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Biomedical subjects

Paul H Edelstein

Publications and source records attributed to Paul H Edelstein.

16 recordsLinked to original sources
PubMed2006

Macrolide resistance in adults with bacteremic pneumococcal pneumonia.

We conducted a case-control study of adults with bacteremic pneumococcal pneumonia to identify factors associated with macrolide resistance. Study participants were identified through population-based surveillance in a 5-county region surrounding Philadelphia. Forty-three hospitals contributed 444 patients, who were interviewed by telephone regarding potential risk factors. In multivariable analyses, prior exposure to a macrolide antimicrobial agent (odds ratio [OR] 2.8), prior flu vaccination (OR 2.0), and Hispanic ethnicity (OR 4.1) were independently associated with an increased probability of macrolide resistance, and a history of stroke was independently associated with a decreased probability of macrolide resistance (OR 0.2). Fifty-five percent of patients with macrolide-resistant infections reported no antimicrobial drug exposure in the preceding 6 months. Among patients who reported taking antimicrobial agents in the 6 months preceding infection, failure to complete the course of prescribed drugs was associated with an increased probability of macrolide resistance (OR 3.4).

Adolescent↗
PubMed2005

Association between fluoroquinolone resistance and mortality in Escherichia coli and Klebsiella pneumoniae infections: the role of inadequate empirical antimicrobial therapy.

BACKGROUND: The prevalence of fluoroquinolone (FQ) resistance among Escherichia coli and Klebsiella pneumoniae has increased markedly in recent years. However, the impact of FQ resistance on mortality remains unknown. METHODS: To identify the association between FQ resistance and mortality, we conducted a retrospective cohort study of hospitalized patients with infections due to FQ-resistant strains and FQ-susceptible strains of E. coli and K. pneumoniae between 1 January 1998 and 30 June 1999. RESULTS: Of 123 patients with FQ-resistant infection, 16 (13.0%) died, compared with 4 (5.7%) of 70 patients with FQ-susceptible infection (odds ratio [OR], 2.47; 95% confidence interval [CI], 0.75-10.53). After adjustment for other significant risk factors and confounders, there remained an independent association between FQ-resistant infection and mortality (adjusted OR, 4.41; 95% CI, 1.03-18.81). Patients with FQ-resistant infection were significantly less likely to have received antimicrobial therapy with activity against the infecting pathogen within the first 24 h and 48 h of infection (P=.002 and P<.001, respectively). The association between FQ resistance and mortality was no longer significant, after adjusting for inadequate empirical therapy. CONCLUSIONS: FQ resistance is an independent risk factor for mortality in patients with health care-acquired E. coli and K. pneumoniae infections. This may be explained, at least in part, by a delay in the initiation of appropriate antimicrobial therapy in patients with FQ-resistant infection. These results highlight the grave clinical consequences of FQ resistance and emphasize the importance of efforts designed to curb the increase in the prevalence of resistance to these agents.

Adult↗
PubMed2005

Impact of pediatric vaccination with pneumococcal conjugate vaccine on the risk of bacteremic pneumococcal pneumonia in adults.

Invasive pneumococcal disease in adults may be declining, reflecting a form of herd protection from a new pediatric pneumococcal conjugate vaccine. Our aim was to determine whether vaccination of children protects adults in the same home from bacteremic pneumococcal pneumonia. We conducted a case-control study with 43 participating hospitals across a five-county region in Pennsylvania. Eligible cases were adults with bacteremic pneumococcal pneumonia identified by the microbiology laboratories at participating hospitals. Controls were healthy adults from the region identified through random digit dialing. Cases and controls were interviewed by telephone. We analyzed vaccine protection in those adults who reported living in homes with at least one child < or =6 years of age. From April 2002 through June 2004, there was a significant decline in the proportion of adult pneumococcal bacteremia due to any of the seven serotypes in the conjugate vaccine (p=0.006). Within this time period, 17% of cases and controls reported living in homes with at least one child < or =6 years of age. In adjusted analysis, vaccination of the youngest child in the home was associated with an 80% reduction in the odds of bacteremic pneumococcal pneumonia among adults with children in the home (OR=0.2, 95% CI 0.1-0.8). We conclude that introduction of a pneumococcal conjugate vaccine for children has reduced the population rate of adult pneumococcal bacteremia due to vaccine serotypes and is associated with a reduced risk of bacteremic pneumococcal pneumonia for adults with children in the home.

Adult↗
PubMed2005

In vitro and intracellular activities of LBM415 (NVP PDF-713) against Legionella pneumophila.

LBM415 activity against extracellular and intracellular Legionella pneumophila was studied. The LBM415 MIC50 for 20 Legionella sp. strains was 4 microg/ml, versus 0.06, 0.25, and <or=0.03 microg/ml for azithromycin, erythromycin, and levofloxacin, respectively. LBM415 (0.5 and 16 microg/ml) reversibly prevented intracellular growth of two L. pneumophila strains and was less active than erythromycin.

Animals↗
PubMed2005

Legionella pneumophila NudA Is a Nudix hydrolase and virulence factor.

We studied the identity and function of the 528-bp gene immediately upstream of Legionella pneumophila F2310 ptsP (enzyme I(Ntr)). This gene, nudA, encoded for a Nudix hydrolase based on the inferred protein sequence. NudA had hydrolytic activity typical of other Nudix hydrolases, such as Escherichia coli YgdP, in that Ap(n)A's, in particular diadenosine pentaphosphate (Ap(5)A), were the preferred substrates. NudA hydrolyzed Ap(5)A to ATP plus ADP. Both ptsP and nudA were cotranscribed. Bacterial two-hybrid analysis showed no PtsP-NudA interactions. Gene nudA was present in 19 of 20 different L. pneumophila strains tested and in 5 of 10 different Legionella spp. other than L. pneumophila. An in-frame nudA mutation was made in L. pneumophila F2310 to determine the phenotype. The nudA mutant was an auxotroph that grew slowly in liquid and on solid media and had a smaller colony size than its parent. In addition, the mutant was more salt resistant than its parent and grew very poorly at 25 degrees C; all of these characteristics, as well as auxotrophy and slow-growth rate, were reversed by transcomplementation with nudA. The nudA mutant was outcompeted by about fourfold by the parent in competition studies in macrophages; transcomplementation almost completely restored this defect. Competition studies in guinea pigs with L. pneumophila pneumonia showed that the nudA mutant was outcompeted by its parent in both lung and spleen. NudA is of major importance for resisting stress in L. pneumophila and is a virulence factor.

Amino Acid Sequence↗
PubMed2004

Pneumococcal resistance to macrolides, lincosamides, ketolides, and streptogramin B agents: molecular mechanisms and resistance phenotypes.

The macrolides, lincosamides, ketolides, and streptogramin B agents (the MLKS(B) antimicrobial agents) have related chemical structures and share similar molecular targets on the 50S ribosomal subunit of Streptococcus pneumoniae. Mutations in rRNA or ribosomal proteins generate a variety of resistance phenotypes. The M phenotype of S. pneumoniae, which predominates in North America, affords low-level resistance to macrolides only (excluding macrolides with 16-member rings) by means of an efflux pump encoded by the mefA gene. The MLS(B) phenotype, which predominates in Europe, affords high-level resistance to macrolides, lincosamides, and streptogramin B agents and arises, in most cases, from dimethylation of adenine 2058 in the 23S rRNA of the 50S ribosomal subunit. Other, less common, phenotypes arise from other 23S rRNA modifications (ML and K phenotypes) or from amino acid substitution (MS(B) phenotype) or insertion (MKS(B) phenotype) into the 50S subunit ribosomal protein L4. In all cases, the decrease in susceptibility to ketolides (for example, telithromycin) is less than the decrease in susceptibility for other MLKS(B) agents.

Amino Acid Substitution↗
PubMed2004

Legionella maceachernii pneumonia in a patient with HIV infection.

We report a case of fatal Legionella maceachernii pneumonia in a 49 year-old man with HIV infection and review the 3 previous reported cases, all of which occurred in individuals with underlying immune defects. Infection with L. maceachernii was attributable to the deaths of all cases. Issues related to the clinical aspects, laboratory identification of this unusual species, and detection of Legionnaires' diseases are discussed.

AIDS-Related Opportunistic Infections↗
PubMed2003

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↗
PubMed2003

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↗
PubMed2003

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↗
PubMed2002

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↗
PubMed2002

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↗