Reaction after re-exposure to trimethoprim-sulfamethoxazole.
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Acquired Immunodeficiency Syndrome↗
Biomedical subjects
J N Galgiani
Publications and source records attributed to J N Galgiani.
Progress in standardizing antifungal susceptibility tests.
In vitro tests of antifungal agents are receiving increasing attention as important procedures for the clinical laboratory. As antifungal agents proliferate, it will become more and more valuable to have available antifungal susceptibility tests to aid in treatment selections based on the specific activities of different drugs against a patient's own isolate. Evidence is accumulating that in vitro tests can significantly correlate with treatment results and thus have the potential to improve patient care. Furthermore, concerted efforts are now underway to improve agreement in test results from different laboratories. As these activities continue, the availability of reliable testing methods for yeasts is likely to occur in the foreseeable future.
Antifungal Agents↗
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.
Adult↗
Extraction of serologic and delayed hypersensitivity antigens from spherules of Coccidioides immitis.
We have used an aqueous toluene extraction procedure to obtain antigens from mature spherules of Coccidioides immitis. This extract contained many antigens as determined by immunoblotting and two-dimensional immunoelectrophoretic studies. These included antigens with specificity for tube precipitin-type antibodies having molecular weights greater than or equal to 100 KDa. The extract also displayed lymphocyte-transforming activity when tested on human peripheral blood mononuclear leukocytes from donors who react to coccidioidal skin tests but elicited no such stimulation of cells from persons whose coccidioidal skin tests were nonreactive. At high concentrations of the extract, lymphocyte transformation did not occur, a finding that could not be explained by nonspecific toxicity. When gel filtration was employed to separate antigens by size, tube precipitin-like activity and specific coccidioidal delayed-type hypersensitivity displayed overlap, although only the latter activity was apparent in lower molecular weight pools.
Animals↗
Quantitative pathology of coccidioidomycosis in acquired immunodeficiency syndrome.
This study examines the laboratory aspects of diagnosis of coccidioidomycosis in 11 patients with acquired immunodeficiency syndrome (AIDS) and the qualitative and quantitative differences between host responses of AIDS and non-AIDS patients who died with disseminated coccidioidomycosis. Material obtained at bronchoscopy confirmed the diagnosis of pulmonary coccidioidomycosis in 67% (6/9) of the patients. Patients with AIDS had a generally poor granulomatous response and statistically significantly increased numbers of spherules in lung tissue compared with non-AIDS patients. Neither antifungal therapy nor duration of clinical disease influenced the number of organisms present. The findings suggest a parallel between AIDS-associated coccidioidomycosis and other granulomatous diseases such as leprosy and schistosomiasis, in which the type of granuloma formation and organism numbers are influenced by the T-lymphocyte milieu.
Acquired Immunodeficiency Syndrome↗
Coccidioidal peritonitis associated with continuous ambulatory peritoneal dialysis.
We report the first three cases of peritonitis due to the fungus Coccidioides immitis occurring during continuous ambulatory peritoneal dialysis (CAPD). At the time of diagnosis, none of the patients had evidence of active infection outside of the peritoneal cavity. Clues suggesting the diagnosis including a previous history of pulmonary coccidioidomycosis, an excess number of eosinophils in the peritoneal fluid, and failure to respond to therapy directed against bacteria. C immitis in peritoneal fluid was more readily isolated on specific fungal culture media than on routine bacterial culture media. In no instances did potassium hydroxide (KOH) preparations of the fluid reveal fungi. Coccidioidal peritonitis during CAPD appears to be a localized form of extrapulmonary coccidioidomycosis that has a relatively benign course once the peritoneal catheter is removed.
Adult↗
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.
Amphotericin B↗
Effects of adenylate cyclase toxin from Bordetella pertussis on human neutrophil interactions with Coccidioides immitis and Staphylococcus aureus.
Bordetella pertussis extract that contained adenylate cyclase toxin produced large increases in human neutrophil cyclic AMP levels and inhibited their oxidative burst, as reflected by luminol-enhanced chemiluminescence and superoxide release. The adenylate cyclase toxin-containing extract blocked neutrophil-mediated inhibition of N-acetylglucosamine incorporation by arthroconidia of Coccidioides immitis in a dose-dependent fashion but had no effect on neutrophil phagocytosis of Candida glabrata and only a slight inhibitory effect on arthroconidial attachment. Neither purified pertussis toxin nor extracts from Bordetella mutants lacking the adenylate cyclase toxin affected neutrophil-mediated inhibition of arthroconidial N-acetylglucosamine incorporation. These studies indicate that adenylate cyclase toxin, alone or in concert with other B. pertussis-elaborated toxins, blocks neutrophil inhibition of arthroconidia, primarily by affecting neutrophil responses other than attachment or phagocytosis.
Acetylglucosamine↗
Coccidioidomycosis during pregnancy. An analysis of ten cases among 47,120 pregnancies.
Previous studies have suggested that coccidioidomycosis during pregnancy is a devastating illness associated with high maternal mortality. However, this concept recently has been challenged. We examined the incidence of coccidioidomycosis during pregnancy in Tucson, Arizona, an area endemic for this infection. After reviewing the records of three separate health care facilities, we found ten cases of coccidioidomycosis among 47,120 pregnancies. Nine of the ten women had no underlying disease. Seven were diagnosed with coccidioidomycosis during either the first or second trimester. Illness resolved in all seven. Three other patients were diagnosed during the first ten days postpartum. While infection was self-limited in one woman, two others developed severe disseminated coccidioidomycosis associated with meningitis. Despite this, there were no maternal deaths. Of eight deliveries, all were uncomplicated and produced healthy infants. In summary, diagnosing coccidioidomycosis during pregnancy is rare. Although we observed no maternal death, our experience suggests that women who develop coccidioidomycosis late in pregnancy are at risk for developing severe disseminated infection.
Adolescent↗
Systemic fungal infections: diagnosis and treatment. I. Coccidioidomycosis.
Coccidioidomycosis is a highly variable disease. Initial respiratory tract infection can lead to self-limited pneumonia, pulmonary complications, and extrapulmonary disease. The early infection requires no therapy, except in immunosuppressed patients and other selected patients. Treatment for pulmonary complications may include surgery for cavities or pyopneumothorax (resulting from rupture of a cavity) and antifungal therapy for chronic pneumonia. The majority of extrapulmonary disease occurs in the skin, bones and joints, or meninges and is an indication for treatment with antifungal agents and sometimes adjunctive surgery. Meningitis is a particularly serious consequence of dissemination and currently is best treated with intrathecal instillation of antifungal agents. Antifungal agents useful in the treatment of coccidioidomycosis are amphotericin B, which is administered intravenously and is relatively toxic, and ketoconazole, which is administered orally and whose toxicities are less serious and reversible. Because studies to compare the efficacy of these two drugs have not been performed, selecting between them for use in individual patients is most rationally based on the pharmacologic differences, which lend themselves to different clinical settings. In future years, new antifungal agents will likely be available, some of which will offer significant advantages over present therapies. Itraconazole is an imidazole related to ketoconazole, which appears to be effective and possibly less toxic than ketoconazole. Fluconazole, another imidazole, has broad antifungal activity, a long serum half-life, and excellent penetration into the cerebrospinal fluid. Thus, the pharmacology of this agent would appear ideal for use in treating coccidioidal meningitis. In addition, other compounds with different modes of action are now under investigation in preclinical studies. It is therefore likely that continued improvements will occur in the coming years in the treatment of this disease.
Amphotericin B↗
Symptoms and routine laboratory abnormalities associated with coccidioidomycosis.
To assess the relationships of various symptoms and other early findings to the diagnosis of primary coccidioidomycosis, we devised a 40-question survey that was completed by 556 college students seeking medical care for illness possibly due to Coccidioides immitis. The results of routine laboratory studies on these patients were also compiled. Of 269 who had coccidioidal antibody determinations and other diagnostic tests, coccidioidomycosis was diagnosed in 36 (13%). By logistic regression procedures, an elevated erythrocyte sedimentation rate, male gender, "red lumps on shins," recent arrival to an endemic area, acuteness of symptoms, and decreased total peripheral blood lymphocyte counts were independent factors positively associated with infection (P less than .05). Relative risk analysis indicated that 60% of patients with four or more of these factors were found to have coccidioidomycosis. Other significantly but not independently associated factors were an increased total leukocyte count, chest pain with breathing, fever, an absence of hoarseness, and an abnormal chest roentgenogram.
Adult↗
Enzyme-linked immunosorbent assay for antigens of Coccidioides immitis: human sera interference corrected by acidification-heat extraction.
We describe the distortion caused by sera from patients with coccidioidomycosis in an enzyme-linked immunosorbent assay (ELISA) for coccidioidal antigen. In experimental mixtures without exogenous antigen, immune sera produced an antigen-like effect. In contrast, in mixtures with a relatively large concentration of exogenous antigen, immune sera obscured antigen activity. In both circumstances, preparing specimens with an acidification-heat extraction procedure before assay rectified serum interference, and only in specimens with no exogenous antigen was the correction incomplete. Other evidence, including direct measurement of anticoccidioidal antibody after extraction, suggested that the residual antigen-like activity was not from persistent antibody. Incorporating the extraction procedure into the ELISA of clinical specimens, we found antigen activity in nine of 15 specimens. We conclude that acidification-heat extraction of sera improves detection of coccidioidal antigens and that coccidioidal antigens are present in some patients with coccidioidal infection.
Acids↗
Itraconazole treatment of experimental systemic candidiasis in male rats.
After intravenous infection with Candida albicans, rats received daily doses of itraconazole for 3 days. All rats receiving 2.5 mg kg-1 day-1 survived while all rats receiving sham-treatment died. With subsequent reduction of the itraconazole dose to 0.63 mg kg-1 day-1, no survival occurred and mortality rates equalled those of the control group.
Animals↗
Antifungal susceptibility tests.
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Antifungal Agents↗
Pharmacology and toxicity of high-dose ketoconazole.
One hundred sixty patients were entered in two multicenter protocols to receive 400 to 2,000 mg of ketoconazole once daily for nonmeningeal or meningeal coccidiodomycosis. For 24 h after administration of all doses, mean concentrations in serum exceeded MICs for Coccidioides immitis (trough concentrations, greater than 1 microgram/ml). Mean peak concentrations occurred 4 to 6 h after administration, ranging from 7 to 17 micrograms/ml for doses of 400 to 2,000 mg. Incremental increases in peak concentrations in serum were greatest at doses of less than or equal to 1,200 mg. To investigate whether long-term therapy altered concentrations in serum, serial data were studied by several methods. The results suggested a trend to increased levels in serum with prolonged therapy, but were not statistically significant. All 168 cerebrospinal fluid (CSF) samples from meningitis patients contained less than or equal to 2.9 micrograms/ml, and only 6 contained greater than 1 microgram/ml. There was no apparent relation between dose, time after dose, site of CSF sampling, or concurrent inflammation and CSF ketoconazole concentration. Neither concentration in serum, toxicity, nor outcome correlated with dose, calculated in milligrams per kilogram at the fixed doses (400-mg increments) under study. Likewise, at the various doses, concentration in serum did not correlate with outcome or toxicity, suggesting that individual drug disposition was not an important factor in outcome or toxicity. Toxicity was reversible, and principal side effects were nausea and vomiting (50%), gynecomastia (21%), decreased libido (13%), alopecia (8%), elevated liver function tests (5%), pruritus (5%), and rash (4%). Gastrointestinal and endocrinologic toxicity were dose related and increased at doses greater than 800 mg. The cumulative percent toxicity requiring discontinuation of drug was 6, 17, 23, and 56% at 400-, 800-, 1,200-, and 1,600-mg doses. Doses of >400 mg are thus markedly more toxic, and efficacy data for nonmeningeal disease have not demonstrated that they are more efficacious.
Clinical Trials as Topic↗
Comparison of relative susceptibilities of Candida species to three antifungal agents as determined by unstandardized methods.
Three groups of isolates, each comprising four isolates of Candida species, were selected for their diversity of susceptibilities to amphotericin B, flucytosine, or ketoconazole. The isolates were distributed in duplicate and in blinded fashion to three laboratories where a total of eight procedures were performed for each drug. From the decoded results, intralaboratory variability among replicate determinations was found usually to fall within a fourfold range. Interlaboratory variation, however, was 16-fold or greater for all isolates, ranging to 50,000-fold differences for some isolates. Relative susceptibilities of isolates within each method could be determined in 11 of the 24 drug-method combinations and agreed with the reference rank order in all but one instance. Our findings underscore the lack of agreement among laboratories for the susceptibility testing of yeasts but indicate that such differences could likely be resolved by standardization without loss of clinical value.
Agar↗
Bordetella pertussis adenylate cyclase: effects of affinity-purified adenylate cyclase on human polymorphonuclear leukocyte functions.
Affinity-purified adenylate cyclase (AC) of Bordetella pertussis, free of contaminating pertussis toxin, was demonstrated to have biological effects on human polymorphonuclear leukocytes (PMN). AC at doses of 25 and 50 micrograms/ml increased intracellular cAMP levels in the phagocytes 7.6- to 23.5-fold, respectively, above basal levels. AC inhibited PMN chemiluminescence, chemotaxis, and superoxide production in a dose-dependent manner. The 50% inhibitory dose for chemotaxis and chemiluminescence was 36.5 micrograms/ml; for superoxide generation it was 71.0 micrograms/ml. Although these PMN metabolic functions were impaired, no effect on phagocytic activity was observed.
Adenylate Cyclase Toxin↗
Coccidioidomycosis in renal dialysis and transplant patients: radiologic findings in 30 patients.
Asymptomatic primary coccidioidal infection is common. After the initial infection is contained, the organism can remain dormant in the body for years. Immunosuppression related to renal transplantation or dialysis may reactivate dormant disease. Thus, symptomatic disease may be seen in those with no known history of previous coccidioidomycosis who have visited endemic areas only briefly. To determine if coccidioidomycosis produces characteristic radiographic findings in renal transplant and dialysis patients, we reviewed the records and radiographs of all patients in either of these two categories who are known to have developed active coccidioidal infection in southern Arizona since 1965. Thirty patients (12 undergoing dialysis and 18 transplant recipients) were identified. We conclude that the radiographic manifestations of pulmonary coccidioidomycosis in renal transplant and dialysis patients are highly variable. Interstitial and alveolar patterns of disease are equally likely to occur. Extrathoracic infection without evidence of pulmonary disease occurred in 11 patients (37%), but was radiographically demonstrable only as septic arthritis or perinephric abscess.
Coccidioidomycosis↗