Shiri Navon-Venezia

Molecular Epidemiology of KPC-Producing Klebsiella pneumoniae Isolates in the United States: Clonal Expansion of Multilocus Sequence Type 258

ABSTRACT Klebsiella pneumoniae carbapenemase (KPC)-producing Enterobacteriaceae have become more common in the United States and throughout the world. We used pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing (MLST) to examine the molecular epidemiology of KPC-producing K. pneumoniae isolates sent to the Centers for Disease Control and Prevention (CDC) for reference testing from 1996 to 2008. A dominant strain, sequence type 258 (ST 258), was found and likely accounts for 70% of the CDCs K. pneumoniae PFGE database. Isolates with PFGE patterns related to ST 258 were identified in 10 of the 19 U.S. states currently reporting KPC-producing K. pneumoniae, in addition to one isolate from Israel. KPC subtyping and analysis of the surrounding genetic environment were subsequently performed on 23 representative isolates. Thirteen isolates identified as ST 258 possessed either blaKPC-2 or blaKPC-3 and some variability in the Tn4401 element upstream of the blaKPC gene. Escherichia coli DH10B was successfully transformed by electroporation with KPC-encoding plasmid DNA from 20 of the 23 isolates. Restriction analysis of plasmid DNA prepared from transformants revealed a diversity of band patterns, suggesting the presence of different plasmids harboring the blaKPC gene, even among isolates of the same ST.

Multidrug-Resistant Pseudomonas aeruginosa: Risk Factors and Clinical Impact

ABSTRACT Pseudomonas aeruginosa, a leading nosocomial pathogen, may become multidrug resistant (MDR). Its rate of occurrence, the individual risk factors among affected patients, and the clinical impact of infection are undetermined. We conducted an epidemiologic evaluation and molecular typing using pulsed-field gel electrophoresis (PFGE) of 36 isolates for 82 patients with MDR P. aeruginosa and 82 controls matched by ward, length of hospital stay, and calendar time. A matched case-control study identified individual risk factors for having MDR P. aeruginosa, and a retrospective matched-cohort study examined clinical outcomes of such infections. The 36 isolates belonged to 12 PFGE clones. Two clones dominated, with one originating in an intensive care unit (ICU). Cases and controls had similar demographic characteristics and numbers of comorbid conditions. A multivariate model identified ICU stay, being bedridden, having high invasive devices scores, and being treated with broad-spectrum cephalosporins and with aminoglycosides as significant risk factors for isolating MDR P. aeruginosa. Having a malignant disease was a protective factor (odds ratio [OR] = 0.2; P = 0.03). MDR P. aeruginosa was associated with severe outcomes compared to controls, including increased mortality (OR = 4.4; P = 0.04), hospital stay (hazard ratio, 2; P = 0.001), and requirement for procedures (OR = 5.4; P = 0.001). The survivors functioned more poorly at discharge than the controls, and more of the survivors were discharged to rehabilitation centers or chronic care facilities. The epidemiology of MDR P. aeruginosa is complex. Critically ill patients that require intensive care and are treated with multiple antibiotic agents are at high risk. MDR P. aeruginosa infections are associated with severe adverse clinical outcomes.

Predictors of Carbapenem-Resistant Klebsiella pneumoniae Acquisition among Hospitalized Adults and Effect of Acquisition on Mortality

ABSTRACT Carbapenem-resistant Klebsiella pneumoniae (CRKP) is an emerging nosocomial pathogen. Little is known about its risk factors or mortality. We performed a case-case-control study to assess the risks for CRKP isolation and a retrospective cohort study to assess mortality in three groups of hospitalized adults: (i) patients from whom CRKP was isolated, (ii) patients from whom carbapenem-susceptible Klebsiella spp. (CSKS) were isolated, and (iii) controls from whom no Klebsiella spp. were isolated. After adjustment for length of stay (LOS), the demographics, comorbidities, and exposures of each case group were compared with those of the controls. Significant covariates were incorporated into LOS-adjusted multivariable models. In the mortality study, we evaluated the effect of CRKP on in-hospital death. There were 48 patients with CRKP isolation (21 died [44%]), 56 patients with CSKS isolation (7 died [12.5%]), and 59 controls (1 died [2%]). Independent risk factors for CRKP isolation were poor functional status (odds ratio [OR], 15.4; 95% confidence interval [CI], 4.0 to 58.6; P < 0.001); intensive care unit (ICU) stay (OR, 17.4; 95% CI, 1.5 to 201.9; P = 0.02); and receipt of antibiotics (OR, 4.4; 95% CI, 1.0 to 19.2; P = 0.05), particularly fluoroquinolones (OR, 7.2; 95% CI, 1.1 to 49.4; P = 0.04). CRKP was independently associated with death when patients with CRKP were compared with patients with CSKS (OR, 5.4; 95% CI, 1.7 to 17.1; P = 0.005) and with controls (OR, 6.7; 95% CI, 2.4 to 18.8; P < 0.001). After adjustment for the severity of illness, CRKP isolation remained predictive of death, albeit with a lower OR (for the CRKP group versus the CSKS group, OR, 3.9; 95% CI, 1.1 to 13.6; and P = 0.03; for the CRKP group versus the controls, OR, 5.0; 95% CI, 1.7 to 14.8; and P = 0.004). CRKP affects patients with poor functional status, an ICU stay, and antibiotic exposure and is an independent predictor of death.

Clinical and Economic Impact of Bacteremia with Extended- Spectrum-β-Lactamase-Producing Enterobacteriaceae

ABSTRACT We studied outcomes of extended-spectrum β-lactamase (ESBL) production in Enterobacteriaceae bacteremia. Inpatients with bacteremia caused by ESBL-producing Escherichia coli, Klebsiella spp., or Proteus spp. (cases) were compared with patients with bacteremia caused by non-ESBL producers (controls). Outcomes included mortality, mortality due to infection, length of stay (LOS), delay in appropriate therapy (DAT), discharge to a chronic care facility, and hospital cost. Ninety-nine cases and 99 controls were enrolled. Thirty-five percent of cases died, versus 18% of controls (odds ratio [OR], 2.5; 95% confidence interval [CI], 1.3 to 4.7; P = 0.01). Thirty percent of cases died due to infection, versus 16% of controls (OR, 2.3; 95% CI, 1.1 to 4.5; P = 0.03). The median LOS after bacteremia for cases was 11 days (interquartile range, 5 to 21), versus 5 days for controls (interquartile range, 3 to 9) (P < 0.001). DAT occurred in 66% of cases, versus 7% of controls (OR, 25.1; 95% CI, 10.5 to 60.2; P < 0.001). Cases were more likely than controls to be discharged to chronic care (52% versus 21%; OR, 4.0; 95% CI, 1.9 to 8.3; P < 0.001). The average hospital cost for cases was 65,509 Israeli shekels, versus 23,538 shekels for controls (P < 0.001). After adjusting for differences between groups by using multivariable analysis, ESBL production remained a significant predictor of mortality (OR, 3.6; 95% CI, 1.4 to 9.5; P = 0.008), increased LOS (1.56-fold; P = 0.001), DAT (OR, 25.1; 95% CI, 10.5 to 60.2; P < 0.001), and increased cost (1.57-fold; P = 0.003). The mean increase in equivalent cost attributable to ESBL production was

Influx of Extended-Spectrum β-Lactamase—Producing Enterobacteriaceae into the Hospital

9,620. ESBL production was associated with severe adverse outcomes, including higher overall and infection-related mortality, increased LOS, DAT, discharge to chronic care, and higher costs.

Worldwide diversity of Klebsiella pneumoniae that produce β-lactamase blaKPC-2 gene.

BACKGROUND The prevalence of infections caused by extended-spectrum beta -lactamase (ESBL)-producing Enterobacteriaceae is increasing worldwide. The influx of these bacteria into hospitals has major implications for infection-control and empirical treatment strategies. METHODS Isolates from 2 patient cohorts--patients with gram-negative bacteremia within 2 days after admission and patients screened for fecal colonization at admission--were assessed for ESBL production. ESBL phenotype was confirmed according to Clinical and Laboratory Standards Institute guidelines. Predictors of ESBL phenotype were examined by univariate and multivariate analyses. RESULTS Of 80 Enterobacteriaceae isolates from blood samples obtained at admission to the hospital, 13.7% produced ESBL. Thirty-eight patients with ESBL-positive isolates and 72 with ESBL-negative isolates were included in a case-control study. Predictors of ESBL production were male sex and nursing home residence (area under receiver operator characteristic curve, 0.7). Of 241 persons screened at admission, 26 (10.8%) had fecal carriage of ESBL-producing Enterobacteriaceae. Predictors of fecal carriage were poor functional status, antibiotic use, chronic renal insufficiency, liver disease, and use of histamine2 blockers (area under receiver operator characteristic curve, 0.8). Four (15.4%) of the 26 individuals with fecal carriage had subsequent bacteremia with ceftazidime-resistant Enterobacteriaceae, compared with 1 (0.5%) noncarrier (odds ratio, 38.9; P<.001). Of 80 ESBL-producing Enterobacteriaceae isolates obtained at admission, 65 were health care associated, and 15 were community acquired. The 15 community-acquired ESBL-producing Enterobacteriaceae belonged to diverse clones. The most prevalent ESBL gene among these isolates was CTX-M-2 (found in 53.3% of the isolates). CONCLUSIONS We report high rates of bacteremia and colonization with ESBL-producing Enterobacteriaceae at admission to our institution, which may undermine infection-control measures and complicate the selection of empirical treatment.

Multidrug-Resistant Acinetobacter baumannii

TOC summary: Clones harboring different plasmids with identical genetic structure could be the origin of worldwide spread.

Emergence of KPC-2 and KPC-3 in Carbapenem-Resistant Klebsiella pneumoniae Strains in an Israeli Hospital

A case-control, epidemiologic, and molecular study of nosocomial MDR A. baumannii showed the existence of multiple clones and a complex epidemiologic pattern.

Update on Pseudomonas aeruginosa and Acinetobacter baumannii infections in the healthcare setting

ABSTRACT Carbapenem resistance due to KPC has rarely been observed outside the United States. We noticed a sharp increase in carbapenem-resistant Klebsiella pneumoniae strains possessing KPC in Tel Aviv Medical Center from 2004 to 2006. Sixty percent of the isolates belonged to a single clone susceptible only to gentamicin and colistin and carried the blaKPC-3 gene, while almost all other clones carried the blaKPC-2 gene. This rapid dissemination of KPC outside the United States is worrisome.

Improved antimicrobial peptides based on acyl-lysine oligomers

Purpose of review Infections with Pseudomonas aeruginosa and Acinetobacter baumannii are of great concern for hospitalized patients, especially with multidrug-resistant strains. This review focuses on recent data that may help us to understand the emergence, spread, and persistence of antibiotic resistance, and summarizes the optional treatment feasible for these resistant bacteria. Recent findings Multidrug-resistant P. aeruginosa and A. baumannii are increasingly causing nosocomial infections; multidrug-resistant clones are spreading into new geographic areas, and susceptible strains are acquiring resistance genes. New extended-spectrum β-lactamases and carbapenemases are emerging, leading to pan-resistant strains. Current studies focus on the effect of antibiotics on gene expression in P. aeruginosa biofilms and their contribution to resistance to therapy. Treatment options for multidrug-resistant P. aeruginosa and A. baumannii infections are limited in most cases to carbapenems. Sulbactam is a treatment option for pan-resistant A. baumannii, and or renewed use of an old drug, colistin, is being entertained for pan-resistant A. baumannii and P. aeruginosa. Immunotherapy is a promising new modality being explored. Prevention of emergence of resistance through combination therapy and pharmacokinetic strategies are studied. Summary The emergence and spread of multidrug-resistant P. aeruginosa and A. baumannii and their genetic potential to carry and transfer diverse antibiotic resistance determinants pose a major threat in hospitals. The complex interplay of clonal spread, persistence, transfer of resistance elements, and cell–cell interaction contribute to the difficulty in treating infections caused by these multidrug-resistant strains. In the absence of new antibiotic agents, new modalities of treatment should be developed.