Posaconazole as salvage treatment of invasive fungal infections in patients with underlying renal impairment.

OBJECTIVES: The aim of this study is to determine the efficacy and safety of posaconazole in patients with underlying renal impairment. Patients and methods We analysed the efficacy and safety of posaconazole in patients with renal impairment in a post hoc subanalysis of a Phase 3, multicentre, open-label trial in patients with invasive fungal infections (IFIs). In the Phase 3 study, 330 patients intolerant of or with IFIs refractory to standard antifungal therapy received posaconazole 800 mg daily in divided doses. In our subanalysis, 238 patients with proven/probable IFIs, including 65 patients with renal impairment (creatinine clearance < 50 mL/min or serum creatinine (sCR) level >2 mg/dL at baseline) and 173 patients with greater renal function [creatinine clearance >/= 50 mL/min (acceptable renal function)], formed the modified intent-to-treat population. Success was defined as complete or partial response, and non-success was defined as stable disease or treatment failure. RESULTS: Overall response rates were similar in the renal impairment group (49%) and in the acceptable renal function (50%) group. Seventeen of the 41 patients with renal impairment and aspergillosis responded. Adverse events occurred in 32/65 (49%) patients with renal impairment and in 72/173 (42%) patients with acceptable renal function. The most common adverse events in both groups were nausea (14% patients with renal impairment versus 8% with acceptable renal function), altered/elevated levels of other medications (8% versus 2%), increased sCR levels (6% versus 0%), vomiting (6% versus 4%), abdominal pain (5% versus 5%) and dizziness (5% versus 1%). CONCLUSIONS: These results suggest that posaconazole is effective and well tolerated in patients with refractory IFIs regardless of renal impairment.

Experimental histoplasmosis in the beige mouse.

Mice carrying the beige mutation (bg/bg) on a C57Bl/6 background were challenged with Histoplasma capsulatum. bg/bg mice had higher mortality and higher lung tissue fungal counts in their lungs than either bg/+ or C57Bl/6 mice challenged with equal inocula. Immunologic studies showed that bg/bg mice developed normal delayed-type hypersensitivity (DTH) reactions to histoplasmin, but had deficient NK cell cytotoxic activity against YAC-1 target cells. Studies of macrophage killing of H. capsulatum in vitro showed that T lymphocytes of either bg/+ or bg/bg mice were able to activate fungal killing by bg/+ but not by bg/bg macrophages. These studies, while not excluding a role for the NK cell, suggest that macrophage dysfunction may be critical in the greater susceptibility of the bg/bg mouse and, by extension, that macrophage function is of major importance in host defense against H. capsulatum.

Successful treatment of cryptococcal meningitis with intraventricular miconazole.

A patient with cryptococcal meningitis retractory to amphotericin B was treated primarily with intraventricular miconazole. All parameters of disease improved, and the patient was dischared after four months of therapy. In selected persons with cryptococcosis, it may be possible to successfully utilize intraventricular miconazole in the absence of concurrent intravenous medication.

High-dose ketoconazole therapy and adrenal and testicular function in humans.

Ketoconazole, an oral antifungal, when given in conventional doses, transiently blocks testosterone synthesis and adrenal response to corticotropin. Higher therapeutic doses (ie, 800 to 1,200 mg/day), even once daily, caused more prolonged blockade. In some men, the serum testosterone concentrations were always subnormal. Bound and free testosterone values were equally diminished. Oligospermia and azospermia after prolonged therapy were noted. Impotence and decreased libido were found. Gynecomastia appeared more common than with lower doses. Depressed response to corticotropin was pronounced. Urine cortisol excretion was depressed. The blockade appeared related to the serum ketoconazole concentration. Instances of normal hormone levels or responsiveness were associated with low ketoconazole concentrations. The hormonal effects were generally unrelated to duration of therapy, although there may have been partial reversal with continued therapy. These effects appeared reversible with discontinuation of therapy. Patients receiving ketoconazole should be considered potentially unable to mount an adrenal stress response and may require testosterone supplementation.

Invasive aspergillosis. Disease spectrum, treatment practices, and outcomes. I3 Aspergillus Study Group.

A review of representative cases of invasive aspergillosis was conducted to describe current treatment practices and outcomes. Eighty-nine physicians experienced with aspergillosis completed case forms on 595 patients with proven or probable invasive aspergillosis diagnosed using modifications of the Mycoses Study Group criteria. Pulmonary disease was present in 56%, with disseminated infection in 19%. The major risk factors for aspergillosis were bone marrow transplantation (32%) and hematologic malignancy (29%), but patients had a variety of underlying conditions including solid organ transplants (9%), AIDS (8%), and pulmonary diseases (9%). Overall, high antifungal failure rates occurred (36%), and complete antifungal responses were noted in only 27%. Treatment practices revealed that amphotericin B alone (187 patients) was used in most severely immunosuppressed patients while itraconazole alone (58 patients) or sequential amphotericin B followed by itraconazole (93 patients) was used in patients who were less immunosuppressed than patients receiving amphotericin B alone. Response rate for patients receiving amphotericin B alone was poor, with complete responses noted in only 25% and death due to or with aspergillosis in 65%. In contrast, patients receiving itraconazole alone or following amphotericin B had death due to or with Aspergillus in 26% and 36%, respectively. These results confirm that mortality from invasive aspergillosis in severely immunosuppressed patients remains high even with standard amphotericin B. Improved responses were seen in the less immunosuppressed patients receiving sequential amphotericin B followed by itraconazole and those receiving itraconazole alone. New approaches and new therapies are needed to improve the outcome of invasive aspergillosis in high-risk patients.

Histoplasmosis in the acquired immunodeficiency syndrome (AIDS): treatment with itraconazole and fluconazole.

The manifestations of histoplasmosis in 20 patients with the acquired immunodeficiency syndrome are presented. In this series, patients were treated with either itraconazole or fluconazole. Twelve patients received treatment with itraconazole at 400 mg/day, including two patients who had not responded to treatment with fluconazole at 100 mg/day. Of the responses, seven were classified as remissions (mean treatment duration of 24 months), two as improvements, and three as failures. Ten patients received fluconazole. Of the responses, three were classified as remissions (mean treatment duration of 12 months), one as improvement, and six as failures. Of the 10 patients treated with fluconazole, five received doses of 100 mg/day, and five were given doses of 400 or 800 mg/day. The differences in outcome among the five patients receiving the lower dose of fluconazole (one remission, one improvement, and three failures) and the five patients given the higher doses of fluconazole (two remissions and three failures) were negligible. One other patient showed signs of histoplasmosis while receiving fluconazole at 50 mg/day for treatment of thrush. Three failures (two treated with itraconazole and one with fluconazole) followed lapses in azole therapy because of associated conditions. Azole therapy was well tolerated. The treatment responses in this pilot series appear promising in comparison with those reported in the literature with amphotericin B or ketoconazole.

Itraconazole: managing mycotic complications in immunocompromised patients.

Patients with immune depression are at increased vulnerability to a variety of mycotic infections. These range from mucosal and disseminated candidiasis to invasive aspergillosis to regional mycoses, such as histoplasmosis and Penicillium morneffei, and the emerging mycoses including zygomycetes, phaeohyphomycetes, Fusarium sp, Trichosporon sp, and others. An increasing variety of antifungal drugs, among which are fluconazole and itraconazole, are used for the treatment of these opportunistic infections. Fluconazole has excellent absorption, linear renal excretion of largely active drug, and limited spectrum, primarily against yeast pathogens such as Candida sp. In its capsule formulation, itraconazole has broader activity, including mycelial pathogens, but suffers from irregular absorption, lack of intravenous formulation, and complex hepatic excretion. Itraconazole has recently undergone reformulation as a solution, which gives significant added advantages in bioavailability and increases the practical applications. It is at present unclear whether voriconazole, SCH56592, or itraconazole solution will be equally potent and have a similar range of applications.

Ketoconazole therapy of progressive coccidioidomycosis. Comparison of 400- and 800-mg doses and observations at higher doses.

One hundred and twelve patients with progressive pulmonary, skeletal, or soft tissue infections caused by Coccidioides immitis were randomly assigned to treatment with 400 or 800 mg per day dosages of ketoconazole. During therapy, if response was unsatisfactory, the protocol provided for treatment with higher doses. With 400 mg, ketoconazole resulted in 23.2 percent successes, which was similar to 32.1 percent successes with 800-mg treatments (p = 0.29). An additional six of 23 patients in whom initial therapy failed and who later received 1,200 or 1,600 mg per day of ketoconazole also showed improvement. However, among patients completing successful courses of therapy, relapses were more frequent in those requiring higher than 400-mg dosages for their success. From these studies, it is concluded that ketoconazole in doses above those currently recommended offer little or no benefit for most patients with non-meningeal forms of coccidioidomycosis.

Itraconazole treatment of coccidioidomycosis. NAIAD Mycoses Study Group.

PURPOSE: The purpose of this study was to assess the tolerance and efficacy of itraconazole in the treatment of coccidioidomycosis. PATIENTS AND METHODS: Fifty-one patients with nonmeningeal coccidioidomycosis were considered for treatment with intraconazole. Forty-nine patients who met study criteria were treated with itraconazole given orally in doses of 100 to 400 mg/day for periods up to 39 months. Of these patients, 12 had osteoarticular disease, 23 had chronic pulmonary disease, and 14 had skin or soft tissue disease. Clinical response was evaluated using a scoring system accounting for lesion number and size, symptoms, culture, and serologic titer. Remission was defined as reduction of the pretreatment score by 50% or more. RESULTS: Patients with osteoarticular, chronic pulmonary, and soft tissue disease improved at similar rates. Because two patients had no scoring assessment for efficacy, they were considered inassessable for efficacy. Forty-seven patients are evaluable. Of these patients, 44 have completed therapy, and three are still receiving itraconazole. Of the 44 patients no longer receiving therapy, 25 (57%) achieved remission. Of the 25 patients achieving remission, four later experienced a relapse. Therapy failed in 19 patients (43%). Of these cases, 16 (36%) were clinical failures and three (7%) developed drug intolerance that precluded continuation of treatment. Evaluation of culture conversions was of limited value in the osteoarticular patients, fewer than half of whom had follow-up biopsies. However, culture conversions were a useful index of response in patients with chronic pulmonary disease. During the course of treatment, serologic titers declined in the two groups with extrapulmonary disease, but not in patients with pulmonary coccidioidomycosis. Possible toxicities were generally mild. CONCLUSION: Itraconazole appears efficacious and very well tolerated in patients with coccidioidomycosis.

Oral fluconazole therapy for patients with acquired immunodeficiency syndrome and cryptococcosis: experience with 22 patients.

PURPOSE: Cryptococcus neoformans causes infections in up to 10 percent of patients with the acquired immunodeficiency syndrome (AIDS). Nearly 50 percent of AIDS patients with previously treated cryptococcal meningitis will experience a relapse within six months. To reduce the likelihood of relapse, a maintenance regimen of amphotericin B is often administered weekly. However, the drug's intravenous route of administration and considerable toxicity have led to a search for alternative antifungal agents. In this report, we document our experience with fluconazole, a new oral triazole antifungal agent. PATIENTS AND METHODS: Twenty-two patients with AIDS and various forms of cryptococcosis were treated in an open-label study with 50 to 400 mg/day of fluconazole. The following laboratory studies were done on a monthly basis: complete blood cell count, liver function tests, serum creatinine level, serum cryptococcal antigen level, and serum fluconazole level. Lumbar puncture was performed in patients with meningitis every four to eight weeks to evaluate cerebrospinal fluid cryptococcal antigen, India ink preparation findings, fungal culture, fluconazole level, and protein, glucose, and cell count. RESULTS: Of seven patients with active culture-positive infections, four showed clinical and microbiologic responses (three of four with meningitis, one of three with extraneural cryptococcosis). Fifteen patients who had already undergone successful amphotericin B therapy for either meningitis (n = 14) or pneumonia (n = 1) received fluconazole as prophylaxis against relapse. Fourteen patients remained free of infection during 11 to 64 weeks of suppressive therapy; one patient with meningitis experienced relapse after 26 weeks of treatment. Reverse reactions were limited to increases in hepatic enzyme levels in four patients. CONCLUSION: These results appear sufficiently encouraging to warrant further trials of this oral agent in the suppression of chronic cryptococcosis and perhaps in the treatment of acute infection.

Treatment of sporotrichosis with itraconazole. NIAID Mycoses Study Group.

PURPOSE: To describe the clinical presentation and outcomes of treatment with itraconazole in patients with sporotrichosis. METHODS: A culture for Sporothrix schenckii or compatible histopathology was required for inclusion in the study. Patients with both cutaneous and systemic sporotrichosis were treated. Patients received from 100 to 600 mg of itraconazole daily for 3 to 18 months. Patients were classified as responders or nonresponders. Responders were further classified as remaining on treatment, relapsed, or free of disease. Nonresponders included patients who failed to respond or progressed during treatment with itraconazole. RESULTS: Twenty-seven patients (mean age: 53 years) were treated with 30 courses of itraconazole. Diabetes mellitus and alcoholism were present in eight and seven patients, respectively. Sites of involvement included lymphocutaneous alone in 9 patients, articular/osseous in 15 (multifocal in 3), and lung in 3. Prior therapy was unsuccessful in 11 patients. Among the 30 courses, there were 25 responders and 5 nonresponders. All 5 nonresponders received at least 200 mg daily of itraconazole for durations that ranged from 6 to 18 months. Of the 25 responders, 7 relapsed 1 to 7 months after treatment durations of 6 to 18 months. Of the 7 who relapsed, 2 are responding to a second course. One responder was lost to follow-up after 10 months of treatment with itraconazole. Of the remaining 17 responders, 3 remain on treatment, and 14 are free of disease over follow-up durations of 6 to 42 months (mean: 17.6 months). Itraconazole was well tolerated with few side effects noted. CONCLUSIONS: These results document the efficacy of itraconazole in the treatment of cutaneous and systemic sporotrichosis.

NIAID Mycoses Study Group Multicenter Trial of Oral Itraconazole Therapy for Invasive Aspergillosis.

BACKGROUND: Invasive aspergillosis is the most common invasive mould infection and a major cause of mortality in immunocompromised patients. Response to amphotericin B, the only antifungal agent licensed in the United States for the treatment of aspergillosis, is suboptimal. METHODS: A multicenter open study with strict entry criteria for invasive aspergillosis evaluated oral itraconazole (600 mg/d for 4 days followed by 400 mg/d) in patients with various underlying conditions. Response was based on clinical and radiologic criteria plus microbiology, histopathology, and autopsy data. Responses were categorized as complete, partial, or stable. Failure was categorized as an itraconazole failure or overall failure. RESULTS: Our study population consisted of 76 evaluable patients. Therapy duration varied from 0.3 to 97 weeks (median 46). At the end of treatment, 30 (39%) patients had a complete or partial response, and 3 (4%) had a stable response, and in 20 patients (26%), the protocol therapy was discontinued early (at 0.6 to 54.3 weeks) because of a worsening clinical course or death due to aspergillosis (itraconazole failure). Twenty-three (30%) patients withdrew for other reasons including possible toxicity (7%) and death due to another cause but without resolution of aspergillosis (20%). Itraconazole failure rates varied widely according to site of disease and underlying disease group: 14% for pulmonary and tracheobronchial disease, 50% for sinus disease, 63% for central nervous system disease, and 44% for other sites; 7% in solid organ transplant, 29% in allogeneic bone marrow transplant patients, and 14% in those with prolonged granulocytopenia (median 19 days), 44% in AIDS patients, and 32% in other host groups. The relapse rates among those who completed therapy and those who discontinued early for possible toxicity were 12% and 40%, respectively; all were still immunosuppressed. CONCLUSION: Oral itraconazole is a useful alternative therapy for invasive aspergillosis with response rates apparently comparable to amphotericin B. Relapse in immunocompromised patients may be a problem. Controlled trials are necessary to fully assess the role of itraconazole in the treatment of invasive aspergillosis.

Randomized trial of itraconazole oral solution for oropharyngeal candidiasis in HIV/AIDS patients.

PURPOSE: Oropharyngeal candidasis (thrush) is the most common opportunistic infection in individuals who are positive for the human immunodeficiency virus (HIV) and those who have progressed to AIDS. Itraconazole has a broad in vitro spectrum of activity, including a wide variety of Candida species. Our study determined the relative efficacy of a new oral solution formulation of itraconazole and fluconazole tablets in the treatment of oropharyngeal candidiasis. PATIENTS AND METHODS: This was a prospective randomized, third-party-blind, multicenter trial conducted at 12 centers in the United States. One hundred seventy-nine HIV-positive patients with mycologically documented oropharyngeal candidiasis were treated with itraconazole oral solution 200 mg/ day for 7 or 14 days, or fluconazole tablets 100 mg/day for 14 days. Severity of disease was scored clinically before treatment and at clinical evaluations on days 3, 7, 14, 21, 35, and 42. Semi-quantitative cultures of mouth washings were also obtained on these days. RESULTS: Both 14-day and 7-day regimens of itraconazole oral solution were equivalent to fluconazole for most efficacy parameters. The clinical response rate was 97% after 14 days of itraconazole and 87% after 14 days of fluconazole. Itraconazole oral solution given for 7 days was also equivalent to fluconazole treatment for 14 days. Approximately one half of patients in all three groups relapsed by 1 month after completion of treatment. There were few adverse reactions to either drug. CONCLUSION: Itraconazole oral solution is well tolerated and offers an alternative at least as effective as fluconazole in the treatment of oropharyngeal candidiasis.

Antifungal agents used in systemic mycoses. Activity and therapeutic use.

The development of the polyene antibiotic, amphotericin B, provided for the first time a drug which was clinically effective in many serious mycotic diseases. Unfortunately, it requires parenteral administration and is often toxic, factors which limit the total cumulative dose which can be given. Efforts to utilise combinations of amphotericin B with other agents were best realised with amphotericin B/flucytosine in cryptococcal meningitis, and to a lesser degree in systemic candidiasis. More recently, the introduction of new imidazoles has extended the range of applications of these drugs to fungal diseases. Two members of this group, miconazole and ketoconazole, are promising agents. Miconazole is a parenterally administered agent for patients acutely ill with candidiasis and other mycotic infections. It may be the drug of choice for Petriellidium boydii infections and it is an attractive alternative to amphotericin B for intrathecal administration to patients with fungal meningitis. Ketoconazole offers much less toxicity, the advantage of oral administration, and the possibility of indefinitely prolonged therapy. However, it does not attain high concentrations in either the urine or cerebrospinal fluid. With the imidazoles, we have entered a new era of antifungal therapy which may produce even better antifungal agents than those currently available.

Disseminated histoplasmosis followed by disseminated coccidioidomycosis.

A case of disseminated histoplasmosis followed later by disseminated coccidioidomycosis is described. The clinical illness and immunologic studies suggest subtle defects that may have existed antecedent to infection and, thus, provided an opportunity for widespread dissemination by these normally nonopportunistic organisms. Poor correlation was noted between the clinical course and in vitro tests of cell-mediated immunity.

Pseudallescheria boydii infections treated with ketoconazole. Clinical evaluations of seven patients and in vitro susceptibility results.

Seven patients infected with Pseudallescheria boydii were treated with oral ketoconazole, 200 to 600 mg/day for one to 13 months. Five patients had pulmonary infections; two had skeletal infections. Improvement of pretreatment abnormalities occurred in five patients, one of whom had concurrent arthrodesis of his infected knee. The other two patients were subsequently healed by surgical resection of their pulmonary lesions. Ketoconazole appeared less active than miconazole against 22 clinical isolates of P boydii when tested by two in vitro methods. We conclude that ketoconazole is effective treatment for some patients infected with P boydii, although this may not be predicted by current in vitro susceptibility tests. Further experience is needed to establish the optimal use of ketoconazole with respect to its dosage, duration of administration and concurrent surgical resection.

Ketoconazole treatment of coccidioidal meningitis.

Fifteen patients with coccidioidal meningitis were treated with high doses of ketoconazole for up to 4 years. Five patients were treated with ketoconazole alone. One clinically failed, one developed hepatotoxicity, and three achieved remission of meningitis. One patient received intrathecal AMB in addition to ketoconazole for only 2 weeks before continuing on ketoconazole alone. He improved, but discontinued ketoconazole because of nausea and vomiting, and suffered a lethal relapse. Nine patients received ketoconazole in combination with prolonged courses of intrathecal AMB. Two patients were failures from nausea and vomiting, and the remaining seven either improved or experienced remission. The clinical responses appeared to be similar in patients receiving high-dose ketoconazole, either alone or combined with AMB, suggesting that there is no clinically significant antagonism of the drugs. Nausea and vomiting are significant limitations of high-dose ketoconazole. Ketoconazole alone is effective in some patients with coccidioidomycotic meningitis.

Systemic fungal infections: diagnosis and treatment. I. Therapeutic agents.

The story of antifungal agents has not been a stately procession from one development to another. For many years there was no agent of value for systemic mycoses. Then, with the advent of amphotericin B, we have had for over two decades essentially one effective agent, but a difficult drug to manipulate. The appearance of ketoconazole, the first systemic drug with relatively little toxicity, along with the appearance of ominous new forms of mycotic diseases, sharply stimulated interest in development of antifungal agents, initially in the azole classes, but now including a variety of other classes as well. We have very little idea how all of these drugs will act independently, and much less how they may interact together. Indeed, one of the most exciting developments is the return to amphotericin B, with repackaging in liposomes having created a markedly less toxic, and possibly much more potent, antifungal agent than "traditional" amphotericin B. There are indeed so many developments under way that the only safe conclusion that can be made is that within a few years current recommendations will be replaced by very different ones for most if not all of the major fungal pathogens.

Systemic mycoses in the 21st century.

This article explores the growing importance of systemic mycoses, considering briefly their present and future roles as infecting agents, and considers the rapid changes occurring in antifungal therapy. This article also speculates on the major developments anticipated for the next decade.

Treatment of chronic murine chromoblastomycosis with the triazole SCH39304.

Congenitally athymic (nu/nu) mice were inoculated sc with 10(5) conidia of Fonsecaea pedrosoi and treated orally from the 1st to the 16th week of infection with either a new triazole, SCH39304, or itraconazole at doses of 20 or 60 mg/kg/day. The volumes of the lesions were measured with calipers at 4 week intervals and compared statistically by the Wilcoxon test. At the end of the experiment, mice were killed and samples of the lesions were examined histopathologically and by electron microscopy. Treatment with itraconazole or SCH39304 significantly reduced lesion sizes as compared with controls. There were no differences between the 2 drugs at the dosages used. Histopathologically, lesions of mice treated with either drug had less inflammation with fewer fungi and more diffuse fibrosis than controls. Electron microscopy showed damage to the fungal cell walls in mice treated with itraconazole or SCH39304, characterized by gaps, fragmentation, and delamination. These studies confirm clinical observations that itraconazole is effective in chromoblastomycosis and suggest that SCH39304 should be considered for clinical evaluation.