Alan M. Sugar

A Randomized Trial Comparing Fluconazole with Amphotericin B for the Treatment of Candidemia in Patients without Neutropenia

Background Amphotericin B has long been the standard treatment for candidemia, but its use is complicated by its toxicity. More recently, fluconazole, a water-soluble triazole with activity against candida species and little toxicity, has become available. We conducted a multicenter randomized trial that compared amphotericin B with fluconazole as treatment for candidemia. Methods To be eligible, patients had to have a positive blood culture for candida species, a neutrophil count ≥ 500 per cubic millimeter, and no major immunodeficiency. Patients were randomly assigned to receive either amphotericin B (0.5 to 0.6 mg per kilogram of body weight per day) or fluconazole (400 mg per day), each continued for at least 14 days after the last positive blood culture. Outcomes were assessed by a group of investigators blinded to treatment assignment. Results Of the 237 patients enrolled, 206 met all entry criteria. The most common diagnoses were renal failure, nonhematologic cancer, and gastrointestinal disease. T...

NIAID mycoses study group multicenter trial of oral itraconazole therapy for invasive aspergillosis

BACKGROUNDnInvasive 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.nnnMETHODSnA 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.nnnRESULTSnOur 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.nnnCONCLUSIONnOral 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.

Prospective Multicenter Surveillance Study of Funguria in Hospitalized Patients

Although fungal urinary tract infections are an increasing nosocomial problem, the significance of funguria is still not clear. This multicenter prospective surveillance study of 861 patients was undertaken to define the epidemiology, management, and outcomes of funguria. Diabetes mellitus was present in 39% of patients, urinary tract abnormalities in 37.7%, and malignancy in 22.2%; only 10.9% had no underlying illnesses. Concomitant nonfungal infections were present in 85%, 90% had received antimicrobial agents, and 83.2% had urinary tract drainage devices. Candida albicans was found in 51.8% of patients and Candida glabrata in 15.6%. Microbiological and clinical outcomes were documented for 530 (61.6%) of the 861 patients. No specific therapy for funguria was given to 155 patients, and the yeast cleared from the urine of 117 (75.5%) of them. Of the 116 patients who had a catheter removed as the only treatment, the funguria cleared in 41 (35.3%). Antifungal therapy was given to 259 patients, eradicating funguria in 130 (50.2%). The rate of eradication with fluconazole was 45.5%, and with amphotericin B bladder irrigation it was 54.4%. Only 7 patients (1.3%) had documented candidemia. The mortality rate was 19.8%, reflecting the multiple serious underlying illnesses found in these patients with funguria.

Idiopathic CD4+ T-Lymphocytopenia -- Four Patients with Opportunistic Infections and No Evidence of HIV Infection

BACKGROUND AND METHODSnWe describe four patients without major risk factors for human immunodeficiency virus (HIV) infection, each of whom presented with severe opportunistic infections and was found to have idiopathic CD4+ T-lymphocytopenia. We performed assays to detect the presence of retroviruses and undertook immunophenotyping of subgroups of peripheral-blood lymphocytes.nnnRESULTSnThe opportunistic infections at presentation included Pneumocystis carinii pneumonia, cryptococcal meningitis (two patients, one with concurrent pulmonary tuberculosis), and histoplasma-induced brain abscess. During 10 to 68 months of observation, none of the four patients had evidence of infection with HIV type 1 or 2 or human T-cell lymphotropic virus type I or II on the basis of epidemiologic, serologic, or polymerase-chain-reaction studies or culture, nor was there any detectable reverse transcriptase activity. Although all the patients had severe, persistent CD4+ T-lymphocytopenia (range, 12 to 293 cells per cubic millimeter), the CD4+ cell count progressively declined in only one and was accompanied by multiple opportunistic infections. All four patients had significantly reduced numbers of circulating CD8+ T cells, natural killer cells, or B cells (or all three).nnnCONCLUSIONSnThese four patients had idiopathic CD4+ T-lymphocytopenia with opportunistic infections but no evidence of HIV infection. Instead of the progressive, selective depletion of CD4+ T cells characteristic of HIV infection, some patients with idiopathic immunodeficiency have stable CD4+ cell counts accompanied by reductions in the levels of several other lymphocyte subgroups.

Mycoses in AIDS patients

The World Health Organization estimates that at least five million people worldwide are infected with human immunodeficiency virus (HIV) Of these about 100,000 are in Asia and Oceania, 500,000 in Europe, 2 million in the Americas and 2.5 million in Africa (Mann, 1989). The acquired immunodeficiency syndrome is characterized by a derangement in cell-mediated immunity leading to opportunistic infections with for example Mycobacterium spp., Candida spp., Cryptococcus neoformans, Pneumocystis carinii, Toxoplasma gondii and Cryptosporidium. The third symposium on Topics in Mycology brought together 265 experts from 32 countries to discuss the epidemiology, immmunological and pathogenetic aspects of AIDS and its opportunistic infections in general and fungal infections in particular. Pneumocystis carinii pneumonia is by far the commonest opportunistic infection in AIDS patients. The nature and classification of P. carinii is still controversial. In search for its true taxonomic affinities an introductory paper formulates a number of key questions. Candidosis is another frequent opportunistic infection. A number of papers discuss the possibility that selective pressures may operate on Candida albicans within the AIDS population and influence its nature: this might have an impact on prophylaxis and curative and/or suppressive therapy.

Efficacy of Voriconazole in Treatment of Murine Pulmonary Blastomycosis

ABSTRACT We evaluated the efficacy of voriconazole, a new broad-spectrum triazole antifungal compound, in the treatment of murine pulmonary blastomycosis. Since mice metabolize voriconazole rapidly, we took advantage of our previous observation that administration of grapefruit juice to mice resulted in suitable serum voriconazole concentrations so that treatment studies with mice could be done (A. M. Sugar and X.-P. Liu, Med. Mycol. 38:209–121, 2000). Our results show that voriconazole prolonged survival in a dose-dependent fashion and that the fungal burden in the lungs was decreased by voriconazole administered at 40 mg/kg of body weight/day. Voriconazole should be studied in humans with blastomycosis.

Successful treatment of Candida osteomyelitis with fluconazole. A noncomparative study of two patients.

We describe two patients with osteomyelitis due to Candida spp. treated with fluconazole, a new triazole antifungal. One patient had extensive involvement of ribs and costochondral regions of the anterior chest, and the other had vertebral infection. Both were cured with courses of 10 and 14 months, with greater than or equal to 1 year of follow-up after fluconazole was discontinued. Fluconazole is an attractive agent for the treatment of Candida osteomyelitis and deserves to be studied more extensively for this indication.

Interaction of Fluconazole and Cyclosporine

Excerpt To the Editor:Fluconazole is a new azole orally administered antifungal agent with a broad spectrum of activity (1). This drug may prove useful in treating infections due toCandidaand other...

Combination Antifungal Therapy in Treatment of Murine Pulmonary Mucormycosis: Roles of Quinolones and Azoles

ABSTRACT Amphotericin B is the only recognized antifungal used in the treatment of mucormycosis. In this study, we evaluated various combinations of amphotericin B, fluconazole, and trovafloxacin or ciprofloxacin in the treatment of murine pulmonary mucormycosis. The combination of fluconazole and a quinolone has a marked effect on the outcome of murine pulmonary mucormycosis. Even though we did not optimize therapy with the drugs, these experiments suggest that azoles, especially fluconazole, in combination with either trovafloxacin or ciprofloxacin were effective in the treatment of this aggressive mycosis in the mouse model.

Fungal infections in the immunocompromised host

With the increased number of immunocompromised patients there has been a concomitant increase in patient morbidity and mortality due to fungi. The etiologic microorganisms vary depending upon the type of immune dysfunction. Patients with malignancies and chemotherapy-induced neutropenia commonly are infected with Candida and Aspergillus. Other ubiquitous fungi such as Rhizopus, Fusarium, and Trichosporon are more frequently implicated as agents of disease in these patients. Patients with cell-mediated immune dysfunction such as acquired immune deficiency syndrome (AIDS) are susceptible to mucocutaneous candidiasis and pulmonary and disseminated cryptococcosis. Histoplasmosis and coccidioidomycosis have been particularly lethal infections in AIDS patients. Contributing factors such as broad-spectrum antibiotic use, intravenous catheterization, malnutrition, hyperalimentation, multiple surgical procedures and/or trauma, and steroids used either singly or in combination may also predispose patients to invasive fungal disease. Definitive diagnosis is often difficult to establish and usually requires invasive biopsy. Delay of culture results due to the time required to process specimens and to allow the fungus to grow also contributes to the poor results of therapy. Biopsy of skin lesions represents a useful technique for making a diagnosis. Recent advances in antifungal therapeutics promise to change the current approach to treatment for several of the mycoses. The availability of new oral azoles with spectra of activity that include aspergillosis and cryptococcosis, which currently require treatment with parenteral amphotericin B, may prove practical for prolonged oral therapy of otherwise lethal mycoses.