Crum-Cianflone, Nancy F. MD, MPH
Coccidioidomycosis, a fungal infection endemic to the southwestern United States, causes 150,000 infections annually. Although most cases are asymptomatic or involve a mild respiratory illness, approximately 3000 persons in the U.S. develop disseminated disease each year. Although the mild form of disease often self-resolves, one that disseminates to the central nervous system, bones, skin, and other extrapulmonary sites requires antifungal therapy. Many cases have progressed despite standard therapy with azoles, such as fluconazole and itraconazole, and/or polyenes, such as amphotericin B or a lipid formulation of this agent. Poor treatment response may be due to the absence of fungicidal action against Coccidioides spp. of these medications and/or poor host immune responses. Novel antifungal medications are needed to treat disease that progresses despite the use of recommended regimens.1 One potential agent may include voriconazole, which became available in 2002; although not approved by the U.S. Food and Drug Administration (FDA) for the treatment of coccidioidomycosis, in vitro data have demonstrated activity against this organism. Voriconazole may be useful in combination with standard treatment agents; however, little clinical data exist in the literature. I report the use of voriconazole in combination with polyenes for salvage therapy in disseminated coccidioidomycosis and provide a review of the literature.
A review of the medical literature was performed by searching MEDLINE (1996-2006), Embase (1996-2006), Cumulative Index to Nursing and Allied Health Literature (1981-2006), and the National Library of Medicine using the search terms "coccidioidomycosis," "Coccidioides," "C. immitis," "Coccidioides immitis," or "valley fever" AND "voriconazole." In addition, abstracts from recent scientific meetings were assessed for cases. Reports with incomplete data or an insufficient course of voriconazole therapy were excluded.2
A 29-year-old white woman presented in December 2005 with a respiratory illness during her third trimester of pregnancy. She had no significant medical history, was HIV-negative, and worked at a naval base in the Central Valley in California. Her pulmonary symptoms resolved without any specific therapy. She delivered a healthy infant in January of 2006. During the succeeding 2 months, she developed progressive bone and joint pains as well as skin lesions. In March of 2006, laboratory tests revealed a white blood count of 8400/μL with 11% eosinophils. Coccidioides spp. serology and complement fixation titer were positive, with a titer of more than 1:256.
The patient was hospitalized at our medical treatment facility for high fevers, severe fatigue, disabling bone pains, and headaches. A chest radiograph was remarkable for mediastinal and hilar adenopathy. A bone scan showed increased uptake in the bilateral distal femoral epicondyles as well as the left wrist (capitate and triquetrum bones); a lumbar puncture had a normal white count and protein level, and the Coccidioides IgG was positive. A skin biopsy showed giant cells with spherules on pathological examination, and the culture grew C. immitis.
The patient was treated with liposomal amphotericin B (AmBisome, Astellas Pharma US Inc, Deerfield, Ill) at 5 mg/(kg · d)−1 and fluconazole 600 mg daily beginning on March 10 to treat both widely disseminated coccidioidomycosis and meningitis. The patient defervesced and was discharged after 5 days of hospitalization. She continued the same antifungal regimen with documented compliance and experienced gradual resolution of symptoms during the next 4 weeks of therapy.
In April, she acutely experienced enlarging neck adenopathy accompanied by dysphagia to both solids and liquids. A computed tomography (CT) scan showed multiple heterogeneous nodal conglomerates (2 × 3 cm) with varying degrees of necrosis from the level of the thyroid cartilage extending into the mediastinum. These lesions surrounded the carotid and jugular vessels with associated mass effect and narrowing; there was shift of the trachea with mild narrowing, as well as significant compression of the esophagus. A laryngoscopy demonstrated a patent airway without laryngeal lesions. A biopsy of the nodal mass revealed Coccidioides spherules, but the culture showed no growth. The patient was found to have splenomegaly with splenic involvement on CT scan, in addition to new skin lesions and areas of bony pain on examination. A repeat bone scan showed new disease involving the metatarsophalangeal joints and iliac bones. A repeat lumbar puncture was unchanged. The serum CF titer remained elevated at 1:256.
Given evidence of progressive disease, the patient was treated with both liposomal amphotericin B (AmBisome) at 7.5 mg/(kg · d)−1 and voriconazole 200 mg twice daily. Over the next 5 weeks, her symptoms regressed with disappearance of dysphagia and decreasing adenopathy by examination and CT imaging. At this time, she developed worsening renal function (creatinine range, 0.6-1.2 mg/dL) and hyperphosphatemia (7.0 mg/dL), despite maximum doses of sevelamer (Renagel, Genzyme Corporation, Cambridge, Mass); the AmBisome dosage was reduced to 5 mg/(kg · d)−1 and then to every-other-day therapy.
A repeat titer was 1:32, and a bone scan showed mild decrease in activity in prior areas of disease with no new foci. The liposomal amphotericin B was discontinued after the patient had received the equivalent of 7.7 g of amphotericin B. The patient remains on oral voriconazole with good response, and there is no evidence of relapse 8 weeks later.
Review of the Literature
In 5 cases, including this case, voriconazole was used for coccidioidal infections that progressed despite standard antifungal therapy (Table 1).3-6 In 2 of the 5 cases, voriconazole was used in combination with liposomal amphotericin B, whereas in the other 3, voriconazole was used alone. In all cases, disease significantly improved (albeit slowly in some reports4,6), and all patients survived. These cases involved a multitude of various sites of disease involvement including soft tissues, bone, skin, and the central nervous system. A summary of the cases is presented in Table 1.
Other occasions where voriconazole was used for the treatment of coccidioidomycosis were identified, but specific patient details were not provided. A report in abstract form reviewed 7 cases of disseminated disease (including 5 cases of meningitis) that initially failed standard therapy. The authors reported successful responses to voriconazole at daily doses of 400 to 600 mg; unfortunately, no long-term follow-up of these patients appears in the literature.7 Another case series reported successful outcomes among 2 of 3 children with refractory disseminated coccidioidomycosis using combination therapy with voriconazole [6 mg/kg loading dosage, followed by 4 mg/(kg · d)−1] and caspofungin [0.7 mg/(kg · d)−1].8 A final report cited a single case of Coccidioides spp. treated with voriconazole, but specific details were not presented.9
This case report and review of the literature demonstrate that voriconazole may lead to clinical improvement when used as salvage therapy for progressive coccidioidomycosis. Despite the apparent use of voriconazole to treat refractory cases of disseminated coccidioidomycosis in the community, few cases on its clinical effectiveness in this setting have been reported in the literature.
Although polyenes and first-generation azoles with known activity against Coccidioides spp. are available,1 treatment of disseminated disease including meningitis and other progressive forms often remains unsatisfactory because of treatment failures and drug-related toxicities. Furthermore, none of the currently available drugs are fungicidal, nor have they been proven to cure this disease.
Novel agents against this endemic mycosis are needed. Voriconazole was approved in May 2002 for the treatment of invasive aspergillosis and refractory fungal infections caused by Scedosporium/Pseudallescheria and Fusarium spp. This second-generation azole was derived by the replacement of one of the triazole rings with a fluoropyrimidine group and an added α-methyl group with expanded activity compared with fluconazole.10 Although it is not FDA-approved for the treatment of coccidioidomycosis, voriconazole has demonstrated in vitro activity against C. immitis and C. posadasii with 90% minimum inhibitory concentrations (MIC) of 0.13 to 0.25 μg/mL.11 The minimum fungicidal concentration has been reported between 0.5 and more than 16 μg/mL, similar to other azoles.12 Like other available agents, voriconazole is fungistatic against Coccidioides spp.
This review demonstrates that voriconazole may be beneficial alone or in combination with polyenes for salvage treatment of coccidioidomycosis. Although some have suggested possible antagonism with both azoles and polyenes, there is a lack of clinical evidence to support this concern. When this dual-therapy approach is used, it is recommended that amphotericin B be discontinued after the disease improves and that azole be continued.1 In addition to its use for skin and bony disease, voriconazole has excellent penetration into the central nervous system and has been successfully used in coccidioidal meningitis.3,5,6
The dose for voriconazole is typically 200 mg twice daily, although some of the cases presented in this article used doses up to 400 mg twice daily.5 Of note, higher doses of voriconazole may result in photosensitivity reactions, which may be because of increased retinol levels caused by voriconazole's effect on the p450-dependent enzymes slowing retinol metabolism.6 Other common side effects include transient visual disturbances and hepatitis.13 The most appropriate dose of voriconazole for the salvage treatment of coccidioidomycosis is unknown; if dosed higher than 400 mg daily are used, careful observation for adverse events is warranted.
Echinocandins (caspofungin) may have activity in difficult cases.14 Caspofungin has shown promise in a murine model, although MIC data have suggested limited activity (8-64 μg/mL). Some reports suggest the minimum effective concentration may be a better in vitro test for activity, as this may have a better correlation with in vivo results.14,15 Clinical data with this agent are limited, with only 3 case reports in the literature,16-18 along with a case series of 3 patients treated with caspofungin and voriconazole.8 There are currently no clinical data regarding other echinocandins, such as micafungin and anidulafungin.
Posaconazole, a recently approved by the FDA for prophylaxis against invasive Aspergillus and Candida infections in severely immunocompromised patients, is also a promising agent in the treatment of coccidioidomycosis. This novel azole has MICs of 0.25 to 1.0 μg/mL and excellent potency against Coccidioides spp. in mice models.19 In fact, one study demonstrated that posaconazole was more than 200-fold as potent as fluconazole and more than 50-fold as potent as itraconazole in decreasing the fungal burden in a murine model.20 Early clinical data with posaconazole (oral suspension 800 mg/d) for disease refractory to conventional antifungal therapy has been promising with 5 of 6 patients experiencing successful outcomes in a recent published report.21 Case series and reports have also reported positive outcomes using posaconazole.22-24 A clinical trial regarding the effectiveness of this agent as salvage therapy is ongoing; in addition, a study comparing the efficacy of posaconazole to other available azole(s) for early disseminated disease is planned.
In the pipeline, there are 2 other potential drugs with efficacy against Coccidioides spp. Nikkomycin Z has demonstrated fungicidal activity (MIC, 0.063 μg/mL) with the potential to eradicate Coccidioides from the lung; phase 1/2 trials are planned.25 Second, ambruticin has also shown activity against Coccidioides spp., but further data are needed.
In summary, standard agents recommended by the recent published guidelines should be used in the treatment of coccidioidomycosis.1 However, for disease that is unresponsive or where patients are intolerant to these medications, voriconazole may be considered. More data on the clinical efficacy of this and other novel antifungal agents along with studies examining the most beneficial drug or combination of antifungal medications in the treatment of coccidioidomycosis are needed.
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