Case 16-2003 - brain abscess.
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Brain Abscess↗
Biomedical subjects
Paul H Edelstein
Publications and source records attributed to Paul H Edelstein.
Activities of tigecycline (GAR-936) against Legionella pneumophila in vitro and in guinea pigs with L. pneumophila pneumonia.
The activities of tigecycline (Wyeth Research) against extracellular and intracellular Legionella pneumophila and for the treatment of guinea pigs with L. pneumophila pneumonia were studied. The tigecycline MIC at which 50% of strains are inhibited for 101 different Legionella sp. strains was 4 micro g/ml versus 0.125 and 0.25 micro g/ml for azithromycin and erythromycin, respectively. Tigecycline was about as active as erythromycin (tested at 1 micro g/ml) against the F889 strain of L. pneumophila grown in guinea pig alveolar macrophages and more active than erythromycin against the F2111 strain. Azithromycin (0.25 micro g/ml) was more active than (F889) or as active as (F2111) tigecycline (1 micro g/ml) in the macrophage model. When tigecycline was given (7.5 mg/kg of body weight subcutaneously once) to guinea pigs with L. pneumophila pneumonia, the mean peak serum and lung levels were 2.3 and 1.8 micro g/ml (1.2 and 1.5 micro g/g) at 1 and 2 h postinjection, respectively. The serum and lung areas under the concentration time curve from 0 to 24 h were 13.7 and 15.8 micro g. h/ml, respectively. Thirteen of 16 guinea pigs with L. pneumophila pneumonia treated with tigecycline (7.5 mg/kg subcutaneously once daily for 5 days) survived for 7 days post-antimicrobial therapy, as did 11 of 12 guinea pigs treated with azithromycin (15 mg/kg intraperitoneally once daily for 2 days). None of 12 guinea pigs treated with saline survived. Tigecycline-treated guinea pigs had average end of therapy lung counts of 1 x 10(6) CFU/g (range, 2.5 x 10(4) to 3.2 x 10(6) CFU/g) versus <1 x 10(2) CFU/g for azithromycin (range, undetectable to 100 CFU/g). A second guinea pig study examined the ability of tigecycline to clear L. pneumophila from the lung after 5 to 9 days of therapy; bacterial concentrations 1 day posttherapy ranged from log(10) 4.2 to log(10) 5.5 CFU/g for four different dosing regimens. Tigecycline is about as effective as erythromycin against intracellular L. pneumophila, but tigecycline inactivation by the test media confounded the interpretation of susceptibility data. Tigecycline was effective at preventing death from pneumonia in an animal model of Legionnaires' disease, warranting human clinical trials of the drug for the disease.
Animals↗
lvgA, a novel Legionella pneumophila virulence factor.
Several novel Legionella pneumophila virulence genes were previously discovered by use of signature-tagged mutagenesis (P. H. Edelstein, M. A. Edelstein, F. Higa, and S. Falkow, Proc. Natl. Acad. Sci. 96:8190-8195, 1999). One of these mutants appeared to be defective in multiplication in guinea pig lungs and spleens, yet it multiplies normally in guinea pig alveolar macrophages. Here we report further characterization of the mutated gene and its protein and the virulence role of the gene. The complete sequence of the gene, now called lvgA, is 627 bp long, and its protein product is approximately 27 kDa in size. lvgA was present in all 50 strains of L. pneumophila tested. No significant nucleic acid or protein homology was found in the GenBank database for the gene, nor were any distinctive motifs discovered in a search of other databases. The expression of both DotA and IcmX in the lvgA mutant was normal. Subcellular fractionation studies localized LvgA to the outer membrane fraction, and protease digestion studies suggested that at least some of the protein is surface expressed. No change in bacterial lipopolysaccharide composition or reactivity to serogroup-specific antisera was detected in the mutant. Growth competition studies with alveolar macrophages showed that the mutant was outcompeted by its parent 3-fold in 24 h and 24-fold in 48 h, in contrast to what was observed with the null phenotype in parallel testing with alveolar macrophages or with the A549 alveolar epithelial cell line. This macrophage defect of the mutant bacterium was due to slower growth, as the mutant invaded alveolar macrophages normally. Electron microscopy showed that the mutant bacterium resided in a ribosome-studded phagosome in alveolar macrophages, with no distinction from its parent. The lvgA mutant was outcompeted by its parent about sixfold in guinea pig lungs and spleens; prolonged observation of infected animals showed no late-onset virulence of the mutant. Transcomplementation of the mutant restored the parental phenotype in guinea pigs. The lvgA mutant was twofold more susceptible to killing by human beta-defensin 2 but not to killing by other cationic peptides, serum complement, or polymorphonuclear neutrophils. lvgA is a novel virulence gene that is responsible for pleiotropic functions involving both extracellular and intracellular bacterial resistance mechanisms.
Animals↗
A 65-kilobase pathogenicity island is unique to Philadelphia-1 strains of Legionella pneumophila.
Nucleotide sequence analysis of an approximately 80-kb genomic region revealed an approximately 65-kb locus that bears hallmarks of a pathogenicity island. This locus includes homologues of a type IV secretion system, mobile genetic elements, and known virulence factors. Comparative studies with other Legionella pneumophila strains and serogroups indicated that this approximately 65-kb locus is unique to L. pneumophila serogroup 1 Philadelphia-1 strains.
Amino Acid Sequence↗
Risk factors for fluoroquinolone resistance in nosocomial Escherichia coli and Klebsiella pneumoniae infections.
BACKGROUND: The incidence of fluoroquinolone (FQ) resistance has increased markedly in recent years. Even in the common nosocomial pathogens Escherichia coli and Klebsiella pneumoniae, in which the emergence of FQ resistance was believed to be unlikely, increasing resistance to these agents has been noted. Risk factors for FQ resistance in these pathogens remain unknown. Although FQs are important components of the present antimicrobial arsenal, their continued usefulness is threatened by rising FQ resistance. OBJECTIVE: To identify risk factors for nosocomial FQ resistance. METHODS: A case-control study of hospitalized patients with infections due to FQ-resistant and FQ-susceptible E coli and K pneumoniae occurring between January 1, 1998, and June 30, 1999. RESULTS: We included 123 patients with nosocomial FQ-resistant infections and 70 randomly selected patients with nosocomial FQ-susceptible infections. Independent risk factors (adjusted odds ratio [95% confidence interval]) for FQ resistance were (1) recent FQ use (5.25 [1.81-15.26]); (2) residence in a long-term care facility (3.65 [1.64-8.15]); (3) recent aminoglycoside use (8.86 [1.71-45.99]); and (4) older age (1.03 [1.01-1.06]). CONCLUSIONS: Recent FQ use, residence in a long-term care facility, recent aminoglycoside use, and older age were all noted to be independent risk factors for FQ resistance among patients with nosocomial E coli and K pneumoniae infections. Efforts should be directed at recognition and modification of these risk factors to curb the rise in FQ resistance and preserve the utility of these agents in the treatment of common nosocomial gram-negative infections.
Adult↗
Predicting the emergence of antimicrobial resistance.
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Anti-Bacterial Agents↗
Extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella species: risk factors for colonization and impact of antimicrobial formulary interventions on colonization prevalence.
OBJECTIVE: The incidence of extended-spectrum beta-lactamase (ESbetaL)-mediated resistance has increased markedly during the past decade. Risk factors for colonization with ESbetaL-producing Escherichia coli and Klebsiella species (ESbetaL-EK) remain unclear, as do methods to control their further emergence. DESIGN: Case-control study. SETTING: Two hospitals within a large academic health system: a 725-bed academic tertiary-care medical center and a 344-bed urban community hospital. PATIENTS: Thirteen patients with ESbetaL-EK fecal colonization were compared with 46 randomly selected noncolonized controls. RESULTS: Duration of hospitalization was the only independent risk factor for ESbetaL-EK colonization (odds ratio, 1.11; 95% confidence interval, 1.02 to 1.21). Of note, 8 (62%) of the patients had been admitted from another healthcare facility. In addition, there was evidence for dissemination of a single K oxytoca clone. Finally, the prevalence of ESbetaL-EK colonization decreased from 7.9% to 5.7% following restriction of third-generation cephalosporins (P = .51). CONCLUSIONS: ESbetaL-EK colonization was associated only with duration of hospitalization and there was no significant reduction following antimicrobial formulary interventions. The evidence for nosocomial spread and the high percentage of patients with ESbetaL-EK admitted from other sites suggest that greater emphasis must be placed on controlling the spread of such organisms within and between institutions.
Academic Medical Centers↗