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Biomedical subjects

A M Sugar

Publications and source records attributed to A M Sugar.

17 recordsLinked to original sources
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↗
PubMed1992

Comparison of amphotericin B with fluconazole in the treatment of acute AIDS-associated cryptococcal meningitis. The NIAID Mycoses Study Group and the AIDS Clinical Trials Group.

BACKGROUND: Intravenous amphotericin B, with or without flucytosine, is usually standard therapy for cryptococcal meningitis in patients with the acquired immunodeficiency syndrome (AIDS). Fluconazole, an oral triazole agent, represents a promising new approach to the treatment of cryptococcal disease. METHODS: In a randomized multicenter trial, we compared intravenous amphotericin B with oral fluconazole as primary therapy for AIDS-associated acute cryptococcal meningitis. Eligible patients, in all of whom the diagnosis had been confirmed by culture, were randomly assigned in a 2:1 ratio to receive either fluconazole (200 mg per day) or amphotericin B. Treatment was considered successful if the patient had had two consecutive negative cerebrospinal fluid cultures by the end of the 10-week treatment period. RESULTS: Of the 194 eligible patients, 131 received fluconazole and 63 received amphotericin B (mean daily dose, 0.4 mg per kilogram of body weight in patients with successful treatment and 0.5 mg per kilogram in patients with treatment failure; P = 0.34). Treatment was successful in 25 of the 63 amphotericin B recipients (40 percent; 95 percent confidence interval, 26 percent to 53 percent) and in 44 of the 131 fluconazole recipients (34 percent; 95 percent confidence interval, 25 percent to 42 percent) (P = 0.40). There was no significant difference between the groups in overall mortality due to cryptococcosis (amphotericin vs. fluconazole, 9 of 63 [14 percent] vs. 24 of 131 [18 percent]; P = 0.48); however, mortality during the first two weeks of therapy was higher in the fluconazole group (15 percent vs. 8 percent; P = 0.25). The median length of time to the first negative cerebrospinal fluid culture was 42 days (95 percent confidence interval, 28 to 71) in the amphotericin B group and 64 days (95 percent confidence interval, 53 to 67) in the fluconazole group (P = 0.25). Multivariate analyses identified abnormal mental status (lethargy, somnolence, or obtundation) as the most important predictive factor of a high risk of death during therapy (P less than 0.0001). CONCLUSIONS: Fluconazole is an effective alternative to amphotericin B as primary treatment of cryptococcal meningitis in patients with AIDS. Single-drug therapy with either drug is most effective in patients who are at low risk for treatment failure. The optimal therapy for patients at high risk remains to be determined.

Acquired Immunodeficiency Syndrome↗
PubMed1992

Fluconazole.

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Animals↗
PubMed1992

Mucormycosis.

Mucormycosis refers to the disease caused by a growing number of members of the Mucorales. Typically an airborne infection, primary disease is initiated in the upper or lower airways and is associated with the clinical development of sinusitis, rhinocerebral mucormycosis, or pulmonary infection. Dissemination of infection to skin, brain, and other sites is less common, but direct extension of the infection to contiguous sites is common if patients do not receive aggressive surgical and medical therapy. Risk factors for the development of mucormycosis include diabetic ketoacidosis; neutropenia; protein-calorie malnutrition; and iron overload, with or without the concomitant use of deferoxamine. This last association has only recently been recognized and has emerged as a major life-threatening complication for patients who are undergoing hemodialysis. Intravenous drug abusers may inject spores of Mucorales with their drugs and may present with space-occupying lesions of the CNS. The underlying immunologic defects that are responsible for predisposing different populations of patients to the development of mucormycosis are not well understood, and there is no unifying theory to explain why most individuals have innate immunity to this group of fungi. Patients with mucormycosis who are managed aggressively (i.e., those who undergo surgical debridement and who receive therapy with iv amphotericin B) may have increased rates of survival. The role of new azole derivatives in the treatment of mucormycosis is unknown.

Amphotericin B↗
PubMed1991

Overview: cryptococcosis in the patient with AIDS.

Cryptococcosis is currently the most common life threatening mycoses found in patients with the acquired immunodeficiency syndrome (AIDS). Extrapulmonary involvement is most frequently seen, especially in the central nervous system and skin. Clinical findings are non-specific, even in patients with meningitis. Threshold for diagnosis of this infection should be low, with serum cryptococcal antigens, blood, urine and sputum cultures for Cryptococcus neoformans performed in febrile AIDS patients. Lumbar puncture should also be performed if unexplained headaches are included in a patient's complaints. There is currently no consensus for the most appropriate treatment strategy and the role of oral azoles versus amphotericin B or amphotericin B with flucytosine remains a serious question in need of further controlled studies. Patients eligible for multicentered trials should be encouraged to participate. Therapy for others should be individualized. This review will address some of these issues.

Acquired Immunodeficiency Syndrome↗
PubMed1991

Macrophage- and oxidant-mediated inhibition of the ability of live Blastomyces dermatitidis conidia to transform to the pathogenic yeast phase: implications for the pathogenesis of dimorphic fungal infections.

Conidia, produced by the mycelial phase of dimorphic fungi, are thought to represent the infectious form of the organism but must complete a transition to the tissue-invasive, yeast-like phase for infection to ensue. Preventing such transition should effectively eliminate pathogenicity. Using Blastomyces dermatitidis as a target, murine bronchoalveolar macrophages preferentially blocked phase transition after 4 h of incubation with conidia, relatively sparing the ability of conidia to produce hyphae. H2O2, in relatively high concentrations, demonstrated the same activity. The effects of H2O2 seem irreversible, since H2O2-treated conidia that germinated at 48 h at 25 degrees C were still unable to produce yeasts over the next 5 days when incubated at 37 degrees C. Catalase could not reverse the macrophage-induced inhibition of phase transition, suggesting that nonoxidative defense mechanisms may be operative in vivo. Since conidia do not form mycelia at temperatures found in mammalian hosts, these effects may represent a novel host defense mechanism against dimorphic fungal pathogens.

Animals↗
PubMed1991

Treatment of murine invasive candidiasis with amphotericin B and cilofungin: evidence for enhanced activity with combination therapy.

The in vivo interactions of cilofungin, an echinocandin antifungal agent, and amphotericin B, a polyene derivative, in a murine model of disseminated candidiasis have been investigated. While single therapy with either drug alone prolonged survival of infected mice, kidney colony counts were not appreciably reduced. In contrast, combination therapy, especially at higher doses of both drugs, resulted in significant prolongation of survival and suppression of growth of yeast cells in the kidneys. Combination therapy of experimental candidiasis with cilofungin and amphotericin B did not result in antagonism; rather, additive or synergistic effects were seen. Future preclinical work with other echinocandin and polyene derivatives should include studies evaluating the in vivo interactions of both classes of compounds.

Amphotericin B↗
PubMed1991

Interactions of amphotericin B and SCH 39304 in the treatment of experimental murine candidiasis: lack of antagonism of a polyene-azole combination.

Mice infected intravenously with Candida albicans were treated with SCH 39304, a new triazole antifungal compound, amphotericin B, or both. Two dose levels of each drug were evaluated in an attempt to identify potential helpful or harmful effects on survival and kidney colony counts. Contrary to theoretical predictions, combination therapy was not antagonistic and some additive or synergistic effects were observed. The results obtained in this study suggest that antagonism between polyene and azole antifungal drugs is not inevitable and that additive or synergistic effects may be possible.

Amphotericin B↗
PubMed1991

Pneumocystis carinii pneumonia complicating somatostatin therapy of Cushing's syndrome in a patient with metastatic pancreatic islet cell carcinoma and Zollinger-Ellison syndrome.

Described is the case of a 73-yr-old woman with metastatic pancreatic islet carcinoma that manifested initially as Zollinger-Ellison syndrome followed by onset of endogenous Cushing's syndrome, who developed Pneumocystis carinii pneumonia while on therapy with a long-acting somatostatin analog. Although P. carinii pneumonia has been observed in patients with Cushing's syndrome associated with other conditions, this is the first reported case in a patient with Zollinger-Ellison syndrome. Heightened awareness of the possibility of opportunistic infections in patients receiving somatostatin therapy for Cushing's syndrome of any cause, particularly Zollinger-Ellison syndrome, may be warranted.

Adenoma, Islet Cell↗
PubMed1990

Attachment of Blastomyces dermatitidis conidia to murine bronchoalveolar macrophages: characterization of binding and elicitation of respiratory burst.

We studied the mechanisms of adherence of Blastomyces dermatitidis conidia to murine bronchoalveolar macrophages and the ability of the conidia to elicit an increase in macrophage O2- production, using an avirulent fungal strain. The number of cell associated conidia was counted by visual inspection of 2 hour macrophage monolayers incubated with conidia and O2- was measured by reduction of ferricytochrome c. Adherence of conidia to bronchoalveolar macrophages was time dependent and reached a plateau after 30 min (36 +/- 5%, 51 +/- 22%, and 36 +/- 17% macrophages with adherent conidia after 15, 30, and 60 min, respectively). Both Ca+2 and Mg+2 were required. The carbohydrates mannose, mannan, fucose, alphamethylmannoside, beta-glucan, galactose, N-acetylglucosamine and chitotriose (100-1000 micrograms/ml) did not inhibit adherence of conidia to macrophages. Trypsin treatment of macrophages or conidia did not affect binding. Conidia did not stimulate bronchoalveolar macrophage production of O2- above baseline concentrations (2.0 +/- 0.9 vs 0.8 +/- 0.5 nmol O2-, p greater than 0.05). We conclude that murine bronchoalveolar macrophage--B. dermatitidis conidia interactions occur primarily by a non-lectin-like attachment and do not result in the production of macrophage derived O2-.

Animals↗
PubMed1990

Treatment of fungal infections in patients infected with the human immunodeficiency virus.

Mycoses due to a variety of organisms have been implicated as opportunistic pathogens in patients infected with HIV. These infections are a cause of significant morbidity and mortality, and most often require life-long antifungal medication to suppress reactivation of the fungal process. With the advent of newer antifungal drugs, such as fluconazole and itraconazole, options are available so that appropriate nontoxic, long-term therapy can be administered. As the number of HIV-infected people increases and their longevity is extended, fungi will continue to pose challenging problems in diagnosis and therapy.

Candidiasis↗
PubMed1979

New rapid assay for nafcillin in serum by spectrofluorometry.

A new, rapid method for measuring serum levels of nafcillin by spectrofluorometry is described. The method involves extraction of 2 ml of acidified serum with n-butyl chloride, subjecting the organic solvent layer to excitation at 340 nm, and measuring the relative intensity of emission fluorescence at 380 nm. An excellent linear correlation exists between serum levels of nafcillin and the relative intensity in a drug concentration range of 0.25 to 150 mug/ml. The results obtained by this spectrofluorometric technique are in complete accord with those obtained by the conventional microbiological assay using Staphylococcus aureus ATCC 6538P. The method is not interfered with by elevated levels of endogenous metabolic products or the presence of other drugs, including a number of antimicrobial agents. The assay is interfered with, however, by the presence of salicylates, for which appropriate correction can easily be made. A salicylate assay employing a spectrofluorometric technique is also described.

Biological Assay↗
PubMed1979

Rapid assay for determination of trimethoprim and sulfamethoxazole levels in serum by spectrofluorometry.

A rapid spectrofluorometric method for determining the levels of both trimethoprim and sulfamethoxazole from the same specimen of serum is described. The method involves stepwise extraction of the specimen first with chloroform at an alkaline pH (pH 9.0) for trimethoprim followed by n-butyl chloride at an acidic pH (pH 2.0) for sulfamethoxazole. To quantitate trimethoprim, the chloroform layer was subjected to fluorometry by exciting the specimen at 295 nm and measuring the relative intensity at 330 nm. To determine sulfamethoxazole levels, the n-butyl chloride layer was subjected to fluorometry by exciting the specimen at 285 nm and measuring the relative intensity at 330 nm. Relative intensities were linear (r greater than 0.99) over the concentration ranges of 0.5 to 40 microgram/ml for trimethoprim and 1 to 400 microgram/ml for sulfamethoxazole. Values obtained by this spectrofluorometric procedure were in excellent agreement with those obtained by a conventional fluorometric assay for trimethoprim and a colorimetric assay for sulfamethoxazole. Elevated levels of endogenous metabolic products and numerous other drugs, including a number of antimicrobial agents, did not interfere with the method. Although salicylates interfere with the determination of sulfamethoxazole, an appropriate correction can be made. This method can also be used to determine the drug levels in cerebrospinal fluid.

Humans↗