ESCMID-EUCIC clinical guidelines on decolonization of multidrug-resistant Gram-negative bacteria carriers.

SCOPE: The aim of these guidelines is to provide recommendations for decolonizing regimens targeting multidrug-resistant Gram-negative bacteria (MDR-GNB) carriers in all settings. METHODS: These evidence-based guidelines were produced after a systematic review of published studies on decolonization interventions targeting the following MDR-GNB: third-generation cephalosporin-resistant Enterobacteriaceae (3GCephRE), carbapenem-resistant Enterobacteriaceae (CRE), aminoglycoside-resistant Enterobacteriaceae (AGRE), fluoroquinolone-resistant Enterobacteriaceae (FQRE), extremely drug-resistant Pseudomonas aeruginosa (XDRPA), carbapenem-resistant Acinetobacter baumannii (CRAB), cotrimoxazole-resistant Stenotrophomonas maltophilia (CRSM), colistin-resistant Gram-negative organisms (CoRGNB), and pan-drug-resistant Gram-negative organisms (PDRGNB). The recommendations are grouped by MDR-GNB species. Faecal microbiota transplantation has been discussed separately. Four types of outcomes were evaluated for each target MDR-GNB:(a) microbiological outcomes (carriage and eradication rates) at treatment end and at specific post-treatment time-points; (b) clinical outcomes (attributable and all-cause mortality and infection incidence) at the same time-points and length of hospital stay; (c) epidemiological outcomes (acquisition incidence, transmission and outbreaks); and (d) adverse events of decolonization (including resistance development). The level of evidence for and strength of each recommendation were defined according to the GRADE approach. Consensus of a multidisciplinary expert panel was reached through a nominal-group technique for the final list of recommendations. RECOMMENDATIONS: The panel does not recommend routine decolonization of 3GCephRE and CRE carriers. Evidence is currently insufficient to provide recommendations for or against any intervention in patients colonized with AGRE, CoRGNB, CRAB, CRSM, FQRE, PDRGNB and XDRPA. On the basis of the limited evidence of increased risk of CRE infections in immunocompromised carriers, the panel suggests designing high-quality prospective clinical studies to assess the risk of CRE infections in immunocompromised patients. These trials should include monitoring of development of resistance to decolonizing agents during treatment using stool cultures and antimicrobial susceptibility results according to the EUCAST clinical breakpoints.

ESCMID-EUCIC clinical guidelines on decolonization of multidrug-resistant Gram-negative bacteria carriers

The aim of these guidelines is to provide recommendations for decolonizing regimens targeting multidrug-resistant Gram-negative bacteria (MDR-GNB) carriers in all settings. Methods: These evidence-based guidelines were produced after a systematic review of published studies on decolonization interventions targeting the following MDR-GNB: third-generation cephalosporinresistant Enterobacteriaceae (3GCephRE), carbapenem-resistant Enterobacteriaceae (CRE), aminoglycoside-resistant Enterobacteriaceae (AGRE), fluoroquinolone-resistant Enterobacteriaceae (FQRE), extremely drug-resistant Pseudomonas aeruginosa (XDRPA), carbapenem-resistant Acinetobacter baumannii (CRAB), cotrimoxazole-resistant Stenotrophomonas maltophilia (CRSM), colistin-resistant Gram-negative organisms (CoRGNB), and pan-drug-resistant Gram-negative organisms (PDRGNB). The recommendations are grouped by MDR-GNB species. Faecal microbiota transplantation has been discussed separately. Four types of outcomes were evaluated for each target MDR-GNB:(a) microbiological outcomes (carriage and eradication rates) at treatment end and at specific post-treatment time-points; (b) clinical outcomes (attributable and all-cause mortality and infection incidence) at the same timepoints and length of hospital stay; (c) epidemiological outcomes (acquisition incidence, transmission and outbreaks); and (d) adverse events of decolonization (including resistance development). The level of evidence for and strength of each recommendation were defined according to the GRADE approach. Consensus of a multidisciplinary expert panel was reached through a nominal-group technique for the final list of recommendations.

Predictors of outcome in patients with severe sepsis or septic shock due to extended-spectrum ß-lactamase-producing Enterobacteriaceae.

PURPOSE: There are few data in the literature regarding sepsis or septic shock due to extended-spectrum ß-lactamases (ESBL)-producing Enterobacteriaceae (E). The aim of this study was to assess predictors of outcome in septic patients with bloodstream infection (BSI) caused by ESBL-E. METHODS: Patients with severe sepsis or septic shock and BSI due to ESBL-E were selected from the INCREMENT database. The primary endpoint of the study was the evaluation of predictors of outcome after 30 days from development of severe sepsis or septic shock due to ESBL-E infection. Three cohorts were created for analysis: global, empirical-therapy and targeted-therapy cohorts. RESULTS: 367 septic patients were analysed. Overall mortality was 43.9% at 30 days. Escherichia coli (62.4%) and Klebsiella pneumoniae (27.2%) were the most frequent isolates. ß-lactam/ß-lactamase inhibitor (BLBLI) combinations were the most empirically used drug (43.6%), followed by carbapenems (29.4%). Empirical therapy was active in vitro in 249 (67.8%) patients, and escalation of antibiotic therapy was reported in 287 (78.2%) patients. Cox regression analysis showed that age, Charlson Comorbidity Index, McCabe classification, Pitt bacteremia score, abdominal source of infection and escalation of antibiotic therapy were independently associated with 30-day mortality. No differences in survival were reported in patients treated with BLBLI combinations or carbapenems in empirical or definitive therapy. CONCLUSIONS: BSI due to ESBL-E in patients who developed severe sepsis or septic shock was associated with high 30-day mortality. Comorbidities, severity scores, source of infection and antibiotic therapy escalation were important determinants of unfavorable outcome.

Detection and characterization of carbapenemase-producing Enterobacteriaceae in wounded Syrian patients admitted to hospitals in northern Israel.

Since 2013, four hospitals in northern Israel have been providing care for Syrian nationals, primarily those wounded in the ongoing civil war. We analyzed carbapenemase-producing Enterobacteriaceae (CPE) isolates obtained from these patients. Isolate identification was performed using the VITEK 2 system. Polymerase chain reaction (PCR) was performed for the presence of bla KPC, bla NDM, and bla OXA-48. Susceptibility testing and genotyping were performed on selected isolates. During the study period, 595 Syrian patients were hospitalized, most of them young men. Thirty-two confirmed CPE isolates were grown from cultures taken from 30 patients. All but five isolates were identified as Klebsiella pneumoniae and Escherichia coli. Nineteen isolates produced NDM and 13 produced OXA-48. Among a further 29 isolates tested, multilocus sequence typing (MLST) showed that ST278 and ST38 were the major sequence types among the NDM-producing K. pneumoniae and OXA-48-producing E. coli isolates, respectively. Most were resistant to all three carbapenems in use in Israel and to gentamicin, but susceptible to colistin and fosfomycin. The source for bacterial acquisition could not be determined; however, some patients admitted to different medical centers were found to carry the same sequence type. CPE containing bla NDM and bla OXA-48 were prevalent among Syrian wounded hospitalized patients in northern Israel. The finding of the same sequence type among patients at different medical centers implies a common, prehospital source for these patients. These findings have implications for public health throughout the region.

Bloodstream infections among carriers of carbapenem-resistant Klebsiella pneumoniae: etiology, incidence and predictors.

Carriers of carbapenem-resistant Klebsiella pneumoniae (CRKP) are increasingly recognised through active surveillance in much of the world. We studied incidence, aetiology and predictors of bloodstream infections (BSI) among such carriers. Via a retrospective cohort study conducted in a tertiary care teaching hospital, we examined occurrence of BSI within 45 days of CRKP carrier detection. Three nested case-control studies were conducted to analyse parameters associated with all-cause (ALL), Gram-negative rod (GNR) and CRKP BSI. Cases and controls were compared with respect to demographics, clinical parameters and recent receipt of antibiotics. A total of 431 patients were identified as CRKP carriers (28% by clinical culture, 72% by rectal surveillance), mean age was 75.2 years. Twenty percent of the patients (n = 85) developed BSI, of them 80% (n = 68) with GNR. Of 83 GNR isolates, 58 (70%) were Enterobacteriaceae, of which 19 were CRKP and 20 were extended-spectrum ß-lactamase (ESBL) producers (23% and 24% of total GNR, respectively); 29% of the GNR isolates were nonfermenters (14.5% Pseudomonas aeruginosa, 14.5% Acinetobacter baumannii). Mechanical ventilation predicted ALL BSI (p = 0.04), whereas Clostridium difficile-associated diarrhoea predicted GNR BSI (p = 0.04). Receipt of broad-spectrum antibiotics (piperacillin-tazobactam, amikacin, imipenem) was significantly associated with ALL BSI or GNR BSI. No exposure independently predicted CRKP BSI. We conclude that patients detected as CRKP carriers are at high risk for BSI within 45 days of detection, primarily with multidrug-resistant GNR. Lack of predictive factors differentiating between pathogens and associated high mortality raises once more the dilemma regarding the appropriate empiric therapy for CRKP carriers who develop severe sepsis.

Risk factors for colonization with extended-spectrum beta-lactamase-producing enterobacteriaceae on admission to rehabilitation centres.

Patients newly admitted to rehabilitation centres are at high risk of colonization with multidrug-resistant bacteria because many of them have experienced prolonged stays in other healthcare settings and have had high exposure to antibiotics. We conducted a prospective study to determine the prevalence of and risk factors for colonization with extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-PE) in this population. Subjects were screened by rectal swab for ESBL-PE within 2 days of admission. Swabs were plated on chromagar ESBL plates and the presence of ESBL was verified by a central laboratory. A multilevel mixed effects model was used to identify risk factors for ESBL-PE colonization. Of 2873 patients screened, 748 (26.0%) were positive for ESBL-PE. The variables identified as independently associated with ESBL-PE colonization were: recent stay in an acute-care hospital for over 2 weeks (OR=1.34; 95% CI, 1.12, 1.6), history of colonization with ESBL-PE (OR=2.97; 95% CI, 1.99, 4.43), unconsciousness on admission (OR=2.59; 95% CI, 1.55, 4.34), surgery or invasive procedure in the past year (OR=1.49; 95% CI, 1.2, 1.86) and antibiotic treatment in the past month (OR=1.80; 95% CI, 1.45, 2.22). The predictive accuracy of the model was low (area under the ROC curve 0.656). These results indicate that ESBL-PE colonization is common upon admission to rehabilitation centres. Some risk factors for ESBL-PE colonization are similar to those described previously; however, newly identified factors may be specific to rehabilitation populations. The high prevalence and low ability to stratify by risk factors may guide infection control and empirical treatment strategies in rehabilitation settings.

Trends and changes in Clostridium difficile diagnostic policies and their impact on the proportion of positive samples: a national survey.

In June 2012, Israeli guidelines for laboratories were published defining the recommended methods for diagnosis of Clostridium difficile infection (CDI). We conducted this survey to examine the effects of the new recommendations on the proportions of rejected and positive samples by the different methods. A survey was mailed to the directors of all general hospital (GH) and health maintenance organization (HMO) clinical microbiology laboratories. The report was divided into two periods, before and after implementation of the guidelines. Surveys were completed by 13/28 GH laboratories and 5/6 HMO laboratories. All 18 of these laboratories used C. difficile toxin (CDT) enzyme immunoassay alone during the first period of the survey. In the second period, nine laboratories (Group A) used CDT-PCR: two of them used this method exclusively while the other seven used it to resolve most (>90%) of the discrepant results (glutamate dehydrogenase antigen (GDH) +/CDT-]. The other nine laboratories (Group B) used combined GDH/CDT assay, using CDT PCR in only a minority (<20%) of GDH+/CDT- cases. The overall proportion of rejected samples increased from 9.5% in the first period to 13.9% in the second (p<0.001). Between the first and second periods the proportion of positive samples increased from 9.0% to 11.6% in group A laboratories (p<0.001), but decreased from 12.9% to 9.7% in group B laboratories (p<0.001). Implementation of the guidelines has resulted in a significant increase in the proportion of rejected samples and in the proportion testing positive, suggesting more appropriate test utilization and improved sensitivity in the laboratory diagnosis of CDI.

Asymptomatic rectal carriage of blaKPC producing carbapenem-resistant Enterobacteriaceae: who is prone to become clinically infected?

Carbapenem-resistant Enterobacteriaceae (CRE) are emerging extremely drug-resistant pathogens; blaKPC is the predominant carbapenemase in Israel. Early detection of asymptomatic rectal carriers is important for infection control purposes. We aimed to determine who among newly identified CRE rectal carriers is prone to have a subsequent clinical specimen with CRE. A matched case-control study was conducted in a tertiary care teaching hospital in Israel. Cases with a primary positive CRE rectal test and subsequent CRE clinical specimens were matched in a 1:2 ratio with CRE rectal carriers who did not develop subsequent CRE clinical specimens (controls). Matching was based on calendar time of primary CRE isolation, whether the primary CRE isolation was ≤ 48 h or > 48 h after hospital admission, and time at risk to have a subsequent clinical specimen. Data were extracted from the patients' medical records and from the hospital's computerized database. One hundred and thirty-two newly identified CRE rectal carriers (44 cases, 88 controls) were included. The median time interval between screening and subsequent clinical specimens was 11 days (range, 3-27); 86% of the clinical specimens were classified as true infections. Independent predictors of subsequent CRE clinical specimens were: admission to the intensive care unit, having a central venous catheter, receipt of antibiotics, and diabetes mellitus. Identification of the risk factors for subsequent infections among CRE-colonized patients can be used to control modifiable risk factors and to direct empirical antimicrobial therapy when necessary.

Carriage of methicillin-resistant Staphylococcus aureus on admission to European rehabilitation centres--a prospective study.

This study aimed to determine the prevalence of and risk factors for methicillin-resistant Staphylococcus aureus (MRSA) carriage among patients newly admitted to rehabilitation centres. It is a prospective study examining MRSA carriage on admission to seven rehabilitation wards in four countries. Risk factors for MRSA carriage were analysed using univariate and multivariate analyses. A total of 1204 patients were studied. Among them, 105 (8.7%) had a positive admission MRSA screening result. The MRSA carriers were more likely to be male, to have had a recent stay in another long-term-care facility or >2 weeks acute-care hospital stay, history of colonization with MRSA, reduced level of consciousness, peripheral vascular disease and pressure sores. In multivariable logistic regression male gender (odds ratio (OR) 2.2, 95% confidence interval (CI) 1.4-3.6, p 0.001), history of MRSA positivity (OR 6.8, 95% CI 3.8-12.3, p <0.001), peripheral vascular disease (OR 2.5, 95% CI 1.2-5, p 0.013), recent stay in another long-term-care facility (OR 2.1, 95% CI 1.3-3.5, p 0.004), or long (>2 weeks) acute-care hospital stay (OR 1.9, 95% CI 1.2-3, p 0.004), remained significant risk factors for MRSA carriage. MRSA carriage is common on admission to rehabilitation centres but less so, than previously described in long-term-care facilities. Male gender, history of MRSA positivity, previous hospitalization and peripheral vascular disease may predict MRSA carriage, and may serve as indicators for using pre-emptive infection control measures.

Molecular epidemiology of methicillin-resistant Staphylococcus aureus in Israel: dissemination of global clones and unique features.

From 2006 to 2009, 315 clinical methicillin-resistant Staphylococcus aureus (MRSA) isolates were collected from 5 hospitals across Israel. Most isolates (64%) were related to the global clones spa types t001-SCCmec-I (SCCmec-I stands for staphylococcal cassette chromosome mec type I) (n = 99; 31%), t002-SCCmec-II (n = 82; 26%), and t008-SCCmec-IV (n = 21; 7%), five of which were identified as MRSA strain USA-300. Seventeen strains unique to Israel were identified. SCCmec types IV and V were common among hospital-acquired isolates.

Impact of multi-drug-resistant Acinetobacter baumannii on clinical outcomes.

We conducted a retrospective matched cohort study to examine the impact of isolation of multi-drug-resistant (MDR) Acinetobacter baumannii on patient outcomes. Cases from whom MDR A. baumannii was isolated in a clinical culture (n = 118) were compared with controls from whom MDR A. baumannii was not isolated (n = 118). Cases and controls were matched according to ward, calendar month of hospitalization, and duration of hospitalization before culture. The following outcomes were compared in multivariable analysis: in-hospital mortality, length of stay, need for mechanical ventilation, and functional status at discharge. MDR A. baumannii was determined to be a pathogen in 72% of cases. In 36% of cases, the patient died, versus 21% of controls (odds ratio [OR] 2.21, 95% confidence interval [CI] 1.17-4.16, P = 0.014). Median length of stay for surviving cases was 17 days, versus 11 for surviving controls (multiplicative effect 1.55, 95% CI 0.99-2.44, P = 0.057). Fifty-two percent of cases required mechanical ventilation, versus 25% of controls (OR 3.72, 95% CI 1.91-7.25, P<0.001); 60% of surviving cases were discharged with reduced functional status, versus 38% of controls (OR 4.4, 95% CI 1.66-11.61, P = 0.003). In multivariable analysis, clinical isolation of MDR A. baumannii remained a significant predictor of mortality (OR 6.23, 95% CI 1.31-29.5, P = 0.021), need for mechanical ventilation (OR 7.34, 95% CI 2.24-24.0, P<0.001), and reduced functional status on discharge (OR 7.93, 95% CI 1.1-56.85, P = 0.039). Thus, MDR A. baumannii acquisition is associated with severe adverse outcomes, including increased mortality, need for mechanical ventilation, and reduced functional status.

Influx of extended-spectrum beta-lactamase-producing enterobacteriaceae into the hospital.

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.

Protocol for the accelerated detection of extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella pneumoniae strains from blood cultures.

The study presented here was performed to evaluate an accelerated protocol for the early detection of organisms producing extended-spectrum beta-lactamase (ESBL). The procedure involved testing isolates directly from positive blood-culture bottles, and a total of 40 clinical isolates (10 ESBL-producing and 10 non-ESBL-producing isolates of both Escherichia coli and Klebsiella pneumoniae) were used. The isolates were inoculated into blood cultures bottles and, upon growth signal, fluid from the bottle was cultured directly onto plates with combination discs containing cefotaxime or ceftazidime with and without clavulanate. Results were compared with those of standard methods for the detection of ESBL. High concordance between the two methods was found, and the direct test showed high sensitivity (95%) and specificity (100%). Use of this accelerated protocol may speed detection of the ESBL phenotype and thereby facilitate the early administration of appropriate antimicrobial therapy.

Factors associated with nosocomial diarrhea and Clostridium difficile-associated disease on the adult wards of an urban tertiary care hospital.

A prospective survey of the adult inpatient population of an urban tertiary care hospital was conducted to determine factors associated with the development of nosocomial diarrhea and the acquisition of Clostridium difficile-associated disease. During the 3-month survey, 98 patients with nosocomial diarrhea were enrolled, and 38 controls were recruited. The controls were patients without diarrhea lying in beds adjacent to the affected patients. Factors significantly associated with nosocomial diarrhea were the administration of a special diet (P=0.02) and receipt of a greater number of different antibiotics (P=0.02). Among the 98 patients with diarrhea, Clostridium difficile toxin B was identified in the stool of 13. Factors found to be associated with the presence of toxin B as compared to other causes of nosocomial diarrhea were a greater number of individual antibiotics used during hospitalization (P=0.02) and receipt of a cephalosporin (P=0.03) or, more specifically, a third-generation cephalosporin (P=0.02). Among patients with nosocomial diarrhea, those who had toxin in their stool had a significantly higher total antibiotic burden (expressed as antibiotic days) than those with diarrhea due to other causes (P=0.01).