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Non-typhoidal Salmonella enterica (NTS) are diverse and important bacterial pathogens consisting of more than 2600 different serovars, with varying host-specificity. Here, we characterized the poultry-associated serovars in Israel, analysed their resistome and illuminated the molecular mechanisms underlying common multidrug resistance (MDR) patterns. We show that at least four serovars including Infantis, Muenchen, Newport and Virchow present a strong epidemiological association between their temporal trends in poultry and humans. Worrisomely, 60% from all of the poultry isolates tested (n = 188) were multidrug resistant, mediated by chromosomal SNPs and different mobile genetics elements. A novel streptomycin-azithromycin resistance island and previously uncharacterized versions of the mobilized Salmonella genomic island 1 (SGI1) were identified and characterized in S. Blockley and S. Kentucky isolates respectively. Moreover, we demonstrate that the acquisition of SGI1 does not impose fitness cost during growth under nutrient-limited conditions or in the context of Salmonella infection in the mouse model. Overall, our data emphasize the role of the poultry production as a pool of specific epidemic MDR strains and autonomous genetic elements, which confer resistance to heavy metals and medically relevant antibiotics. These are likely to disseminate to humans via the food chain and fuel the increasing global antibiotic resistance crisis., (© 2019 Society for Applied Microbiology and John Wiley & Sons Ltd.)

Little evidence exists addressing the clinical value of adding gentamicin to ampicillin for invasive listeriosis. A multicenter retrospective observational study of nonpregnant adult patients with invasive listeriosis (primary bacteremia, central nervous system (CNS) disease, and others) in 11 hospitals in Israel between the years 2008 and 2014 was conducted. We evaluated the effect of penicillin-based monotherapy compared with early combination therapy with gentamicin, defined as treatment started within 48 h of culture results and continued for a minimum of 7 days. Patients who died within 48 h of the index culture were excluded. The primary outcome was 30-day all-cause mortality. A total of 190 patients with invasive listeriosis were included. Fifty-nine (30.6%) patients were treated with early combination therapy, 90 (46.6%) received monotherapy, and 44 (22.8%) received other treatments. Overall 30-day mortality was 20.5% (39/190). Factors associated with mortality included lower baseline functional status, congestive heart failure, and higher sequential organ failure assessment score. Source of infection, treatment type, and time from culture taken date to initiation of effective therapy were not associated with mortality. In multivariable analysis, monotherapy was not significantly associated with increased 30-day mortality compared with early combination therapy (OR 1.947, 95% CI 0.691-5.487). Results were similar in patients with CNS disease (OR 3.037, 95% CI 0.574-16.057) and primary bacteremia (OR 2.983, 95% CI 0.575-15.492). In our retrospective cohort, there was no statistically significant association between early combination therapy and 30-day mortality. A randomized controlled trial may be necessary to assess optimal treatment.

Background: Bezlotoxumab is a human monoclonal antibody against Clostridium difficile toxin B indicated to prevent C. difficile infection (CDI) recurrence (rCDI) in adults at high risk for rCDI. This post hoc analysis of pooled monocolonal antibodies for C.difficile therapy (MODIFY) I/II data assessed bezlotoxumab efficacy in participants with characteristics associated with increased risk for rCDI., Methods: The analysis population was the modified intent-to-treat population who received bezlotoxumab or placebo (n = 1554) by risk factors for rCDI that were prespecified in the statistical analysis plan: age ≥65 years, history of CDI, compromised immunity, severe CDI, and ribotype 027/078/244. The proportion of participants with rCDI in 12 weeks, fecal microbiota transplant procedures, 30-day all cause and CDI-associated hospital readmissions, and mortality at 30 and 90 days after randomization were presented., Results: The majority of enrolled participants (75.6%) had ≥1 risk factor; these participants were older and a higher proportion had comorbidities compared with participants with no risk factors. The proportion of placebo participants who experienced rCDI exceeded 30% for each risk factor compared with 20.9% among those without a risk factor, and the rCDI rate increased with the number of risk factors (1 risk factor: 31.3%; ≥3 risk factors: 46.1%). Bezlotoxumab reduced rCDI, fecal microbiota transplants, and CDI-associated 30-day readmissions in participants with risk factors for rCDI., Conclusions: The risk factors prespecified in the MODIFY statistical analysis plan are appropriate to identify patients at high risk for rCDI. While participants with ≥3 risk factors had the greatest reduction of rCDI with bezlotoxumab, those with 1 or 2 risk factors may also benefit., Clinical Trials Registration: NCT01241552 (MODIFY I) and NCT01513239 (MODIFY II).

Background: Bacteremia is associated with high morbidity and mortality rates. Initiation of inadequate empiric antibiotic therapy is associated with a worse outcome. The aim of this study was to establish the prevalence and the factors associated with inappropriate empiric antibiotic therapy in patients hospitalized with bacteremia., Methods: A cross-sectional study was conducted during January 2010-December 2011 at the medical wards of the Chaim Sheba Medical Center, Israel. The records of all patients with bacteremia were reviewed. Clinical and laboratory characteristics, bacteremic pathogens and antimicrobial agents were retrieved from the medical records. Factors associated with appropriateness of empiric antibiotic therapy were assessed., Results: A total of 681 eligible adults were included in the study. Antibiotic therapy was found to be inappropriate in 138 (20.2%) patients (95% C.I. 17.2-23.2). The rate of appropriateness was not related to the type of antibiotic regimen and the type of bacteria. Patients with healthcare-associated infections were more likely to be administrated inappropriate antibiotic therapy. Patients with primary bloodstream infections were also more likely to be administrated inappropriate antibiotic therapy. Empiric combination therapy was more likely to be appropriate than monotherapy, except for an aminoglycosides-based combination., Conclusions: Combination empiric antibiotic therapy should be considered in patients with healthcare-associated infections and in those with primary bloodstream infections.

Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) infections are increasingly documented worldwide. We recently identified two major CA-MRSA clones in Israel: USA300 and t991. Here, we assessed clinical outcomes by CA-MRSA clones and the physicians' treatment approach to CA-MRSA infections. All community-onset, clinical MRSA isolates detected during 2011-2013 by Maccabi Healthcare Services were collected and characterized phenotypically and genotypically; data were collected retrospectively from electronic medical records. Of 309 patients with MRSA infections, 64 were identified as CA-MRSA (21 %). Of the CA-MRSA infections, 72 % had skin and soft tissue infections (SSTIs), 38 % were Panton-Valentine leukocidin (PVL)+, the major clone being USA300 (n = 13, 54 %). Of PVL- isolates (n = 40, 62 %), t991 was the major clone. Age was the only predictor for PVL+ CA-MRSA infection (p < 0.001). Patients with PVL+ CA-MRSA had higher incidence of SSTI recurrences (1.061 vs. 0.647 events per patient/per year, p < 0.0001) and were more likely to have the SSTI drained (64 % vs. 21 %, p = 0.003) when compared to PVL- CA-MRSA. USA300 was more common among adults, while t991 was more common among children (p = 0.002). The physician's referral to culture results and susceptibility were the only predictors of appropriate antibiotic therapy (p < 0.001). However, only a minority of physicians referred to culture results, regardless of subspecialties. PVL+ CA-MRSA isolates caused significantly more recurrences of SSTIs and increased the need for drainage compared with PVL- isolates. Physicians' awareness of CA-MRSA as a cause of SSTIs in the community was suboptimal. Culturing of pus-producing SSTIs is crucial for providing adequate antimicrobials and elucidating MRSA epidemiology.

Background: Complicated skin and skin structure infections (cSSSIs) frequently result in hospitalization with significant morbidity and mortality., Methods: In this phase 3b/4 parallel, randomized, open-label, comparative study, 531 subjects with cSSSI received tigecycline (100 mg initial dose, then 50 mg intravenously every 12 hrs) or ampicillin-sulbactam 1.5-3 g IV every 6 hrs or amoxicillin-clavulanate 1.2 g IV every 6-8 hrs. Vancomycin could be added at the discretion of the investigator to the comparator arm if methicillin-resistant Staphylococcus aureus (MRSA) was confirmed or suspected within 72 hrs of enrollment. The primary endpoint was clinical response in the clinically evaluable (CE) population at the test-of-cure (TOC) visit. Microbiologic response and safety were also assessed. The modified intent-to-treat (mITT) population comprised 531 subjects (tigecycline, n = 268; comparator, n = 263) and 405 were clinically evaluable (tigecycline, n = 209; comparator, n = 196)., Results: In the CE population, 162/209 (77.5%) tigecycline-treated subjects and 152/196 (77.6%) comparator-treated subjects were clinically cured (difference 0.0; 95% confidence interval [CI]: -8.7, 8.6). The eradication rates at the subject level for the microbiologically evaluable (ME) population were 79.2% in the tigecycline treatment group and 76.8% in the comparator treatment group (difference 2.4; 95% CI: -9.6, 14.4) at the TOC assessment. Nausea, vomiting, and diarrhea rates were higher in the tigecycline group., Conclusions: Tigecycline was generally safe and effective in the treatment of cSSSIs., Trial Registration: ClinicalTrials.gov NCT00368537.

Pseudomonas aeruginosa is an uncommon cause of bacteremia upon hospital admission (UHA) and the chosen empirical antimicrobial therapy may not cover it appropriately. In a multicenter prospective study conducted in Israel, we evaluated risk factors for in-hospital mortality in patients with P. aeruginosa bacteremia UHA and determined the influence of delay in adequate empirical antimicrobial therapy on patients' outcome. Seventy-six adult patients with P. aeruginosa bacteremia within 72 h of hospital admission were included. Demographic, clinical, and treatment data were collected. Microbiological adequacy of empirical therapy was determined. Severe sepsis or septic shock at admission (OR, 21.9; P < 0.001), respiratory or unknown sources of bacteremia (OR, 11.5; P = 0.003), recent hospitalization (OR, 6.2; P = 0.032), and poor functional status (OR, 5.8; P = 0.029) were identified as independent predictors of mortality. Inadequate empirical antimicrobial therapy was marginally associated with increased mortality only among patients who presented with severe sepsis or septic shock (P = 0.051)., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Parents' wish for antibiotics is a significant determinant of antibiotic prescription for their children. The objective of the study was to assess the effect of an educational intervention on parents' attitudes towards antibiotic use. Parents accompanying their children to primary pediatric clinics of Jerusalem-Hashfela District of Maccabi Healthcare Services responded to a survey regarding their wish for antibiotic treatment. Two groups of parents were surveyed: A (control) in a pre-intervention period and B (intervention) during the intervention period. The intervention included posters, pamphlets, and drawing booklets for children in the waiting rooms. A per-protocol analysis that included from group B only parents that stated they noticed the educational material (B1) was also performed. Eight hundred and sixty-eight parents were surveyed during the pre-intervention period and 688 parents during the intervention period. Children's median age was 4 years (8 days-16 years). Most (86%) of the parents were mothers. Groups were similar in socio-demographic characteristics and children's medical complaints. Factors associated with parent's low expectation for antibiotics were a general negative attitude to antibiotics (OR 1.66, 95% CI 1.20-2.30), current upper respiratory tract symptoms (OR 0.29, 95% CI 0.21-0.39), advanced knowledge regarding antibiotics (OR 1.72, 95% CI 1.26-2.34), and being in group B (intervention) (OR 1.47, 95% CI 1.08-2.00). The effect of the intervention was greater in the per-protocol analysis (OR 1.75, 95% CI 1.20-2.55). A simple educational intervention was effective in reducing parents' expectation for antibiotics but was significantly more effective when parents reported they noticed the campaign. Improving parents' knowledge regarding antibiotics can reduce parents' wish for antibiotic treatment.

Background: Telavancin is a lipoglycopeptide bactericidal against gram-positive pathogens., Methods: Two methodologically identical, double-blind studies (0015 and 0019) were conducted involving patients with hospital-acquired pneumonia (HAP) due to gram-positive pathogens, particularly methicillin-resistant Staphylococcus aureus (MRSA). Patients were randomized 1:1 to telavancin (10 mg/kg every 24 h) or vancomycin (1 g every 12 h) for 7-21 days. The primary end point was clinical response at follow-up/test-of-cure visit., Results: A total of 1503 patients were randomized and received study medication (the all-treated population). In the pooled all-treated population, cure rates with telavancin versus vancomycin were 58.9% versus 59.5% (95% confidence interval [CI] for the difference, -5.6% to 4.3%). In the pooled clinically evaluable population (n = 654), cure rates were 82.4% with telavancin and 80.7% with vancomycin (95% CI for the difference, -4.3% to 7.7%). Treatment with telavancin achieved higher cure rates in patients with monomicrobial S. aureus infection and comparable cure rates in patients with MRSA infection; in patients with mixed gram-positive/gram-negative infections, cure rates were higher in the vancomycin group. Incidence and types of adverse events were comparable between the treatment groups. Mortality rates for telavancin-treated versus vancomycin-treated patients were 21.5% versus 16.6% (95% CI for the difference, -0.7% to 10.6%) for study 0015 and 18.5% versus 20.6% (95% CI for the difference, -7.8% to 3.5%) for study 0019. Increases in serum creatinine level were more common in the telavancin group (16% vs 10%)., Conclusions: The primary end point of the studies was met, indicating that telavancin is noninferior to vancomycin on the basis of clinical response in the treatment of HAP due to gram-positive pathogens.

Background: Heteroresistant vancomycin-intermediate Staphylococcus aureus (hVISA) infections are emerging, but their clinical significance remains unclear. Our objective was to compare patients who had hVISA bacteremia with patients who had methicillin-resistant S. aureus (MRSA) bacteremia., Methods: A total of 27 case patients with hVISA bacteremia were compared with 223 control patients with MRSA bacteremia. Medical records of all patients were reviewed, and factors independently associated with infection-related mortality were assessed by logistic regression., Results: Patients with hVISA bacteremia were not significantly different from those with MRSA bacteremia with respect to age, comorbidities, duration of hospital stay, and infection-attributable mortality. However, the median duration of bacteremia among patients with hVISA was significantly longer than that among patients with MRSA (12 vs. 2 days; P = .005), and patients with hVISA had a greater prevalence of complications, such as endocarditis (18.5% vs. 3.6%; P = .007) and osteomyelitis (25.9% vs. 7.2%, respectively; P = .006). Rifampin resistance emerged more frequently among hVISA isolates than among MRSA isolates (44% vs. 5.9%; P < .001). Factors independently associated with infection-related mortality in all patients were age, Charlson comorbidity index, female sex, and being bedridden., Conclusions: hVISA bacteremia was significantly associated with prolonged bacteremia duration, greater rates of complications, and emergence of rifampin resistance, compared with MRSA bacteremia. However, no significant difference in mortality existed between patients with hVISA bacteremia and those with MRSA bacteremia.

A 3-day course of azithromycin was compared with the 10 days of other antibiotics, which general practitioners routinely use as therapy for community acquired pneumonia (CAP). The study was a prospective open labelled, randomised, multicentre, comparative study from five family clinics. Patients with clinical and radiological evidence of pneumonia were included. The pneumonia resolved in 98.4% (61/62) of patients treated with azithromycin and in 87% (40/46) of patients treated with other antibiotics (P < 0.017). Restitution of normal function at home (2.3 +/- 1.2 and 4.3 +/- 2.6 days) and return to work (3.4 +/- 2.0 and 5.5 +/- 3.1 days) was more rapid among the group treated with azithromycin ( P < 0.001). Three days of azithromycin was more convenient and cost effective than the comparators used to treat pneumonia.

In a retrospective 10-year analysis of 3,536 patient-unique isolates, Acinetobacter baumannii imipenem susceptibility declined from 98.1 (1990) to 64.1% (2000), and ciprofloxacin susceptibility decreased from 50.5 to 13.1%. Imipenem median zone diameters decreased from 27. 7 (1997) to 18.8 mm (2000). No outbreaks were detected. Two clusters were identified for 41 strains genotyped by pulsed-field gel electrophoresis, but imipenem resistance was not clonal.