Comparative evaluation of the efficacy and safety of two doses of terbinafine (500 and 1000 mg day(-1)) in the treatment of cutaneous or lymphocutaneous sporotrichosis.

The aim of this study was to evaluate the safety and efficacy of oral terbinafine (500 and 1000 mg day(-1)) in the treatment of cutaneous or lymphocutaneous sporotrichosis. A culture for Sporothrix schenckii was required for inclusion into this multicentre, randomized, double-blind, parallel-group study. Patients received either 250 mg b.i.d. or 500 mg b.i.d. oral terbinafine for up to a maximum of 24 weeks and were assessed up to 24 weeks post-treatment. The main efficacy outcome measure was cure, defined as no lesion and absence of adenopathy at the end of follow-up. Adverse events (AEs), laboratory tests, vital signs and ophthalmological examinations were also assessed. Sixty-three patients (14-85 years of age) were treated with 500 mg day(-1) (n = 28) or 1000 mg day(-1) terbinafine (n = 35). The majority of patients were cured after 12-24 weeks of treatment, and the response was dose-dependent throughout the study and at the end of follow-up. The cure rate was significantly higher in patients treated with 1000 mg day(-1) terbinafine compared with those treated with 500 mg day(-1) terbinafine (87% vs. 52%, respectively; P = 0.004). There were no cases of relapse after 24 weeks of follow-up in the 1000 mg day(-1) terbinafine group, compared with six relapses in the terbinafine 500 mg day(-1) group. Terbinafine was well tolerated and the frequency of drug-related AEs was slightly higher in the 1000 mg treatment group. Both doses of terbinafine were well-tolerated and effective for the treatment of sporotrichosis. The 1000 mg day(-1) terbinafine dose was more efficacious than 500 mg day(-1) in the treatment of cutaneous or lymphocutaneous sporotrichosis.

The impact of culture isolation of Aspergillus species: a hospital-based survey of aspergillosis.

The term "aspergillosis" comprises several categories of infection: invasive aspergillosis; chronic necrotizing aspergillosis; aspergilloma, or fungus ball; and allergic bronchopulmonary aspergillosis. In 24 medical centers, we examined the impact of a culture positive for Aspergillus species on the diagnosis, risk factors, management, and outcome associated with these diseases. Most Aspergillus culture isolates from nonsterile body sites do not represent disease. However, for high-risk patients, such as allogeneic bone marrow transplant recipients (60%), persons with hematologic cancer (50%), and those with signs of neutropenia (60%) or malnutrition (30%), a positive culture result is associated with invasive disease. When such risk factors as human immunodeficiency virus infection (20%), solid-organ transplantation (20%), corticosteroid use (20%), or an underlying pulmonary disease (10%) are associated with a positive culture result, clinical judgment and better diagnostic tests are necessary. The management of invasive aspergillosis remains suboptimal: only 38% of patients are alive 3 months after diagnosis. Chronic necrotizing aspergillosis, aspergilloma, and allergic bronchopulmonary aspergillosis have variable management strategies and better short-term outcomes.

Differential transcription factor expression in human mononuclear cells in response to amphotericin B: identification with complementary DNA microarray technology.

STUDY OBJECTIVE: To identify genes differentially expressed in human monocytic cells exposed to amphotericin B in vitro. DESIGN: In vitro experiment. SETTING: Hospital laboratory. MATERIAL: Human mononuclear cell line, THP-1. INTERVENTION: Human mononuclear cells were exposed to amphotericin B or media alone for 6 hours. After exposure, total RNA was isolated and reverse transcribed to complementary DNA. Differences in probe hybridization observed during blotting were measured, and genes with altered regulation were described by using human complementary DNA microarray technology. MEASUREMENTS AND MAIN RESULTS: Of 588 genes represented on the array, 16 transcripts were found to be upregulated and 4 transcripts were downregulated in response to amphotericin B. These findings suggest that amphotericin B alters the expression of genes in human monocytic cells that play a role in many cellular functions, including immune response, signal transduction, and cell differentiation. CONCLUSION: Amphotericin B induces alterations in human cell gene transcription. These changes could be used to evaluate differences in toxicity or efficacy observed in patients receiving this agent.

Intravenous itraconazole.

OBJECTIVE: To review the pharmacology, mycology, chemistry, pharmacokinetics, efficacy, safety, tolerability, dosage, administration, and economic issues of intravenous itraconazole. DATA SOURCES: A MEDLINE search from 1978 to June 2000 of the English-language literature and an extensive review of meeting abstracts was conducted. Due to the paucity of published information concerning the pharmacokinetics, efficacy, and safety of the intravenous formulation of intravenous itraconazole, additional information was obtained from the manufacturer. DATA EXTRACTION: Data from in vitro and preclinical studies, as well as Phase II and III clinical trials, were included. DATA SYNTHESIS: The triazole antifungal agent itraconazole is available in a cyclodextrin-based intravenous formulation. Intravenous itraconazole is indicated for the treatment of pulmonary and extrapulmonary blastomycosis; histoplasmosis, including chronic cavitary pulmonary disease and disseminated, nonmeningeal histoplasmosis; and pulmonary and extrapulmonary aspergillosis in patients who are intolerant of or who are refractory to amphotericin B. This formulation provides quicker and more consistent therapeutic concentrations than the oral formulations. Clinical data comparing the efficacy of intravenous itraconazole with that of amphotericin B are lacking. CONCLUSIONS: Intravenous itraconazole offers a less toxic alternative for patients with pulmonary and extrapulmonary blastomycosis, histoplasmosis, and aspergillosis who cannot receive oral medications or who are intolerant of or refractory to amphotericin B.

Amphotericin B induces expression of genes encoding chemokines and cell adhesion molecules in the human monocytic cell line THP-1.

Amphotericin B is known to elicit immunomodulatory effects on neutrophil, monocyte, and lymphocyte function. It also has been shown to induce the release of proinflammatory cytokines from human monocytes and macrophages. Release of these cytokines has been associated with the infusion-related toxicity observed after administration of this drug. The present study demonstrates that amphotericin B increases mRNA for the chemokines interleukin (IL)-8, monocyte chemoattractant protein (MCP)-1, and macrophage inflammatory protein (MIP)-1beta, as well as the cell adhesion molecules intercellular adhesion molecule (ICAM)-1 and CD44 in the human monocytic cell line THP-1. Amphotericin B increased the concentrations of IL-8, MCP-1, and MIP-1beta in a dose-dependent fashion. Amphotericin B also induced expression of ICAM-1 but not CD44 in these cells. Production of these proteins in response to amphotericin B may play a role in the immunomodulatory activity and toxicity of this antifungal agent.

Practice guidelines for the management of patients with blastomycosis. Infectious Diseases Society of America.

Guidelines for the treatment of blastomycosis are presented; these guidelines are the consensus opinion of an expert panel representing the National Institute of Allergy and Infectious Diseases Mycoses Study Group and the Infectious Diseases Society of America. The clinical spectrum of blastomycosis is varied, including asymptomatic infection, acute or chronic pneumonia, and extrapulmonary disease. Most patients with blastomycosis will require therapy. Spontaneous cures may occur in some immunocompetent individuals with acute pulmonary blastomycosis. Thus, in a case of disease limited to the lungs, cure may have occurred before the diagnosis is made and without treatment; such a patient should be followed up closely for evidence of disease progression or dissemination. In contrast, all patients who are immunocompromised, have progressive pulmonary disease, or have extrapulmonary disease must be treated. Treatment options include amphotericin B, ketoconazole, itraconazole, and fluconazole. Amphotericin B is the treatment of choice for patients who are immunocompromised, have life-threatening or central nervous system (CNS) disease, or for whom azole treatment has failed. In addition, amphotericin B is the only drug approved for treating blastomycosis in pregnant women. The azoles are an equally effective and less toxic alternative to amphotericin B for treating immunocompetent patients with mild to moderate pulmonary or extrapulmonary disease, excluding CNS disease. Although there are no comparative trials, itraconazole appears more efficacious than either ketoconazole or fluconazole. Thus, itraconazole is the initial treatment of choice for nonlife-threatening non-CNS blastomycosis.

Practice guidelines for the management of patients with sporotrichosis. For the Mycoses Study Group. Infectious Diseases Society of America.

UNLABELLED: The recommendations for the treatment of sporotrichosis were derived primarily from multicenter, nonrandomized treatment trials, small retrospective series, and case reports; no randomized, comparative treatment trials have been reported. Most cases of sporotrichosis are non life-threatening localized infections of the skin and subcutaneous tissues that can be treated with oral antifungal agents. The treatment of choice for fixed cutaneous or lymphocutaneous sporotrichosis is itraconazole for 36 months. The preferred treatment for osteoarticular sporotrichosis also is itraconazole, but therapy must be continued for at least 12 months. Pulmonary sporotrichosis responds poorly to treatment. Severe infection requires treatment with amphotericin B; mild to moderate infection can be treated with itraconazole. Meningeal and disseminated forms of sporotrichosis are rare and usually require treatment with amphotericin B. AIDS patients most often have disseminated infection and require life-long suppressive therapy with itraconazole after initial use of amphotericin B. OVERVIEW: Sporotrichosis is caused by the dimorphic fungus Sporothrix schenckii, which is found throughout the world in decaying vegetation, sphagnum moss, and soil. The usual mode of infection is by cutaneous inoculation of the organism. Pulmonary and disseminated forms of infection, although uncommon, can occur when S. schenckii conidia are inhaled. Infections are most often sporadic and usually associated with trauma during the course of outdoor work. Infection can also be related to zoonotic spread from infected cats or scratches from digging animals, such as armadillos. Outbreaks have been well-described and often are traced back to activities that involved contaminated sphagnum moss, hay, or wood. Most cases of sporotrichosis are localized to the skin and subcutaneous tissues. Dissemination to osteoarticular structures and viscera is uncommon and appears to occur more often in patients who have a history of alcohol abuse or immunosuppression, especially AIDS. Spontaneous resolution of sporotrichosis is rare, and treatment is required for most patients. Although sporotrichosis localized to skin and subcutaneous tissues is readily treated, management of osteoarticular, other localized visceral, and disseminated forms of sporotrichosis is difficult. OBJECTIVE: The objective of these guidelines is to provide recommendations for the treatment of various forms of sporotrichosis. OUTCOMES: The desired outcomes of treatment include eradication of S. schenckii from tissues, resolution of symptoms and signs of active infection, and return of function of involved organs. In persons with AIDS, eradication of the organism may not be possible, but clinical resolution should be attained and subsequently maintained with suppressive antifungal therapy. EVIDENCE: The English-language literature on the treatment of sporotrichosis was reviewed. Although randomized, blinded, controlled treatment trials were sought, none were found to have been performed for the treatment of sporotrichosis. Therefore, most weight was placed on those reports that were derived from multicenter trials of specific treatment modalities for sporotrichosis. Small series from a single institution and individual case reports were accorded less importance. VALUES: The highest value was placed on clinical efficacy and the ability of the antifungal regimen to eradicate the organism, but safety, tolerability, and cost of therapy were also valued. BENEFITS AND COSTS: The benefits of successfully treating sporotrichosis accrue primarily for the patient. Because this infection is not spread from person-to-person, public health aspects of treatment are of minor importance. Most forms of sporotrichosis are not life-threatening; thus, therapy is aimed at decreasing morbidity, improving quality of life, and allowing the patient to return to occupational and familial pursuits. (ABSTRACT TRUNCATED)

Administration of crushed extended-release pentoxifylline tablets: bioavailability and adverse effects.

The pharmacokinetics of crushed and intact pentoxifylline tablets were compared, and the frequency of adverse effects was evaluated. Intact 400-mg extended-release pentoxifylline tablets, crushed 400-mg tablets, intact 600-mg tablets, and crushed 600-mg tablets were given sequentially to 10 healthy male volunteers. Blood samples were collected at time 0, at 30-minute intervals for the first three hours, and at 4, 6, 8, 12, and 24 hours after the dose and analyzed by capillary gas chromatography for pentoxifylline and three major metabolites. The bioavailability of the crushed tablets relative to the intact tablets was 156% for the 400-mg strength and 137% for the 600-mg strength. The area under the plasma drug concentration-time curve from 0 to 24 hours (AUC0-24) for the 400-mg tablets (crushed and intact) differed significantly from that for the 600-mg tablets; there was no significant difference between intact 400-mg and intact 600-mg tablets or crushed 400-mg and crushed 600-mg tablets. The maximum plasma drug concentration (Cmax) was significantly greater and the time to maximum concentration (t(max)) significantly shorter for crushed tablets than intact tablets. The 400-mg crushed tablet caused mild nausea in three subjects. The 600-mg crushed tablet caused both moderate nausea and dizziness in seven subjects and diaphoresis, headache, and vomiting in one subject each. Cmax was higher and tmax shorter when pentoxifylline tablets were administered crushed rather than intact, and the increase in maximum plasma concentrations appeared to cause dose-related adverse effects; crushing the tablets did not decrease the relative bioavailability.

Amphotericin B-induced interleukin-1beta expression in human monocytic cells is calcium and calmodulin dependent.

Amphotericin B remains the agent of choice for treatment of severe fungal infections. Its use is hindered by adverse effects, including infusion-related fever, chills, and hypotension, as well as nephrotoxicity with secondary anemia, hypokalemia, and hypomagnesemia. Amphotericin B-induced transcription and expression of interleukin (IL)-1beta by human monocytes is believed to be involved in mediating infusion-related adverse effects. It is shown here that agents that increase intracellular calcium [Ca++]i (A23187 and thapsigargin) in human monocytic cells also induce IL-1beta expression. Furthermore, amphotericin B-induced IL-1beta expression is attenuated by the calmodulin antagonist calmidazolium. Amphotericin B 5.41 microM increases [Ca++]i by up to 300 nM in these cells. In the presence of a nominal calcium buffer or EGTA, amphotericin B-induced IL-1beta expression is attenuated. Thus, amphotericin B acts as an ionophore to increase [Ca++]i and activates calmodulin-mediated expression of IL-1beta in human monocytes.

Amphotericin B activation of human genes encoding for cytokines.

Amphotericin B has been shown to cause release of cytokines, including interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha), from monocytes and macrophages. Human and murine monocytic cell lines were used to evaluate the effects of amphotericin B on the transcription of IL-1alpha, IL-1beta, and TNF-alpha and the transcription and production of soluble IL-1 receptor antagonist (sIL-1Ra). The effects of inhibitors of transcription and translation on amphotericin B-induced IL-1beta expression in a human monocytic cell line were also evaluated. Amphotericin B markedly increased IL-1beta and TNF-alpha mRNA levels, with peak levels occurring by 4 h. Amphotericin B induced production of sIL-1Ra in a dose-dependent fashion and induced sIL-1Ra mRNA, with peak levels at 24 h. Cycloheximide and actinomycin D resulted in a dose-dependent decrease in amphotericin B-induced IL-1beta expression at 2 h. Thus, amphotericin B induces gene expression for IL-1beta, TNF-alpha, and IL-1Ra in human and murine monocytic cells.

Antifungal therapy during pregnancy.

Careful consideration of the benefit to the mother and the risk to the fetus is required when prescribing antifungal therapy in pregnancy. Imidazoles are considered safe as topical therapy for fungal skin infections during pregnancy. Nystatin is minimally absorbed and is effective for vaginal therapy. Although vaginal use of the imidazoles is probably safe during the later stages of pregnancy, their systemic absorption is higher than when applied to the skin. The systemic antifungal drug with which there has been the most experience in pregnancy is amphotericin B. There have been no reports of teratogenesis attributed to this agent. There is evidence to suggest that fluconazole exhibits dose-dependent teratogenic effects; however, it appears to be safe at lower doses (150 mg/day). Ketoconazole, flucytosine, and griseofulvin have been shown to be teratogenic and/or embryotoxic in animals. Iodides have been associated with congenital goiter and should not be used during pregnancy.

Susceptibilities of clinical and laboratory isolates of Blastomyces dermatitidis to ketoconazole, itraconazole, and fluconazole.

Eighteen isolates of Blastomyces dermatitidis were evaluated for their in vitro susceptibilities to ketoconazole, itraconazole, and fluconazole. The MIC ranges were 0.1 to 0.4 microg/ml for ketoconazole, < or =0.018 to 0.07 microg/ml for itraconazole, and 2.5 to 4.0 microg/ml for fluconazole. The ranges for the minimal lethal concentrations were 0.2 to 0.8 microg/ml for ketoconazole, < or =0.018 to 0.07 microg/ml for itraconazole, and 10 to 40 microg/ml for fluconazole. Itraconazole was the most active agent against B. dermatitidis in vitro, while fluconazole was the least active. These results correlate with the clinical efficacies noted to date with doses of these agents used to treat blastomycosis.

Reliability and validity of rigid lift and pelvic leveling device method in assessing functional leg length inequality.

Clinicians commonly include an assessment of leg length inequality (LLI) as a component of a musculoskeletal examination. Little research is available, however, documenting reliability and validity of clinical methods for assessing LLI. The purpose of this study was to determine the reliability and validity of assessing functional LLI using a pelvic leveling device. Subjects were 19 women and 13 men between the ages of 18 and 55 who reported having a diagnosed or suspected LLI. Clinical determination of LLI was made by placing rigid lifts under the suspected shorter lower extremity until the leveling device indicated that the iliac crests were level. This measurement was made twice by one investigator and once by a second investigator. Standing radiographic measurements of LLI using rigid lifts were used to establish validity of the clinical method. Intraclass correlation coefficients [ICC(2,1)] and absolute difference values were computed to assess reliability and validity. The mean absolute difference between the two clinical measurements of LLI by the same investigator was 0.29 cm (+/- 0.52), with an ICC = 0.84. The mean absolute difference between clinical measurements of LLI by the two investigators was 0.49 cm (+/- 0.46), with an ICC = 0.77. The ICC and mean absolute difference reflecting agreement between radiographic measurements and clinical measurements of LLI was 0.64 and 0.58 cm (+/- 0.58), respectively, for one investigator and 0.76 and 0.55 cm (+/- 0.37), respectively, for the second investigator. The intratester reliability, intertester reliability, and validity assessments included instances in which paired observations disagreed regarding which lower extremity was the shorter lower extremity. Factors that may be associated with the unacceptable reliability and validity of the clinical assessment method include asymmetric positioning of the ilia, body composition of the patient, and design of the clinical instrument. The authors discuss clinical implications related to assessment of LLI.

Endemic blastomycosis in Mississippi: epidemiological and clinical studies.

In order to clarify the epidemiology and clinical spectrum of endemic blastomycosis, we reviewed the charts of 326 culture and/or histologically proven cases of blastomycosis in Mississippi from 1979 to 1988. Cases were dispersed throughout the state, but counties in central and south-central Mississippi reported 63% of all blastomycosis cases. The average annual incidence rate was 1.3 cases per 100,000 population. The majority of cases were in men (male to female ratio 1.7:1), and most patients were aged in their third through seventh decades (82%). Outdoor occupations were noted for only 28.9% of cases. Cases occurred throughout the year with no significant seasonal peak. Although 55% saw a physician within 7 days of onset of illness, 29% presented after 1 month. Despite early presentation, diagnosis was often delayed for more than 1 month (43.3%). Single organs were involved in 82.8% of cases. For all cases, organ systems involved included lungs (91.4%), skin (18.1%), bone (4.3%), genitourinary system (1.8%), and central nervous system (1.2%). The presence of skin or bone disease was associated with multiorgan involvement. Thirty-three patients died (11.5%), 6 of whom received no therapy. Patients who died were significantly older than those who survived. A successful outcome without relapse was noted in 86.5% of amphotericin B-treated patients and in 81.7% of ketoconazole-treated patients. The relapse rate for ketoconazole-treated patients was higher than for amphotericin B-treated patients (14% and 3.9% respectively).

Treatment of blastomycosis with higher doses of fluconazole. The National Institute of Allergy and Infectious Diseases Mycoses Study Group.

Recent clinical data suggest that fluconazole at daily doses of 200 to 400 mg for at least 6 months is moderately effective therapy for non-life-threatening blastomycosis. To examine the usefulness of higher doses of fluconazole therapy for this disorder, we conducted a multicenter, randomized, open-label study to determine the efficacy and safety of two different daily doses of fluconazole (400 and 800 mg) in the treatment of non-life-threatening blastomycosis. Of 39 patients evaluable for efficacy analysis, 34 (87%) were successfully treated, including 89% and 85% of patients who received 400 and 800 mg, respectively. Five (83%) of six patients for whom prior antifungal therapy had failed were successfully treated. The mean duration of therapy was 8.9 months for successfully treated patients. Nineteen patients (48%) reported adverse events, although most were minor. We conclude that fluconazole at daily doses of 400 to 800 mg for at least 6 months is effective therapy for non-life-threatening blastomycosis.

Amphotericin B enzyme-linked immunoassay for clinical use: comparison with bioassay and HPLC.

OBJECTIVE: To evaluate a new enzyme-linked immunosorbent assay (ELISA) for amphotericin B in serum samples. Results are compared with those obtained by HPLC and bioassay. DESIGN: Comparison of results obtained by ELISA, HPLC, and bioassay. METHODS: We developed a new ELISA using a polyclonal rabbit antibody to measure serum amphotericin B concentrations. Blinded samples of amphotericin B in concentrations of 0.15-78 micrograms/mL were prepared in human serum and assayed simultaneously by the ELISA, HPLC, and bioassay. The results of each assay were derived from standard curves and evaluated by using the Table Curve 2D computer program. These data were compared by using correlation analysis with evaluation of Pearson's correlation coefficient by Student's t-test. RESULTS: ELISA and bioassay compared favorably at amphotericin B concentrations of 0.3-20 micrograms/mL with a correlation coefficient of r = 0.993, while ELISA and HPLC compared with a correlation coefficient of r = 0.944. The average coefficient of variation over the range 0.3-20.0 micrograms/mL was 28% +/- 7% for HPLC, 26% +/- 9% for ELISA, and 13% +/- 4% for bioassay. Comparison of all three assays revealed the highest correlation with the ELISA assay (r = 0.998) for the range of concentrations (0.3-20 micrograms/mL) routinely achieved. Samples containing concentrations in excess of 20 micrograms/mL could be diluted. Desiccation for concentrations less than 0.3 microgram/mL was not tested. CONCLUSION: The determination of serum amphotericin B concentrations by ELISA gave results similar to those obtained by a bioassay and HPLC technique. Although variability appears greater with ELISA, the ease of performing yjis assay expedites the evaluation of amphotericin B concentrations from lipid formulations without interference from coadministered antibacterials of azole antifungals.

Amphotericin B enzyme-linked immunosorbent assay.

Our purpose was to develop and characterize an enzyme-linked immunosorbent assay (ELISA) which could measure the concentration of amphotericin B in serum. Amphotericin B was assayed by competition ELISA. Multiwell ELISA plates coated with amphotericin B (1.0 micrograms/ml) conjugated to bovine serum albumin were used to test replicates of serum samples spiked with amphotericin B. Purified rabbit polyclonal antibody against amphotericin B (1.4 micrograms/ml) was added subsequent to the instillation of samples spiked with unknown amounts of amphotericin B. Experiments were performed to test the sensitivity, specificity, precision, and accuracy of the assay. The ability to measure lipid-associated amphotericin B was also evaluated in preliminary studies. Analysis of reference samples containing amphotericin B yielded a traditional sigmoidal curve. The limits of detection were 0.15 to 156 micrograms/ml. The sensitivity of the assay was affected by light and temperature exposure. Assay specificity was altered only by the presence of nystatin, a polyene antifungal agent similar to amphotericin B. Intrarun (coefficient of variation = 3.0%) and interrun (coefficient of variation = 12.8%) coefficients of variation were calculated and were comparable to those in similar assays. The assay's correlation coefficient (r = 0.907) demonstrated a statistically significant correlation between the optical density of the sample and the concentration of drug in the sample. The amphotericin B ELISA's ease, precision, and overall accuracy suggest that this assay could be used for assessments of serum amphotericin B concentrations. Multiple research questions concerning the role of serum amphotericin B concentrations in toxicity and efficacy have gone unanswered because of the labor-intensive nature of the assays which have been available to date. The ability to easily and rapidly measure 40 duplicate samples containing amphotericin B should also prove to be a distinct advantage for clinical research or reference laboratories in addressing these questions.

Alopecia associated with fluconazole therapy.

OBJECTIVE: To describe the association between fluconazole and reversible alopecia. DESIGN: A retrospective survey of 1) patients enrolled in NIAID Mycoses Study Group (MSG) protocols involving the long-term use of fluconazole for treatment of endemic mycoses and 2) patients treated with fluconazole outside of a protocol setting but by the MSG investigators who were MSG members. SETTING: 26 MSG sites in the United States. PATIENTS: 33 patients with various deep and superficial mycoses who developed alopecia while receiving fluconazole. RESULTS: 11 of 26 investigators reported a total of 33 patients with substantial alopecia related to fluconazole therapy. Underlying mycoses included blastomycosis, sporotrichosis, histoplasmosis, cryptococcosis, coccidioidomycosis, and mucosal candidiasis. In separate MSG studies, 17 of 136 (12.5%) and 8 of 40 (20%) patients had substantial reversible alopecia associated with fluconazole therapy. Eight patients who were not in the protocol had similar adverse effects. Twenty-nine of 33 patients (88%) received at least 400 mg of fluconazole daily for a mean of 7.1 months. Alopecia developed a median of 3 months after initiation of fluconazole therapy and involved the scalp in all patients. Other sites were involved in about one third of patients. Three patients required wigs because of extensive hair loss. Alopecia resolved within 6 months of discontinuation of fluconazole therapy or reduction of the daily dose by at least 50%. CONCLUSIONS: Alopecia appears to be a common adverse event associated with higher-dose (400 mg/d) fluconazole given for 2 months or longer. This effect may be severe but is reversed by discontinuing fluconazole therapy or substantially reducing the daily dose.

Fluconazole in the treatment of chronic pulmonary and nonmeningeal disseminated coccidioidomycosis. NIAID Mycoses Study Group.

PURPOSE: To determine the efficacy and safety of fluconazole as treatment for coccidioidomycosis. PATIENTS AND METHODS: This was a multicenter, open-label, single-arm study. Of 78 patients enrolled, 22 had soft-tissue, 42 had chronic pulmonary, and 14 had skeletal coccidioidomycosis. Forty-nine had at least one concomitant disease, 7 of whom had HIV infection. Patients were given oral fluconazole 200 mg/d. Nonresponders were increased to 400 mg/d. Treatment courses were long: a mean of 323 +/- 230 days at 200 mg and 433 +/- 178 days at 400 mg. Predefined assessment of disease-related abnormalities was performed at the time of enrollment and repeated at least every 4 months. A satisfactory response was defined as any reduction of baseline abnormality by month 4 and at least 51% reduction by month 8. RESULTS: Among 75 evaluable patients, a satisfactory response was observed in 12 (86%) of the 14 patients with skeletal, 22 (55%) of the 40 patients with chronic pulmonary, and 16 (76%) of the 21 patients with soft-tissue disease. Five patients (7%) required modification of treatment due to toxicity. Forty-one patients who responded were followed off drug. Fifteen (37%) of them experienced reactivation of infection. CONCLUSION: Fluconazole 200 or 400 mg/d is well tolerated and a moderately effective treatment for chronic pulmonary or nonmeningeal disseminated coccidioidomycosis. The relapse rate following therapy is high. Treatment trials with higher doses appear warranted. The relative efficacy of fluconazole versus other azoles or amphotericin B remains unknown.

Fluconazole penetration into the human prostate.

Fluconazole concentrations in the serum and prostate of human volunteers undergoing transurethral resection for benign prostatic hypertrophy were measured. There was a high correlation (r = 0.783) between serum (mean = 6.6 micrograms/ml) and tissue (mean = 1.9 micrograms/g) fluconazole concentrations, and these data were used to construct a model for local tissue concentrations.