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Background Early reports described an increased risk of herpes zoster following receipt of mRNA-based COVID-19 vaccines. The objective was to assess whether COVID-19 vaccine is associated with varicella-zoster virus–induced neurologic disease (VZV-ND). Methods This multicenter retrospective case-control study with a test-negative design was conducted at 12 hospitals in Israel. We included all patients admitted with VZV-ND between January 2020 and December 2021 and matched controls with a negative polymerase chain reaction result for VZV in cerebrospinal fluid. Results We identified 188 patients meeting the case definition of VZV-ND who were admitted during the study period. Cases were matched with 376 controls. There was no significant variation in the incidence of VZV-ND between 1 year preceding and 1 year following the deployment of BNT162b2 in Israel. Analysis of persons who had received at least 1 dose of COVID-19 vaccine (n = 259) showed similar proportions of VZV-ND and non–VZV-ND in 4 intervals (30, 42, 50, 60 days) following the last vaccine dose. The median time from the last vaccine dose to hospitalization with a neurologic syndrome was 53 days (IQR, 25–128) and 82 days (IQR, 36–132) for VZV-ND and non–VZV-ND, respectively, not reaching statistical significance (P =.056). The rate of VZV-ND in vaccinated patients was no different from the rate in the unvaccinated group (30.9% vs 35.4%, P =.2). Conclusions We did not find an association between COVID-19 vaccine and VZV-ND. Since COVID-19 vaccine is now recommended yearly, every fall and winter, establishing the safety of the vaccine is of great importance. [ABSTRACT FROM AUTHOR]

We report an outbreak of Candida auris across multiple healthcare facilities in Israel. For the period of May 2014-May 2022, a total of 209 patients with C. auris infection or colonization were identified. The C. auris incidence rate increased 30-fold in 2021 (p = 0.00015), corresponding in time with surges of COVID-19-related hospitalization. Multilocus sequence typing revealed hospital-level outbreaks with distinct clones. A clade III clone, imported into Israel in 2016, accounted for 48.8% of typed isolates after January 2021 and was more frequently resistant to fluconazole (100% vs. 63%; p = 0.00017) and voriconazole (74% vs. 5.2%; p<0.0001) than were non-clade III isolates. A total of 23% of patients had COVID-19, and 78% received mechanical ventilation. At the hospital level, outbreaks initially involved mechanically ventilated patients in specialized COVID-19 units and then spread sequentially to ventilated non-COVID-19 patients and nonventilated patients. [ABSTRACT FROM AUTHOR]

Background: Previous studies demonstrated a 'weekend effect' and a 'night effect' of increased mortality among patients admitted during weekends or night shifts, presumably due to understaffing. Aims: To examine whether death during hospitalisation follows a similar effect regardless of admission time. Methods: A retrospective cohort study among deceased patients hospitalised in the internal medicine wing of a tertiary medical centre in Israel, between 2019 and 2020. Demographic and medical data were retrieved from electronic medical charts. Causes of death were specifically categorised. We applied statistical models to test for differences in mortality using incidence rate ratio (IRR) according to the day, time and cause of death. Results: One thousand, two hundred and seventy‐eight deceased patients were included. All‐cause mortality was similar between weekends and weekdays. When sepsis was the cause of death, higher IRR were demonstrated on Fridays in comparison with weekdays (IRR 1.4; 95% confidence interval (CI) 1.1–1.9; P < 0.05). Other causes of death were not consistent with a 'weekend effect'. Mortality during night shifts was higher in comparison with the afternoon (IRR 1.5; 95% CI 1.3–4.7) and similar to the morning (IRR 1; 95% CI 0.9–1.2). Conclusion: Our study did not find a pattern of 'weekend effect' or 'night effect' on all‐cause mortality among hospitalised patients in internal medicine wards. Our findings suggest that perhaps specifically death from sepsis, and not all‐cause mortality, can be used as a surrogate for the measurement of understaffing or quality of care in the internal ward. [ABSTRACT FROM AUTHOR]

Introduction: Reports regarding the external validity of randomized controlled trials (RCTs) are scarce. We aimed to assess the population external validity of an investigator-initiated RCT on the duration of antibiotics for the treatment of Gram-negative bacteremia by comparing patients included in the RCT to patients that were not included in the trial. Methods: Hospitalized patients with Gram-negative bacteremia were recruited into an RCT and randomized to receive 7 or 14 days of covering antibiotic therapy in Israel and Italy from 2013 to 2017. In a concomitant observational study, RCT participants were compared with patients who fulfilled the inclusion criteria but were not included in the trial due to participation in other trials, discharge before approached by researchers, refusal to participate, or unwillingness of the treating physician to allow participants' recruitment. Results: Six hundred and four RCT patients were compared with 613 nonincluded patients. Almost 50% of nonincluded patients (288/613) were dependent on others for activities of daily living at baseline compared to 37.7% of RCT participants (228/604). Dementia was nearly 2-fold more frequent in nonincluded patients than those included (5.9% [36/613] versus 3.6% [22/604], p = 0.07). Patients who were not included in the RCT were more likely to acquire their infection in the hospital (53.3% [327/613] versus 29.1% [176/604], p < 0.001). The primary composite outcome of mortality, clinical failure, readmissions, or extended hospitalization at 90 days occurred in 353 of 613 nonincluded patients (57.6%) compared to 299 of 604 RCT participants (49.6%), p = 0.005. However, on multivariate analysis noninclusion in the RCT was not an independent risk factor for clinical failure and mortality. Conclusions: RCTs, even with broad eligibility criteria, do not represent the whole spectrum of patients and leave out a population with more severe illness for whom the evidence is lacking. [ABSTRACT FROM AUTHOR]

Background Chronic kidney disease (CKD) is a risk factor for severe coronavirus disease 2019 (COVID-19). We aimed to evaluate the real-life effectiveness of the BNT162b2 messenger RNA vaccine for a range of outcomes in patients with CKD compared with matched controls. Methods Data from Israel's largest healthcare organization were retrospectively used. Vaccinated CKD [estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2] and maintenance dialysis patients were matched to vaccinated controls without CKD (eGFR ≥60 ml/min/1.73 m2) according to demographic and clinical characteristics. Study outcomes included documented infection with severe acute respiratory syndrome coronavirus 2, symptomatic infection, COVID-19-related hospitalization, severe disease and death. Vaccine effectiveness was estimated as the risk ratio (RR) at days 7–28 following the second vaccine dose, using the Kaplan–Meier estimator. Effectiveness measures were also evaluated separately for various stages of CKD. Results There were 67 861 CKD patients not treated with dialysis, 2606 hemodialysis (HD) patients and 70 467 matched controls. The risk of severe disease {RR 1.84 [95% confidence interval (CI) 0.95–2.67]} and death [RR 2.00 (95% CI 0.99–5.20)] was increased in nondialysis CKD patients compared with controls without CKD following vaccination. For the subgroup of patients with eGFR <30 ml/min/1.73 m2, the risk of severe disease and death was increased compared with controls [RR 6.42 (95% CI 1.85–17.51) and RR 8.81 (95% CI 1.63–13.81), respectively]. The risks for all study outcomes were increased in HD patients compared with controls. Conclusion Two doses of the BNT162b2 vaccine were found to be less efficient for patients with eGFR <30 ml/min/1.73 m2. Risk in HD patients is increased for all outcomes. These results suggest prioritizing patients with eGFR <30 ml/min/1.73 m2 for booster shots, pre- and post-exposure prophylaxis and early COVID-19 therapy. [ABSTRACT FROM AUTHOR]

Background: We aimed to review the current state, challenges, and needs of antimicrobial stewardship programs (ASPs) in adult solid organ transplantation (SOT) centers in Israel. Methods: We conducted a survey using electronic questionnaires sent during February 2022 to infectious disease (ID) consultants of SOT centers, encompassing general and organ‐specific ASP issues. Results: All six centers performing adult SOTs in Israel participated. The institutional ASPs in all centers included SOT recipients, and five centers had specific stewardship activities targeting SOT recipients. ASP activities were performed by ID consultants in all centers, with clinical pharmacists in most. ASP protocols and activity scope were highly variable. Formulary restriction with pre‐authorization was used in all centers. Antibiotic allergy was addressed in ASP guidelines in half of the centers. Peri‐transplantation antibiotic, antifungal, and antiviral prophylactic regimens varied based on center, transplanted organ, and patient risk group. Approaches to surveillance cultures, diagnosis and treatment of various graft infections were also variable. ASP outcome measurement was not performed in all centers. The main challenges and barriers to successful ASP implementation were difficulty in defining appropriate durations of therapy for certain infections, high rates of antimicrobial resistance (AMR), and lack of dedicated ASP teams. Conclusion: Antimicrobial stewardship in SOT centers in Israel is performed by ID consultants and practices vary. Challenges are related to high AMR rates, insufficient evidence to support practices, lack of dedicated ASP teams, and lack of outcome measurement. There is an urgent need to establish a national collaborative program including all SOT centers. [ABSTRACT FROM AUTHOR]

Objective: To identify risk factors for functional decline after hospitalization for Gram-negative bacteremia. Patients and methods: A prospective cohort study based on a randomized controlled trial conducted between January 1, 2013 and August 31, 2017 in Israel and Italy. Hospitalized patients with Gram-negative bacteremia who survived until day 90 and were not bedridden at baseline were included. The primary end point was functional decline at 90 days. Results: Five hundred and nine patients were included. The median age of the cohort was 71 years (interquartile range [IQR], 60–80 years), 46.4% (236/509) were male and 352 of 509 (69%) patients were independent at baseline. Functional decline at 90 days occurred in 24.4% of patients (124/509). In multivariable analysis; older age (odds ratio [OR], 1.03; for an one-year increment, 95% confidence interval [CI] 1.01–1.05), functional dependence in instrumental activities of daily living at baseline (OR, 4.64; 95% CI 2.5–8.6), low Norton score (OR, 0.87; 95% CI 0.79–0.96) and underlying comorbidities: cancer (OR, 2.01; 95% CI 1.14–3.55) and chronic pulmonary disease (OR, 2.23 95% CI 1.12–4.42) and longer length of hospital stay (OR 1.09; for one-day increment, 95% CI 1.04–1.15) were associated with functional decline. Appropriate empirical antibiotic treatment was associated with lower rates of functional decline within 90 days (OR, 0.4; 95% CI 0.21–0.78). Conclusions: Patients surviving bloodstream infections have poor long term trajectories after clinical recovery and hospital discharge. This has vast implications for patients, their family members and health policy makers. [ABSTRACT FROM AUTHOR]

Few studies have addressed external validity of randomized controlled trials in infectious diseases. We aimed to assess the external validity of an investigator-initiated trial on treatment for uncomplicated urinary tract infection. In the original study, women (n = 513) with urinary tract infection were randomized to nitrofurantoin or fosfomycin treatment in three countries between 2013 and 2017. In the present study we compared women who were screened for enrolment but excluded to women who participated in the trial, both groups in Israel. The primary outcome was the rate of emergency department index visits resulting in hospitalization within 28 days. We compared 127 included to 110 excluded patients. The most common reasons for exclusion were logistic difficulties in recruitment and antibiotic use in the preceding month. Included patients tended to be older [39 (IQR 29–59) vs. 35.5 (IQR 24–56.25 years)], more likely to have history of recurrent infection and had more urinary symptoms. Among excluded patients, 13.6% (15/110) had initial visits resulting in hospitalization compared to 3.1% (4/127) of included participants (p =.003). The rate of emergency department visits within 28 days was similar in both groups. Clinical and microbiological failures were significantly more common in included patients [26% (33/127) vs. 1.8% (2/110), p <.001; 7.9% (10/127) vs. 0% (0/110), p =.003; respectively]. While differences were observed between included and excluded patients, the excluded group did not represent a more 'complicated' population. The present study shows the importance of collecting data on patients excluded from randomized controlled trials. [ABSTRACT FROM AUTHOR]

Background: Population external validity is the extent to which an experimental study results can be generalized from a specific sample to a defined population. In order to apply the results of a study, we should be able to assess its population external validity. We performed an investigator-initiated randomized controlled trial (RCT) (AIDA study), which compared colistin-meropenem combination therapy to colistin monotherapy in the treatment of patients infected with carbapenem-resistant Gram-negative bacteria. In order to examine the study's population external validity and to substantiate the use of AIDA study results in clinical practice, we performed a concomitant observational trial.Methods: The study was conducted between October 1st, 2013 and January 31st, 2017 (during the RCTs recruitment period) in Greece, Israel and Italy. Patients included in the observational arm of the study have fulfilled clinical and microbiological inclusion criteria but were excluded from the RCT due to receipt of colistin for > 96 h, refusal to participate, or prior inclusion in the RCT. Non-randomized cases were compared to randomized patients. The primary outcome was clinical failure at 14 days of infection onset.Results: Analysis included 701 patients. Patients were infected mainly with Acinetobacter baumannii [78.2% (548/701)]. The most common reason for exclusion was refusal to participate [62% (183/295)]. Non-randomized and randomized patients were similar in most of the demographic and background parameters, though randomized patients showed minor differences towards a more severe infection. Combination therapy was less common in non-randomized patients [31.9% (53/166) vs. 51.2% (208/406), p = 0.000]. Randomized patients received longer treatment of colistin [13 days (IQR 10-16) vs. 8.5 days (IQR 0-15), p = 0.000]. Univariate analysis showed that non-randomized patients were more inclined to clinical failure on day 14 from infection onset [82% (242/295) vs. 75.5% (307/406), p = 0.042]. After adjusting for other variables, non-inclusion was not an independent risk factor for clinical failure at day 14.Conclusion: The similarity between the observational arm and RCT patients has strengthened our confidence in the population external validity of the AIDA trial. Adding an observational arm to intervention studies can help increase the population external validity and improve implementation of study results in clinical practice.Trial Registration: The trial was registered with ClinicalTrials.gov, number NCT01732250 on November 22, 2012. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background Gram-negative bacteremia is a major cause of morbidity and mortality in hospitalized patients. Data to guide the duration of antibiotic therapy are limited. Methods This was a randomized, multicenter, open-label, noninferiority trial. Inpatients with gram-negative bacteremia, who were afebrile and hemodynamically stable for at least 48 hours, were randomized to receive 7 days (intervention) or 14 days (control) of covering antibiotic therapy. Patients with uncontrolled focus of infection were excluded. The primary outcome at 90 days was a composite of all-cause mortality; relapse, suppurative, or distant complications; and readmission or extended hospitalization (>14 days). The noninferiority margin was set at 10%. Results We included 604 patients (306 intervention, 298 control) between January 2013 and August 2017 in 3 centers in Israel and Italy. The source of the infection was urinary in 411 of 604 patients (68%); causative pathogens were mainly Enterobacteriaceae (543/604 [90%]). A 7-day difference in the median duration of covering antibiotics was achieved. The primary outcome occurred in 140 of 306 patients (45.8%) in the 7-day group vs 144 of 298 (48.3%) in the 14-day group (risk difference, –2.6% [95% confidence interval, –10.5% to 5.3%]). No significant differences were observed in all other outcomes and adverse events, except for a shorter time to return to baseline functional status in the short-course therapy arm. Conclusions In patients hospitalized with gram-negative bacteremia achieving clinical stability before day 7, an antibiotic course of 7 days was noninferior to 14 days. Reducing antibiotic treatment for uncomplicated gram-negative bacteremia to 7 days is an important antibiotic stewardship intervention. Clinical Trials Registration NCT01737320. [ABSTRACT FROM AUTHOR]

Background: The association between bacteriuria and adverse pregnancy outcomes has been extensively described. The current practice of screening all pregnant women for bacteriuria is challenged by recent studies. We aimed to evaluate pregnancy outcomes among women with a positive urine culture, to assess the significance of positive urinary nitrites in this setting. Methods: This was a retrospective cohort study at the emergency department (ED) of the Helen Schneider Hospital for Women, Israel, during 2014–2018. This included all gravida women >18 years old within the 20th week of pregnancy or above, admitted to the ED with diverse complains, who had urinalysis collected and subsequently had a positive urine culture. Clinical and obstetric characteristics were stratified by positive vs. negative nitrites in urinalysis. The primary outcome was premature delivery, and the secondary outcomes were a composite outcome of all recorded pregnancy complications and the significance of urinalysis in predicting urinary tract infection (UTI). Results: Overall, 874 pregnant women with a positive urine culture were included. Of them, 721 (79%) patients had a negative nitrite in their urine exam (NNU-group) and 153 (21%) had a positive nitrite in their urine exam (PNU-group). Escherichia coli was the most common pathogen, with significantly higher rates of growth in the PNU-group vs. NNU-group [129 (84.3%) vs. 227 (38.4%), P < 0.001]. Premature delivery was recorded with no association of symptomaticity or nitrite status. Among symptomatic women with classic symptoms of UTI, PNU was significantly associated with decreased risk for major peripartum complications [odds ratio (OR) with 95% confidence interval (CI) of 0.22 (0.05–0.94)]. Conclusion: Our findings support that PNU among symptomatic pregnant women with UTI-related symptoms was associated with lower risk of developing major adverse obstetrical outcomes. [ABSTRACT FROM AUTHOR]

Background. Little is known about Plasmodium malariae, a relatively rare cause of malaria in returned travelers. Recently, polymerase chain reaction (PCR) use for malaria diagnosis has enhanced specificity of P. malariae detection. The study objective was to describe the unique aspects of P. malariae diagnosis and clinical course in travelers. Methods. Malaria is a reportable disease in Israel. All PCR-proven P. malariae monoinfections in Israeli travelers between January 2008 and January 2017 were retrieved from the Ministry of Health Reference Parasitology Laboratory. Data regarding method and timing of diagnosis, clinical characteristics, and laboratory testing were collected from patient charts. Results. Eighteen patients with P. malariae were included. All cases were acquired in Africa. During the study period, the relative proportion of P. malariae increased (2%-10% of all malaria cases). Malaria was identified by blood smear in 10 of 18 patients (56%) on admission, and by rapid antigen test in 5 of 18 (29%) patients only, while P. malariae speciation was correctly identified by smear in 2 of 18 (11%) patients. Though all patients reported fever, only 4 of 18 (22%) described a quartan fever course. In 7 of 18 (39%) patients, malaria was contracted despite prophylactic treatment. Five patients had prolonged prepatent periods (median, 55 days), all of whom received prior prophylaxis. Conclusions. The relative proportion of P. malariae is on the rise. Diagnosis in routine clinical settings is inadequate due to the low sensitivity and specificity of blood smears. PCR should be considered when clinical suspicion is high. Prophylaxis failure, which caused delayed clinical presentation, was documented. [ABSTRACT FROM AUTHOR]

Background: Methicillin-resistant Staphylococcus aureus (MRSA) bacteraemia is a serious infection resulting in 20-50 % 90-day mortality. The limitations of vancomycin, the current standard therapy for MRSA, make treatment difficult. The only other approved drug for treatment of MRSA bacteraemia, daptomycin, has not been shown to be superior to vancomycin. Surprisingly, there has been consistent in-vitro and in-vivo laboratory data demonstrating synergy between vancomycin or daptomycin and an anti-staphylococcal β-lactam antibiotic. There is also growing clinical data to support such combinations, including a recent pilot randomised controlled trial (RCT) that demonstrated a trend towards a reduction in the duration of bacteraemia in patients treated with vancomycin plus flucloxacillin compared to vancomycin alone. Our aim is to determine whether the addition of an anti-staphylococcal penicillin to standard therapy results in improved clinical outcomes in MRSA bacteraemia.Methods/design: We will perform an open-label, parallel-group, randomised (1:1) controlled trial at 29 sites in Australia, New Zealand, Singapore, and Israel. Adults (aged 18 years or older) with MRSA grown from at least one blood culture and able to be randomised within 72 hours of the index blood culture collection will be eligible for inclusion. Participants will be randomised to vancomycin or daptomycin (standard therapy) given intravenously or to standard therapy plus 7 days of an anti-staphylococcal β-lactam (flucloxacillin, cloxacillin, or cefazolin). The primary endpoint will be a composite outcome at 90 days of (1) all-cause mortality, (2) persistent bacteraemia at day 5 or beyond, (3) microbiological relapse, or (4) microbiological treatment failure. The recruitment target of 440 patients is based on an expected failure rate for the primary outcome of 30 % in the control arm and the ability to detect a clinically meaningful absolute decrease of 12.5 %, with a two-sided alpha of 0.05, a power of 80 %, and assuming 10 % of patients will not be evaluable for the primary endpoint.Discussion: Key potential advantages of adding anti-staphylococcal β-lactams to standard therapy for MRSA bacteraemia include their safety profile, low cost, and wide availability.Trial Registration: ClinicalTrials.gov Identifier: NCT02365493 . Registered 24 February 2015. [ABSTRACT FROM AUTHOR]

Background: Management of partially-treated, community-acquired bacterial meningitis (PCBM) is commonly compromised by lack of microbiological diagnosis. We aimed to analyze the impact of FilmArray Meningitis-Encephalitis (FA-ME) PCR on the management of PCBM.Methods: Comparison of treatment variables of PCBM cases between two periods, before (6.5 years, control group) and after (2 years, study group) the application of FA-ME PCR assay.Results: The total duration of antimicrobial treatment in the study group (n = 8) was significantly shorter than the control group (n = 23) (9.5 ± 3.7 days vs. 15.2 ± 5 days, p = 0.007). The percentage of narrow-spectrum regimens was significantly higher in the study group (78 ± 11% vs. 40 ± 9%, p = 0.03). There was a significant difference in implementation of antimicrobial chemoprophylaxis for close contacts (4/8 (50%) vs. 1/23 (4%), p = 0.01).Conclusions: The use of FA-ME PCR provides significant benefits in the management of PCBM by shortening duration of antibiotic treatment, increasing the use of narrow-spectrum regimens, and allowing proper administration of antimicrobial chemoprophylaxis.Trial Registration: The study was approved and retrospectively registered by the Tel-Aviv Sourasky Medical Center ( 0378-17-TLV , 10/17/2017) and Rabin Medical Center ( 0270-18-RMC , 11/11/2018) Ethics committees and conforms to recognized standards. [ABSTRACT FROM AUTHOR]

To identify predictors of 30-day survival in elderly patients with coronavirus disease 2019 (COVID-19). Retrospective cohort study including patients with COVID-19 aged ≥65 years hospitalized in six European sites (January 2020 to May 2021). Data on demographics, comorbidities, clinical characteristics, and outcomes were collected. A predictive score (FLAMINCOV) was developed using logistic regression. Regression coefficients were used to calculate the score. External validation was performed in a cohort including elderly patients from a major COVID-19 centre in Israel. Discrimination was evaluated using the area under the receiver operating characteristic curve (AUC) in the derivation and validation cohorts. Survival risk groups based on the score were derived and applied to the validation cohort. Among 3010 patients included in the derivation cohort, 30-day survival was 74.5% (2242/3010). The intensive care unit admission rate was 7.6% (228/3010). The model predicting survival included independent functional status (OR, 4.87; 95% CI, 3.93–6.03), a oxygen saturation to fraction of inspired oxygen (SpO 2 /FiO 2) ratio of >235 (OR, 3.75; 95% CI, 3.04–4.63), a C-reactive protein level of <14 mg/dL (OR, 2.41; 95% CI, 1.91–3.04), a creatinine level of <1.3 (OR, 2.02; 95% CI, 1.62–2.52) mg/dL, and absence of fever (OR, 1.34; 95% CI, 1.09–1.66). The score was validated in 1174 patients. The FLAMINCOV score ranges from 0 to 15 and showed good discrimination in the derivation (AUC, 0.79; 95% CI, 0.77–0.81; p < 0.001) and validation cohorts (AUC, 0.79; 95% CI, 0.76–0.81; p < 0.001). Thirty-day survival ranged from 39.4% (203/515) to 95.3% (634/665) across four risk groups according to score quartiles in the derivation cohort. Similar proportions were observed in the validation set. The FLAMINCOV score identifying elderly with higher or lower chances of survival may allow better triage and management, including intensive care unit admission/exclusion. [ABSTRACT FROM AUTHOR]

Objective: Carbapenems are considered treatment of choice for bacteremia caused by potential AmpC-producing bacteria, including Enterobacter spp. We aimed to compare mortality following carbapenem vs. alternative antibiotics for the treatment of Enterobacter spp. bacteremia. Patients and Methods: We conducted a retrospective study in two centers in Israel. We included hospitalized patients with Enterobacter bacteremia treated with third-generation cephalosporins (3GC), piperacillin/tazobactam, quinolones, or carbapenem monotherapy as the main antibiotic in the first week of treatment, between 2010 and 2017. Cefepime was excluded due to nonavailability during study years. The primary outcome was 30-day all-cause mortality. Univariate and multivariate analyses were conducted, introducing the main antibiotic as an independent variable. Results: Two hundred seventy-seven consecutive patients were included in the analyses. Of these, 73 were treated with 3GC, 39 with piperacillin/tazobactam, 104 with quinolones, and 61 with carbapenems. All-cause 30-day mortality was 16% (45 patients). The type of antibiotics was not significantly associated with mortality on univariate or multivariate analyses. With carbapenems as reference, adjusted odds ratios (ORs) for mortality were 0.708, 95% confidence interval (CI) 0.231–2.176 with 3GC; OR 1.172, 95% CI 0.388–3.537 with piperacillin/tazobactam; and OR 0.586, 95% CI 0.229–1.4 with quinolones. The main antibiotic was not associated with repeated growth of Entrobacter spp. in blood cultures or other clinical specimens. Resistance development was observed with 3GC and piperacillin/tazobactam. Conclusions: Carbapenem treatment was not advantageous to alternative antibiotics, including 3GC, among patients with Enterobacter spp. bacteremia in an observational study. [ABSTRACT FROM AUTHOR]

Background: Colistin-carbapenem combinations are synergistic in vitro against carbapenem-resistant Gram-negative bacteria. We aimed to test whether combination therapy improves clinical outcomes for adults with infections caused by carbapenem-resistant or carbapenemase-producing Gram-negative bacteria.Methods: A randomised controlled superiority trial was done in six hospitals in Israel, Greece, and Italy. We included adults with bacteraemia, ventilator-associated pneumonia, hospital-acquired pneumonia, or urosepsis caused by carbapenem-non-susceptible Gram-negative bacteria. Patients were randomly assigned (1:1) centrally, by computer-generated permuted blocks stratified by centre, to intravenous colistin (9-million unit loading dose, followed by 4·5 million units twice per day) or colistin with meropenem (2-g prolonged infusion three times per day). The trial was open-label, with blinded outcome assessment. Treatment success was defined as survival, haemodynamic stability, improved or stable Sequential Organ Failure Assessment score, stable or improved ratio of partial pressure of arterial oxygen to fraction of expired oxygen for patients with pneumonia, and microbiological cure for patients with bacteraemia. The primary outcome was clinical failure, defined as not meeting all success criteria by intention-to-treat analysis, at 14 days after randomisation. This trial is registered at ClinicalTrials.gov, number NCT01732250, and is closed to accrual.Findings: Between Oct 1, 2013, and Dec 31, 2016, we randomly assigned 406 patients to the two treatment groups. Most patients had pneumonia or bacteraemia (355/406, 87%), and most infections were caused by Acinetobacter baumannii (312/406, 77%). No significant difference between colistin monotherapy (156/198, 79%) and combination therapy (152/208, 73%) was observed for clinical failure at 14 days after randomisation (risk difference -5·7%, 95% CI -13·9 to 2·4; risk ratio [RR] 0·93, 95% CI 0·83-1·03). Results were similar among patients with A baumannii infections (RR 0·97, 95% CI 0·87-1·09). Combination therapy increased the incidence of diarrhoea (56 [27%] vs 32 [16%] patients) and decreased the incidence of mild renal failure (37 [30%] of 124 vs 25 [20%] of 125 patients at risk of or with kidney injury).Interpretation: Combination therapy was not superior to monotherapy. The addition of meropenem to colistin did not improve clinical failure in severe A baumannii infections. The trial was unpowered to specifically address other bacteria.Funding: EU AIDA grant Health-F3-2011-278348. [ABSTRACT FROM AUTHOR]

Background: Surgical myotomy is the best therapeutic option for patients with achalasia. The minimally invasive technique is considered to be the preferred method for many surgeons. Robotic-assisted laparoscopic myotomy has several advantages over conventional laparoscopic surgery. These benefits include more accurate incisions that may result in a lower rate of intra-operative complications., Objectives: To describe our technique of performing robotic-assisted Heller myotomy and to review the initial results of this procedure., Methods: All patients undergoing robotic-assisted Heller myotomy for achalasia between the years 2012-2018 at Rabin Medical Center were retrospectively reviewed from our institutional prospective database., Results: Thirty patients underwent robotic-assisted Heller myotomy for achalasia. Mean operative time was 77 minutes (range 47-109 minutes) including docking time of the robotic system. There were no cases of conversion to laparoscopic or open surgery. There were no cases of intra-operative perforation of the mucosa. None of the patients had postoperative morbidity or mortality. Good postoperative results were achieved in 25 patients. Four patients required additional intervention (3 had endoscopic dilatations and 1 with known preoperative endstage achalasia had undergone esophagectomy). One patient was lost to follow-up., Conclusions: Robotic-assisted Heller myotomy is a safe technique with a low incidence of intra-operative esophageal perforation compared to the laparoscopic approach. We believe that robotic-assisted surgery should be the procedure of choice to treat achalasia.

Importance: Patients with cancer undergoing treatment are at high risk of COVID-19 following SARS-CoV-2 infection; however, their ability to produce an adequate antibody response to messenger RNA SARS-CoV-2 vaccines is unclear., Objective: To evaluate rates of antispike (anti-S) antibody response to a BNT162b2 vaccine in patients with cancer who are undergoing systemic treatment vs healthy controls., Design, Setting, and Participants: This prospective cohort study included 102 adult patients with solid tumors undergoing active intravenous anticancer treatment and 78 controls who received the second dose of the BNT162b2 vaccine at least 12 days before enrollment. The controls were taken from a convenience sample of the patients' family/caregivers who accompanied them to treatment. The study was conducted between February 22, 2021, and March 15, 2021 at Davidoff Cancer Center at Beilinson Hospital (Petah Tikva, Israel)., Interventions: Blood samples were drawn from the study participants. Serum samples were analyzed and the titers of the IgG antibodies against SARS-CoV-2 spike receptor-binding domain were determined using a commercially available immunoassay. Seropositivity was defined as 50 or greater AU/mL., Main Outcomes and Measures: The primary outcome was the rate of seropositivity. Secondary outcomes included comparisons of IgG titers and identifying factors that were associated with seropositivity using univariate/multivariable analyses., Results: The analysis included 180 participants, which comprised 102 patients with cancer (median [interquartile range (IQR)] age, 66 [56-72] years; 58 men [57%]) and 78 healthy controls (median [IQR] age, 62 [49-70] years; 25 men [32%]). The most common tumor type was gastrointestinal (29 [28%]). In the patient group, 92 (90%) were seropositive for SARS-CoV 2 antispike IgG antibodies after the second vaccine dose, whereas in the control group, all were seropositive. The median IgG titer in the patients with cancer was significantly lower than that in the controls (1931 [IQR, 509-4386] AU/mL vs 7160 [IQR, 3129-11 241] AU/mL; P < .001). In a multivariable analysis, the only variable that was significantly associated with lower IgG titers was treatment with chemotherapy plus immunotherapy (β, -3.5; 95% CI, -5.6 to -1.5)., Conclusions and Relevance: In this cohort study of patients with cancer who were receiving active systemic therapy, 90% of patients exhibited adequate antibody response to the BNT162b2 vaccine, although their antibody titers were significantly lower than those of healthy controls. Further research into the clinical relevance of lower titers and their durability is required. Nonetheless, the data support vaccinating patients with cancer as a high priority, even during therapy.

Introduction: The optimal treatment for extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae bloodstream infections has yet to be defined. Retrospective studies have shown conflicting results, with most data suggesting the non-inferiority of beta-lactam-beta-lactamase inhibitor combinations compared with carbapenems. However, the recently published MERINO trial failed to demonstrate the non-inferiority of piperacillin-tazobactam to meropenem. The potential implications of the MERINO trial are profound, as widespread adoption of carbapenem treatment will have detrimental effects on antimicrobial stewardship in areas endemic for ESBL and carbapenem-resistant bacteria. Therefore, we believe that it is justified to re-examine the comparison in a second randomised controlled trial prior to changing clinical practice., Methods and Analysis: PeterPen is a multicentre, investigator-initiated, open-label, randomised controlled non-inferiority trial, comparing piperacillin-tazobactam with meropenem for third-generation cephalosporin-resistant Escherichia coli and Klebsiella bloodstream infections. The study is currently being conducted in six centres in Israel and one in Canada with other centres from Israel, Italy and Canada expected to join. The two primary outcomes are all-cause mortality at day 30 from enrolment and treatment failure at day seven (death, fever above 38°C in the last 48 hours, continuous symptoms, increasing Sequential Organ Failure Assessment Score or persistent blood cultures with the index pathogen). A sample size of 1084 patients was calculated for the mortality endpoint assuming a 12.5% mortality rate in the control group with a 5% non-inferiority margin and assuming 100% follow-up for this outcome., Ethics and Dissemination: The study is approved by local and national ethics committees as required. Results will be published, and trial data will be made available., Trial Registration Numbers: ClinicalTrials.gov Registry (NCT03671967); Israeli Ministry of Health Trials Registry (MOH&#95;2018-12-25&#95;004857)., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The Flavobacteriaceae family includes rare pathogens in children; Chryseobacterium indologenes and Elizabethkingia meningosepticum are the most common pathogenic species, with a wide range of clinical presentations and high mortality rate. Although rare, diagnosis is important due to inherent resistance to multiple antibiotics, especially those typically prescribed for empiric treatment of aerobic Gram-negative bacterial infections., Methods: A multicenter retrospective study conducted in 5 Israeli hospitals, describing Flavobacteriaceae bacteremia confirmed by positive blood culture from 1998 to 2018., Results: Thirteen cases were included; 9 isolates were C. indologenes. Bacteremia was nosocomial or healthcare-associated in all cases. Bacteremia was associated with young age (median, 1 year, range 24 days-17 years), with only 2 (15.4%) cases in neonates, Central line-associated bloodstream infection as a source (5/13, 38%) and malignancy (7/13, 54.8%). Thirty-day all-cause mortality was 23% (3/13). Ninety-one percent of isolates were susceptible to trimethoprim-sulfamethoxazole, 82% to piperacillin-tazobactam and 92% to ciprofloxacin., Conclusions: C. indologenes and E. meningosepticum are rare, nosocomial- or healthcare-associated pediatric bacteremia pathogens. Bacteremia was associated with young age, but in contrast to the literature, the majority of our cases were older than the neonatal age period. In addition, they were associated with central line-associated bloodstream infection and malignancy. The most adequate antibiotics according to resistance patterns were ciprofloxacin, trimethoprim-sulfamethoxazole and piperacillin-tazobactam.

Aim: Most cases of Clostridium difficile infections (CDI) occur in patients aged 65 years and older. Older age is associated with increased mortality. Risk factors for mortality in patients aged 80 years and older are not well recognized., Methods: We analyzed retrospective data including 184 patients aged 80 years and older hospitalized with CDI during 2009-2014. We aimed to delineate risk factors for short- and long-term mortality., Results: The 30-day mortality was 33.2%; 1-year mortality was 64.7%. Median survival was 110 days (interquartile range 24-655 days). All four patients who underwent colectomy died. Risk factors for 30-day mortality in multivariate analysis were diabetes mellitus, low albumin and therapy other than metronidazole monotherapy, the latter probably reflecting higher severity of disease rather than a true predictor of mortality. Risk factors for long-term mortality analyzed in Cox regression were albumin ≤2.5 g/dL (HR 0.58, 95% CI 0.395-0.850), presentation with sepsis (HR 0.597, 95% CI 0.408-0.873), a non-independent activities of daily living baseline status (HR 0.460, 95% CI 0.236--0.897) and Charlson score (HR 0.867, 95% CI 0.801-0.938). None of the traditional severity indices for CDI (such as leukocytosis or creatinine increase) proved to be predictors of mortality over the age of 80 years., Conclusions: The prognosis of old patients with CDI is dismal. Considering the high mortality, efforts to prevent CDI should be first priority in patients aged 80 years and older. Assessment of albumin levels should be part of the evaluation at presentation and considered when choosing treatment, rather than standard severity indexes for CDI. Geriatr Gerontol Int 2017; 17: 1378-1383., (© 2016 Japan Geriatrics Society.)

Background: Traditional wisdom suggests that infections in older patients have atypical presentation, including blunted febrile response. Data are scarce., Design: We analyzed data from a prospectively collected database on presentation of infection in 4,308 patients, and compared the presentation of older patients (≥ 75 years) versus adults (< 75 years)., Settings: Single tertiary medical center., Participants: Patients admitted with suspected bacterial infection during 2002-2004 and 2010-2011., Measurements: We evaluated clinical presentation on day of admission, including vital signs and laboratory parameters., Results: No difference in fever values as a presenting sign of infection was found between older patients and adults (median fever 38.3°C, interquartile range [IQR] 37.4-39.0°C; and 38.4°C, IQR 37.3-39.0°C, respectively, P = 0.08). Median leukocyte count was significantly higher in older patients (median 11.60, IQR 8.30-15.72 in older patients; 10.84, 7.50-15.00 in adults, P < 0.001). Presentation with septic shock, acute renal failure, and reduced consciousness was significantly more common in older patients. These findings were also consistent in the subgroups of bacteremic patients and patients with microbiologically documented infection., Conclusion: Elevated fever and leukocytosis were found to be at least equally common in older patients compared to younger adults as part of the presentation of infection.

Objective: To show non-inferiority of trimethoprim-sulfamethoxazole compared with vancomycin for the treatment of severe infections due to meticillin resistant Staphylococcus aureus (MRSA)., Design: Parallel, open label, randomised controlled trial., Setting: Four acute care hospitals in Israel., Participants: Adults with severe infections caused by MRSA susceptible to trimethoprim-sulfamethoxazole and vancomycin. Patients with left sided endocarditis, meningitis, chronic haemodialysis, and prolonged neutropenia were excluded., Interventions: Trimethoprim-sulfamethoxazole 320 mg/1600 mg twice daily versus vancomycin 1 g twice daily for a minimum of seven days and then by indication., Main Outcome Measures: The primary efficacy outcome was treatment failure assessed at day 7, consisting of death, persistence of haemodynamic instability or fever, stable or worsening Sequential Organ Failure Assessment score, and persistence of bacteraemia. The primary safety outcome was all cause mortality at day 30. Non-inferiority was defined by a difference of less than 15% for treatment failure., Results: 252 patients were included in the trial, of whom 91 (36%) had bacteraemia. No significant difference in treatment failure was seen for trimethoprim-sulfamethoxazole (51/135, 38%) versus vancomycin (32/117, 27%)-risk ratio 1.38 (95% confidence interval 0.96 to 1.99). However, trimethoprim-sulfamethoxazole did not meet the non-inferiority criterion-absolute difference 10.4% (95% confidence interval -1.2% to 21.5%). For patients with bacteraemia, the risk ratio was 1.40 (0.91 to 2.16). In a multivariable logistic regression analysis, trimethoprim-sulfamethoxazole was significantly associated with treatment failure (adjusted odds ratio 2.00, 1.09 to 3.65). The 30 day mortality rate was 32/252 (13%), with no significant difference between arms. Among patients with bacteraemia, 14/41 (34%) treated with trimethoprim-sulfamethoxazole and 9/50 (18%) with vancomycin died (risk ratio 1.90, 0.92 to 3.93)., Conclusions: High dose trimethoprim-sulfamethoxazole did not achieve non-inferiority to vancomycin in the treatment of severe MRSA infections. The difference was particularly marked for patients with bacteraemia. Trial registration Clinical trials NCT00427076., (© Paul et al 2015.)

Objective: To determine the prevalence, characteristics, and risk factors for nosocomial infections (NIs) in children postcardiac surgery and hospitalized in a pediatric intensive care unit (PICU)., Design: Case control study., Setting: PICU of a tertiary care university-affiliated medical center., Patients and Controls: Between January 1, 1999 and December 31, 2002, 356 children underwent cardiac surgery and were admitted to the PICU (381 admissions). There were 146 episodes (91 patients) of NI according to the Centers for Disease Control and Prevention criteria. The control group (92 patients) was drawn as a random sample from admissions with no evidence of NI., Measurements and Main Results: Data retrieved from medical records included demographic information, type of operation, complexity score, extrinsic risk factors (invasive devices, postoperative complications, etc.), specific pathogens, therapeutic interventions, and outcome. There were 146 episodes of NI during 381 admissions, yielding a nosocomial infection ratio of 38.3%, and a prevalence of PICU-acquired infection of 24.4% (93 admissions with NI out of a total of 381 admissions). The most common NI sites were the bloodstream and the lower respiratory tract (65.8% and 16.4%, respectively). The main causative organisms were Coagulase negative Staphylococcus, Klebsiella pneumonia, and Candida spp. (18.8%, 16.7%, and 15%, respectively). Multivariate analysis revealed the following risk factors for NI: age < 2 months, congenital malformations, post operative complications, and open-chest procedure. The crude mortality rate for patients with NI was 23.7%, compared with 2.2% for patients without NI (p < 0.001). Predictors for mortality in patients with NI were post operative complications, open-chest procedure, sepsis, and urinary tract infection., Conclusions: Our results draw attention to the importance of NI and their influence on survival in pediatric patients undergoing cardiac surgery. Prevention and control measures may reduce these infections and subsequently reduce morbidity and mortality in this vulnerable population.

Background: Prediction of bloodstream infection at the time of sepsis onset allows one to make appropriate and economical management decisions., Methods: The TREAT computerized decision-support system uses a causal probabilistic network, which is locally calibrated, to predict cases of bacteremia. We assessed the system's performance in 2 independent cohorts that included patients with suspected sepsis. Both studies were conducted in Israel, Italy, and Germany. Data were collected prospectively and were entered into the TREAT system at the time that blood samples were obtained for culture. Discriminative power was assessed using a receiver-operating characteristics curve., Results: In the first cohort, 790 patients were included. The area under the receiver-operating characteristics curve for prediction of bacteremia using the TREAT system was 0.68 (95% confidence interval [CI], 0.63-0.73). We used TREAT's prediction values to draw thresholds defining a low-, intermediate-, and high-risk groups for bacteremia, in which 3 (2.4%) of 123, 62 (12.8%) of 483, and 55 (29.9%) of 184 patients were bacteremic, respectively. In the second cohort, 1724 patients were included. The area under the receiver-operating characteristics curve was 0.70 (95% CI, 0.67-0.73). The prevalence of bacteremia observed in the low-, intermediate-, and high-risk groups defined by the first cohort were 1.3% (4 of 300 patients), 13.2% (150 of 1139 patients), and 28.1% (80 of 285 patients), respectively. The low-risk groups in the 2 cohorts comprised 15%-17% of all patients. Performance was stable in the 3 sites., Conclusions: Using variables available at the time that blood cultures were performed, the TREAT system successfully stratified patients on the basis of the risk for bacteremia. The system's predictions were stable in 3 locations. The TREAT system can define a low-risk group of inpatients with suspected sepsis for whom blood cultures may not be needed.