John N. Galgiani

The role of understaffing in central venous catheter-associated bloodstream infections

OBJECTIVE To determine risk factors for central venous catheter-associated bloodstream infections (CVC-BSI) during a protracted outbreak. DESIGN Case-control and cohort studies of surgical intensive care unit (SICU) patients. SETTING A university-affiliated Veterans Affairs medical center. PATIENTS Case-control study: all patients who developed a CVC-BSI during the outbreak period (January 1992 through September 1993) and randomly selected controls. Cohort study: all SICU patients during the study period (January 1991 through September 1993). MEASUREMENTS CVC-BSI or site infection rates, SICU patient clinical data, and average monthly SICU patient-to-nurse ratio. RESULTS When analyzed by hospital location and site, only CVC-BSI in the SICU had increased significantly in the outbreak period compared to the previous year (January 1991 through December 1991: pre-outbreak period). In SICU patients, CVC-BSI were associated with receipt of total parenteral nutrition [TPN]; odds ratio, 16; 95% confidence interval, 4 to 73). When we controlled for TPN use, CVC-BSI were associated with increasing severity of illness and days on assisted ventilation. SICU patients in the outbreak period had shorter SICU and hospital stays, were younger, and had similar mortality rates, but received more TPN compared with patients in the pre-outbreak period. Furthermore, the patient-to-nurse ratio significantly increased in the outbreak compared with the pre-outbreak period. When we controlled for TPN use, assisted ventilation, and the period of hospitalization, the patient-to-nurse ratio was an independent risk factor for CVC-BSI in SICU patients. CONCLUSIONS Nursing staff reductions below a critical level, during a period of increased TPN use, may have contributed to the increase in CVC-BSI in the SICU by making adequate catheter care difficult. During healthcare reforms and hospital downsizing, the effect of staffing reductions on patient outcome (i.e., nosocomial infection) needs to be critically assessed.

NIAID mycoses study group multicenter trial of oral itraconazole therapy for invasive aspergillosis

BACKGROUND Invasive aspergillosis is the most common invasive mould infection and a major cause of mortality in immunocompromised patients. Response to amphotericin B, the only antifungal agent licensed in the United States for the treatment of aspergillosis, is suboptimal. METHODS A multicenter open study with strict entry criteria for invasive aspergillosis evaluated oral itraconazole (600 mg/d for 4 days followed by 400 mg/d) in patients with various underlying conditions. Response was based on clinical and radiologic criteria plus microbiology, histopathology, and autopsy data. Responses were categorized as complete, partial, or stable. Failure was categorized as an itraconazole failure or overall failure. RESULTS Our study population consisted of 76 evaluable patients. Therapy duration varied from 0.3 to 97 weeks (median 46). At the end of treatment, 30 (39%) patients had a complete or partial response, and 3 (4%) had a stable response, and in 20 patients (26%), the protocol therapy was discontinued early (at 0.6 to 54.3 weeks) because of a worsening clinical course or death due to aspergillosis (itraconazole failure). Twenty-three (30%) patients withdrew for other reasons including possible toxicity (7%) and death due to another cause but without resolution of aspergillosis (20%). Itraconazole failure rates varied widely according to site of disease and underlying disease group: 14% for pulmonary and tracheobronchial disease, 50% for sinus disease, 63% for central nervous system disease, and 44% for other sites; 7% in solid organ transplant, 29% in allogeneic bone marrow transplant patients, and 14% in those with prolonged granulocytopenia (median 19 days), 44% in AIDS patients, and 32% in other host groups. The relapse rates among those who completed therapy and those who discontinued early for possible toxicity were 12% and 40%, respectively; all were still immunosuppressed. CONCLUSION Oral itraconazole is a useful alternative therapy for invasive aspergillosis with response rates apparently comparable to amphotericin B. Relapse in immunocompromised patients may be a problem. Controlled trials are necessary to fully assess the role of itraconazole in the treatment of invasive aspergillosis.

Antifungal susceptibility testing.

Unlike antibacterial susceptibility testing, reliable antifungal susceptibility testing is still largely in its infancy. Many methods have been described, but they produce widely discrepant results unless such factors as pH, inoculum size, medium formulation, incubation time, and incubation temperature are carefully controlled. Even when laboratories agree upon a common method, interlaboratory agreement may be poor. As a result of numerous collaborative projects carried out both independently and under the aegis of the Subcommittee on Antifungal Susceptibility Testing of the National Committee for Clinical Laboratory Standards, the effects of varying these factors have been extensively studied and a standard method which minimizes interlaboratory variability during the testing of Candida spp. and Cryptococcus neoformans has been proposed. This review summarizes this work, reviews the strengths and weaknesses of the proposed susceptibility testing standard, and identifies directions for future work.

An insight into the antifungal pipeline: selected new molecules and beyond

Invasive fungal infections are increasing in incidence and are associated with substantial mortality. Improved diagnostics and the availability of new antifungals have revolutionized the field of medical mycology in the past decades. This Review focuses on recent developments in the antifungal pipeline, concentrating on promising candidates such as new azoles, polyenes and echinocandins, as well as agents such as nikkomycin Z and the sordarins. Developments in vaccines and antibody-based immunotherapy are also discussed. Few therapeutic products are currently in active development, and progression of therapeutic agents with fungus-specific mechanisms of action is of key importance.

Practice Guidelines for the Treatment of Coccidioidomycosis

Management of patients diagnosed with coccidioidomycosis involves defining the extent of infection and assessing host factors that predispose to disease severity. Patients with relatively localized acute pulmonary infections and no risk factors for complications often require only periodic reassessment to demonstrate resolution of their self-limited process. On the other hand, patients with extensive spread of infection or at high risk of complications because of immunosuppression or other preexisting factors require a variety of treatment strategies that may include antifungal therapy, surgical debridement, or both. Amphotericin B is often selected for treatment of patients with respiratory failure due to Coccidioides immitis or rapidly progressive coccidioidal infections. With other more chronic manifestations of coccidioidomycosis, treatment with fluconazole, itraconazole, or ketoconazole is common. Duration of therapy often ranges from many months to years, and, for some patients, chronic suppressive therapy is needed to prevent relapses.

Decrease in nosocomial Clostridium difficile-associated diarrhea by restricting clindamycin use.

The spectrum of Clostridium difficile infection ranges from asymptomatic carriage to self-limited diarrhea, pseudomembranous colitis, toxic megacolon, and colonic perforation. Symptomatic infections cause substantial nosocomial morbidity and mortality. Infections often extend hospital stays and add an additional

Detection of amphotericin B-resistant Candida isolates in a broth-based system

2000 to

Comparative genomic analyses of the human fungal pathogens Coccidioides and their relatives.

5000 per episode to costs of health care; in addition, patients commonly relapse [1]. Certain antimicrobial agents (ampicillin, cephalosporins, and clindamycin) particularly predispose patients to the development of C. difficile infection, but virtually every antimicrobial agent has been implicated. Outbreaks of C. difficile diarrhea are associated with the use of specific antimicrobial agents [2-5]. However, when epidemics occur, it is difficult to determine which, if any, control measures have been effective, particularly those directed at control of antimicrobial agent use. Beginning in 1990, an outbreak of C. difficile diarrhea was identified at the Veterans Affairs Medical Center in Tucson, Arizona. The epidemic was eventually terminated after identifying an association of C. difficile infection with clindamycin use and after instituting clindamycin restriction. In this report, we describe the outbreak, identify a predominant clindamycin-resistant strain of C. difficile by restriction endonuclease analysis, document the association of illness with clindamycin use, and show a decreased frequency of clinical cases and the epidemic strain after clindamycin restriction. Methods The Veterans Affairs Medical Center where the epidemic occurred is a Deans Hospital affiliate of the University of Arizona. Hospital discharges and daily census figures showed no significant differences for the 5 years before and during the outbreak; they average 6619 384 patient admissions per year and a census of 168 patients per day. The infection control program is administered by two nurse specialists under the supervision of an infectious diseases physician. The frequency of C. difficileassociated diarrhea has been monitored since 1986 by continuous review of microbiology reports of stool specimens submitted for C. difficile culture or toxin assay. Antibiotic use is restricted for most staff physicians and housestaff to a hospital formulary, and nonformulary antimicrobial agents are only available with approval from an infectious diseases physician. For at least the past 15 years, the formulary has included clindamycin (Cleocin; Upjohn Company, Kalamazoo, Michigan) and has excluded oral vancomycin. Stool specimens from patients with diarrhea who are suspected by their primary care physicians of having colitis were tested for C. difficile. All specimens were tested for cytotoxin by cell culture assay [5] before December 1991 and by latex agglutination [5, 6] thereafter. All specimens tested for cytotoxin and all specimens with a positive latex test result were cultured on cycloserine-mannitol blood agar to isolate C. difficile [7]. For purposes of case definition, all patients who had diarrhea in association with a positive assay for C. difficile-stool cytotoxin or for latex agglutination and who had recent antibiotic therapy (within 60 days) were considered to have C. difficile infection. Diarrhea was defined as 4 or more loose or unformed stools in a 24- to 36-hour period; all specimens submitted to the laboratory were tested. Typing of C. difficile organisms was done on all available unique isolates by restriction of total organism DNA with Hind III restriction endonuclease followed by agarose gel electrophoresis, as previously described [8]. Organism groups and types were determined from comparison with a library of more than 250 types [8]. Clindamycin susceptibility was determined for selected isolates of C. difficile using a microdilution method in Wilkins-Chalgren broth. Clindamycin dilutions were 0.125, 1.0, and 4.0 g/mL. Plates were incubated for 48 hours in an anaerobic glove box. The organism was considered resistant to clindamycin if the minimal inhibitory concentration (MIC) was greater than 4.0 g/mL. Susceptibility to imipenem, penicillin G, amoxicillin-clavulanic acid, ticarcillin-clavulanic acid, metronidazole, and ciprofloxacin were also tested by the same microdilution method. To test for the significance of differences, we used the Fisher exact test for categorical variables and the Mann-Whitney U test for continuous variables. To test for the significance of associations, we used the Dunnett multiple range test [9]. Results Description of the Outbreak In July 1990, 8 patients who had C. difficile infection (15.8 infections per 1000 discharges) were identified at our center (Figure 1). For the previous 33 months, the average monthly incidence (mean SD) had been 1.5 1.1 infections (2.6 infections per 1000 discharges) diagnosed from a mean of 15 stool specimens per month submitted for toxin assay (10% of submitted specimens positive per month). Through July 1991, the incidence of new patients was fivefold higher than this norm, averaging 7.7 infections per month (a total of 101 patients), with all but 1 of these months exceeding the 95% surveillance threshold (4 or more patients per month, normal mean + 2 SD). The mean number of unique patient specimens submitted increased to 36 per month, of which 28% were positive for toxin during this period. Of toxin-positive specimens, 71% and 65% were culture positive before and during the epidemic, respectively. Both the group of 439 isolates tested before the epidemic and the 334 isolates tested during the epidemic that were toxin negative yielded C. difficile in culture 5% of the time. Figure 1. Number of cases of Clostridium difficile -associated diarrhea detected each month before and after clindamycin restriction. The clinical symptoms for approximately 90% of the patients were abrupt onset of abdominal distention, cramping, and profuse diarrhea. Clostridium difficile infection resulted in intestinal infarction and eventual death of one patient. In most patients, diarrhea did not begin to resolve until after institution of specific treatment with either metronidazole or oral vancomycin. The epidemic was recognized within 1 month of its inception, and several attempts at control were instituted, including hospital staff education, increased use of gloves by nursing staff when assisting patients, and improvement of environmental hygiene. Educational efforts began in early August 1990 and were carried out through the remaining calendar year. The medical center staff who participated in the educational process included attending physicians, housestaff, nursing, and housekeeping personnel. The objectives of the educational programs included a review of the epidemiology, transmission, and clinical presentation of C. difficile. Emphasis was placed on prevention of C. difficile transmission through hand washing, glove use, timely changing of gloves, and increased availability of gloves. In addition, routine environmental sanitation practices were reviewed for thoroughness, with emphasis placed on patient-related items, such as bedside commodes and bathrooms. None of these efforts appeared to alter the frequency of the new cases. Organism typing by restriction endonuclease analysis was carried out on isolates of C. difficile from 10 patients diagnosed in November and December of 1990 and from 48 other patients diagnosed from January through July of 1991. Seventeen restriction endonuclease analysis patterns were identified, indicating a high degree of polymorphism. However, isolates from 34 (59%) of the patients had an identical restriction endonuclease analysis pattern, type J7 (Figure 2), with only 1 to 5 isolates representing each of the other types. Figure 2. Restriction endonuclease analysis patterns of Clostridium difficile strains isolated during and after the epidemic. The susceptibility to clindamycin of six strains of C. difficile, isolated from patients from Tucson (Veterans Affairs Medical Center), is shown in Table 1. All six isolates were susceptible to penicillin G, imipenem, amoxicillin-clavulanate, ticarcillin-clavulanate, and metronidazole and were resistant to ciprofloxacin (data not shown). Both J7 type strains were resistant to clindamycin. Table 1. Clindamycin Susceptibility of Six Outbreak Isolates of Various Restriction Endonuclease Analysis Types Analysis of Clindamycin Use Associated with Clostridium difficile Infections Several lines of evidence linked clindamycin use with the epidemic. First, before the onset of the epidemic, clindamycin use markedly increased. For the years 1986 through 1989, the average amount of clindamycin dispensed was 315 grams per month. In 1990, clindamycin use was 489 grams per month, an increase of 41% compared with the previous year (P < 0.001). Second, in a survey conducted by the College of American Pathologists in 1989 of 220 teaching facilities, our center ranked in the 99th percentile for clindamycin use [10]. This level of use was higher than for any other antimicrobial agent on our formulary (Table 2). Third, administration of clindamycin was significantly more likely to be associated with C. difficile infection than was administration of other commonly used antimicrobial agents (Table 2). Infected patients were three to nine times as likely to have received clindamycin compared with another antimicrobial agent. The association of C. difficile infection with clindamycin was greater than for each of the other antimicrobial agents (all P < 0.05 using the Dunnett multiple range test [9] for clindamycin compared with various antimicrobial agents). Table 2. Relation of Antibiotic Use and Clostridium difficileassociated Diarrhea The association of increased clindamycin use with the increased frequency of C. difficile infection was examined further by analyzing the temporal relation (Figure 3). For the 19 months ending in July 1991, a positive relation was found between clindamycin use in either the curr

Multicenter evaluation of a broth macrodilution antifungal susceptibility test for yeasts.

Because of the limited ability of the National Committee for Clinical Laboratory Standards proposed M27P methodology to detect resistance to amphotericin B by Candida isolates, we sought to identify alternative media and pH conditions that could reliably identify resistant isolates. Antibiotic Medium 3 broth (also known as Penassay broth) buffered to pH 5 or pH 7 produced superior results and readily identified a series of resistant isolates.

Disposition of ketoconazole, an oral antifungal, in humans.

While most Ascomycetes tend to associate principally with plants, the dimorphic fungi Coccidioides immitis and Coccidioides posadasii are primary pathogens of immunocompetent mammals, including humans. Infection results from environmental exposure to Coccidiodies, which is believed to grow as a soil saprophyte in arid deserts. To investigate hypotheses about the life history and evolution of Coccidioides, the genomes of several Onygenales, including C. immitis and C. posadasii; a close, nonpathogenic relative, Uncinocarpus reesii; and a more diverged pathogenic fungus, Histoplasma capsulatum, were sequenced and compared with those of 13 more distantly related Ascomycetes. This analysis identified increases and decreases in gene family size associated with a host/substrate shift from plants to animals in the Onygenales. In addition, comparison among Onygenales genomes revealed evolutionary changes in Coccidioides that may underlie its infectious phenotype, the identification of which may facilitate improved treatment and prevention of coccidioidomycosis. Overall, the results suggest that Coccidioides species are not soil saprophytes, but that they have evolved to remain associated with their dead animal hosts in soil, and that Coccidioides metabolism genes, membrane-related proteins, and putatively antigenic compounds have evolved in response to interaction with an animal host.