especially if the sample would require an invasive procedure. However, decrease in the complement fixation antibody titer is felt to be an important marker of disease resolution in disseminated coccidioidomycosis. Data on follow-up serology, by any method, was only provided for 3 of the 6 patients in this report.
Commentary
Despite the small number of patients reported in this paper and the technical issues of accurately determining a successful response, posaconazole shows promise as another agent for use in disseminated coccidioidomycosis, as well as other invasive fungal infections. Like other triazole antifungal agents, posaconazole blocks the synthesis of ergosterol, the predominant sterol in the cell membrane of many fungal pathogens. In vitro, posaconazole has a broad spectrum of antifungal activity, demonstrating activity not only against Coccidioides, but also Aspergillus, zygomycetes, Candida, and numerous other fungi, including Cryptococcus, Blastomyces dermatitidis, and Histoplasma species.2
Numerous studies have been presented at international meetings or published on the use of posaconazole. In patients with chronic granulomatous disease (CGD) whose invasive mold infections were unresponsive to voriconazole, posaconazole treatment led to a complete response in 7 of 8 patients.3 Another clinical study demonstrated the efficacy of posaconazole in 4 of 8 patients with invasive fungal infection refractory to voriconazole.4 Finally, an open-label multicenter clinical trial using posaconazole for salvage therapy in 330 patients with invasive fungal infections showed successful outcomes of varying degrees in aspergillosis, fusariosis, chromoblastomycosis, mycetoma, and coccidioidomycosis.5
In Europe, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Evaluation Agency (EMEA) has recently issued a positive opinion recommending the approval of posaconazole for treatment of invasive aspergillosis, fusariosis, chromoblastomycosis, mycetoma, and coccidioidomycosis in patients whose infections are refractory or intolerant to other therapies.6 Posaconazole would be marketed in the European Union as a suspension dosed at 400 mg twice daily under the brand name Noxafil. Posaconazole is also currently under FDA review for approval in the United States.
Posaconazole has a large volume of distribution, is highly protein bound, and is primarily excreted in an unchanged form in the feces.7 Therefore, dosage adjustments in patients with varying degrees of chronic renal disease are not felt to be needed.8 It should be used with caution in patients with severe hepatic impairment. Administration of posaconazole with ergot alkaloids, CYP3A4 substrates known to prolong the QTc interval and HMG-CoA reductase inhibitors, is contraindicated. Posaconazole treatment-related serious adverse events in patients with invasive fungal infections included increased hepatic enzymes, nausea, rash, and vomiting (1% each).9 To date, there is no in vitro or in vivo evidence of antagonization with other antifungal compounds, leaving open the possibility for posaconazole’s future use in combination antifungal treatment strategies; an increasingly common clinical practice, but an area lacking in controlled studies.
References
- Catanzaro A, et al. Fluconazole in the Treatment of Chronic Pulmonary and Nonmeningeal Disseminated Coccidioidomycosis: NIAID Mycoses Study Group. Am J Med. 1995;98:249-256.
- Keating GM. Posaconazole. Drugs. 2005;65:1553-1567.
- Segal BH, et al. Posaconazole as Salvage Therapy in Patients with Chronic Granulomatous Disease and Invasive Filamentous Fungal Infection. Clin Infect Dis. 2005;40:1684-1688.
- Herbtrecht R, et al. Posaconazole as Salvage Therapy for Invasive Fungal Infections Unresponsive to Voriconazole. Abstracts for the 44th Interscience Conference on Antimicrobial Agents and Chemotherapy (Washington, DC). 2004.
- Raad I, et al. Posaconazole Salvage Therapy for Invasive Fungal Infections. Abstracts of the 44th Interscience Conference on Antimicrobial Agents and Chemotherapy (Washington, DC). 2004.
- European Medicines Agency. Committee for Medicinal Products for Human Use, Summary of Opinion for Posaconazole SP. 27 July 2005. 5 Sept. 2005. www.emea.eu.int
- Groll AH, Walsh TJ. Posaconazole: Clinical Pharmacology and Potential for Management of Fungal Infections. Expert Rev Anti Infect Ther. 2005;3:467-487.
- Courtney R, et al. Posaconazole Pharmacokinetics, Safety, and Tolerability in Subjects with Varying Degrees of Chronic Renal Disease. J Clin Pharmacol. 2005;45:185-192.
- Schering-Plough Corporation. Jul 28, 2005 News Release. Sept 5, 2005. www.schering-plough.com
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