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* From the Santa Clara Valley Medical Center/Stanford University (Dr. Stevens), San Jose, CA; Hospital Universitario Dr. J. E. Gonzalez (Dr. Rendon), Nuevo Leon, Mexico; Hospital de Infectologia CMN La Raza (Dr. Gaona-Flores), La Raza PB, Mexico; University of California at San Diego Medical Center (Dr. Catanzaro), San Diego, CA; University of Texas Health Sciences Center (Drs. Anstead and Graybill), San Antonio, TX; Schering-Plough Research Institute (Dr. Pedicone), Kenilworth, NJ.
Correspondence to: David A. Stevens, MD, Division of Infectious Diseases, Department of Medicine, Santa Clara Valley Medical Center, 751 South Bascom Ave, San Jose, CA 95128-2699; e-mail: stevens{at}stanford.edu
Abstract
Background: Coccidioides infections often result in chronic relapsing disease that presents a challenge to the currently available therapy. Posaconazole, an oral extended-spectrum triazole agent, has been shown in vitro and in vivo to have potent activity against this fungus.
Methods: An open-label multinational study of posaconazole, 800 mg/d, administered in divided doses for the treatment of invasive fungal infection that has been refractory to previous therapy was conducted. The data were reviewed by an independent data review committee (DRC). Fifteen patients met the criteria for proven coccidioidal infection and disease refractory to previous therapy. Success was a complete or partial response; nonsuccess was stable disease, lack of response to therapy, or undetermined response.
Results: The sites of coccidioidal infection were pulmonary (seven patients) and disseminated (eight patients). Patients were refractory to previous therapy (including amphotericin B with or without an azole) for a median duration of 306 days. At the end of treatment (posaconazole treatment duration, 34 to 365 days), therapy for 11 of 15 patients (73%) was considered to be successful by the DRC. Four responses were complete and seven were partial; these included five patients with pulmonary sites and six patients with disseminated sites. In responders, improvement was seen within months of the initiation of therapy. Five patients received therapy for 
12 months. The side effects were minimal.
Conclusions: Therapy for coccidioidomycosis remains a clinical challenge, especially when patients have not responded to therapy with drugs that were recommended in treatment guidelines. The success rate (73%) achieved in this case series suggests that oral posaconazole should be considered as an important agent for the treatment of refractory coccidioidomycosis.
Key Words: antifungal • azole • coccidioidomycosis • posaconazole
Coccidioidomycosis is one of the most difficult mycoses to treat, related to the exponential method of replication and the tendency to form suppuration and granulomas, which may hamper tissue resolution and drug penetration.1 Oral azole therapy has been an important contribution to disease management, but the currently available drugs require long-term therapy for responses, and relapse after apparently successful therapy is common.123 Posaconazole4 is fungicidal against Coccidioides in vitro56 and is the most curative drug in animal models,56 where it has been demonstrated to be > 200-fold and > 10-fold to 20-fold, respectively, more potent than fluconazole and itraconazole.5 A preliminary report of a dose-finding clinical study47 has suggested that there was responsiveness of coccidioidomycosis to the initial therapy for chronic disease at lower doses than are currently being studied for the treatment of deep mycoses. The present multicenter international collaboration investigated therapy with posaconazole for coccidioidomycosis that was refractory to the currently available therapy and utilized doses greater than those studied previously.7
Materials and Methods
Entry
Patients were eligible to participate if they were 13 years old. Coccidioidomycosis, for study entry, was defined to be proven or probable by standardized criteria.8 A patient with refractory coccidioidomycosis was defined as having received an adequate duration of prior licensed antifungal therapy to evaluate response, as alsoP verified after the study by an external Data Review Committee (DRC), which was formed for the review of several posaconazole open trials in invasive mycoses. The DRC consisted of 15 experienced investigators and clinicians who were familiar with the treatment of mycoses and 2 experts in the radiography of invasive fungal infections. Three members of the DRC reviewed a given case, and determined eligibility and outcomes using protocol-defined criteria after 1, 3, and 6 months of therapy and at the end of treatment on the protocol. The DRC was not informed of the patient’s institution, which prior therapy had been given, or the outcome of the case as scored by the investigator independently. In addition, the same number of comparable coccidioidomycosis cases not treated with posaconazole were admixed with the posaconazole-treated pool for DRC assessment, so the DRC was not aware whether a patient had been treated with posaconazole or not. These control cases also had not responded to prior therapy and were given salvage therapy with other agents.
With respect to the duration of prior therapy, all patients included in the study had received at least 40 days of prior appropriate antifungal therapy at conventional doses or higher doses. The definition of "refractory" also required the DRC to have determined that the patient had failed to improve or that progression of disease while receiving prior therapy had occurred. "Failure to improve" required one or more of the following: lack of improvement in signs, symptoms, or imaging findings; continued isolation of Coccidioides or histopathologic demonstration of spherules and/or endospores while receiving therapy; rising titers of coccidioidal complement-fixing antibody or other surrogate marker of disease progression while receiving therapy; or combination of microscopic examination per criteria8 with persistence of clinical symptoms referable to the original site of disease for which therapy had been initiated. "Progression of disease" required either the worsening of attributable signs, symptoms, or imaging; or documentation of a new site of disseminated infection while receiving therapy. "Intolerance of prior therapy" (not required for study entry) was defined as organ toxicity grade 3; adverse events were recorded and categorized using a standardized system,9 nephrotoxicity, or idiosyncratic reactions related to prior conventional antifungal therapy. Nephrotoxicity was defined as two serum creatinine determinations, at least 1 day apart, that were more than twice the upper limit of normal (ULN), recurrent elevation of creatinine to more than twice the ULN on resumption of prior antifungal therapy, or the elevation of serum creatinine level to more than twice the baseline value.
Exclusion criteria included the following: pregnancy or lactation; use of inadequate contraception in women with child-bearing potential; concurrent progressive neurologic disease; a need for artificial ventilation with little likelihood of extubation within 24 h after study entry; a history of serious or severe hypersensitivity to azoles; or the use of medications known to interact with azoles, with the potential then of toxicity resulting from the use of those medications, within 10 days of study entry or of the use of drugs that lower azole serum concentrations10 within 7 days of study entry. Additional exclusion criteria were as follows: ECG results showing a prolonged QTc interval (ie, 20% above normal) within 7 days of study entry; a need for concomitant systemic antifungal agents during the study period; the presence of abnormal hepatic function test results (alanine aminotransferase or aspartate aminotransferase levels > 10 times the ULN); or anticipated survival for < 72 h.
The study protocol was reviewed and approved by an institutional review board or independent ethics committee at each site. Before receiving the first dose, each patient (or a legal representative) provided written informed consent in accordance with the Declaration of Helsinki.
Whenever possible, doses were to be administered with food or liquid nutritional supplement. Patients were to receive posaconazole for 28 days and for 7 days after the complete resolution of all symptoms. All patients were prescribed 400 mg twice daily orally as a 40 mg/mL suspension; ostensibly, all but one patient took this dose for their entire study course (patient 3 took this dose for most of her course, but at times less). Compliance issues caused the interruption of therapy in some patients. Some patients received 200 mg four times daily for a portion of the study, usually while hospitalized or per physician order. Although the maximum protocol-defined duration of treatment was 12 months, patients deemed by the investigator to require ongoing further therapy could then be enrolled in other nonrandomized treatment protocols.
Three of the patients’ courses have been published in part, including in a group of six patients with refractory coccidioidomycosis, by the investigators.11 The prior study did not utilize the protocol criteria, evaluations, or methodology of the present study.
Evaluation of Outcome
The following modified intention-to-treat analysis for study inclusion was used: patient receipt of at least one dose of posaconazole, plus satisfying the definitions just enumerated. Outcome was defined by the DRC as a complete response (ie, the absence of any findings compatible with continued disease activity) or a partial response (ie, the partial resolution of coccidioidal disease and the absence of worsening at any site). The primary efficacy end point was a response to pretherapy abnormalities at the end of treatment. A nonsuccessful outcome was defined as the absence of improvement in attributable symptoms, signs, and radiographic abnormalities (stable disease) or deterioration in attributable clinical or radiographic abnormalities that necessitated alternative antifungal therapy or resulted in death (failure). Stable disease was grouped with the latter subcategory as "failure." The term unevaluable was utilized by the DRC if the information supplied was insufficient to make an outcome determination. Investigators ascribed the relationship of each adverse event to posaconazole (possible, probable, or definite) and whether the event necessitated the premature discontinuation of therapy or hospitalization.
Blood samples were collected for routine hematologic and chemistry evaluations at 1, 3, and 6 months during treatment and at the final posttherapy visit. A standard 12-lead ECG was obtained at baseline and week 4.
Results
Demographics and Prior Therapy
Fifteen patients were studied. Five patients were determined by the DRC to meet the definition of intolerant, as well as refractory. Four patients were > 60 years old (Table 1
). Six patients were men. Five patients were white; the others belonged to races or ethnic groups that, epidemiologic studies indicate, have a propensity for the development of severe coccidioidal infection.1 Eight patients had serious underlying diseases, several of which were associated with immunosuppression. Eleven patients (73%) had coccidioidal disease present for > 1 year prior to receiving posaconazole therapy, and 5 patients had coccidioidal disease > 4 years. Thus, this cohort was largely composed of patients with chronic coccidioidomycosis. Ten patients had pulmonary coccidioidal disease, with a variety of manifestations, as follows: 5 patients had bone and/or joint disease (3 with multiple sites of skeletal disease); 5 patients had soft-tissue disease (4 had paravertebral abscesses); 4 patients had skin disease; 3 patients had extrapulmonary lymph node disease; 1 patient had CNS disease; 1 patient had choroidal ocular disease12; and 1 patient possibly had the rare entity of coccidioidal endocarditis (the total adds up to > 15, as patients may have had more than one system involved with coccidioidal disease). Thus, the cohort may be characterized as having severe coccidioidal disease.1
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400 days prior to receiving posaconazole (Table 1). Fourteen patients had received other azoles, 8 patients had received an amphotericin preparation, 7 patients had received both, and 2 patients had undergone pulmonary surgery as well as antifungal chemotherapy prior to receiving posaconazole (Table 1) [the total adds to up > 15, as patients may have had more than one prior therapy]. Of those patients who had been treated with azoles, 5 of 14 patients received > 400 mg daily, greater than conventional doses,123 which was a presumed dose escalation because of a lack of response to conventional doses. Thus, overall, these patients had received intensive prior therapy.
Duration of Posaconazole Therapy
The patients received a range of 34 days to 1 year of continuous therapy on the protocol (Table 2
). Some patients interrupted therapy, became noncompliant, or both, or continued therapy while not receiving this protocol (ie, the drug became available through compassionate clearance or another protocol); thus, two patients received 13 and 24 months of total posaconazole therapy. Twelve of 15 patients received 6 months of treatment while in the study. Three of the patients had adjunctive surgery as part of their treatment for coccidioidomycosis (Table 2).
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When the evaluable sites of disease were analyzed separately, there appeared to be generally uniform responsiveness by the sites. There were nine patients with pulmonary disease; eight patients were judged to have responded at the site (two with complete responses). Of the patients with bone and joint disease, four of five patients were assessed as having responded at the site (one with complete response), as were four of five patients with soft-tissue disease, three of four patients with skin disease (one complete response), three of three patients with (extrapulmonary) lymph node disease (one complete response), as well as the one patient with meningitis. (The number of complete responses at sites could exceed the total number of complete responses, as each site was evaluated independently in this tally.)
Six patients’ outcomes were assessable by serial (ie, two or more) culture status determinations while receiving therapy; follow-up cultures were not available in several patients because of clinical resolution at the disease site and the absence of a specimen to culture. Five patients had a positive culture finding pretherapy and a negative culture posttherapy (two from bronchoscopy specimens, one from sputum cultures, one from cerebrospinal fluid, and one from synovial fluid). The other patient remained culture-positive from a sputum sample.
Time to Response
After 1 month of therapy, the conditions of 11 of 15 patients (73%) were deemed to have improved compared to baseline; after 3 months of therapy, 7 of 14 patients (50%) [1 other patient had not responded to therapy and died before the 3-month evaluation); and after 6 months of therapy, 10 of 13 patients (77%). Two of the three nonresponders at 6 months were later declared to be responders. One of the responders, at 6 months, later was ultimately deemed a failure. Another patient had exited the study earlier as a failure, resumed therapy, and responded at the 6-month evaluation. (One patient had exited the study before the 6-month evaluation.)
Thus responses were generally prompt. The variability in response rates between months 1 and 3 reflects the sometimes variable course of coccidioidomycosis while receiving therapy. Therefore, the time to a durable response (ie, a response that, once attained, then remained) was studied. Five patients had a response beginning at 1 month that was sustained for 6 months and to the end of the study (another such patient was also deemed to be a responder at 3-month evaluation and then was lost to follow-up). Three other patients had responses beginning at the 6-month evaluation that persisted to the end of their study course (this applied to an additional patient until scored, finally, as unevaluable because of inadequate data). Two other patients had responses that began after the 6-month evaluation and persisted to the end of their study period. (Three patients did not respond to therapy.)
Possible Adverse Effects
Seven patients had no possible side effects according to the investigators. No patients had possible side effects causing the interruption or discontinuation of therapy, and none had adverse effects that were definitely attributed to the drug. There were five patients with side effects that were deemed to be probably due to the drug (abdominal pain, two patients; nausea, two patients; diarrhea, one patient). Of the adverse effects deemed to be possibly related to the drug, two patients each had headache, hyperreflexia, and alopecia; a variety of possible effects were reported once each. Thus, the drug appears to be well-tolerated in long-term therapy in patients with chronic disease.
Follow-up After This Posaconazole Protocol
A problem with the evaluation of some prior publications on therapy for patients with an often relapsing and remitting disease such as coccidioidomycosis is the absence of postprotocol information. Follow-up information was not available in most of our patients after their study and evaluation period concluded. However, the data indicate that one complete responder is continuing posaconazole therapy while not continuing with the protocol. Two partial responders exited the study owing to noncompliance. One patient, who had been deemed to be unevaluable, interrupted therapy on treatment day 42, was treated on another posaconazole protocol for 13 months, and then became noncompliant; the patient was deemed to have had a successful outcome by the investigator on that protocol. One partial responder interrupted therapy after 1 year, then resumed under another posaconazole protocol and recrudesced on therapy 1.4 years later. The patient then underwent a therapeutic surgical procedure, and the dose was increased to 1,200 mg/d. The patient then received another year of posaconazole therapy at that dose, but colonic coccidioidomycosis that was unresponsive to therapy with voriconazole, interferon-
, and fluconazole, 1,600 mg/d, developed. The patient died with a perforated bowel and active pulmonary coccidioidomycosis 25 months after exiting our study. The other study death occurred in a patient who interrupted posaconazole therapy at 34 days, in whom the clinical findings then met the definition of failure; 39 days later, the patient died of aspergillosis.
Discussion
The study documents the responsiveness to posaconazole used for salvage therapy of chronic coccidioidomycosis that was refractory to prior therapy. It is consistent with recent suggestions13 for the organization of salvage therapy trials. This study cohort had, in addition, important comorbidities. Posaconazole was well tolerated. The response to posaconazole did not appear to be related to patients’ demographic characteristics, including race, underlying conditions, the site of infection, or type or length of prior antifungal therapy, although a larger population of treated patients would be needed to assess these variables adequately. Our outcome conclusion is congruent with assessments of posaconazole from animal model studies5; an initial, short dose-finding study7; and a prior, smaller, single-site experience.11 This conclusion applies to multiple sites of coccidioidal disease, except, at this time, to coccidioidal meningitis. Culture reversion was documented in most instances where this could be assessed. The response rate in this study compares favorably with that in initial open studies of miconazole,14 ketoconazole,1516 itraconazole,1718 or fluconazole1920 as therapy for disseminated nonmeningeal coccidioidomycosis. Those studies included some patients who did not respond to therapy (failures) or who had experienced relapses with prior therapy. Most publications on therapy for coccidioidomycosis have reported on open trials because of the difficulty in accruing sufficient numbers of patients in a timely fashion, with one exception. In that trial,2 for the primary efficacy measure, response at 8 months, response rates were 50% with fluconazole and 63% with itraconazole; response rates at 12 months were 57% and 72%, respectively. In that trial, the exclusion of patients with extensive prior exposure to antifungal agents during that episode of infection disqualified at least some patients with infections that were refractory to standard therapy.
Questions remain for further studies. A randomized trial for initial therapy (or for initial therapy plus therapy for relapsed disease) of disseminated coccidioidomycosis (populations that would be less ill than that studied here) would allow a direct comparison with therapy using other azoles.2 Whether longer periods of posaconazole therapy than that studied here could produce superior results is of interest. Meningitis is the most devastating form of coccidioidal disease and is the most difficult to treat21; posaconazole results in that entity would be of great interest; posaconazole has demonstrated activity against other CNS mycoses in experimental animals and man.2223 Recent publications24 have documented posaconazole efficacy in salvage therapy for other mycoses.
Acknowledgements
We thank Gavin Corcoran and Cathy Bruno for assistance.
Footnotes
Abbreviations: DRC = data review committee; ULN = upper limit of normal
This study was supported by Schering-Plough Research Institute.
Dr. Stevens has participated on consultancy/advisory boards for Schering-Plough, and has received research funding from Schering-Plough. Dr. Rendon has received research funding/grants from a commercial entity for this or related studies. Dr. Catanzato has participated in advisory boards and has received research funding/grants for University of California at San Diego clinical research and consulting. Dr. Anstead has received payment for participation in advisory boards and speakers’ bureau for Schering-Plough and has received grants/funding from Schering-Plough. Dr. Pedicone is an employee of and shareholder in Schering-Plough. Dr. Graybill has participated in speakers’ panels and consultancy/advisory boards for Schering-Plough, and has received research funding from Schering-Plough. Dr. Gaona-Flores has no conflicts of interest to declare.
Received for publication January 12, 2007. Accepted for publication May 8, 2007.
References
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