Background: Widespread antibiotic use has been associated with increases in both bacterial resistance and nosocomial infection. Objective: To characterize the impact of hospital-wide clindamycin restriction on the incidence of Clostridium difficile-associated diarrhea and on antimicrobial prescribing practices. Design: Prospective, observational cohort study. Setting: University-affiliated Veterans Affairs Medical Center. Patients: Hospitalized patients with symptomatic diarrhea. Measurements: Clinical data on individual patients and data on antibiotic use were obtained from hospital pharmacy records. Hospital-wide use of antimicrobial agents was monitored. Isolates of C. difficile underwent antimicrobial susceptibility testing and molecular typing. Results: An outbreak of C. difficile-associated diarrhea was caused by a clonal isolate of clindamycin-resistant C. difficile and was associated with increased use of clindamycin. Hospital-wide requirement of approval by an infectious disease consultant of clindamycin use led to an overall reduction in clindamycin use, a sustained reduction in the mean number of cases of C. difficile-associated diarrhea (11.5 cases/month compared with 3.33 cases/month; P < 0.001), and an increase in clindamycin susceptibility among C. difficile isolates (9% compared with 61%; P < 0.001). A parallel increase was noted in the use of and costs associated with other antibiotics with antianaerobic activity, including cefotetan, ticarcillin-clavulanate, and imipenem-cilastin. The hospital realized overall cost savings as a result of the decreased incidence of C. difficile-associated diarrhea. Conclusions: Hospital formulary restriction of clindamycin is an effective way to decrease the number of infections due to C. difficile. It can also lead to a return in clindamycin susceptibility among isolates and can effect cost savings to the hospital.

The activity of methicillin, oxacillin, vancomycin, imipenem and FK037 against 106 isolates of staphylococci was assessed using a microbroth dilution method with low (10(5) cfu/mL) and high (10(7) cfu/mL) inoculum sizes. Overall, FK037, an oxime-type cephem antibiotic, was as active as imipenem, but less active than vancomycin (MIC90s 25, 25 and 6.25 mg/L, respectively) at the lower inoculum. Efficiency of plating experiments were also performed to characterize phenotypic expression of resistance to FK037, imipenem and methicillin. Five of 24 isolates and 18 of 24 isolates contained subpopulations resistant to FK037 and imipenem, respectively. In a rabbit model of endocarditis, FK037 was equally effective as other antibiotics tested in the treatment of methicillin-sensitive Staphylococcus aureus infection. In the treatment of endocarditis due to a homotypic methicillin-resistant S. aureus, FK037 and vancomycin were the most active antibiotics. The presence of subpopulations resistant to imipenem and FK037, as demonstrated by efficiency of plating and high inoculum MIC testing, did not correlate with antibiotic effectiveness in the rabbit model of endocarditis. Cultures of vegetation material following treatment with imipenem and FK037 demonstrated a lower frequency of organisms resistant to FK037 when compared with imipenem. Thus FK037 shows in-vitro and in-vivo activity against some methicillin-resistant staphylococcal species.

Twenty-three beta-lactamase (beta-lac)-producing, highly gentamicin-resistant Enterococcus faecalis isolates collected over a 7-year period from the same hospital were examined by pulsed-field gel electrophoresis of SmaI-digested genomic DNA. The beta-lac(+) isolates appeared to form a single clonal group, which had been previously designated the mid-Atlantic pattern, Eleven variations of the mid-Atlantic clone, differing by one to six bands, were identified; some of the changes were likely due to plasmid bands, However, a number of isolates had indistinguishable patterns, including some recovered over a 4-year period, There was a surprising lack of movement of the beta-lac determinant to other strains, although this trait was transferable in vitro by conjugation. We conclude that a single clone (the mid-Atlantic clone) of beta-lac(+) E. faecalis has remained endemic in this hospital for at least 7 years, The reason(s) for the apparent lack of spread to other strains of E. faecalis is unknown.

Increasing antibiotic resistance in the enterococci, including the capacity for beta-lactamase production and the development of high-level aminoglycoside resistance, has complicated the treatment of serious enterococcal infections, which often require synergistic antibiotic combinations for cure. We utilized the rabbit model of aortic valve endocarditis to investigate the effects of various antibiotics, alone and in combination, against a multiply antibiotic-resistant isolate of Enterococcus faecalis. Female New Zealand White rabbits were infected with either a beta-lactamase-producing, gentamicin-resistant isolate of E. faecalis or a non-beta-lactamase-producing, aminoglycoside-susceptible isolate, and the mean log10 CFU per gram of vegetation were determined. The most active agents were low-dose ampicillin-sulbactam (200 mg/kg of body weight per day), high-dose ampicillin-sulbactam (400 mg/kg of body weight per day), and vancomycin (150 mg/kg of body weight per day), which reduced the titers of bacteria by 2.27, 2.76, and 2.85 log10 (CFU/g, respectively, compared with controls. While ampicillin-sulbactam and vancomycin were equally efficacious in reducing titers of bacteria in vegetations, no animals were cured (defined as < 2 log10 CFU/g of vegetation) by either agent, whether treatment was continued for 3 or 7 days. The addition of gentamicin was not associated with increased killing in rabbits infected with the aminoglycoside-resistant isolate. Both high-dose ampicillin-sulbactam and vancomycin regimens demonstrated significant, continued reduction in bacterial titers with the longer periods of treatment (P < or = 0.05); 7-day treatment with high-dose ampicillin-sulbactam produced a greater reduction in bacterial titers in vegetation than 7-day treatment with vancomycin (P < or = 0.05). We conclude that ampicillin-sulbactam and vancomycin are equally effective in the treatment of experimental endocarditis due to beta-lactamase-producing, highly gentamicin-resistant E. faecalis. The optimum therapy for such infections in humans is not known.

Beta-Lactamase-producing, aminoglycoside-resistant strains of Enterococcus faecalis have been isolated from different geographic areas and are endemic at our institution. We report the isolation of a beta-lactamase-producing, aminoglycoside-resistant strain of E. faecium. The beta-lactamase was plasmid mediated and transferable with high frequency into a plasmid-free E. faecalis recipient strain. MICs suggested that the E. faecium strain also contained intrinsic (chromosomal) resistance to penicillins.

OBJECTIVE:To investigate the risk factors, clinical features, molecular epidemiology, and treatment outcomes associated with an outbreak of infections due to beta-lactamase-producing, high-level gentamicin-resistant Enterococcus faecalis.DESIGN:Case-control and molecular genetics study.SETTING:Tertiary care Veterans Affairs hospital.PATIENTS:Sixty-five patients infected or colonized with beta-lactamase-producing high-level gentamicin-resistant E. faecalis (case patients) were matched and compared with 65 randomly selected patients infected or colonized with beta-lactamase-negative, gentamicin-susceptible E. faecalis.MEASUREMENTS AND MAIN RESULTS:During the 20-month study period, 124 of 1506 isolates (8.2%) of E. faecalis from 70 patients were found to produce beta-lactamase. Univariate analysis showed older age, higher APACHE II score, nosocomial acquisition, recent surgical procedure, total parenteral nutrition, and antibiotic treatment to be significantly associated with the acquisition of beta-lactamase-producing, high-level gentamicin-resistant E. faecalis. A multivariate analysis, done using stepwise multiple logistic regressions, showed that only two variables remained significant: an APACHE II score greater than 6 (odds ratio, 9.5; 95% CI, 4.4 to 20.3) and antibiotic treatment (odds ratio, 10.2; CI, 4.5 to 23.2). The mortality rate for case patients was 7.7% (5 of 65 patients; CI, 1.2% to 14.2%); no control patient died. Of 23 infections occurring in case patients, 13 were treated with "inappropriate" antibiotics (regimens that included a beta-lactamase-unstable antibiotic); 2 patients improved and 11 had complete resolution of disease. "Appropriate" treatments (regimens that included a beta-lactamase-stable antibiotic) were used in 10 patients; 5 of 10 infections were fatal. Restriction enzyme digests of total chromosomal DNA showed nearly identical patterns for selected isolates of beta-lactamase-producing, high-level gentamicin-resistant E. faecalis, suggesting dissemination through the hospital of a single strain of E. faecalis.CONCLUSIONS:Fatal infections were observed despite treatment with beta-lactamase-stable antibiotics. The risk for infection or colonization with beta-lactamase-producing, high-level gentamicin-resistant E. faecalis was strongly associated with severe underlying disease (acute physiology and chronic health evaluation [APACHE] II score, greater than 6) and previous antibiotic treatment. These results may be useful in targeting high-risk patients for infection-control interventions.

Beta-lactamase-producing (Bla+) enterococci have been reported in three states and two countries. Pulsed-field gel electrophoresis was used to compare 14 Bla+ Enterococcus (Streptococcus) faecalis isolated from hospitalized patients in seven states and three continents. The restriction endonuclease digestion patterns of isolates from Connecticut, Massachusetts, Lebanon, and Argentina were all markedly different, indicating that these were different strains. However, isolates from Delaware, Texas, Pennsylvania (Philadelphia and Pittsburgh), Florida, and Virginia were similar, indicating that these isolates were derivates of a single strain. This conclusion was supported by hybridization using individual fragments as probes. Spread of Bla+ enterococci within the hospital setting was also demonstrated. These findings illustrate the value of pulsedfield gel electrophoresis for epidemiologic analyses and support the importance of identifying and containing organisms with new resistance properties in an effort to decrease their transmission to and from, as well as within, hospitals.

Using a daily questionnaire, we prospectively studied 277 physicians from two hospital medical services for incidents of exposure to blood and body fluids and barrier use before and after the implementation of universal precautions. We found that implementation significantly increased the frequency of barrier use during exposure incidents from 54% before implementation to 73% after implementation of universal precautions. Implementation led to a decrease in the number of exposure incidents that resulted in direct contact with blood and body fluids (actual exposures), from 5.07 to 2.66 exposures per physician per patient care month, and to an increase in averted exposures in which direct contact was prevented by the use of barrier devices, from 3.41 exposures per patient care month before implementation to 5.90 exposures per patient care month after implementation. Implementation affected neither the types of body fluid or procedures involved nor the overall rate of exposure incidents (8.5 per patient care month) but, through an increase in barrier use, it did prevent direct contact with blood and body fluids and thus converted what would have been an actual exposure into an averted one. We conclude that universal precautions were effective in reducing the risk of occupational exposures among physicians on a medical service.

An organism resembling Bacillus alvei was isolated from the lung and pleural fluid of an immunocompetent patient. The isolate differed from the type strain of B. alvei in its ability to reduce nitrate and its inability to produce dihydroxyacetone and acetylmethylcarbinol. The isolate was resistant to ciprofloxacin and showed intermediate susceptibility to vancomycin.

beta-Lactamase-producing (BL+), aminoglycoside-resistant (AR) Enterococcus faecalis is endemic in our hospital, having caused widespread colonization and infection. Suitable therapy for infections caused by these organisms has been problematic. We compared the antimicrobial and bactericidal activities, by broth macrodilution and time-kill methods, of several antibiotics, alone and in combination, against BL+, AR isolates of E. faecalis and determined the transmissibility of antibiotic resistance markers. Ampicillin-sulbactam, imipenem, daptomycin, and ciprofloxacin were the most active antibiotics with MICs for 90% of isolates tested of 2, 1, 2, and 1 microgram/ml, respectively, against inocula of 10(3) and 10(5) CFU/ml. Little inoculum effect was noted with imipenem, vancomycin, daptomycin, or ciprofloxacin, while the addition of sulbactam to ampicillin partially inhibited the effect of the increased inoculum. Penicillin-sulbactam and ampicillin-sulbactam combinations in a 2:1 ratio were most frequently bactericidal (greater than or equal to 3-log10-unit decrease in bacterial titers at 24 h for 13 of 20 isolates), followed by daptomycin (8 of 20 isolates) and ciprofloxacin (2 of 20 isolates). Bactericidal activity was not demonstrated for imipenem or teicoplanin. beta-Lactamase production and aminoglycoside resistance were associated with a 60- to 65-MDa plasmid which was easily transferred to a plasmid-free E. faecalis recipient. The 840-bp beta-lactamase gene probe hybridized to purified plasmid DNA from BL+ donor isolates of E. faecalis and transconjugants but not from BL- isolates. Ampicillin-sulbactam and daptomycin (an investigational antibiotic) seem to be reasonable choices for the empiric therapy of presumed enterococcal infections in hospitals in which BL+, AR E. faecalis strains are isolated. Their use should ideally be supported by tests for bactericidal activity.

In summary, we have described a patient with AIDS and a previously unreported cause of biliary tract obstruction. The incidence of cryptococcal visceral lymphadenitis in patients with AIDS and disseminated cryptococcosis is unknown, but, if present, is probably clinically silent in most instances. However, in the differential diagnosis of abdominal pain and cholestasis in such patients, one should consider major biliary duct obstruction due to cryptococcal lymphadenitis.

Stomatococcus mucilaginosus was isolated from the blood of a patient with endocarditis and a past history of drug abuse and aortic valve replacement. At autopsy, Gram stain of the aortic valve revealed gram-positive cocci. Our isolate was atypical for S. mucilaginosus in that colonies were nonmucoid and nonadherent to agar surfaces. Cellular capsules were demonstrated by light and electron microscopy. Phenotypic characteristics identified by conventional methods as well as profile numbers obtained by using two commercial identification systems for staphylococci, the API Staph-Ident and the dms Staph Trac, are presented. Practical tests that differentiate S. mucilaginosus from the genera Micrococcus and Staphylococcus include growth on nutrient agar containing salt and lysostaphin susceptibility. Additional tests that helped differentiate our isolate from group D streptococci included hydrolysis of L-pyrrolidonyl-beta-naphthylamide and streptococcal serogrouping.

Because of the immunosuppressive therapy received by patients undergoing cardiac transplantation, disseminated infections, including disseminated fungal infections, often develop. Disseminated coccidioidomycosis developed in a 23-year-old man soon after undergoing orthotopic cardiac transplantation. Clinical manifestations included an unusual rash, severe myositis and arthropathy, a rapid downhill course, and pathologic evidence of widespread fungal invasion, including invasion of the cardiac graft. Detailed travel and geographic histories, and perhaps skin testing and antibody determinations for geographic-specific pathogens, should be part of the preoperative evaluation of all transplant candidates.

Because of the immunosuppressive therapy received by patients undergoing cardiac transplantation, disseminated infections, including disseminated fungal infections, often develop. Disseminated coccidioidomycosis developed in a 23-year-old man soon after undergoing orthotopic cardiac transplantation. Clinical manifestations included an unusual rash, severe myositis and arthropathy, a rapid downhill course, and pathologic evidence of widespread fungal invasion, including invasion of the cardiac graft. Detailed travel and geographic histories, and perhaps skin testing and antibody determinations for geographic-specific pathogens, should be part of the preoperative evaluation of all transplant candidates.

We observed elevated MICs of penicillin antibiotics while performing agar dilution susceptibility testing of strains of Clostridium difficile on supplemented brain heart infusion agar, an effect which was completely eliminated by the exclusion of L-cysteine from the medium. L-Cysteine antagonizes the activity of penicillins against C. difficile, most likely by direct inactivation of the antibiotic.

A high-performance liquid chromatographic method for the measurement of moxalactam concentrations in serum was modified to permit the simultaneous measurement of both moxalactam and cefazolin. We then studied whether the simultaneous administration of both moxalactam and cefazolin to normal subjects would produce profiles of serum concentration versus time which were the same as those obtained after the administration of each drug individually. Six healthy adults received a 30-min infusion of cefazolin (10 mg/kg), followed in 2 days by the same dose of moxalactam. After 2 days, both antibiotics were administered together. A two-compartment model was found to adequately characterize the data, and the serum concentration curve for each drug when given alone was statistically identical to that obtained after simultaneous administration. Cefazolin was found to produce a significantly greater peak serum concentration (105 +/- 14 versus 81 +/- 21 microgram/ml) and a significantly greater area under the curve (218 +/- 42 versus 157 +/- 19 . microgram h/ml). The terminal half-life of moxalactam was not significantly longer than for cefazolin (2.2 +/- 0.6 versus 2.0 +/- 0.6 h, respectively). The method of simultaneous administration may have distinct advantages over conventional methods for studies of comparative tissue penetration.