JAC Advance Access originally published online on June 9, 2004
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Journal of Antimicrobial Chemotherapy 2004 54(1):292-294; doi:10.1093/jac/dkh306
JAC vol.54 no.1 © The British Society for Antimicrobial Chemotherapy 2004; all rights reserved.
Correspondence |
Treatment of meningeal coccidioidomycosis with caspofungin
1 Department of Medicine, Brooke Army Medical Center, 3851 Roger Brooke Drive, Fort Sam Houston, TX 78234; 2 College of Pharmacy, University of Houston, 1441 Moursund Street, Houston, TX 77030, USA
Keywords: echinocandins , meningitis , Coccidioides
Sir,
Current mainstays of therapy for disseminated coccidioidomycosis are fluconazole and itraconazole, with amphotericin B chiefly reserved for refractory cases. Lifelong azole therapy is suggested for those with meningitis.1 Despite the use of these agents, many patients still relapse with disease progression often leading to death. Many of the new and investigational antifungal agents have been evaluated for activity against Coccidioides immitis in vitro and in limited animal studies. Those agents identified to have potential for use in coccidioidomycosis include voriconazole, caspofungin and posaconazole.2 We present a case report describing the presumed failure of caspofungin to treat a person with disseminated coccidioidomycosis complicated by chronic fungal meningitis.
A 23-year-old African-American male developed disseminated coccidioidomycosis with chronic meningitis after an environmental exposure while working as a truck driver in Arizona in the Spring of 2002. Initially, he was seen at an outside facility after developing mental status changes. Following his initial diagnosis, he was treated with amphotericin B and then a lipid-based formulation of amphotericin B, the change prompted by renal dysfunction. He was discharged on oral fluconazole. He was first seen in our system after a referral from the Emergency Department for re-evaluation and follow-up. At that time, he was not taking his fluconazole either as ordered or at all. His dose of fluconazole was increased to 800 mg daily as an outpatient, but after several episodes of mental status changes and reports of medical non-adherence, he was admitted to our institution for further evaluation and therapy. At the time of this admission in August 2002, he was found to have multiple subcutaneous and retroperitoneal abscesses, painful lower extremity bony lesions, as well as continued meningitis with mild-moderate hydrocephalus. CSF parameters showed pleocytosis, abnormal protein concentration, and a coccidioidal complement fixation (CF) antibody titre of 1:4 in the CSF (Table 1). Serum CF titre at that time was 1:256. All coccidioidal CF antibody testing was carried out at the University of California at Davis Coccidioidomycosis Serology Laboratory of Dr D. Pappagianis. His bony lesions, subcutaneous and retroperitoneal abscesses were treated surgically and fluconazole therapy continued. He responded initially to this therapy, with CSF WBC improving to 9 cells/mm3 (96% mononuclear cells) in February of 2003. Unfortunately, his medical non-adherence continued and episodes of delusional psychosis led to attempts to deliver his therapy by direct observation. In July 2003, his CSF parameters had worsened and CSF CF antibody titres were noted to be 1:8. As a result of continued questions of medical non-adherence, and his CSF parameters, his therapy was changed to directly-observed oral voriconazole at 400 mg, and later 600 mg/day. The patient continued to clinically deteriorate on outpatient therapy, with increased delusional thinking, leading to repeat hospitalization in September 2003 for re-evaluation of therapy. At admission, he was treated with intravenous liposomal amphotericin B and a ventriculoperitoneal CSF shunt was placed. At the time of shunt placement, a lumbar intrathecal catheter and reservoir were also placed for potential future use. On liposomal amphotericin B, he again developed acute renal insufficiency, leading to withdrawal of that agent and initiation of a trial of caspofungin. He was given a loading dose of 70 mg intravenously, and 50 mg/day thereafter of caspofungin. During 22 days of echinocandin therapy, our patient developed right ankle pain, but otherwise did not appear to worsen or improve clinically. Bone scan carried out on the 19th day of this therapy found increased uptake about his ankle, a site previously involved. A similar scan carried out a month earlier had shown no areas of increased activity. The only positive CSF culture obtained during our care of this patient was obtained on the 11th day of caspofungin therapy. Susceptibility testing of this isolate, carried out at the Fungus Testing Laboratory, University of Texas Health Science Center at San Antonio, revealed the MIC of caspofungin to be 1.0 mg/L at both 24 and 48 h of incubation. Testing also revealed the 48 h MICs of amphotericin B, fluconazole, voriconazole and posaconazole to be 0.5, 8, 0.125 and 0.125 mg/L, respectively. Serum and CSF concentration of caspofungin was measured on days 5 and 16 of therapy. This testing, carried out by University of Houston Anti-infective Research Laboratories, Houston, TX, found serum concentrations of 2.7 and 5.5 mg/L, respectively, but no detectable drug in his CSF. On the 20th day of caspofungin therapy, high-dose oral fluconazole was restarted and 2 days later, caspofungin was stopped and intrathecal amphotericin B was initiated. His clinical condition and CSF parameters did not improve on this therapy either, and 39 days later his course was complicated by an acute intracerebral haemorrhage and mitral valve vegetation potentially secondary to a line-associated MRSA bacteraemia. He became hypotensive and comatose, and after his family decided not to pursue further aggressive surgical or medical therapy, life support was withdrawn and the patient expired.
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Fluconazole, itraconazole, intravenous and, occasionally, intrathecal amphotericin B are the current drugs used in the treatment of coccidioidomycosis. The search for more effective therapies has recently resulted in the evaluation of lipid-based formulations of amphotericin B, the new broad-spectrum azoles, and the echinocandin caspofungin in this disease.2–6 In a recently reported rabbit model of coccidioidal meningitis, intravenously administered liposomal amphotericin B (AmBisome) was shown to be superior to oral fluconazole or conventional intravenous amphotericin B.3 These data in part prompted our initial attempt to treat with this agent. Another recent report described the successful treatment of a human case of coccidioidal meningitis with voriconazole.5 Unfortunately, our patient failed to respond to this agent, even after more than 2 months of directly-observed therapy. Lutz et al.6 published in vitro data with posaconazole showing good fungicidal activity against C. immitis. They also noted posaconazole to be superior in activity to fluconazole or itraconazole in a murine model of disseminated non-meningeal coccidioidomycosis. Although posaconazole has been used in several unpublished cases of coccidioidomycosis, it has not been approved by the FDA and was not available to us to treat this particular patient. Caspofungin is the first of a new class of antifungal agents, the echinocandins, which targets the fungal cell wall itself via interruption of ß-1,3 glucan synthesis.7 Current literature review shows no clinical data regarding use of caspofungin in the treatment of coccidioidomycosis. In 2001, Gonzalez et al.4 showed in vitro data that predicted poor efficacy of caspofungin against coccidioidomycosis based on MIC measurements. However, in their murine model of non-meningeal coccidioidomycosis, they were able to achieve significant reduction in end organ fungal burdens with one coccidioidal isolate and a survival rate of
80% with doses 5 mg/kg.4 These data and the limited alternative options led us to provide a trial of caspofungin therapy to our patient. This case demonstrates the severe morbidity and mortality that is still associated with disseminated coccidioidal disease, especially meningitis. The decision to treat him with caspofungin was made after ventriculoperitoneal shunting, intolerance to liposomal amphotericin B, and failure of two azole therapies. Our patient did not appear to respond to this therapy over its short course. Caspofungin was not detected in his CSF, but was found at a concentration above the tested MIC for his organism in his serum. Despite this, he also suffered a relapse of his coccidioidal bony disease while on caspofungin. Our patient ultimately did not respond to any form of therapy. Determining the best course of therapy in treating coccidioidal meningitis remains a therapeutic challenge. Further in vitro and in vivo studies need to be done with the newer antifungal agents to fully characterize their potential roles in our armamentarium against this formidable disease. Perhaps larger doses of caspofungin may ultimately prove beneficial in this infection, but our experience would make us reluctant to use caspofungin at the current standard dose in patients with coccidioidomycosis.
Disclaimer
The views expressed are those of the authors and do not reflect the official policy or position of the Department of the Army, Department of Defense, or the U.S. Government.
Footnotes
* Corresponding author. Tel: +1-210-916-3847; Fax: +1-210-916-0388; Email: duane.hospenthal{at}amedd.army.mil
References
1 . Galgiani, J. N., Ampel, N. M., Catanzaro, A. et al. (2000). Practice guidelines for the treatment of coccidioidomycosis. Clinical Infectious Diseases 30, 658–61.[CrossRef][Web of Science][Medline]
2 . Deresinski, S. C. (2001). Coccidioidomycosis: efficacy of new agents and future prospects. Current Opinion in Infectious Diseases 14, 693–6.[Web of Science][Medline]
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Clemons, K. V., Sobel, R. A., Williams, P. L. et al. (2002). Efficacy of intravenous liposomal amphotericin B (AmBisome) against coccidioidal meningitis in rabbits. Antimicrobial Agents and Chemotherapy 46, 2420–6.
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Gonzalez, G. M., Tijerina, R., Najvar, L. K. et al. (2001). Correlation between antifungal susceptibilities of Coccidioides immitis in vitro and antifungal treatment with caspofungin in a mouse model. Antimicrobial Agents and Chemotherapy 45, 1854–9.
5 . Cortez, K. J., Walsh, T. J. & Bennett, J. E. (2003). Successful treatment of coccidioidal meningitis with voriconazole. Clinical Infectious Diseases 36, 1619–22.[CrossRef][Medline]
6 . Lutz, J. E., Clemons, K. V., Aristizabal, B. H. et al. (1997). Activity of the triazole SCH 56592 against disseminated murine coccidioidomycosis. Antimicrobial Agents and Chemotherapy 41, 1558–61.[Abstract]
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Letscher-Bru, V. & Herbrecht, R. (2003). Caspofungin: the first representative of a new antifungal class. Journal of Antimicrobial Chemotherapy 51, 513–21.
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