A systematic review of the epidemiology of carbapenem-resistant Enterobacteriaceae in the United States

BackgroundCarbapenem-resistant Enterobacteriaceae (CRE) pose an urgent public health threat in the United States. An important step in planning and monitoring a national response to CRE is understanding its epidemiology and associated outcomes. We conducted a systematic literature review of studies that investigated incidence and outcomes of CRE infection in the US.MethodsWe performed searches in MEDLINE via Ovid, CDSR, DARE, CENTRAL, NHS EED, Scopus, and Web of Science for articles published from 1/1/2000 to 2/1/2016 about the incidence and outcomes of CRE at US sites.ResultsFive studies evaluated incidence, but many used differing definitions for cases. Across the entire US population, the reported incidence of CRE was 0.3–2.93 infections per 100,000 person-years. Infection rates were highest in long-term acute-care (LTAC) hospitals. There was insufficient data to assess trends in infection rates over time. Four studies evaluated outcomes. Mortality was higher in CRE patients in some but not all studies.ConclusionWhile the incidence of CRE infections in the United States remains low on a national level, the incidence is highest in LTACs. Studies assessing outcomes in CRE-infected patients are limited in number, small in size, and have reached conflicting results. Future research should measure a variety of clinical outcomes and adequately adjust for confounders to better assess the full burden of CRE.

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title: Carbapenem-resistant Enterobacteriaceae: epidemiology and prevention.
abstract: Over the past 10 years, dissemination of Klebsiella pneumoniae carbapenemase (KPC) has led to an increase in the prevalence of carbapenem-resistant Enterobacteriaceae (CRE) in the United States. Infections caused by CRE have limited treatment options and have been associated with high mortality rates. In the previous year, other carbapenemase subtypes, including New Delhi metallo-β-lactamase, have been identified among Enterobacteriaceae in the United States. Like KPC, these enzymes are frequently found on mobile genetic elements and have the potential to spread widely. As a result, preventing both CRE transmission and CRE infections have become important public health objectives. This review describes the current epidemiology of CRE in the United States and highlights important prevention strategies.

title: The global spread of healthcare-associated multidrug-resistant bacteria: a perspective from Asia.
abstract: Since antibiotics were first used, each new introduced class has been followed by a global wave of emergent resistance, largely originating in Europe and North America where they were first used. Methicillin-resistant Staphylococcus aureus spread from the United Kingdom and North America across Europe and then Asia over more than a decade. Vancomycin-resistant enterococci and Klebsiella pneumoniae carbapenemase-producing K. pneumoniae followed a similar path some 20 years later. Recently however, metallo-β-lactamases have originated in Asia. New Delhi metallo-β-lactamase-1 was found in almost every continent within a year of its emergence in India. Metallo-β-lactamase enzymes are encoded on highly transmissible plasmids that spread rapidly between bacteria, rather than relying on clonal proliferation. Global air travel may have helped facilitate rapid dissemination. As the antibiotic pipeline offers little in the short term, our most important tools against the spread of antibiotic resistant organisms are intensified infection control, surveillance, and antimicrobial stewardship.

title: Antimicrobial-Resistant Pathogens Associated With Healthcare-Associated Infections: Summary of Data Reported to the National Healthcare Safety Network at the Centers for Disease Control and Prevention, 2011–2014
abstract: To describe antimicrobial resistance patterns for healthcare-associated infections (HAIs) that occurred in 2011–2014 and were reported to the Centers for Disease Control and Prevention’s National Healthcare Safety Network.  Data from central line–associated bloodstream infections, catheter-associated urinary tract infections, ventilator-associated pneumonias, and surgical site infections were analyzed. These HAIs were reported from acute care hospitals, long-term acute care hospitals, and inpatient rehabilitation facilities. Pooled mean proportions of pathogens that tested resistant (or nonsusceptible) to selected antimicrobials were calculated by year and HAI type.  Overall, 4,515 hospitals reported that at least 1 HAI occurred in 2011–2014. There were 408,151 pathogens from 365,490 HAIs reported to the National Healthcare Safety Network, most of which were reported from acute care hospitals with greater than 200 beds. Fifteen pathogen groups accounted for 87% of reported pathogens; the most common included Escherichia coli (15%), Staphylococcus aureus (12%), Klebsiella species (8%), and coagulase-negative staphylococci (8%). In general, the proportion of isolates with common resistance phenotypes was higher among device-associated HAIs compared with surgical site infections. Although the percent resistance for most phenotypes was similar to earlier reports, an increase in the magnitude of the resistance percentages among E. coli pathogens was noted, especially related to fluoroquinolone resistance.  This report represents a national summary of antimicrobial resistance among select HAIs and phenotypes. The distribution of frequent pathogens and some resistance patterns appear to have changed from 2009–2010, highlighting the need for continual, careful monitoring of these data across the spectrum of HAI types.  Control Hosp Epidemiol 2016;1–14

title: Emergence of carbapenem‐resistant Enterobacteriaceae in Orange County, California, and support for early regional strategies to limit spread
abstract: The east‐to‐west spread of carbapenem‐resistant Enterobacteriaceae (CRE) represents an opportunity to explore strategies to limit spread in nonendemic areas. We evaluated CRE emergence and regional support for containment strategies.  A 17‐question cross‐sectional survey was administered to infection prevention programs in Orange County, CA (31 hospitals serving 3 million residents), between January and September 2014. Questions addressed newly detected hospital‐ and community‐onset CRE cultures (2008‐2013), current CRE control strategies, and support for prevention strategies for a hypothetical regional intervention.  Among 31 hospitals, 21 (68%, representing 17 infection prevention programs) completed the survey. CRE was scarcely detected between 2009‐2010; within 4 years, 90% of hospitals reported CRE, with 2.5‐fold higher community‐onset than hospital‐onset CRE. Between 2011 and 2013, annual CRE incidence increased 4.7‐fold (1.4‐6.3 cases/10,000 admissions). Support for a regional CRE prevention bundle was unanimous. Although 22% bathed patients positive for CRE with chlorhexidine gluconate and 11% actively screened for CRE, 86% and 57%, respectively, would consider these strategies in a regional intervention.  CRE epidemiology in Orange County parallels early progression previously seen in now‐endemic areas, representing an opportunity to consider interventions to prevent endemic spread. Many facilities would consider proactive strategies, such as chlorhexidine bathing, in the setting of a regional collaborative.

title: Spread of Carbapenem-Resistant Enterobacteriaceae Among Illinois Healthcare Facilities: The Role of Patient Sharing.
abstract: Carbapenem-resistant Enterobacteriaceae (CRE) spread regionally throughout healthcare facilities through patient transfer and cause difficult-to-treat infections. We developed a state-wide patient-sharing matrix and applied social network analyses to determine whether greater connectedness (centrality) to other healthcare facilities and greater patient sharing with long-term acute care hospitals (LTACHs) predicted higher facility CRE rates.



We combined CRE case information from the Illinois extensively drug-resistant organism registry with measures of centrality calculated from a state-wide hospital discharge dataset to predict facility-level CRE rates, adjusting for hospital size and geographic characteristics.



Higher CRE rates were observed among facilities with greater patient sharing, as measured by degree centrality. Each additional hospital connection (unit of degree) conferred a 6% increase in CRE rate in rural facilities (relative risk [RR] = 1.056; 95% confidence interval [CI], 1.030-1.082) and a 3% increase among Chicagoland and non-Chicago urban facilities (RR = 1.027; 95% CI, 1.002-1.052 and RR = 1.025; 95% CI, 1.002-1.048, respectively). Sharing 4 or more patients with LTACHs was associated with higher CRE rates, but this association may have been due to chance (RR = 2.08; 95% CI, .85-5.08; P = .11).



Hospitals with greater connectedness to other hospitals in a statewide patient-sharing network had higher CRE burden. Centrality had a greater effect on CRE rates in rural counties, which do not have LTACHs. Social network analysis likely identifies hospitals at higher risk of CRE exposure, enabling focused clinical and public health interventions.

title: Multicenter Clinical and Molecular Epidemiological Analysis of Bacteremia Due to Carbapenem-Resistant Enterobacteriaceae (CRE) in the CRE Epicenter of the United States
abstract: Although the New York/New Jersey (NY/NJ) area is an epicenter for carbapenem-resistant Enterobacteriaceae (CRE), there are few multicenter studies of CRE from this region. We characterized patients with CRE bacteremia in 2013 at eight NY/NJ medical centers and determined the prevalence of carbapenem resistance among Enterobacteriaceae bloodstream isolates and CRE resistance mechanisms, genetic backgrounds, capsular types (cps), and antimicrobial susceptibilities. Of 121 patients with CRE bacteremia, 50% had cancer or had undergone transplantation. The prevalences of carbapenem resistance among Klebsiella pneumoniae, Enterobacter spp., and Escherichia coli bacteremias were 9.7%, 2.2%, and 0.1%, respectively. Ninety percent of CRE were K. pneumoniae and 92% produced K. pneumoniae carbapenemase (KPC-3, 48%; KPC-2, 44%). Two CRE produced NDM-1 and OXA-48 carbapenemases. Sequence type 258 (ST258) predominated among KPC-producing K. pneumoniae (KPC-Kp). The wzi154 allele, corresponding to cps-2, was present in 93% of KPC-3-Kp, whereas KPC-2-Kp had greater cps diversity. Ninety-nine percent of CRE were ceftazidime-avibactam (CAZ-AVI)-susceptible, although 42% of KPC-3-Kp had an CAZ-AVI MIC of ≥4/4 μg/ml. There was a median of 47 h from bacteremia onset until active antimicrobial therapy, 38% of patients had septic shock, and 49% died within 30 days. KPC-3-Kp bacteremia (adjusted odds ratio [aOR], 2.58; P = 0.045), cancer (aOR, 3.61, P = 0.01), and bacteremia onset in the intensive care unit (aOR, 3.79; P = 0.03) were independently associated with mortality. Active empirical therapy and combination therapy were not associated with survival. Despite a decade of experience with CRE, patients with CRE bacteremia have protracted delays in appropriate therapies and high mortality rates, highlighting the need for rapid diagnostics and evaluation of new therapeutics.

title: Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement
abstract: David Moher and colleagues introduce PRISMA, an update of the QUOROM guidelines for reporting systematic reviews and meta-analyses

title: Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses
abstract: The quality assessment of non-randomized studies is an important component of a thorough meta-analysis of nonrandomized studies. Low quality studies can lead to a distortion of the summary effect estimate. Recent guidelines for the reporting of meta-analyses of observational studies recommend the assessment of the study quality (MOOSE) . In principal, three categories of quality assessments tools are available: scales, simple checklists, or checklists with a summary judgment (for details see Sanderson et al. 2007 ). The results of the quality assessment can be used in several ways such as forming inclusion criteria for the meta-analysis, informing a sensitivity analysis or metaregression, weighting studies, or highlighting areas of methodological quality poorly addressed by the included studies . It has been criticized that the use of summary scores involve inherent weighting of component items including items that may not be related to the validity of the study findings . Sanderson et al.  recently identified overall 86 tools for assessing the quality of non-randomized studies. Their review "highlighted the lack of a single obvious candidate tool for assessing quality of observational epidemiological studies" . In the field of randomized trials, it has been shown that the choice of quality scale can dramatically influence the interpretation of meta-analyses, and can even reverse conclusions regarding the effectiveness of an intervention . Wells et al.  proposed a scale for assessing the quality of published non-randomized studies in meta-analyses,

title: Statewide Surveillance of Carbapenem-Resistant Enterobacteriaceae in Michigan
abstract: Carbapenem-resistant Enterobacteriaceae (CRE) are clinically challenging, threaten patient safety, and represent an emerging public health issue. CRE reporting is not mandated in Michigan.  The Michigan Department of Community Health–led CRE Surveillance and Prevention Initiative enrolled 21 facilities (17 acute care and 4 long-term acute care facilities) across the state. Baseline data collection began September 1, 2012, and ended February 28, 2013 (duration, 6 months). Enrolled facilities voluntarily reported cases of Klebsiella pneumoniae and Escherichia coli according to the surveillance algorithm. Patient demographic characteristics, laboratory testing, microbiology, clinical, and antimicrobial information were captured via standardized data collection forms. Facilities reported admissions and patient-days each month.  One-hundred two cases over 957,220 patient-days were reported, resulting in a crude incidence rate of 1.07 cases per 10,000 patient-days. Eighty-nine case patients had test results positive for K. pneumoniae, whereas 13 had results positive for E. coli. CRE case patients had a mean age of 63 years, and 51% were male. Urine cultures (61%) were the most frequently reported specimen source. Thirty-five percent of cases were hospital onset; sixty-five percent were community onset (CO), although 75% of CO case patients reported healthcare exposure within the previous 90 days. Cardiovascular disease, renal failure, and diabetes mellitus were the most frequently reported comorbid conditions. Common ris k factors included surgery within the previous 90 days, recent infection or colonization with a multidrug-resistant organism, and recent exposures to antimicrobials, especially third- or fourth-generation cephalosporins.  CRE are found throughout Michigan healthcare facilities. Implementing a regional, coordinated surveillance and prevention initiative may prevent CRE from becoming hyperendemic in Michigan.

title: Carbapenem-resistant Enterobacteriaceae and the correlation between carbapenem and fluoroquinolone usage and resistance in the US military health system.
abstract: Whether carbapenem or fluoroquinolone usage is correlated with carbapenem-resistant Enterobacteriaceae (CRE) has not been investigated at the level of an entire US nationwide managed health care system. We analyzed 75 million person-years of surveillance and 1,969,315 cultures from all 266 hospitals in the geographically dispersed US military health system. Incidences of CRE remained under 1 case per 100,000 person-years. Incidences of CRE increased relative to 2005 baseline levels in 3 of 7 subsequent years, then decreased in 2012 (P<0.05). Incident proportions of carbapenem resistance (CR) differed significantly among years, geographical regions, and bacterial species. Although use and resistance strongly correlated (R>0.80) for several "drug-bug" combinations, none were significant at the national or facility level. One exception was that inpatient consumption of fluoroquinolones was significantly correlated (P=0.0007) with CR in Escherichia coli when data from the major referral centers of the Southern and Northern regions were combined.

title: Epidemiology of Carbapenem-Resistant Enterobacteriaceae in 7 US Communities, 2012-2013.
abstract: Carbapenem-resistant Enterobacteriaceae (CRE) are increasingly reported worldwide as a cause of infections with high-mortality rates. Assessment of the US epidemiology of CRE is needed to inform national prevention efforts.



To determine the population-based CRE incidence and describe the characteristics and resistance mechanism associated with isolates from 7 US geographical areas.



Population- and laboratory-based active surveillance of CRE conducted among individuals living in 1 of 7 US metropolitan areas in Colorado, Georgia, Maryland, Minnesota, New Mexico, New York, and Oregon. Cases of CRE were defined as carbapenem-nonsusceptible (excluding ertapenem) and extended-spectrum cephalosporin-resistant Escherichia coli, Enterobacter aerogenes, Enterobacter cloacae complex, Klebsiella pneumoniae, or Klebsiella oxytoca that were recovered from sterile-site or urine cultures during 2012-2013. Case records were reviewed and molecular typing for common carbapenemases was performed.



Demographics, comorbidities, health care exposures, and culture source and location.



Population-based CRE incidence, site-specific standardized incidence ratios (adjusted for age and race), and clinical and microbiological characteristics.



Among 599 CRE cases in 481 individuals, 520 (86.8%; 95% CI, 84.1%-89.5%) were isolated from urine and 68 (11.4%; 95% CI, 8.8%-13.9%) from blood. The median age was 66 years (95% CI, 62.1-65.4 years) and 284 (59.0%; 95% CI, 54.6%-63.5%) were female. The overall annual CRE incidence rate per 100<000 population was 2.93 (95% CI, 2.65-3.23). The CRE standardized incidence ratio was significantly higher than predicted for the sites in Georgia (1.65 [95% CI, 1.20-2.25]; P < .001), Maryland (1.44 [95% CI, 1.06-1.96]; P = .001), and New York (1.42 [95% CI, 1.05-1.92]; P = .048), and significantly lower than predicted for the sites in Colorado (0.53 [95% CI, 0.39-0.71]; P < .001), New Mexico (0.41 [95% CI, 0.30-0.55]; P = .01), and Oregon (0.28 [95% CI, 0.21-0.38]; P < .001). Most cases occurred in individuals with prior hospitalizations (399/531 [75.1%; 95% CI, 71.4%-78.8%]) or indwelling devices (382/525 [72.8%; 95% CI, 68.9%-76.6%]); 180 of 322 (55.9%; 95% CI, 50.0%-60.8%) admitted cases resulted in a discharge to a long-term care setting. Death occurred in 51 (9.0%; 95% CI, 6.6%-11.4%) cases, including in 25 of 91 cases (27.5%; 95% CI, 18.1%-36.8%) with CRE isolated from normally sterile sites. Of 188 isolates tested, 90 (47.9%; 95% CI, 40.6%-55.1%) produced a carbapenemase.



In this population- and laboratory-based active surveillance system in 7 states, the incidence of CRE was 2.93 per 100<000 population. Most CRE cases were isolated from a urine source, and were associated with high prevalence of prior hospitalizations or indwelling devices, and discharge to long-term care settings.

title: Rising Rates of Carbapenem-Resistant Enterobacteriaceae in Community Hospitals: A Mixed-Methods Review of Epidemiology and Microbiology Practices in a Network of Community Hospitals in the Southeastern United States
abstract: Describe the epidemiology of carbapenem-resistant Enterobacteriaceae (CRE) and examine the effect of lower carbapenem breakpoints on CRE detection.  Retrospective cohort.  Inpatient care at community hospitals.  All patients with CRE-positive cultures were included.  CRE isolated from 25 community hospitals were prospectively entered into a centralized database from January 2008 through December 2012. Microbiology laboratory practices were assessed using questionnaires.  A total of 305 CRE isolates were detected at 16 hospitals (64%). Patients with CRE had symptomatic infection in 180 cases (59%) and asymptomatic colonization in the remainder (125 cases; 41%). Klebsiella pneumoniae (277 isolates; 91%) was the most prevalent species. The majority of cases were healthcare associated (288 cases; 94%). The rate of CRE detection increased more than fivefold from 2008 (0.26 cases per 100,000 patient-days) to 2012 (1.4 cases per 100,000 patient-days; incidence rate ratio (IRR), 5.3 [95% confidence interval (CI), 1.22–22.7]; P = .01). Only 5 hospitals (20%) had adopted the 2010 Clinical and Laboratory Standards Institute (CLSI) carbapenem breakpoints. The 5 hospitals that adopted the lower carbapenem breakpoints were more likely to detect CRE after implementation of breakpoints than before (4.1 vs 0.5 cases per 100,000 patient-days; P < .001; IRR, 8.1 [95% CI, 2.7–24.6]). Hospitals that implemented the lower carbapenem breakpoints were more likely to detect CRE than were hospitals that did not (3.3 vs 1.1 cases per 100,000 patient-days; P = .01).  The rate of CRE detection increased fivefold in community hospitals in the southeastern United States from 2008 to 2012. Despite this, our estimates are likely underestimates of the true rate of CRE detection, given the low adoption of the carbapenem breakpoints recommended in the 2010 CLSI guidelines.

title: Outcomes of carbapenem-resistant Enterobacteriaceae isolation: matched analysis.
abstract: Carbapenem-resistant Enterobacteriaceae (CRE) isolation is associated with poor outcomes. The matched cohort study design enables investigation of specific role of resistance in contributing to patients' outcomes. Patients with CRE were matched to 3 groups: (1) patients with extended-spectrum β-lactamase-producing Enterobacteriaceae (ESBL), (2) patients with carbapenem-susceptible non-ESBL Enterobacteriaceae, and (3) uninfected controls.



Patients with CRE isolated at Detroit Medical Center (September 1, 2008, to August 31, 2009) were matched (1:1 ratio) to the 3 groups based on (1) bacteria type, (2) hospital/facility, (3) unit/clinic, (4) calendar year, and (5) time at risk (ie, from admission to culture). Multivariable logistic regression models for outcomes were constructed.



Ninety-one patients with CRE were enrolled. CRE isolation was not an independent predictor for in-hospital mortality in any of the models (ie, vs uncolonized controls, vs ESBL, vs non-ESBL Enterobacteriaceae, and vs all 3 non-CRE groups combined), despite high significance of association in bivariate analyses. CRE isolation was independently associated with deterioration in functional status [odds ratio, 9; P = .002] and being discharged to a long-term care facility after being admitted to the hospital from home [odds ratio, 13.7; P < .001].



Underlying condition and comorbidities are the principal factors responsible for in-hospital mortality in CRE infections; however, in-hospital mortality is not independently correlated to the offending pathogen. In addition, we found that the pathogen contributes significantly to patients' degree of morbidity.

title: Risk Factors and Clinical Impact of Klebsiella pneumoniae Carbapenemase-Producing K. pneumoniae
abstract: Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae is an emerging pathogen with serious clinical and infection control implications. To our knowledge, no study has specifically examined risk factors for KPC-producing K. pneumoniae or its impact on mortality.  To identify risk factors for infection or colonization with KPC-producing K. pneumoniae, a case-control study was performed. Case patients with KPC-producing K. pneumoniae were compared with control subjects with carbapenem-susceptible K. pneumoniae. A cohort study evaluated the association between KPC-producing K. pneumoniae and in-hospital mortality.  Fifty-six case patients and 863 control subjects were identified. In multivariable analysis, independent risk factors for KPC-producing K. pneumoniae were (1) severe illness (adjusted odds ratio [AOR], 4.31; 95% confidence interval [CI], 2.25–8.25), (2) prior fluoroquinolone use (AOR, 3.39; 95% CI, 1.50, 7.66), and (3) prior extended-spectrum cephalosporin use (AOR, 2.55; 95% CI, 1.18, 5.52). Compared with samples from other anatomic locations, K. pneumoniae isolates from blood samples were less likely to harbor KPC (AOR, 0.33; 95% CI, 0.12, 0.86). KPC-producing K. pneumoniae was independently associated with in-hospital mortality (AOR, 3.60; 95% CI, 1.87–6.91).  KPC-producing K. pneumoniae is an emerging pathogen associated with significant mortality. Our findings highlight the urgent need to develop strategies for prevention and infection control. Limiting use of certain antimicrobials, specifically fluoroquinolones and cephalosporins, use may be effective strategies.

title: Outcomes of Carbapenem-Resistant Klebsiella pneumoniae Infection and the Impact of Antimicrobial and Adjunctive Therapies
abstract: Carbapenem-resistant Klebsiella pneumoniae is an emerging healthcare-associated pathogen.  To describe the epidemiology of and clinical outcomes associated with carbapenem-resistant K. pneumoniae infection and to identify risk factors associated with mortality among patients with this type of infection.  Mount Sinai Hospital, a 1,171-bed tertiary care teaching hospital in New York City.  Two matched case-control studies.  In the first matched case-control study, case patients with carbapenem-resistant K. pneumoniae infection were compared with control patients with carbapenem-susceptible K. pneumoniae infection. In the second case-control study, patients who survived carbapenem-resistant K. pneumoniae infection were compared with those who did not survive, to identify risk factors associated with mortality among patients with carbapenem-resistant K. pneumoniae infection.  There were 99 case patients and 99 control patients identified. Carbapenem-resistant K. pneumoniae infection was independently associated with recent organ or stem-cell transplantation (P = .008), receipt of mechanical ventilation (P = .04), longer length of stay before infection (P = .01), and exposure to cephalosporins (P = .02) and carbapenems (P < .001). Case patients were more likely than control patients to die during hospitalization (48% vs 20%; P < .001) and to die from infection (38% vs 12%; P < .001). Removal of the focus of infection (ie, debridement) was independently associated with patient survival (P = .002). The timely administration of antibiotics with in vitro activity against carbapenem-resistant K. pneumoniae was not associated with patient survival.  Carbapenem-resistant K. pneumoniae infection is associated with numerous healthcare-related risk factors and with high mortality. The mortality rate associated with carbapenem-resistant K. pneumoniae infection and the limited antimicrobial options for treatment of carbapenem-resistant K. pneumoniae infection highlight the need for improved detection of carbapenem-resistant K. pneumoniae infection, identification of effective preventive measures, and development of novel agents with reliable clinical efficacy against carbapenem-resistant K. pneumoniae.

title: Mortality associated with carbapenem‐resistant Klebsiella pneumoniae infections in liver transplant recipients
abstract: Resistant bacterial infections are important causes of morbidity and mortality after liver transplantation (LT). This was a retrospective cohort study evaluating the outcomes associated with carbapenem‐resistant Klebsiella pneumoniae (CRKP) infections after LT. In a 2005‐2006 cohort of 175 consecutive LT recipients, 91 infection episodes were observed in 61 patients (35%). The mortality rate 1 year after LT was 18% (32/175). Enterococcus (43%) and Klebsiella species (37%) were the most frequently isolated bacteria. CRKP infections occurred in 14 patients, and 10 of these patients (71%) died. Seven of these deaths occurred within 30 days of the CRKP infection. The median time to the onset of CRKP infections was 12 days (range = 1‐126 days) after LT. The survival rate was significantly lower for patients with a CRKP infection versus patients without a CRKP infection (29% versus 86%, log‐rank P < 0.001). In a multivariate analysis, the only pre‐LT and post‐LT clinical variables significantly associated with death were a Model for End‐Stage Liver Disease score ≥ 30 (hazard ratio = 3.4, P = 0.04) and a post‐LT CRKP infection (hazard ratio = 4.9, P = 0.007). In conclusion, the outcomes associated with CRKP infections in LT recipients are poor. Because the optimal treatment strategies for CRKP infections remain undefined, improved preventive strategies are needed to curtail the devastating impact of CRKP in LT recipients. Liver Transpl 18:468–474, 2012.

title: Containment of a country-wide outbreak of carbapenem-resistant Klebsiella pneumoniae in Israeli hospitals via a nationally implemented intervention.
abstract: During 2006, Israeli hospitals faced a clonal outbreak of carbapenem-resistant Klebsiella pneumoniae that was not controlled by local measures. A nationwide intervention was launched to contain the outbreak and to introduce a strategy to control future dissemination of antibiotic-resistant bacteria in hospitals.



In March 2007, the Ministry of Health issued guidelines mandating physical separation of hospitalized carriers of carbapenem-resistant Enterobacteriaceae (CRE) and dedicated staffing and appointed a professional task force charged with containment. The task force paid site visits at acute-care hospitals, evaluated infection-control policies and laboratory methods, supervised adherence to the guidelines via daily census reports on carriers and their conditions of isolation, provided daily feedback on performance to hospital directors, and intervened additionally when necessary. The initial intervention period was 1 April 2007-31 May 2008. The primary outcome measure was incidence of clinically diagnosed nosocomial CRE cases.



By 31 March 2007, 1275 patients were affected in 27 hospitals (175 cases per 1 million population). Prior to the intervention, the monthly incidence of nosocomial CRE was 55.5 cases per 100,000 patient-days. With the intervention, the continuous increase in the incidence of CRE acquisition was halted, and by May 2008, the number of new monthly cases was reduced to 11.7 cases per 100,000 patient-days (P<.001). There was a direct correlation between compliance with isolation guidelines and success in containment of transmission (P=.02). Compliance neutralized the effect of carrier prevalence on new incidence (P=.03).



A centrally coordinated intervention succeeded in containing a nationwide CRE outbreak after local measures failed. The intervention demonstrates the importance of strategic planning and national oversight in combating antimicrobial resistance.

title: Klebsiella pneumoniae Carbapenemase (KPC)-Producing K. pneumoniae at a Single Institution: Insights into Endemicity from Whole-Genome Sequencing
abstract: The global emergence of Klebsiella pneumoniae carbapenemase-producing K. pneumoniae (KPC-Kp) multilocus sequence type ST258 is widely recognized. Less is known about the molecular and epidemiological details of non-ST258 K. pneumoniae in the setting of an outbreak mediated by an endemic plasmid. We describe the interplay of blaKPC plasmids and K. pneumoniae strains and their relationship to the location of acquisition in a U.S. health care institution. Whole-genome sequencing (WGS) analysis was applied to KPC-Kp clinical isolates collected from a single institution over 5 years following the introduction of blaKPC in August 2007, as well as two plasmid transformants. KPC-Kp from 37 patients yielded 16 distinct sequence types (STs). Two novel conjugative blaKPC plasmids (pKPC_UVA01 and pKPC_UVA02), carried by the hospital index case, accounted for the presence of blaKPC in 21/37 (57%) subsequent cases. Thirteen (35%) isolates represented an emergent lineage, ST941, which contained pKPC_UVA01 in 5/13 (38%) and pKPC_UVA02 in 6/13 (46%) cases. Seven (19%) isolates were the epidemic KPC-Kp strain, ST258, mostly imported from elsewhere and not carrying pKPC_UVA01 or pKPC_UVA02. Using WGS-based analysis of clinical isolates and plasmid transformants, we demonstrate the unexpected dispersal of blaKPC to many non-ST258 lineages in a hospital through spread of at least two novel blaKPC plasmids. In contrast, ST258 KPC-Kp was imported into the institution on numerous occasions, with other blaKPC plasmid vectors and without sustained transmission. Instead, a newly recognized KPC-Kp strain, ST941, became associated with both novel blaKPC plasmids and spread locally, making it a future candidate for clinical persistence and dissemination.

title: Clostridium difficile Infection Among Veterans Health Administration Patients
abstract: To report on the prevalence and incidence of Clostridium difficile infection (CDI) from 2009 to 2013 among Veterans Healthcare Administration patients DESIGN A retrospective descriptive analysis of data extracted from a large electronic medical record (EMR) database SETTING Data were acquired from VHA healthcare records from 2009 to 2013 that included outpatient clinical visits, long-term care, and hospitalized care as well as pharmacy and laboratory information.  In 2009, there were 10,207 CDI episodes, and in 2013, there were 12,143 CDI episodes, an increase of 19.0%. The overall CDI rate increased by 8.4% from 193 episodes per 100,000 patient years in 2009 to 209 episodes per 100,000 patient years in 2013. Of the CDI episodes identified in 2009, 58% were identified during a hospitalization, and 42% were identified in an outpatient setting. In 2013, 44% of the CDI episodes were identified in an outpatient setting.  This is one of the largest studies that has utilized timely EMR data to describe the current CDI epidemiology at the VHA. Despite an aging population with greater burden of comorbidity than the general US population, our data show that VHA CDI rates stabilized between 2011 and 2013 following increases likely attributable to the introduction of the more sensitive nucleic acid amplification tests (NAATs). The findings in this report will help establish an accurate benchmark against which both current and future VA CDI prevention initiatives can be measured.  Control Hosp. Epidemiol. 2015;36(9):1038–1045

title: 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.

title: Attributable Mortality Rate for Carbapenem-Resistant Klebsiella pneumoniae Bacteremia
abstract: To determine the attributable (direct) mortality and morbidity caused by carbapenem-resistant Klebsiella pneumoniae bacteremia.  A matched retrospective, historical cohort design, using a stepwise procedure to stringendy match the best control subjects to the best case subjects.  A 1,000-bed tertiary-care university teaching hospital.  Case subjects were defined as adult patients with carbapenem-resistant K. pneumoniae bacteremia during the period from October 2005 through October 2008. Control subjects were defined as patients who were very similar to case subjects except that they did not have bacteremia.  Matching potential control subjects to case subjects was performed at a 1:1 ratio using a computerized record system. The criteria used included same hospitalization period, similar Charlson comorbidity index, same underlying disease, same age within 10 years, and same sex. Demographic and clinical characteristics were collected from medical records.  During the study period, 319 patients developed an infection due to carbapenem-resistant K. pneumoniae. Of these 319 patients, 39 (12.2%) developed a bloodstream infection, for an overall rate of 0.59 episodes of carbapenem-resistant K. pneumoniae bacteremia per 10,000 patient-days. We excluded 7 patients from our study, leaving a total of 32 case subjects in our cohort. Case subjects were significandy more likely than control subjects (n = 32) to require care in an intensive care unit (12 case subjects [37.5%] vs 3 control subjects [9.4%]), ventilator support (17 case subjects [53.1%] vs 8 control subjects [25%]), and use of a central venous catheter (19 case subjects [59.4%] vs 9 control subjects [28.1%]). For case subjects, the crude mortality rate was 71.9% (ie, 23 of the 32 case subjects died); for control subjects, the crude mortality rate was 21.9% (ie, 7 of the 32 control subjects died) (P < .001. For case subjects, the attributable mortality was 50% (95% confidence interval [CI], 15.3%-98.6%). A mortality risk ratio of 3.3 (95% CI, 2.9-28.5) was found for case subjects with carbapenem-resistant K. pneumoniae bacteremia.  Patients with carbapenem-resistant K. pneumoniae require more intensive and invasive care. We have shown that the crude and attributable mortality rates associated with carbapenem-resistant K. pneumoniae bacteremia were striking.

title: Effects of clinical breakpoint changes in CLSI guidelines 2010/2011 and EUCAST guidelines 2011 on antibiotic susceptibility test reporting of Gram-negative bacilli.
abstract: The aim of this study was to analyse the effects of clinical breakpoint changes in CLSI 2010 and 2011 guidelines and EUCAST 2011 guidelines on antibiotic susceptibility testing (AST) reports.



In total, 3713 non-duplicate clinical isolates of Enterobacteriaceae, Pseudomonas aeruginosa, Stenotrophomonas maltophilia and Acinetobacter baumannii were analysed. Inhibition zone diameters were determined for β-lactams, carbapenems, fluoroquinolones, aminoglycosides and trimethoprim/sulfamethoxazole. CLSI 2009-11 and EUCAST 2011 clinical breakpoints were applied.



Changes in resistance as defined per the guidelines affected individual species and drug classes differently. The cefepime resistance rate in Escherichia coli and Enterobacter cloacae increased from 2.1% and 1.3% to 8.2% and 6.9%, respectively, applying CLSI 2009-11 versus EUCAST 2011 guidelines. Ertapenem resistance rates in E. cloacae increased from 2.6% with CLSI 2009 to 7.2% for CLSI 2010 and 2011, and to 10.1% when applying EUCAST 2011. Cefepime and meropenem resistance rates in P. aeruginosa increased from 12.2% and 20.6% to 19.8% and 27.7%, respectively, comparing CLSI 2009-11 with EUCAST 2011. Tobramycin and gentamicin resistance rates in A. baumannii increased from 15.9% and 25.4% to 34.9% and 44.4% applying CLSI 2009-11 versus EUCAST 2011.



Higher resistance rates reported due to breakpoint changes in CLSI and EUCAST guidelines will result in increasing numbers of Gram-negative bacilli reported as multidrug resistant. AST reports classifying amoxicillin/clavulanic acid, cefepime or carbapenem resistance will lead clinicians to use alternative agents. Upon implementation of the EUCAST guidelines, laboratories should be aware of the implications of modified drug susceptibility testing reports on antibiotic prescription policies.