Biomedical subjects
Publications and source records attributed to S Shadomy.
A multi-center study of 1,838 clinical isolates established the accuracy of diffusion susceptibility tests with 30-mug cephalothin disks and 30-mug cefamandole disks. The same interpretive zone standards can be applied to tests with either disk but the two drugs cannot be tested interchangeably.
The mode of action of 5-fluorocytosine (5-FC) was studied in three isolates of pathogenic Aspergillus with varying degrees of susceptibility to the drug. Distribution studies showed that susceptibility or resistance to 5-FC was not dependent on uptake of the drug. While only a small percentage of the total 5-FC taken up was found in the RNA fraction of the cells, most remained in the acid-soluble intracellular pool. 5-FC, 5-fluorouracil (5-FU) and 5-fluorodeoxyuridine monophosphate (5-Fd-UMP) were among metabolites identified in the pool. In addition, fluoroorotic acid appeared to be a major constituent of the metabolites derived from 5-FC. The aspergilli also were capable of utilizing cytosine as a nitrogen source and this is suggested as a possible mechanism of resistance. A dual mode of action for 5-FC in the aspergilli is proposed. This consists of, first, incorporation of 5-FU into RNA and, second, inhibition of DNA synthesis by production of 5-FdUMP.
R41,400 is a recently synthesized, water-soluble imidazole. Its antifungal properties were compared in vitro with those of miconazole using an agar dilution procedure and 175 isolates of human fungal pathogens. The filamentous forms of Histoplasma capsulatum and Blastomyces dermatitidis were inhibited by less than or equal to 2 microgram of either drug/ml; Coccidioides immitis was inhibited by less than or equal to 0.5 microgram of R41,400/ml. Among the yeasts tested, Cryptococcus neoformans and Candida parapsilosis were the most susceptibel to the two drugs, whereas Candida albicans and Candida tropicalis were the least susceptible; 0.5 microgram of either drug/ml was inhibitory for 90%-100% of tested isolates of C. neoformans but for only less than or equal to 20% of isolates of C. albicans, C. tropicalis, and Torulopsis glabrata. Both drugs were inhibitory for most isolates of Trichophyton and Microsporum species at concentrations of less than or equal to 4 microgram/ml; Epidermophyton floccosum was uniquely susceptible to both drugs.
The reliability of the standardized 30-mug cephalothin disk and that of an experimental 30-mug cefaclor disk in predicting probable clinical susceptibility to cefaclor were compared. Quantitative determinations of cefaclor susceptibility were measured by the World Health Organization International Collaborative Study agar dilution procedure; diffusion disk tests were performed by the standardized U.S. Food and Drug Administration disk test. The cephalothin disk erred in predicting probable susceptibility in 52% of isolates of Enterococcus spp. resistant to 16 mug or less of cefaclor per ml; the cefaclor disk did not. The cephalothin disk erred in correctly predicting susceptibility in only 20% of cefaclor-susceptible isolates of Enterobacter spp.; the cefaclor disk correctly predicted susceptibility for 70%. These results indicate the need for further evaluation of a separate cefaclor disk for use in susceptibility testing with this new cephalosporin.
The in vitro antimicrobial activities of BL-S786, cefoxitin, and cefamandole against 90 isolates of Enterobacteriaceae, including Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Enterobacter cloacae and E. aerogenes, were studied by using an agar dilution procedure. Comparison of geometric mean minimal inhibitory concentrations showed that BL-S786 was half as active as cefamandole against Enterobacter species, 2 to 4 times more active than cefamandole against all other species, and 4 to 25 times more active than cefoxitin against all species. In vivo experiments employed acute protection tests in infected mice, using five isolates each of the five genera. Drugs were administered intramuscularly in two doses 3 h apart at dosages of 2.5, 5, 10, 20, and 40 mg per mouse. In most instances, BL-S786 was the most efficacious drug, being some 1.3 to 9.1 times more active than cefoxitin in all experiments and 1.5 to 8.7 times more active than cefamandole in most experiments. BL-S786 and cefamandole were comparable in activity in experiments with E. aerogenes, whereas BL-S786 was superior in experiments with E. cloacae.
A method for the rapid, quantitative determination of 5-fluorocytosine (5-FC) in serum by high-performance liquid chromatography (HPLC) has been developed. After initially ultrafiltrating the serum, a portion was injected onto a cation exchange column. 5-FC was separated by using an ammonium-phosphate buffer as the mobile phase and detected by ultraviolet absorption at 254 nm. Quantitation of 5-FC was based on the linear relationship between peak area in the chromatograms and known concentrations of 5-FC in a set of serum standards (prepared by adding from 10 to 200 micrograms of 5-FC to 1-ml aliquots of pooled human serum). This method was compared with the standard microbiological method for 5-FC. Advantages of the HPLC method include: Determination of 5-FC levels within 30 min; lack of interference from other antimicrobial drugs, particularly amphotericin B; more accurate determination of true 5-FC level, particularly at concentrations of less than 25 micrograms/ml or greater than 100 micrograms/ml; and ease with which the assay may be automated for routine use.
Netilmicin is a new, semisynthetic aminoglycoside antibiotic active against some gentamicin-resistant gram-negative bacteria. In this study we compared a 10-mug netilmicin disk with the standardized 10-mug gentamicin disk in terms of their abilities to predict probable clinical susceptibility to netilmicin. The agar dilution procedure of the International Collaborative Study of the World Health Organization and the U.S. Food and Drug Administration standardized disk test procedure were used. The gentamicin disk failed to predict the clinical susceptibility to netilmicin of 26 of 118 isolates previously shown by the agar dilution technique to to be netilmicin susceptible. The netilmicin disk correctly predicted probable susceptibility of all 26 isolates, including 20 shown by the agar dilution procedure to be resistant to gentamicin. These studies demonstrate the need for a separate netilmicin disk for use in agar diffusion disk susceptibility tests.
A retrospective review of therapeutic failures of miconazole in three patients is presented. Miconazole, a new imidazole derivative, is a broad-spectrum antifungal agent purportedly effective topically, orally, and parenterally against a number of species of fungi. Three patients with the following culturally proven deep fungal infections were treated with miconazole: (i) destructive arthritis (Sporothrix schenckii), (ii) meningoencephalitis (Cryptococcus neoformans), and (iii) disseminated aspergillosis (Aspergillus fumigatus). All the organisms were susceptible in vitro to 1.56 mug or less of miconazole per ml using a broth dilution technique. In each patient, miconazole administered intravenously in dosages of 30 mg/kg per day failed to control or eradicate infection. Miconazole serum levels ranged from <0.5 to 4.35 mug/ml as determined by radial diffusion bioassay. Cerebrospinal fluid levels were virtually undetectable. In one patient (C. neoformans), miconazole was given intraventricularly in doses of 15 mg without response. Therapeutic failures were attributed to suboptimal body fluid levels of miconazole. The reason(s) for such low levels of activity was not clear, but may have been poor penetrance into tissues, in vitro inactivation, and/or unusually rapid excretion. Untoward reactions from miconazole included fever, chills, nausea, vomiting, and phlebitis.
Ambruticin (W7783) was evaluated in vivo in mice subacutely or nonlethally infected with Histoplasma capsulatum. Results were compared with those obtained with amphotericin B, the drug of choice in human histoplasmosis. In one experiment, ambruticin was shown to be capable of curing infected animals as evidenced by totally negative liver and spleen cultures obtained when mice were sacrificed after 4 weeks of oral treatment with 150 mg of drug per kg per day. The 50% cure dose for ambruticin was between 75 and 150 mg/kg per day; the 50% cure dose for oral amphotericin B in this experiment was between 1.56 and 6.25 mg/kg per day. In a second experiment, both oral ambruticin (150 mg/kg per day) and oral amphotericin B (25 mg/kg per day) were again curative, but to a lesser degree than in the first experiment. Biological cures were obtained with both drugs after 3 and 4 weeks of treatment but not after 2 weeks.
The in vitro antifungal inhibitory activities of ambruticin and of various antifungal drugs of choice against 190 fungal pathogens representative of the major human mycoses were compared using a modification of the ICS agar dilution technique. Ambruticin compared favorably with amphotericin B and miconazole when tested against the dimorphic pathogens Coccidioides immitis, Histoplasma capsulatum, and Blastomyces dermatitidis and against Aspergillus fumigatus. Miconazole was the most active compound against Sporothrix schenckii, Allescheria (Petriellidium) boydii, and selected dematiaceous fungi, with ambruticin giving minimal inhibitory, concentrations from 3- to 74-fold higher. Ambruticin compared unfavorably with amphotericin B and 5-fluorocytosine when tested against Candida and Torulopsis species. Ambruticin was not as active in vitro as tolnaftate when tested against the three genera of dermatophytic fungi, but compared favorably with miconazole.
In vitro susceptibilities of 78 isolates of pathogenic filamentous fungi to the imidazole compounds R34,000 and miconazole and to amphotericin B were determined using an agar dilution technique. Allescheria boydii, Sporothrix schenckii and the dematiaceous fungi (Cladosporium, Fonsecaea and Phialophora spp.) were most susceptible to miconazole with minimum inhibitory concentration (MIC) values ranging from less than or equal to 0.25 to 32 microgram/ml and with geometric mean MIC (G-MIC) values of 0.56-1.24 microgram/ml. Isolates of Aspergillus fumigatus were more susceptible to amphotericin B and miconazole than to R34,000 with G-MIC values of 1.20 and 3.48 microgram/ml, respectively. Coccidioides immitis, Histoplasma capsulatum and Blastomyces dermatitidis were highly susceptible to all three drugs (G-MICs greater than 1 microgram/ml); R34,000 was the most active of the three compounds against C. immitis (G-MIC = 0.44 microgram/ml).
A 48-year-old male custodian and part-time gardener was hospitalized for treatment of renal tuberculosis. Sputum cultures failed to reveal mycobacteria, but Sporothrix schenckii was isolated over an eight-month period. In the absence of clinical or roentgenographic evidence of active lung disease, we postulate the saprophytic existence of S schenckii in this patient's tracheobronchial tree. Recognition of this state would obviate the need for the commonly accepted therapy for pulmonary sporotrichosis, amphotericin B.
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The susceptibilities of 216 isolates of pathogenic and commensal yeasts to 5-fluorocytosine were tested by a disk diffusion technique with use of 1- and 10-microgram disks. Minimal inhibitory concentrations (MICs) were determined by an agar dilution procedure with yeast morphology agar, pH 5.0, supplemented with 0.25 mg of thiamine/dl. Zones of inhibition produced by the two disks were correlated with paired MIC values. An MIC of 16 micrograms/ml, the upper limit of probable clinical susceptibility, correlated with zones of 14 mm and 25 mm, respectively, for the 1- and 10-microgram disks. With these values as interpretative breakpoints, the 1-microgram disk would have failed to predict clinical susceptibility with 25% of the suceptible isolates of Candida species other than Candida albicans, with 14% of the susceptible isolates of Cryptococcus neoformans, with 7% of the susceptible isolates of C. albicans, and with one of the 25 susceptible isolates of Torulopsis glabrata. The 10-microgram disk would have failed to predict susceptibility with only two isolates of Candida species.
The in vitro inhibitory activities of cefaclor and and cefatrizine, two new orally absorbed cephalosporin antibiotics, against 44 isolates of anaerobic pathogenic bacteria were measured using the agar dilution procedure of the World Health Organization-International Collaborative Study. Tests also were performed with cephalexin, cephaloglycin, and cephadrine, as well as with the parenteral cephamycin antibiotic cefoxitin. Cefoxitin was the most active antibiotic and inhibited the majority of isolates at a concentration of less than or equal to 4 microgram/ml. None of the oral cephalosporins was clearly superior against all of the anaerobic isolates; only cephadrine and cefatrizine appeared to have any potential clinical value.
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The ability of some exogenously supplied purines, pyrimidines, and their nucleosides to antagonize the in vitro fungistatic activity of 5-fluorocytosine (5-FC) in Aspergillus species was examined. All compounds tested except thymidine were capable of altering the minimal inhibitory concentration of 5-FC for seven strains of aspergilli tested. In most instances, there was a reciprocal correlation between the ability of a compound to antagonize the fungistatic activity of 5-FC and the quantity of 5-FC taken up by cells in the presence of the compound over a 72-h period.
A radial diffusion bioassay for miconazole, which employs Candida stellatoidea as the indicator organism, is described. Results from three patients treated with the drug are presented.