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Infections due to extended-spectrum β-lactamase (ESBL)-producing Enterobacterales are an increasingly common problem. For many of these infections, no oral treatment options are available. The activity of amoxicillin-clavulanate combined with ceftibuten or cefpodoxime was evaluated against a group of Escherichia coli and Klebsiella pneumoniae clinical isolates possessing a variety of CTX-M- and SHV-type ESBLs; some possessed bla TEM1 as well. In time-kill studies, the combination of subinhibitory concentrations of amoxicillin-clavulanate with ceftibuten was bactericidal and synergistic for all strains with an amoxicillin-clavulanate MIC ≤32 μg/mL, regardless of the type of ESBL and the cephalosporin minimal inhibitory concentration (MIC). The combination with cefpodoxime was also bactericidal and synergistic against all but one of these strains. These combinations were further tested against two strains of K. pneumoniae and one E. coli in a sepsis model using Galleria mellonella larvae. The combination of amoxicillin-clavulanate with ceftibuten demonstrated a synergistic survival benefit against all three strains. The combination with cefpodoxime also improved survival against the two K. pneumoniae strains, but not the E. coli strain. These findings support combining amoxicillin-clavulanate with ceftibuten, and possibly cefpodoxime, for the treatment of infections due to ESBL producers and suggest that having an amoxicillin-clavulanate MIC of 32 μg/mL or less may predict activity at clinically achievable concentrations. Clinical studies are warranted to further evaluate this therapeutic approach.

Multidrug-resistant strains of Klebsiella pneumoniae are a problem in many hospitals. In 1999, the molecular epidemiology of K. pneumoniae with extended-spectrum beta-lactamases (ESBLs) was studied at 15 hospitals in Brooklyn. Of 824 unique patient isolates, 34% were presumptive ESBL producers. Of this subset, 34% were susceptible to cefoxitin, 42% to ciprofloxacin, 48% to ceftriaxone, 55% to piperacillin-tazobactam, 57% to amikacin, and 86% to cefepime. Ribotype analysis revealed 87 unique types. However, 2 clusters accounted for 35% of isolates and were present in most of the hospitals. One cluster was significantly more resistant to most antibiotics. Although there was a predominance of SHV-5, considerable heterogeneity of beta-lactamases was evident, even among isolates of the same cluster. A correlation was found between the use of cephalosporins and the prevalence of ESBL-producing strains of K. pneumoniae at each hospital. Our data suggest that there is an advanced outbreak of multidrug-resistant K. pneumonia infection that is affecting all Brooklyn hospitals.

Background: Carbapenems are important agents for treating nosocomial gram-negative infections. Carbapenem-resistant bacteria have become increasingly problematic in certain regions. This study determined the citywide prevalence and molecular epidemiological features of carbapenem-resistant Acinetobacter baumannii and Pseudomonas aeruginosa in Brooklyn, NY., Methods: All unique patient isolates of A baumannii and P aeruginosa were collected from 15 Brooklyn hospitals from July 1, 1999, through September 30, 1999. Antibiotic susceptibilities, the genetic relatedness of resistant isolates, and the relationship between antibiotic use and resistance rates were determined., Results: A total of 419 isolates of A baumannii and 823 isolates of P aeruginosa were collected. For A baumannii, 53% were resistant to meropenem and/or imipenem, and 12% were resistant to all standard antibiotics. Ribotyping revealed that a single clone accounted for 62% of the samples and was isolated from patients at all 15 hospitals. The rate of carbapenem resistance was associated with cephalosporin use at each hospital (P =.004). For P aeruginosa, 24% were resistant to imipenem, 5% to amikacin, and 15% to 29% to other antipseudomonal agents. Ribotyping revealed that 3 clones accounted for nearly half of the isolates and were shared by most hospitals., Conclusions: Approximately 400 patients were infected or colonized with carbapenem-resistant A baumannii and P aeruginosa during a 3-month period in 1999. A few strains have spread widely throughout hospitals in this region. The prevalence of resistant A baumannii seems to be correlated with cephalosporin use. Multiresistant hospital-acquired bacteria should be viewed as a serious public health issue rather than an individual hospital's problem. An intensive coordinated effort will be needed to effectively address this problem.

Fifty-two isolates of Streptococcus pneumoniae were characterized by pulsed-field gel electrophoresis (PFGE) and automated ribotyping by using HindIII and PvuII. HindIII ribotypes correlated well with PFGE. PvuII produced fewer bands and was less discriminatory. Automated ribotyping with HindIII is an accurate method for genetic fingerprinting of S. pneumoniae and can complement PFGE.

In November 1997, all Enterobacteriaceae isolated at 15 hospitals in Brooklyn were collected. Extended-spectrum beta-lactamases (ESBLs) were present in 44% of 409 Klebsiella pneumoniae isolates. Six isolates had reduced susceptibility to carbapenems, including two that were not susceptible to any of the antibiotics tested. Pulsed field gel electrophoresis revealed a commonality of resistant isolates within and between hospitals. The occurrence of ESBLcontaining isolates was associated with cephalosporin usage (P = 0.055). ESBLs were present in 4.7% of Escherichia coli and 9.5% of Proteus mirabilis isolates. It is concluded that ESBL-producing Enterobacteriaceae are endemic in Brooklyn, are spread between hospitals, and may be associated with cephalosporin usage.

In 1995, changes in our hospital formulary were made to limit an outbreak of vancomycin-resistant enterococci and resulted in decreased usage of cephalosporins, imipenem, clindamycin, and vancomycin and increased usage of beta-lactam/beta-lactamase-inhibitor antibiotics. In this report, the effect of this formulary change on other resistant pathogens is described. Following the formulary change, there was a reduction in the monthly number (mean +/- SD) of patients with methicillin-resistant Staphylococcus aureus (from 21.9 +/- 8.1 to 17.2 +/- 7.2 patients/1,000 discharges; P = .03) and ceftazidime-resistant Klebsiella pneumoniae (from 8.6 +/- 4.3 to 5.7 +/- 4.0 patients/1,000 discharges; P = .02). However, there was an increase in the number of patients with cultures positive for cefotaxime-resistant Acinetobacter species (from 2.4 +/- 2.2 to 5.4 +/- 4.0 patients/1,000 discharges; P = .02). Altering an antibiotic formulary may be a possible mechanism to contain the spread of selected resistant pathogens. However, close surveillance is needed to detect the emergence of other resistant pathogens.

Purpose: Three patients with acute hepatitis B virus infection were identified who had been hospitalized on the same medical ward during a 19-day period several months earlier. An investigation was undertaken to determine if nosocomial transmission had occurred., Subjects and Methods: A cohort study of patients admitted to the medical ward during the 19-day period in 1995 was conducted. In addition, we reviewed medical charts and laboratory records of all patients with acute hepatitis B virus infection who had been admitted to the hospital from 1992 through October 1996 to identify other cases with possible nosocomial acquisition., Results: The 3 patients who had developed acute hepatitis B infection 2 to 5 months after hospitalization on the same medical ward had diabetes mellitus but no identified risk factors for hepatitis B infection. A source patient with diabetes mellitus and hepatitis B "e" antigenemia also was present on the same medical ward at the same time; all 4 patients were infected with the same viral subtype (adw2). Diabetes mellitus and fingerstick monitoring were associated with illness (P <0.001). Through the review of medical charts and laboratory records, 11 additional cases of suspected nosocomial acquisition via fingersticks were identified in 1996, including two clusters involving an unusual subtype of hepatitis B virus (adw4). The fingerstick device employed had a reusable base onto which disposable lancet caps were inserted. There was ample opportunity for cross-contamination among patients because deficiencies in infection control practices, particularly failure to change gloves between patients, were reported by nurses and patients with diabetes mellitus., Conclusion: Transmission during fingerstick procedures was the most likely cause of these cases of nosocomial hepatitis B infection. Contamination probably occurred when healthcare workers failed to change gloves between patients undergoing fingerstick monitoring, although other means of contamination cannot be ruled out.

Vancomycin-resistant enterococci (VRE) often contaminate the hospital environment. We examined the activity of commonly used disinfectants against eight strains of VRE, using a quantitative suspension test method. Isopropyl alcohol and sodium hypochlorite were highly effective. Hydrogen peroxide was ineffective for all strains. After 10 minutes of incubation (the manufactures' recommended time of exposure), three phenolic and three quaternary ammonium compounds also were highly effective. After 3 minutes of exposure, however, occasional failures did occur. With the exception of 3% hydrogen peroxide, most disinfectants appear to be active against VRE.

There is no uniformly accepted method for detecting colonization with vancomycin-resistant enterococci (VRE). The sensitivities of five culture methods were determined for patients known to harbor VRE. Of 189 inpatients, 101 were found to harbor VRE by at least one method. Three methods detected fewer than half of the cultures. Campylobacter agar identified 70% of patients. Enterococcosel broth (containing vancomycin and aztreonam) identified 88% and may be preferred over other media for routine surveillance.

Antibiotic resistant strains of enterococci are being isolated with increasing frequency. Effective treatment of infections caused by Enterococcus faecium resistant to ampicillin, vancomycin and aminoglycosides has not been established. We studied the activity of ramoplanin, a new lipoglycopeptide antibiotic, against two strains of multidrug resistant E. faecium. In time kill studies, ramoplanin was bactericidal against both strains, but not in the presence of 50% serum. The combination of ramoplanin and penicillin was bactericidal even in the presence of serum. In rabbits with experimental endocarditis neither penicillin nor ramoplanin significantly reduced vegetation colony counts when given alone, although ramoplanin significantly reduced spleen and kidney bacterial counts of both strains. The combination of ramoplanin plus penicillin resulted in a significant reduction of vegetation bacterial counts (-3.2 and -3.7 log10 cfu/g for strains VA3 and MMC3, respectively, P < 0.01). All spleen cultures and 9 out of 10 kidney cultures from each strain were sterile following combination therapy. While ramoplanin will not be available for parenteral therapy, further research into the development of other lipoglycopeptide antibiotics is warranted.

Fluconazole-resistant Candida species are an emerging problem. In this report, the in vitro activity of C. zeylanicum against fluconazole-resistant and-susceptible Candida isolates is described. The MICs of the bark of C. zeylanicum ranged from < 0.05-30 mg/ml, and were slightly better than commercially available cinnamon powder. Trans-cinnamaldehyde and O-methoxycinnamaldehyde had MICs of 0.03-0.5 mg/ml. The MICs of selected cinnamon candies and gums generally ranged from 25-100 mg/ml. Five patients with HIV infection and oral candidiasis received a commercially available cinnamon preparation for one week. There of the five patients had improvement of their oral candidiasis. Clinical trials will be necessary to determine the usefulness of cinnamon for the treatment of mucosal candidiasis.

Clinafloxacin, a new quinolone antibiotic with enhanced activity against Gram-positive bacteria, has demonstrated in-vitro activity against multidrug-resistant Enterococcus faecium, particularly when combined with penicillin. Rabbits with experimental endocarditis due to a multidrug-resistant strain of E. faecium were treated with clinafloxacin and/or penicillin. After three days of therapy, significant reduction of bacterial concentrations were found in vegetations, kidneys, and spleens of animals treated with clinafloxacin. The combination of clinafloxacin and penicillin was significantly better in reducing vegetation bacterial concentrations compared to the other groups (-4.4 log10 cfu/g compared with control). Serum levels of clinafloxacin consistently exceeded the MIC of the strain, and clinafloxacin-resistant isolates could not be detected. Clinafloxacin demonstrated promising activity in vivo against multidrug-resistant E. faecium, and further studies are warranted.

The combination of ampicillin and ciprofloxacin displayed bactericidal in-vitro activity against two strains of Enterococcus faecium which were highly resistant to ampicillin, vancomycin, and aminoglycosides. This antibiotic combination was used to treat rabbits with experimental endocarditis caused by these strains. Although a significant decrease in vegetation bacterial counts occurred with one strain, the degree of killing did not approach that of penicillin with an aminoglycoside against susceptible enterococci.

The effectiveness of ciprofloxacin and/or novobiocin therapy was assessed for experimental endocarditis caused by three strains of Enterococcus faecium resistant to ampicillin, vancomycin, and aminoglycosides. Rabbits with endocarditis caused by two of the strains had a significant decrease in bacterial counts in vegetations when treated with both antibiotics. Further studies using combination therapy with ciprofloxacin plus novobiocin for multidrug resistant strains of E. faecium are warranted.

Enterococci resistant to ampicillin, vancomycin, and/or aminoglycosides are a growing clinical problem. We studied the in vitro activity of the new fluoroquinolone clinafloxacin (PD 127,391) against 15 clinical isolates of multidrug-resistant Enterococcus faecium. In kill-kinetic studies, clinafloxacin (1 microgram/ml) was bactericidal against 7 of 12 susceptible isolates, although substantial regrowth occurred in 4 isolates at 48 h. The addition of ampicillin (20 micrograms/ml) resulted in bactericidal activity in all 12 isolates, and no regrowth was seen. For three isolates resistant to clinafloxacin, effective killing was not observed at these concentrations of antibiotics. Clinafloxacin with ampicillin shows promising activity against many of these multiply resistant enterococci.

Multidrug-resistant Enterococcus faecium has emerged as a serious pathogen for which no effective therapy has been established. In this report, we describe the activities of two peptide antibiotics, ramoplanin and daptomycin, against 15 isolates of E. faecium resistant to vancomycin, ampicillin, and aminoglycosides using time-kill experiments. Both antibiotics were rapidly bactericidal when tested in broth; however, the addition of 50% serum resulted in significant regrowth. The combination of ampicillin with either ramoplanin or daptomycin largely prevented this regrowth. These peptide antibiotics showed good activity against these pathogens. While the development of daptomycin has been halted, ramoplanin may hold promise for the therapy of multidrug-resistant E. faecium, especially when combined with ampicillin.

The use of antibiotic-impregnated polymethylmethacrylate (PMMA) cement beads for the local delivery of antibiotics in the treatment of chronic osteomyelitis has become a standard orthopaedic practice. The increasing resistance to antibiotics of organisms associated with orthopaedic infections has led to interest in the incorporation of more effective antibiotics into PMMA cement. Ciprofloxacin, a synthetic fluoroquinolone, is potent against a broad spectrum of bacteria associated with osteomyelitis. In this study, strands of ciprofloxacin-impregnated PMMA cement beads were prepared with 0.2, 0.5, or 1.0 g of ciprofloxacin per 40 g of PMMA. The elution concentration of ciprofloxacin was at least 1-2 mcg/ml for 7 days (0.2 g), 30 days (0.5 g), and 42 days (1.0 g). This concentration is equivalent to the minimum inhibitory concentration for the common pathogens associated with osteomyelitis. Concurrent systemic and local ciprofloxacin therapy appears to be a method for the treatment of chronic osteomyelitis.

Enterococci have emerged as significant nosocomial pathogens. Enterococci with resistance to commonly used antibiotics are appearing more frequently. We encountered at our institution several infections caused by Enterococcus faecium with high-level resistance to ampicillin, vancomycin, and gentamicin. The optimal antibiotic therapy for serious infections with unusually resistant enterococci has not been established. Using time-kill studies, we tested the effectiveness of various antibiotic combinations against 15 isolates of multidrug-resistant enterococci. No antibiotic was consistently effective when used alone. The combination of ampicillin plus ciprofloxacin was bactericidal for the 12 isolates for which the ciprofloxacin MIC was < or = 8 micrograms/ml. The combination of ciprofloxacin plus novobiocin also demonstrated activity against these isolates. No combination was found to be bactericidal for the remaining three isolates, which were highly ciprofloxacin resistant. These antibiotic combinations may be important for the future treatment of serious infections caused by these resistant pathogens.

Levels of vancomycin in serum are traditionally believed to be unaffected by hemodialysis. By both in vivo and in vitro techniques, the effects of a newer, more permeable dialyzer membrane on vancomycin concentrations were investigated. Six patients who were receiving vancomycin and undergoing maintenance hemodialysis with polyacrylonitrile dialyzer membranes had postdialysis levels in serum that were 63% of predialysis levels; the intradialytic half-life was 5.7 h. Vancomycin concentrations in serum exiting the dialyzer were 68% of those simultaneously entering the dialyzer at the beginning of dialysis. When polyacrylonitrile and conventional cellulose membranes were perfused in vitro with a recirculating solution of vancomycin, vancomycin concentrations fell to 39 and 91%, respectively, of the original concentration. The vancomycin concentration in the ultrafiltrate collected from the polyacrylonitrile membranes was only 23% of the original perfusate concentration. A significant decrease in the serum vancomycin concentration may occur during hemodialysis with newer high-flux dialyzer membranes. It appears that vancomycin binds to polyacrylonitrile membranes; this binding does not require the presence of protein and is affected by the pH of the perfusate.

The annual number of cases of culture-proven extrapulmonary tuberculosis (TB) at our hospital increased from 47 cases in 1983 to 113 cases in 1988. At least 43% (199) of 464 consecutive patients with extrapulmonary TB during this 6-year period were infected with the human immunodeficiency virus (HIV); since HIV serologic testing was not performed routinely the true HIV prevalence is likely to be higher. Of the HIV-infected patients, 59% were intravenous drug users, 31% were Haitian, 3% were homosexual males, 1% were perinatally-infected infants, and 6% did not have a known risk factor for HIV infection. Ninety-eight percent of the HIV-infected patients were black (84%) or hispanic (14%). The HIV-infected patients were more likely than the control patients to have either disseminated, genitourinary, intra-abdominal, mediastinal, or concurrent pulmonary TB. Fever was nearly universal among the HIV-infected patients, but was absent in about one-third of the control patients. Among untreated HIV-infected patients, disease progression was rapid and nearly always fatal. Among HIV-infected patients who received treatment, the response to therapy, as judged by hospital survival and time to defervescence, was similar to that of the control patients. Despite the extensive tuberculous dissemination among the HIV-infected patients, the diagnosis of TB was difficult and often delayed. In addition to the decrease in tuberculin reactivity and the atypical chest radiograph patterns, there was a need to consider other HIV-related infections in the differential diagnosis. Although sputum specimens grew M. tuberculosis in greater than 90% of the HIV-infected patients in whom they were obtained, sputum AFB stains were positive in less than 50%. Blood and urine specimen cultures were positive in 56% and 77% of the HIV-infected patients in whom these specimens were obtained, but did not provide a means of early diagnosis. Cerebrospinal fluid and pleural fluid were abnormal in nearly all patients with involvement of these sites but were rarely AFB-positive and were, therefore, only suggestive of TB. Procedures such as biopsies and aspirates of peripheral lymph nodes, visceral lymph nodes, liver, and bone marrow provided the highest immediate diagnostic yields with rates between 50% and 90%. These procedures must be considered early in the course of illness in HIV-infected patients with suspected extrapulmonary TB due to the rapidly progressive nature of this often fatal but usually treatable infection.

Bacterial myonecrosis is a medical and surgical emergency and prompt surgical intervention is critically important. A variety of microorganisms have been isolated from patients with necrotizing soft-tissue infections. These infections are frequently polymicrobial in etiology, but occasionally a single microorganism is isolated. This report describes a case of crepitant myonecrosis from infection with Salmonella serogroup B.

Purpose: Our goal was to examine the clinical significance of hyperbilirubinemia in patients with Staphylococcus aureus endocarditis. In addition, preliminary data concerning the possible mechanism of cholestasis observed during S. aureus septicemia are presented., Patients and Methods: This study had two parts: a clinical investigation and a laboratory investigation. In the former, patients with endocarditis were identified through chart review. Those with admission total serum bilirubin levels of 2.0 mg/dl or greater were considered to have hyperbilirubinemia. In the latter investigation, the hepatic storage capacity and transport maximum for sulfobromophthalein (BSP), an organic dye that is rapidly taken up and excreted by the liver, were determined by measuring the change in serum concentration and the corresponding hepatic removal rate at various BSP infusion rates. Measurements were conducted before and after the infusion of Escherichia coli-derived lipopolysaccharide in some rabbits, after the infusion of resuspended S. aureus in others, and after the infusion of lipoteichoic acid in the remainder., Results: Eleven of 47 consecutive patients with S. aureus endocarditis were noted to have hyperbilirubinemia without clinical or laboratory evidence of hepatic bacterial infection. Compared with the remaining 36 patients, these 11 patients had a significantly lower mean platelet count and a higher serum creatinine level and white blood cell count. Although none of the 47 patients were hypotensive on admission, four of the 11 hyperbilirubinemic patients died of overwhelming sepsis, compared with two of the 36 remaining patients (p less than 0.05). When one of the clinical isolates of S. aureus or lipoteichoic acid was infused into conscious rabbits, there was a marked decrease in the hepatic transport maximum and an increase in the relative hepatic storage capacity of sulfobromophthalein. Similar changes were noted following the administration of lipopolysaccharide., Conclusion: Our data suggest that the presence of hyperbilirubinemia in patients with S. aureus sepsis may identify persons at high risk of dying from overwhelming sepsis. It further suggests that lipoteichoic acid may play an important role in causing defective hepatic excretory function that is responsible for hyperbilirubinemia.

The excretion of sulfobromophthalein (BSP) is determined by hepatic uptake (storage capacity) and secretion (transport maximum). We calculated the BSP excretion data in six rabbits by measuring the rate of rise of BSP at various infusion rates. The relative storage capacity was determined to be 0.34 +/- 0.13 mg.mg-1.dl-1.kg-1. The transport maximum was calculated to be 0.91 +/- 0.12 mg.min-1.kg-1. These results compare closely with previously reported results using more direct measurements that require anesthesia and surgical cannulation of the biliary tree. Repeated studies were easily performed. Our method provides a reliable and simple technique to study the effects of various conditions or substances on BSP excretion in conscious, unanesthetized rabbits.

The cases of 17 patients with tuberculous pericarditis were reviewed. Thirteen patients had effusive pericarditis, and 10 had surgical drainage of the effusion. No deaths were due to pericardial tamponade; this appears to be related to earlier recognition of major pericardial effusions by echocardiography. In 2 patients clinical evidence of pericardial constriction developed while they were on a regimen of therapy, and in another 2 patients, echocardiography revealed pericardial thickening after resolution of the effusion. A pericardial window is recommended for the short-term management of patients suspected of having tuberculous pericarditis with a major pericardial effusion by echocardiography. If a thickened pericardium is found during the window procedure, early pericardiectomy is strongly encouraged.