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Biomedical subjects

G Medoff

Publications and source records attributed to G Medoff.

At least 19 recordsLinked to original sources
PubMed1992

Candidemia in a tertiary care hospital: epidemiology, risk factors, and predictors of mortality.

Demographic information, risk factors, therapy, and outcome for all patients who had candidemia at Barnes Hospital, St. Louis, between 1 September 1988 and 1 September 1989 were retrospectively reviewed. One hundred six candidemic patients were identified, representing 0.5% of all medical and surgical discharges and 0.33% of total patient discharges. These percentages represent a 20-fold increase in the incidence of candidemia at our hospital in comparison with that during 1976-1979. Candida albicans was the most frequently isolated species (63%), followed by Candida tropicalis (17%), Candida glabrata (13%), Candida parapsilosis (6.5%), and Candida krusei (0.9%). Overall mortality was 57%, and 14 (23%) of 60 deaths occurred within 48 hours of the detection of candidemia. Mortality was associated with higher APACHE II scores (25 for nonsurvivors vs. 16 for survivors; P = .0001), the presence of a rapidly fatal underlying illness (P = .0009), and sustained positivity of blood cultures (P = .02). In cases of sustained candidemia, the isolation of non-albicans Candida species also correlated with increased mortality (8 of 8 vs. 10 of 21; P = .005). Thirty candidemic patients (28%) did not receive any antifungal therapy, and 19 (63%) of these untreated patients died. Eleven untreated patients (37%) survived without sequelae. There has been a marked increase in the incidence of candidemia in our institution that is associated with a high overall mortality. Candidemia lasting less than 24 hours was associated with a lower mortality than was that of longer duration. Severity of illness and duration of candidemia should be used as stratifying factors in prospective studies to determine optimum therapy.

Adolescent↗
PubMed1992

Evaluation of new antifungal drugs for the treatment of systemic fungal infections. Infectious Diseases Society of America and the Food and Drug Administration.

These guidelines are applicable to all fungal pathogens that produce systemic infections in humans. Specific examples are provided whenever they might clarify special issues. Systemic fungal infections usually are divided into two broad categories: endemic systemic fungal diseases, which occur classically in healthy hosts, and opportunistic fungal diseases, which occur almost exclusively in patients with impaired host defenses. Both the increasing frequency of disseminated histoplasmosis and coccidioidomycosis in patients with AIDS and the occurrence of candidemia due to vascular-line infections have begun to blur this distinction. The fungi included in these guidelines are Histoplasma capsulatum, Coccidioides immitis, Blastomyces dermatitidis, Candida species, Cryptococcus neoformans, Aspergillus species, and Sporothrix schenckii. Diagnosis of infections caused by these fungi should be based on culture of infected body fluids or tissues whenever possible. Cryptococcal and coccidioidal meningitis are exceptions. Amphotericin B remains the standard comparative agent for most new agents. Further studies of the efficacy of new oral agents used alone or after a hospital course of amphotericin B are needed. The agents currently available are usually inadequate for eradication of fungal infections in patients with AIDS, who may need prolonged treatment. Final assessment for these patients may need to be classified as clinical cure with presumed microbiologic persistence.

Antifungal Agents↗
PubMed1992

Typing of Histoplasma capsulatum by restriction fragment length polymorphisms in a nuclear gene.

We previously described yps-3, a Histoplasma-specific nuclear gene probe useful in the identification of Histoplasma capsulatum. By using restriction fragment length polymorphisms (RFLPs) of DNA detected by the yps-3 gene and mitochondrial DNA, 76 clinical and soil isolates of H. capsulatum were classified. The majority of North American isolates obtained from endemic regions of the midwestern United States were members of the previously characterized class 2, although four clinical isolates from different patients with AIDS from that region were grouped in class 1 with the temperature-sensitive Downs strain. A Florida soil isolate (FLS1) was placed in class 4 on the basis of RFLP with both probes. Two American Type Culture Collection strains (G184B and G186B) from Panama were grouped into class 3 by this analysis. A group of five H. capsulatum isolates obtained from patients with AIDS in New York City were typed into a new class 5 on the basis of yps-3 polymorphisms; those organisms fell into two broad mitochondrial DNA patterns, designated 5b and 5c. Two new isolates from Panama were also members of this broad yps-3 class 5 group, but they exhibited a distinct mitochondrial DNA profile (class 5a). A sixth class was detected in DNA obtained from a patient with AIDS from Panama; that DNA had unique RFLP profiles with respect to both probes. These observations suggest that the Histoplasma-specific yps-3 gene probe is a sensitive tool for typing H. capsulatum in clinical specimens. Additionally, these studies provide molecular support for the hypothesis that AIDS-associated histoplasmosis in nonendemic areas is due to reactivation of a previously acquired infection.

Acquired Immunodeficiency Syndrome↗
PubMed1992

Contamination of flexible fiberoptic bronchoscopes with Mycobacterium chelonae linked to an automated bronchoscope disinfection machine.

Between December 5, 1989, and September 25, 1990, Mycobacterium chelonae was isolated from endoscopic or bronchial washings in 14 patients on a single clinical service. A phenotypically unique strain of M. chelonae subspecies abscessus that was highly resistant to cefoxitin (MIC greater than 256 micrograms/ml) and different from 13 control isolates of M. chelonae recovered elsewhere in the hospital was identified in all these patients and the rinse water from the bronchoscope disinfecting machine. None of the outbreak patients had evidence of invasive M. chelonae disease. Aggressive infection control measures on the disinfecting machine, including use of sterile water in the wash and rinse cycles, increasing the 2% alkaline glutaraldehyde exposure time, frequent replacement of the glutaraldehyde, and disinfection of the machine, failed to eradicate the M. chelonae, presumably because of the presence of a biofilm inside the machine. Rinsing the scopes with 70% alcohol after automated disinfection eliminated the outbreak strain. This study demonstrates that automated bronchoscope disinfecting machines may become heavily contaminated with mycobacteria that resist usual disinfection, resulting in a source of bronchoscope contamination.

Bronchoscopes↗
PubMed1992

Antimicrobial use in otolaryngeal infections: general considerations.

With the development of numerous new antimicrobials and the improved efficacy of existing agents, more infections are being treated successfully, but the benefits of one agent over another have become an issue of subtle distinctions. Some clinical studies of new drugs have inherent drawbacks in their design and may not yield a comprehensive picture of antimicrobial characteristics in a wide range of patient types and diseases. Studies should therefore be carefully evaluated to determine whether a real advantage exists for a new agent. At Barnes Hospital (St Louis, Missouri), antimicrobials are chosen for the formulary on the basis of efficacy, toxicity, and cost. One or two agents are selected from a group of "therapeutic equivalents." Nonformulary agents or uses must be approved by the infectious disease staff. Evaluation and discussion of therapy with formulary and nonformulary drugs educates house staff, who can then use approved agents with greater knowledge and skill.

Anti-Bacterial Agents↗
PubMed1991

Characterization of CARE-1: Candida albicans repetitive element-1.

A middle repetitive DNA element, Candida albicans repetitive element-1 (CARE-1) has been isolated from the pathogenic yeast C. albicans. CARE-1 appears to be species-specific and constitutes approx. 0.045% of total C. albicans DNA, or a reiteration frequency of about two to twelve copies per haploid genome. The CARE-1 element has been detected on several C. albicans chromosomes separated by field-inversion gel electrophoresis, suggesting that the element is dispersed. Interstrain variation was observed in the number and distribution of hybridizing bands. The element is well conserved, since no nucleotide (nt) heterogeneity was observed when the sequences of two CARE-1 family members isolated from two different chromosomes (A and B) of C. albicans were compared. CARE-1 possesses 467 bp and is characterized by several stretches of A's and T's, short direct repeats and shows no significant homology to any known nt sequence.

Base Sequence↗
PubMed1991

Systemic fungal infections: an overview.

Increasingly more common, these infections pose diagnostic and therapeutic problems. The distinction between primary infection in healthy hosts and opportunistic infection in the immunocompromised remains clinically useful. Three major diseases in each category are discussed. A promising therapeutic advance is the introduction of orally administered azoles.

Antifungal Agents↗
PubMed1991

Structure-activity study of inhibition of amphotericin B (Fungizone) binding to sterols, toxicity to cells, and lethality to mice by esters of sucrose.

The effects of four monoesters of sucrose with different acyl chain lengths (palmitate, C16; myristate, C14; laurate, C12; and caprate, C10) on the aggregation state of amphotericin B (AmB), its binding to cholesterol and ergosterol, its toxicity to cells, and its lethality to mice were determined. In solution, all four of these esters inhibited AmB binding to cholesterol more than to ergosterol; this effect correlated with the ester-induced shift from the mainly aggregated form of AmB to the mainly monomeric form. In experiments with cells, the esters inhibited the toxicity of AmB to mouse erythrocytes and cultured mouse fibroblast L-929 cells more than its toxicity to Candida albicans cells. When injected intravenously with AmB, these esters decreased AmB lethality to mice. In all of these assays, the ester with the shortest chain length (caprate) was much less potent than the other three esters. Our results indicate a correlation between in vitro and in vivo assays and suggest that the in vitro and in vivo selectivity of AmB may be enhanced by surface-active agents which modulate the aggregation state of AmB.

Amphotericin B↗
PubMed1990

Lysis of human promyelocytic HL-60 cells by amphotericin B in combination with 2-chloroethyl-1-nitrosoureas: role of the carbamoylating activity of nitrosoureas.

The combinations of amphotericin B (AmB) with 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) or 2-cyclohexyl isocyanate, the carbamoylating decomposition product of CCNU, were more potent in lysing HL-60 cells than the combinations of AmB with 1,3-bis-(2-chloroethyl)-1-nitrosourea (BCNU) or 2-chloroethyl isocyanate, the carbamoylating decomposition product of BCNU. The noncarbamoylating nitrosoureas 1-(2-chlorethyl)-3-(2,6-dioxo-3-piperydyl)-1-nitrosourea and 2-[3-(2-chloroethyl)-3-nitrosoureido]-D-glucopyranose did not alter AmB effects on HL-60 cells. These results indicate that the potentiating action of CCNU and BCNU on the lytic effects of AmB is associated with the carbamoylating activity of these nitrosoureas. It is likely that the greater carbamoylating activity of CCNU, compared to BCNU, is responsible for the differences in potency of the two AmB-drug combinations.

Amphotericin B↗
PubMed1990

Temperature-sensitive variants of Histoplasma capsulatum isolated from patients with acquired immunodeficiency syndrome.

Histoplasma capsulatum isolates from three St. Louis area AIDS patients with disseminated histoplasmosis were found to be closely related to the temperature-sensitive, previously unique, Downs strain based on growth phenotype and restriction fragment length polymorphisms (RFLP) involving mitochondrial DNA, ribosomal DNA, and the yps-3 gene. H. capsulatum isolates from five non-AIDS patients in the St. Louis area with disseminated histoplasmosis or chronic pulmonary histoplasmosis had the growth phenotype and RFLP pattern characteristic of most strains isolated from other regions of the USA.

Acquired Immunodeficiency Syndrome↗
PubMed1990

In vitro and in vivo activities of Sch 39304, fluconazole, and amphotericin B against Histoplasma capsulatum.

The antifungal activities of amphotericin B and two triazoles, Sch 39304 and fluconazole, were tested against Histoplasma capsulatum. In this study Sch 39304 compared favorably with amphotericin B in treating histoplasmosis in normal and leukopenic mice, whereas fluconazole was much less active. The differences in the efficacies of the triazoles appeared to be due to differences in their pharmacokinetics and the dosage schedule that was used. For amphotericin B there was a good correlation between in vitro and in vivo efficacy, but this was not true of the triazole derivatives. These results further demonstrate that, with the methods used in this study, in vitro susceptibility testing of triazoles may not be predictive of in vivo activity against isolates of H. capsulatum.

Amphotericin B↗
PubMed1989

Concentration dependent dual effect of the monolauryl ester of sucrose on the antifungal activity and absorption spectra of amphotericin B (Fungizone).

A mild detergent, the monolauryl ester of sucrose (LS), at concentrations which ranged from 0.008 to 0.03%, enhanced amphotericin B (AmB) toxicity against Saccharomyces cerevisiae and Cryptococcus neoformans cells. At higher concentrations, 0.06 to 2.5%, LS inhibited AmB effects on these two fungi. We analyzed changes in the absorption spectrum of AmB induced by LS at these two concentration ranges by comparing ratios (R values) of AmB absorbance at 409 nm, the wavelength characteristic of non-aggregated (monomeric) AmB, to absorbance at 328 nm, the wavelength characteristic of aggregated AmB. Low concentrations of LS caused a decrease in R, whereas the higher LS concentrations increased R. Therefore, LS had concentration-dependent dual effects on the antifungal activity of AmB which correlated with shifts in the physical states of AmB. The concentration range of LS required to inhibit the antifungal effects of AmB was about 1000-fold greater than the previously reported concentrations required to inhibit AmB toxicity to mammalian cells (Gruda, I., Gauthier, E., Elberg, S., Brajtburg, J. and Medoff, G. (1988) Biochem. Biophys. Res. Commun. 154, 954-958). This suggests that LS may be a useful agent to decrease AmB toxicity to host cells without affecting the antifungal effects. Moreover, increase in AmB toxicity induced by low concentrations of LS suggests the possibility that synergistic interaction between fatty acid esters and polyene antibiotics may have therapeutic value.

Amphotericin B↗
PubMed1989

Comparison of the separation of Candida albicans chromosome-sized DNA by pulsed-field gel electrophoresis techniques.

Pulsed-field gel electrophoresis techniques were used to study chromosome-sized DNA molecules of C. albicans. Chromosome-sized DNA of two strains of Candida albicans has been resolved into 8 bands by orthogonal-field-alternation gel electrophoresis (OFAGE). Six bands were observed in chromosomal preparations of C. albicans using field-inversion gel electrophoresis (FIGE). Differences in the electrophoretic mobilities of bands of the strains of C. albicans examined suggests that chromosome-length polymorphisms exist and make it difficult to correlate the banding patterns among strains. These correlations were facilitated, however, by assignment of C. albicans chromosomes by hybridization using a collection of cloned DNA probes specific for each of the 8 observed bands. Southern blotting showed that the 6 FIGE bands consisted of 4 singlets and 2 comigrating doublets, accounting for the 8 bands observed by OFAGE analysis. The agreement between OFAGE and FIGE analysis suggests that the C. albicans haploid genome contains a minimum of 8 chromosomes.

Candida albicans↗
PubMed1989

Antimicrobial misuse in patients with positive blood cultures.

PURPOSE: Inappropriate antimicrobial use was examined among a randomly and prospectively selected cohort of patients with at least one positive result of blood cultures. This misuse was then analyzed with respect to hospital charges and length of stay (LOS). PATIENTS AND METHODS: The study consisted of 70 patients (average age, 58.5 years) who had not undergone bone marrow transplantation. Patient charts were reviewed daily for the following information: clinical signs and symptoms of infection, pertinent laboratory data, culture results, detailed data on each antimicrobial in every antimicrobial regimen and their appropriateness, hospital charges, LOS, diagnostic and procedure codes, and discharge status. Three severity of illness variables were generated. Inappropriate antimicrobial use was described according to one of 12 categories. RESULTS: The percent of antimicrobial misuse, defined as the proportion of days of administration of antimicrobials on which one or more antimicrobials were judged inappropriate, was found to be 22.3%. After adjustment for severity of illness and diagnosis, this average inappropriateness correlated with 4.2 additional hospitalization days and $5,368 additional hospital charges. CONCLUSION: Our results cannot distinguish among several possible reasons for these associations, including direct causality (e.g., toxicity and prolonged hospitalization for antimicrobial use) and indirect links such as inappropriate utilization of other resources and influences of severity of illness on antimicrobial use not accounted for in our equations. Nevertheless, the magnitude of the association gives import to the desirability of further studies.

Anti-Infective Agents↗
PubMed1989

Effects of ascorbic acid on the antifungal action of amphotericin B.

Ascorbic acid enhanced the lethal but not the permeabilizing effects of amphotericin B on Candida albicans and Cryptococcus neoformans cells. Two other ene-diol acids, D-erythorbate and dihydroxyfumarate, also enhanced the lethal action of amphotericin B on Can. albicans. Maleic acid and gulanolactone, compounds structurally related to ascorbic acid but not containing the ene-diol group, had no such effect. It is assumed that ascorbic acid and the two other ene-diol acids acting as pro-oxidants augmented the oxidation-dependent killing of fungal cells induced by amphotericin B.

Amphotericin B↗