A pilot study of the management of uncomplicated candidemia with a standardized protocol of amphotericin B.

We evaluated an amphotericin treatment strategy on the basis of duration of candidemia and clinical findings. Patients without neutropenia who had uncomplicated candidemia received 200 mg of amphotericin B over 5-7 days if they had had 1 day of positive cultures (PC group). The clinical cure rate was 93% (95% confidence interval [CI], 77%-99%; n=29 episodes) in the SC group, with no relapses (median follow-up, 272 days). The clinical cure rate was 83% (95% CI, 64%-94%; n=29 episodes) in the PC group, with 1 relapse (4.2%). The results of this pilot study suggest that patients with candidemia may be stratified into risk groups on the basis of the duration of positive blood cultures and other clinical findings. Decisions about the duration of therapy can be made 4-7 days after initiation of treatment. Carefully selected patients with transient uncomplicated candidemia may be safely treated with a short course of amphotericin B. Further prospective validation of this concept should be undertaken particularly to evaluate the impact on low-frequency late complications (e.g., endophthalmitis).

New challenges to the therapy of systemic fungal infections.

In summary, the recent increase in frequency of systemic fungal infections has stimulated the development of new antifungal agents which are easier to use and which have decreased toxicity. This has resulted in increase in use, and along with this, the appearance of fungi resistant to antifungal agents. The medical community will have to come to terms with this newly emerging problem.

Screening of physicians for tuberculosis.

OBJECTIVE: To determine the prevalence of tuberculous infection among a sample of physicians at Barnes Hospital and to determine the frequency of tuberculin skin testing and the adequacy of follow-up for physicians with positive tuberculin skin tests. DESIGN: Convenience sample. SETTING: 1,000-bed, university-affiliated tertiary care hospital. SUBJECTS: Physicians attending departmental conferences were screened for tuberculosis. Prior history of tuberculosis, antituberculous therapy, BCG vaccination, and previous tuberculin skin test results were obtained with a standardized questionnaire. Tuberculin skin tests were performed on those who were previously skin-test negative. OUTCOME MEASURE: Tuberculosis infection, prophylactic therapy. RESULTS: Eighty-six (24.5%) of 351 physicians in the study were skin test positive by history or currently performed skin test. Of 61 who reported a previously reactive skin test, 40 (66%) had been eligible for isoniazid prophylaxis, but only 15 (37.5%) of 40 had completed at least six months of therapy. Of 290 physicians reporting a previously negative skin test, 25 conversions (8.6%) were identified. Previously undiagnosed, asymptomatic pulmonary tuberculosis was identified in one physician. CONCLUSIONS: Infection with Mycobacterium tuberculosis is common among physicians. Physicians were screened irregularly for tuberculosis, and the use of prophylactic therapy was inconsistent. Aggressive tuberculosis screening programs for healthcare workers should be instituted (Infect Control Hosp Epidemiol 1994;15:95-100).

Evaluation of rooms with negative pressure ventilation used for respiratory isolation in seven midwestern hospitals.

OBJECTIVE: To determine the number and efficacy of respiratory isolation facilities in St. Louis hospitals and to assess the mechanisms in place for evaluating function of hospital ventilation systems. DESIGN: A prospective multi-hospital surveillance study using direct observation and a standardized questionnaire. SETTING: Seven hospitals (including university-affiliated large teaching, private community, private teaching, and private nonteaching adult hospitals, and one pediatric teaching hospital) in St. Louis, Missouri. MEASUREMENTS: Actual direction of airflow in rooms designated for respiratory isolation was measured using smokesticks. Hospital demographic information, respiratory isolation policies, and frequency of ventilation tests were provided by infection control personnel. RESULTS: One hundred twenty-one (3.4%) of 3,574 hospital rooms were designed to have negative pressure ventilation suitable for respiratory isolation. The percentage of isolation rooms in each institution ranged from 0.4% (92 of 486) to 93% (39 of 42). Only three (43%) of seven hospitals had intensive care respiratory isolation rooms, and none had isolation rooms in the emergency department. No hospital had tested routinely the efficacy of the negative pressure ventilation, and two (28%) of seven had tested airflow for the first time in the past year. We tested 115 (95%) of 121 isolation rooms. With the doors closed, 52 (45%) of 115 designated negative pressure rooms actually had positive airflow to the corridor. The number of negative pressure rooms and the presence or absence of anterooms did not predict correct direction of airflow. There was a significant difference among hospitals in the percentage of designated isolation rooms that had truly negative pressure (P < 0.0001). Hospital age, size, and type correlated with correct direction of airflow (P < 0.0001). CONCLUSION: In the hospitals studied, only a small number of rooms were designated for respiratory isolation, and the performance of these was not tested routinely. High-risk areas including intensive care units and emergency rooms were not equipped to provide respiratory isolation. The direction of airflow in respiratory isolation rooms was not always correct and should be evaluated frequently.

Results of a rubella screening program for hospital employees: a five-year review (1986-1990).

The Barnes Hospital Employee Health Service (St. Louis, Missouri) rubella screening program was evaluated over the 5-year period between January 1, 1986, and December 31, 1990. A total of 6,969 new employees were hired, and 6,115 (87.7%) were screened for evidence of rubella immunity by the Employee Health Service. Rubella serology was performed on 5,893 (96.4%) of the screened employees, while 222 (3.6%) had documentation of prior rubella vaccination or rubella infection. The absence of immunity was identified in 325 employees or 5.3% of all those screened. Women were more frequently screened by the Employee Health Service than were men (p < 0.0001), and blacks were more frequently screened than were non-Hispanic Caucasians (p < 0.0001). Physicians were less frequently screened than were other departmental groups (p < 0.0001). The rate of seronegativity for each year of hire varied from 4.45 to 6.76%, but these differences were not significant. Logistic regression analysis demonstrated that 5-year birth cohorts correlated significantly with serologic status. Employees born in 1960-1964 were least likely to be seronegative, and employees born in 1970 or later were most likely to be seronegative. Sex, race, and department group were not predictive of serologic status, although significant differences in results from different rubella assays were detected. Only 13.8% of seronegative employees were subsequently vaccinated by the Employee Health Service. This study demonstrates a lower seronegativity rate than did previous studies. It identifies groups of employees likely to escape rubella screening and low vaccination rates. It finds increasing seronegativity among employees born after 1964 that correlates with the reported increasing rates of rubella in the United States.

Formulary control of antimicrobial usage. What price freedom?

Formulary controls are the most common and probably the most effective method for controlling abuse of antimicrobial agents in hospitalized patients. Such programs may include restriction of both the number of agents available and the way these agents may be used. These programs have been demonstrated to control pharmacy expenditures. Other potential advantages include reductions in the incidence of adverse drug reactions and the antimicrobial resistance among the hospital flora, and improvements in the overall quality of prescribing of antimicrobials. There are few data to document such benefits, however. Potential disadvantages are also poorly documented but include inconvenience for prescribing physicians, increased administrative costs, prescribing errors, and increased antimicrobial resistance. Antimicrobial control programs will likely remain common, but the availability of new information technologies should enable a transition to systems based on concurrent assessment of antimicrobial appropriateness with immediate feedback to the prescribing physician.

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.

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.

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.

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.

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.

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.

Antibiotic misuse in two clinical situations: positive blood culture and administration of aminoglycosides.

Antibiotic use was examined among randomly and prospectively selected cohorts of 79 patients with a positive blood culture and 88 patients given aminoglycosides for a variety of reasons. Appropriateness of antibiotic use was judged daily for each agent according to specific criteria of misuse. For patients with a positive blood culture, 14.3% of antibiotic-days were judged inappropriate in some regard, while for patients given aminoglycosides, 10.2% of antibiotic-days were thought to be inappropriate. The patterns of misuse were similar for the two groups despite disparate selection criteria. The unnecessary use of antibiotics was the single most common type of misuse in both groups, but errors in dosing collectively accounted for nearly one-half of antibiotic misuse. These results suggest that a variety of factors are responsible for misuse of antibiotics. Although the data presented do not allow conclusions about the optimal methods for control of antibiotic misuse, they imply that a multifaceted approach is probably required.

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.

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.

Inhibition of amphotericin B (Fungizone) toxicity to cells by egg lecithin-glycocholic acid mixed micelles.

Mixed micelles prepared from egg lecithin and the sodium salt of glycocholic acid markedly inhibited amphotericin B toxicity to mammalian cells without significantly affecting the antifungal effects of the drug.

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.

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.

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.

Comparison of fluconazole with amphotericin B in treatment of histoplasmosis in normal and immunosuppressed mice.

The activities of fluconazole and amphotericin B against Histoplasma capsulatum were investigated. The minimum inhibitory concentrations ranged from 0.12 to 0.47 microgram/mL for amphotericin B and from 16 to 250 micrograms/mL for fluconazole. Fluconazole given orally twice a day for 6 consecutive days compared favorably with amphotericin B given intraperitoneally once every other day for a total of six doses in the treatment of histoplasmosis in normal and leukopenic mice.