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Biomedical subjects

A M Sugar

Publications and source records attributed to A M Sugar.

At least 37 records · Page 2Linked to original sources
PubMed1995

Cryptococcal pneumonia in AIDS: is cryptococcal meningitis preceded by clinically recognizable pneumonia?

Identification of cryptococcal infection while it is still in its pulmonary phase might improve the prognosis for patients with AIDS who contract cryptococcosis. Since cryptococcal pneumonia is infrequently diagnosed in the AIDS patient, especially compared with the frequency of diagnosis of cryptococcal meningitis, this retrospective study was designed to investigate the frequency of pulmonary complaints in the months before diagnosis of cryptococcal meningitis. The medical records of 18 patients diagnosed with cryptococcal meningitis were analyzed. Of 18 patients, 14 (78%) had respiratory symptoms during the 4-month period before meningitis appeared, as compared with nine of 18 (50%) at the time of diagnosis and four of 16 (25%) in the 4 months following diagnosis. Seven of the 14 cases of pulmonary disease prediagnosis were of unknown etiology; three were eventually diagnosed as cryptococcal infections during evaluation of the meningitis. The remaining eight infections were attributed to bacteria, respiratory viruses, or Pneumocystis carinii, although three of these cultures also contained yeast, presumed to be Candida species, which were not further examined. Our data suggest the importance of singling out AIDS patients who may have pulmonary cryptococcosis. Cryptocococcsis should be included in the differential diagnosis of pulmonary infection in HIV-positive patients with CD4+ lymphocyte counts < 200/mm3, and full identification of yeasts recovered from sputum or bronchoalveolar lavage fluid cultures should be done. A larger study should be undertaken to better define the incidence of clinically recognizable pulmonary cryptococcosis in AIDS patients.

AIDS-Related Opportunistic Infections↗
PubMed1995

Comparison of three methods of antifungal susceptibility testing with the proposed NCCLS standard broth macrodilution assay: lack of effect of phenol red. National Committee for Clinical Laboratory Standards.

Three microtiter plate adaptations of the NCCLS proposed standard for antifungal susceptibility testing were evaluated and compared to the NCCLS broth macrodilution method. Thirteen different fungi, including yeasts and moulds were studied. The first microtiter based method was performed exactly as described for the tube dilution assay, with the exception of performance of the assay in 100 microliter in wells of the microtiter plate. The second assay was the same as the first, except for the deletion of phenol red from the RPMI 1640. The third microtiter assay was based on the reduction of the formazan dye, XTT, after only 24 hours of incubation. All three microtiter methods compared favorably with the macrodilution method, when visually read after either 24 or 48 hours of incubation. Minimum inhibitory concentrations obtained by the XTT assay were usually lower than those obtained by the methods requiring a visual end point determination. Results were reproducible and comparable to those obtained with the NCCLS method. We conclude that microtiter plate adaptation of the NCCLS proposed standard is feasible and the presence of phenol red does not alter the results with the drugs tested. A 24 hour assay using XTT may provide a quicker and more quantitative method of susceptibility testing of fungi. Further investigation of this approach is warranted.

Fungi↗
PubMed1995

Intravascular catheter exchange and duration of candidemia. NIAID Mycoses Study Group and the Candidemia Study Group.

During a comparative trial of amphotericin B vs. fluconazole for treatment of candidemia in nonneutropenic patients, data on the management of intravascular catheters were collected. Complete records were available for 91% of the 206 study patients. For the subset of patients with a catheter in place at the time of their first positive blood culture, removal and replacement of all intravascular catheters without exchange over a guidewire from a preexisting line on or before the first day the study drug was administered were associated with a reduction in the subsequent mean duration (+/- SE) of candidemia, from 5.6 +/ -0.8 days to 2.6 +/- 0.5 days (P < .001).

Amphotericin B↗
PubMed1995

Paracoccidioidomycosis and AIDS: an overview.

The scarcity of reported cases of paracoccidioidomycosis and AIDS remains unexplained. We review the details of the 27 cases reported in the medical literature. Paracoccidioidomycosis occurs in patients with advanced AIDS who are not receiving prophylaxis for Pneumocystis carinii pneumonia with trimethoprim-sulfamethoxazole, which is also effective against Paracoccidioides brasiliensis. Clinical manifestations include prolonged fever, weight loss, generalized lymphadenopathy, splenomegaly, hepatomegaly, and skin rash. Diagnosis can often be made by direct microscopic examination and culture of the fungus from skin and lymph node specimens and occasionally from sputum, blood, spinal fluid, and bone marrow specimens. Since antibodies to P. brasiliensis are occasionally detected, the diagnosis should not be ruled out for patients whose serology is negative. Despite specific therapy with different regimens, the overall mortality of paracoccidioidomycosis among patients with AIDS is high (30%). The prognosis can be improved by earlier diagnosis and aggressive therapy with amphotericin B, followed by lifelong immunosuppressive therapy with trimethoprim-sulfamethoxazole. Health care providers caring for human immunodeficiency virus-infected patients who live or have resided in areas in which paracoccidioidomycosis is endemic must be aware of the possibility that this systemic mycosis may occur and have potentially severe consequences.

AIDS-Related Opportunistic Infections↗
PubMed1995

Interactions between human bronchoalveolar macrophages and Blastomyces dermatitidis conidia: demonstration of fungicidal and fungistatic effects.

The effects of human bronchoalveolar macrophages (BAMs) on Blastomyces dermatitidis conidia were investigated. Macrophage monolayers were incubated for 5 days with or without interferon (IFN)-gamma or macrophage colony-stimulating factor (M-CSF) before challenge with conidia for 48 h at 37 degrees C. Hyphal growth (germination) was inhibited 12% by resident BAMs (P < .05). In contrast, resident BAMs blocked conidial phase transition by 88% (P < .05). Intermediate forms, aggregates of large cells in clums (not conidia or yeasts by morphologic criteria), appeared after incubation with BAMs and grew into typical yeasts once removed from the BAMs. IFN-gamma and M-CSF inhibited the ability of BAMs to block phase transition but not germination. Human BAMs demonstrated fungicidal and fungistatic activity against B. dermatitidis conidia independent of reactive oxygen intermediates and had greater effects on phase transition than on germination. The phase transition-associated fungicidal and fungistatic activities of BAMs were inhibited by IFN-gamma and M-CSF.

Blastomyces↗
PubMed1995

Combination therapy of murine invasive candidiasis with fluconazole and amphotericin B.

A study was performed to assess the in vivo relevance of the in vitro antagonism between fluconazole and amphotericin B against Candida albicans. Combinations of fluconazole and amphotericin B were explored for their efficacies against acute (100% mortality in 2 to 5 days) or less acute (100% mortality in 30 days) invasive candidiasis infections in mice with healthy immune systems and immunocompromised mice. Treatment efficacy was assessed by protection from mortality and/or a reduction in the fungal burden in tissue. In models of acute infection in mice with healthy immune systems or less acute infection in immunocompromised mice, combinations of fluconazole and amphotericin B were superior to fluconazole alone, and the effects were at least additive. Combination therapy was at least as efficacious as amphotericin B alone. In a different model of less acute infection in mice with healthy immune systems, combinations of fluconazole and amphotericin B showed no interactions and were no better than either drug alone. We conclude that combination therapy with fluconazole and amphotericin B is not antagonistic in vivo, in contrast to published in vitro studies, and, consequently, suggest that combination therapy should be considered in the management of clinical candidiasis.

Amphotericin B↗
PubMed1995

Treatment of murine pulmonary blastomycosis with SCH 51048, a broad-spectrum triazole antifungal agent.

The in vitro and in vivo activities of a new broad-spectrum triazole derivative, SCH 51048, against Blastomyces dermatitidis were evaluated. As determined by using the new National Committee for Clinical Laboratory Standards proposed standard for susceptibility testing of yeasts, SCH 51048 was the most active of the four agents tested in vitro against 13 strains of B. dermatitidis. In a well-described murine model of acute pulmonary blastomycosis, SCH 51048 was comparable to amphotericin B and at least 30 times more active than itraconazole. On the basis of these experiments, clinical evaluation of SCH 51048 for the use in treatment of human blastomycosis should proceed.

Animals↗
PubMed1995

Cloning and nucleotide sequence of a specific DNA fragment from Paracoccidioides brasiliensis.

We cloned and sequenced a species-specific 110-bp DNA fragment from Paracoccidioides brasiliensis. The DNA fragment was generated by PCR with primers complementary to the rat beta-actin gene under a low annealing temperature. Comparison of the nucleotide sequence, after excluding the primers, with those in the GenBank database identified approximately 60% homology with an exon of a major surface glycoprotein gene from Pneumocystis carinii and a fragment of unknown function in Saccharomyces cerevisiae chromosome VIII. By Southern hybridization analysis, the 32P-labelled fragment detected 1.0- and 1.9-kb restriction fragments within whole-cell genomic DNA of P. brasiliensis digested with HindIII and PstI, respectively, but failed to hybridize to genomic DNAs from Candida albicans, Blastomyces dermatitidis, Cryptococcus neoformans, Aspergillus fumigatus, Saccharomyces cerevisiae, Pneumocystis carinii, rat tissue, or humans under low-stringency hybridization conditions. Additionally, the specific DNA fragment from three different P. brasiliensis isolates (Pb18, RP18, RP17) was amplified by PCR with primers mostly complementary to nonactin sequences of the 110-bp DNA fragment. In contrast, there were no amplified products from other fungus genomic DNAs previously tested, including Histoplasma capsulatum. To date, this is the first species-specific DNA fragment cloned from P. brasiliensis which might be useful as a diagnostic marker for the identification and classification of different P. brasiliensis isolates.

Animals↗
PubMed1994

A randomized trial comparing fluconazole with amphotericin B for the treatment of candidemia in patients without neutropenia. Candidemia Study Group and the National Institute.

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 > or = 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. There was no statistically significant difference in outcome: of the 103 patients treated with amphotericin B, 81 (79 percent) were judged to have been treated successfully, as were 72 of the 103 patients treated with fluconazole (70 percent P = 0.22; 95 percent confidence interval for the difference, -5 to 23 percent). The bloodstream infection failed to clear in 12 patients in the amphotericin group and 15 in the fluconazole group; the species most commonly associated with failure was Candida albicans. There were 41 deaths in the amphotericin group and 34 deaths in the fluconazole group (P = 0.20). Intravascular catheters appeared to be the most frequent source of candidemia. There was less toxicity with fluconazole than with amphotericin B. CONCLUSIONS: In patients without neutropenia and without major immunodeficiency, fluconazole and amphotericin B are not significantly different in their effectiveness in treating candidemia.

Amphotericin B↗
PubMed1994

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.

AIDS-Related Opportunistic Infections↗
PubMed1994

Synthesis of heat-shock proteins in mycelia and yeast forms of Paracoccidioides brasiliensis.

The induction of heat-shock proteins has been postulated to play a role not only in thermo-adaptation, but also in phase transition of the dimorphic fungi. In this study, we used yeast and mycelial forms of the thermally dimorphic fungus Paracoccidioides brasiliensis to evaluate the effect of temperature on the induction of the heat-shock response. We also evaluated protein synthesis by P. brasiliensis caused by exposure to low pH and H2O2. Analysis of protein synthesis by SDS-PAGE disclosed that P. brasiliensis mycelia increased synthesis of all major constitutive proteins when stressed at 37 degrees C and increased synthesis of three non-constitutive proteins of 134, 82 and 28 kDa at 40 degrees C. Yeasts incubated at 40 degrees C showed decreased synthesis of five constitutive proteins (136, 98, 62, 57 and 54 kDa) and the appearance of three new proteins (134, 82 and 28 kDa). There was a decrease in the synthesis of all major constitutive proteins except for three proteins of 141, 136 and 16 kDa when yeast cells were incubated at 25 degrees C. When stressed by low pH and H2O2, P. brasiliensis yeast increased synthesis of one (134 kDa) and five (134, 104, 82, 52 and 40 kDa) non-constitutive proteins, respectively. P. brasiliensis mycelia and yeast forms disclosed the same profile of protein synthesis when stressed at temperatures that trigger phase transition (37 degrees C for mycelia; 25 degrees C for yeast).(ABSTRACT TRUNCATED AT 250 WORDS)

Autoradiography↗
PubMed1994

Saperconazole therapy of murine disseminated candidiasis: efficacy and interactions with amphotericin B.

The efficacy of a new triazole antifungal agent, saperconazole, in a murine model of disseminated candidiasis was studied. Mice were intravenously infected with Candida albicans blastoconidia and treated for 14 days with oral saperconazole, intraperitoneal amphotericin B, or a combination of these. Amphotericin B alone was the most efficacious in prolonging survival and in decreasing renal colony counts, usually with complete sterilization of the kidneys by the end of the treatment course. Saperconazole improved survival rates and effected a decrease in renal colony counts, but kidneys were not microbiologically sterilized. Combination therapy with saperconazole and amphotericin B did not result in a decrease in the efficacy of amphotericin B by either end point (survival or renal colony counts). High-pressure liquid chromatographic analysis of saperconazole concentrations in serum indicated low levels of absorption of the drug. We conclude that saperconazole is effective in the treatment of murine invasive candidiasis and that the theoretical concern about adverse interactions between the two drugs does not apply to the dosages studied in these experiments.

Absorption↗
PubMed1993

Idiopathic CD4+ T-lymphocytopenia--four patients with opportunistic infections and no evidence of HIV infection.

BACKGROUND AND METHODS: We 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. RESULTS: The 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). CONCLUSIONS: These 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.

Adult↗
PubMed1993

Reduced amphotericin toxicity in an albumin vehicle.

Amphotericin B systemically infused into anesthetized rats at the rate of 0.4 mg/kg body weight over 20 min reproducibly induced renal vasoconstriction and renal cortical hypoxemia. By contrast, when infused with albumin (3 g/dl), amphotericin B did not reduce renal blood flow and did not affect renal cortical oxygenation. In vitro, hemolysis induced by amphotericin was also markedly reduced in the presence of albumin. Albumin did not appear to reduce the antibiotic effect of amphotericin in vitro. It was concluded that amphotericin B toxicity may be considerably reduced if administered in an albumin vehicle.

Albumins↗
PubMed1992

A controlled trial of fluconazole or amphotericin B to prevent relapse of cryptococcal meningitis in patients with the acquired immunodeficiency syndrome. The NIAID AIDS Clinical Trials Group and Mycoses Study Group.

BACKGROUND: After primary treatment for cryptococcal meningitis, patients with the acquired immunodeficiency syndrome (AIDS) require some form of continued suppressive therapy to prevent relapse. METHODS: We conducted a multicenter, randomized trial that compared fluconazole (200 mg per day given orally) with amphotericin B (1 mg per kilogram of body weight per week given intravenously) in patients with AIDS who had completed primary therapy for cryptococcal meningitis with amphotericin B (greater than or equal to 15 mg per kilogram). To be eligible, patients had to have at least two negative cultures of cerebrospinal fluid immediately before randomization. The primary end point was relapse of cryptococcal disease as confirmed by biopsy or culture. RESULTS: Of 218 patients initially enrolled, 119 were assigned to fluconazole and 99 to amphotericin B. Twenty-three patients were found not to have met the entry criteria; six other patients assigned to amphotericin B did not receive it and were lost to follow-up. Of the remaining 189 patients, after a median follow-up of 286 days 14 of 78 receiving amphotericin B (18 percent) and 2 of 111 assigned to fluconazole (2 percent) had relapses of symptomatic cryptococcal disease (P less than 0.001 by Fisher's exact test). There was a difference of 19 percent in the estimated probability of remaining relapse-free at one year between the fluconazole group (97 percent) and the amphotericin B group (78 percent) (95 percent confidence interval, 7 percent to 31 percent; P less than 0.001). Serious drug-related toxicity was more frequent in the amphotericin B group (P = 0.02), as were bacterial infections (P = 0.004) and bacteremia (P = 0.002). CONCLUSIONS: Fluconazole taken by mouth is superior to weekly intravenous therapy with amphotericin B to prevent relapse in patients with AIDS-associated cryptococcal meningitis after primary treatment with amphotericin B.

Acquired Immunodeficiency Syndrome↗