Carbapenem-resistant Acinetobacter baumannii (CRAB) is an important threat to hospitalized patients. The virulence of A. baumannii varies between strains and geographic locations, which is believed to be related to its genetic plasticity. A comprehensive evaluation of virulence factor (VF) content of CRAB across genetically related clones is lacking. Therefore, we aimed to determine the evolution of VFs among 246 CRAB isolates belonging to major STs, ST2 and ST3. We used WGS to assess 136 VFs and found that 110 VFs were present in most isolates (49 VFs were universally present, 61 were ubiquitous) and 25 occurred sporadically. The distribution of the 25 sporadic VF genes was homogenous in ST3 but heterogeneous in ST2. Within ST2, we found high intra-clade homogeneity and high inter-clade heterogeneity of VFs. The homogeneity of VF content in ST2 clades and its uniformity in ST3 suggest a distant evolutionary segregation of VFs at the root of ST/clade divergence. VF content reflects remote events resulting in minimal variation between isolates belonging to the same ST/clade. Thus, the alleged differences in virulence of CRAB strains between geographical locations reflect differences in clonal distribution.

OBJECTIVES:People living with HIV (PLHIV) who are coinfected with tuberculosis are at risk for negative health outcomes. This study describes the tuberculosis incidence in Israel and identifies high-risk groups. METHODS:This 42-year study includes all tuberculosis cases reported in Israel after HIV diagnosis. Fine-Gray models were adjusted to three timeframes, according to the availability of antiretroviral treatment (ART): 1981-1996 (pre-ART), 1997-2016 (ART), 2017-2023 (immediate ART upon detection). RESULTS:Of all 12,004 PLHIV, 413 (3.4%) developed tuberculosis: 132 (7.4%) between 1981 and 1996; 263 (3.6%) between 1997 and 2016; and 18 (0.6%) between 2017 and 2023, P <0.001. Non-Israeli-born citizen PLHIV were at higher risk for developing tuberculosis than Israeli-born citizens (0.5 vs 0.05 per 100 person-years, respectively; P <0.001). Risk factors for developing tuberculosis among 6933 Israeli PLHIV included being heterosexual, originating from endemic countries (hazard ratio [HR] 17.8, 95% confidence interval [CI]: 9.7-32.6, P <0.01), intravenous drug users (HR = 12.9, 95% CI: 6.8-24.5, P <0.01), and being diagnosed with HIV in 1981-1996 and 1997-2016 (HR = 5.6, 95% CI: 2.3-13.9, P <0.01 and HR = 2.5, 95% CI: 1.0-6.0, P = 0.05, respectively). CONCLUSIONS:Tuberculosis incidence among PLHIV was highest among migrants from endemic countries and intravenous drug users. Tuberculosis incidence declined after the introduction of ART and was further reduced when ART was provided immediately upon detection.

Previous studies analyzing differences in mortality associated with carbapenemase type in patients with a variety of infections caused by carbapenemase-producing Enterobacterales (CPE) have produced conflicting results. We performed a multinational multicenter retrospective cohort study. Adult patients with blood-stream infections (BSI) caused by CPE between 2015 and 2020 were included. The primary outcome was 14-day mortality; 28-day mortality and microbiological failure were secondary outcomes. Clinical and microbiological data were collected and analyzed using conditional logistic regression. A total of 360 patients were identified of whom 226 had infections caused by KPC-producing isolates, 109 by NDM-producing isolates and 25 by other carbapenemases. Definitive therapy was colistin-based in 35.1

Recruitment of patients with critical priority antimicrobial-resistant (AMR) bacteria into drug approval randomized controlled trials (RCTs) has not been successful to date. Approaching from the viewpoint of clinician-investigators and learning from the experience of AMR-focused investigator-initiated trials, we present suggestions to improve feasibility and efficiency of RCTs evaluating patients with severe infections caused by carbapenem-resistant Gram-negative or other AMR bacteria. Considerations address the trials' eligibility criteria, whether the focus of the trial is pathogen- or syndrome-targeted, trials' case report forms and monitoring, informed consent strategies for the recruitment of extremely ill patients, team dedication and incentives to run the trial and alternative trial designs. Evidence on the effects of new drugs against the AMR that these drugs target is weak and needs to be improved through better industry-academic collaboration, taking advantage of the different strengths of industry-led and investigator-initiated research.

Colistin heteroresistance (HR) refers to a bacterial population comprised of several subpopulations with different levels of resistance to colistin. In this study, we discuss the classic form of HR, in which a resistant subpopulation exists within a predominantly susceptible population. We investigated the prevalence of colistin HR and its evolution into full resistance among 173 clinical carbapenem-resistant Acinetobacter baumannii isolates and examined the effect of HR on clinical outcomes. To determine HR, we performed population analysis profiling. Our results showed a high prevalence of HR (67.1%). To examine evolution of HR strains into full resistance, the HR strains were grown in colistin-containing broth, transferred onto colistin-containing plates, and colonies on these plates were transferred into colistin-free broth. Many of the HR strains (80.2%) evolved into full resistance, 17.2% reverted to HR, and 2.6% were borderline. We used logistic regression to compare 14-day clinical failure and 14-day mortality between patients infected by HR versus susceptible non-HR carbapenem-resistant A. baumannii. In the subgroup of patients with bacteremia, HR was significantly associated with 14-day mortality. IMPORTANCE To our knowledge, this is the first large-scale study to report on HR in Gram-negative bacteria. We described the prevalence of colistin HR in a large sample of carbapenem-resistant A. baumannii isolates, the evolution of many colistin HR isolates to a resistant phenotype following colistin exposure and withdrawal, and the clinical consequences of colistin HR. We found a high prevalence of HR among clinical carbapenem-resistant A. baumannii isolates; most evolved into a resistant phenotype following colistin exposure and withdrawal. In patients treated with colistin, evolution of HR A. baumannii into full resistance could lead to higher rates of treatment failure and contribute to the reservoir of colistin-resistant pathogens in health care settings.

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.

There is no consensus regarding optimal duration of antibiotic therapy for Pseudomonas aeruginosa bacteremia. We aimed to evaluate the impact of short antibiotic course. We present a retrospective multicenter study including patients with P. aeruginosa bacteremia during 2009–2015. We evaluated outcomes of patients treated with short (6–10 days) versus long (11–15 days) antibiotic courses. The primary outcome was a composite of 30-day mortality or bacteremia recurrence and/or persistence. Univariate and inverse probability treatment-weighted (IPTW) adjusted multivariate analysis for the primary outcome was performed. To avoid immortal time bias, the landmark method was used. We included 657 patients; 273 received a short antibiotic course and 384 a long course. There was no significant difference in baseline characteristics of patients. The composite primary outcome occurred in 61/384 patients in the long-treatment group (16%) versus 32/273 in the short-treatment group (12%) (p = 0.131). Mortality accounted for 41/384 (11%) versus 25/273 (9%) of cases, respectively. Length of hospital stay was significantly shorter in the short group [median 13 days, interquartile range (IQR) 9–21 days, versus median 15 days, IQR 11–26 days, p = 0.002]. Ten patients in the long group discontinued antibiotic therapy owing to adverse events, compared with none in the short group. On univariate and multivariate analyses, duration of therapy was not associated with the primary outcome. In this retrospective study, 6–10 days of antibiotic course for P. aeruginosa bacteremia were as effective as longer courses in terms of survival and recurrence. Shorter therapy was associated with reduced length of stay and less drug discontinuation.

Background: To describe the use of wall painting as part of an intervention to control an outbreak of carbapenemresistant Acinetobacter baumannii (CRAB). Methods: An interrupted time-series analysis was performed analyzing an intervention in a neurosurgical intensive care unit (NSICU) and an inpatient hematology department in a tertiary level medical center in Israel. The intervention involved wall painting using a water based acrylic paint following patient discharge and terminal cleaning with sodium troclosene as part of an infection control bundle for an outbreak of CRAB in a NSICU and concurrent outbreaks of carbapenem-resistant Enterobacteriaceae (CRE) colonization/infection in the same NSICU and the hematology department. Results: Between January 2013 and December 2018, 122 patients hospitalized in the NSICU were identified with new CRAB colonization/infection. The median incidence in the periods prior to/post intervention were 2.24/ 1000 HD (interquartile range [IQR] 0.84-2.90/1000) vs. 0/1000 HD (IQR 0-0.49/1000), respectively. Poisson regression indicated a decrease of 92% in the CRAB incidence following the intervention onset (relative risk [RR] 0.080, 95% confidence interval [CI] 0.037-0.174, p < 0.001). Forty-seven patients in the NSICU and 110 in the hematology department were colonized/infected with CRE in the same time period; a significant change was not observed following the start of the intervention in either department (for NSICU RR 1.236, 95% CI 0.370-4.125, p = 0.731; for hematology RR 0.658, 95% CI 0.314-1.378, p = 0.267). Conclusions: A. baumannii is able to survive on environmental surfaces despite decontamination efforts; wallpainting as part of a bundle may be a successful infection control measure.

Background: Antimicrobial susceptibility testing (AST) is the standard of care for treating bacterial in-fections. In randomized clinical trials of new antimicrobials, AST might not be performed or reported in real time. Objectives: To determine local, real-time laboratory AST performance, its usage in the trial flow, quality control (QC) of the local testing, central AST performance and the effect of using AST categorization on the trials' primary outcomes. Data sources: We systematically searched PubMed, Embase, PsychINFO and Web of Science. Eligibility criteria: We included registered randomized controlled trials published in journals between January 2015 and December 2019. Participants and interventions: We included trials comparing different antibiotics for the treatment of infections caused predominantly by Gram-negative bacteria. Methods: Primary outcomes for different trial populations were extracted and differences between trial arms were compared for patients with infections caused by susceptible versus non-susceptible bacteria. Results are described narratively. Results: Of 32 randomized trials, 25 trials reported that local AST was performed, 1312 reported the local laboratory AST methods, no trial reported QC, but post-hoc referral for AST at a reference laboratory was common. Patients' outcomes were superior when patients with infections due to susceptible and non -susceptible pathogens were compared post hoc (median difference 14%, interquartile range 8%-24%) in trials allowing this comparison (seven antimicrobials), except for colistin, where 14-day mortality was 9% higher when patients were treated with colistin for colistin-susceptible versus colistin-resistant carbapenem-resistant Acinetobacter baumannii. When excluding patients with pathogens that were non-susceptible to either antimicrobial in the trials, the difference in the primary outcome between the trial arms was reduced in five out of six trials. Conclusions: Trials should perform AST to guide patient inclusion or exclusion from the study and consider the impact of the central laboratory susceptibility results on the study outcomes when using post-hoc reference testing. Andrew Henderson, Clin Microbiol Infect 2021;27:1746 (c) 2021 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

BACKGROUND:Pseudomonas aeruginosa bacteraemia is a common and serious infection. No consensus exists regarding whether definitive combination therapy is superior to monotherapy. We aimed to evaluate the impact of combination therapy on mortality.METHODS:This was a multicentre retrospective study (nine countries, 25 centres), including 1277 patients with P. aeruginosa bacteraemia during 2009-15. We evaluated the association between β-lactam plus aminoglycoside or quinolone combination therapy versus β-lactam monotherapy and mortality. The primary outcome was 30 day all-cause mortality. Univariate and multivariate Cox regression analyses were conducted, introducing combination as a time-dependent variable. Propensity score was conducted to adjust for confounding for choosing combination therapy over monotherapy.RESULTS:Of 1119 patients included, 843 received definitive monotherapy and 276 received combination therapy (59% aminoglycoside and 41% quinolone). Mortality at 30 days was 16.9% (189/1119) and was similar between combination (45/276; 16.3%) and monotherapy (144/843; 17.1%) groups (P = 0.765). In multivariate Cox regression, combination therapy was not associated with reduced mortality (HR 0.98, 95% CI 0.64-1.53). No advantage in terms of clinical failure, microbiological failure or recurrent/persistent bacteraemia was demonstrated using combination therapy. Likewise, adverse events and resistance development were similar for the two regimens.CONCLUSIONS:In this retrospective cohort, no mortality advantage was demonstrated using combination therapy over monotherapy for P. aeruginosa bacteraemia. Combination therapy did not improve clinical or microbiological failure rates, nor affect adverse events or resistance development. Our finding of no benefit with combination therapy needs confirmation in well-designed randomized controlled trials.

OBJECTIVES:The Israeli national policy for containing carbapenemase-producing Enterobacterales (CPE) includes a protocol allowing for discontinuation of carrier status following spontaneous decolonization. We examined the strategy's effectiveness based on carbapenemase type. METHODS:We performed a retrospective cohort study comparing individuals colonized with KPC- or NDM-producing Enterobacterales who underwent the process of isolation discontinuation. The primary outcome was reversion of carrier status, i.e. re-identification of the same CPE species following isolation discontinuation. We used survival analysis to estimate overall hazard ratio and performed competing-risks analysis using a Fine-Gray subdistribution hazard model and cause-specific hazard ratios. RESULTS:Between 1 January 2006 and 1 January 2019 we identified 1694 individuals who met inclusion criteria, including 1337 (78.9%) carriers of KPC-producing Enterobacterales, 305 (18.0%) carriers of NDM-producing Enterobacterales and 52 (3.1%) carriers of dual KPC-/NDM-producing Enterobacterales. A total of 134 individuals (7.9%) had reversion of carrier status: 9.1% (121/1337) and 4.3% (13/305) of individuals with KPC- and NDM-producing Enterobacterales, respectively. The subdistribution hazard ratio of status reversion was not increased among carriers of NDM producers compared with KPC producers (0.567, 95% CI 0.320-1.000], p 0.052). Cause-specific hazard ratios yielded similar results (0.522, 95% CI 0.291-0.937, p 0.029. CONCLUSIONS:Carriage of NDM-producing Enterobacterales was not associated with higher rates of reversion to carrier status following spontaneous decolonization than was carriage of KPC-producing Enterobacterales.

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.

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.

Background The spread of antimicrobial resistance (AMR) is of worldwide concern. Public health policymakers and pharmaceutical companies pursuing antibiotic development require accurate predictions about the future spread of AMR. Aim We aimed to identify and model temporal and geographical patterns of AMR spread and to predict future trends based on a slow, intermediate or rapid rise in resistance. Methods We obtained data from five antibiotic resistance surveillance projects spanning the years 1997 to 2015. We aggregated the isolate-level or country-level data by country and year to produce country–bacterium–antibiotic class triads. We fitted both linear and sigmoid models to these triads and chose the one with the better fit. For triads that conformed to a sigmoid model, we classified AMR progression into one of three characterising paces: slow, intermediate or fast, based on the sigmoid slope. Within each pace category, average sigmoid models were calculated and validated. Results We constructed a database with 51,670 country–year–bacterium–antibiotic observations, grouped into 7,440 country–bacterium–antibiotic triads. A total of 1,037 triads (14%) met the inclusion criteria. Of these, 326 (31.4%) followed a sigmoid (logistic) pattern over time. Among 107 triads for which both sigmoid and linear models could be fit, the sigmoid model was a better fit in 84%. The sigmoid model deviated from observed data by a median of 6.5%; the degree of deviation was related to the pace of spread. Conclusion We present a novel method of describing and predicting the spread of antibiotic-resistant organisms.

BACKGROUND:We evaluated whether carbapenem-colistin combination therapy reduces the emergence of colistin resistance, compared to colistin monotherapy, when given to patients with infections due to carbapenem-resistant Gram-negative organisms.METHODS:This is a pre-planned analysis of a secondary outcome from a randomized, controlled trial comparing colistin monotherapy with colistin-meropenem combination for the treatment of severe infections caused by carbapenem-resistant, colistin-susceptible Gram-negative bacteria. We evaluated rectal swabs taken on Day 7 or later for the presence of new colistin-resistant (ColR) isolates. We evaluated the emergence of any ColR isolate and the emergence of ColR Enterobacteriaceae (ColR-E).RESULTS:Data were available for 214 patients for the primary analysis; emergent ColR organisms were detected in 22 (10.3%). No difference was observed between patients randomized to treatment with colistin monotherapy (10/106, 9.4%) versus patients randomized to colistin-meropenem combination therapy (12/108, 11.1%; P = .669). ColR-E organisms were detected in 18/249 (7.2%) patients available for analysis. No difference was observed between the 2 treatment arms (colistin monotherapy 6/128 [4.7%] vs combination therapy 12/121 [9.9%]; P = .111). Enterobacteriaceae, as the index isolate, was found to be associated with development of ColR-E (hazard ratio, 3.875; 95% confidence interval, 1.475-10.184; P = .006).CONCLUSIONS:Carbapenem-colistin combination therapy did not reduce the incidence of colistin resistance emergence in patients with infections due to carbapenem-resistant organisms. Further studies are necessary to elucidate the development of colistin resistance and methods for its prevention.

Background. The optimal antibiotic regimen for Pseudomonas aeruginosa bacteremia is controversial. Although beta-lactam monotherapy is common, data to guide the choice between antibiotics are scarce. We aimed to compare ceftazidime, carbapenems, and piperacillin-tazobactam as definitive monotherapy. Methods. A multinational retrospective study (9 countries, 25 centers) including 767 hospitalized patients with P. aeruginosa bacteremia treated with beta-lactam monotherapy during 2009-2015. The primary outcome was 30-day all-cause mortality. Univariate and multivariate, including propensity-adjusted, analyses were conducted introducing monotherapy type as an independent variable. Results. Thirty-day mortality was 37/213 (17.4%), 42/210 (20%), and 55/344 (16%) in the ceftazidime, carbapenem, and piperacillin-tazobactam groups, respectively. Type of monotherapy was not significantly associated with mortality in either univariate, multivariate, or propensity-adjusted analyses (odds ratio [OR], 1.14; 95% confidence interval [CI], 0.52-2.46, for ceftazidime; OR, 1.3; 95% CI, 0.67-2.51, for piperacillin-tazobactam, with carbapenems as reference in propensity adjusted multivariate analysis; 542 patients). No significant difference between antibiotics was demonstrated for clinical failure, microbiological failure, or adverse events. Isolation of P. aeruginosa with new resistance to antipseudomonal drugs was significantly more frequent with carbapenems (36/206 [17.5%]) versus ceftazidime (25/201 [12.4%]) and piperacillin-tazobactam (28/332 [8.4%] (P=.007). Conclusions. No significant difference in mortality, clinical, and microbiological outcomes or adverse events was demonstrated between ceftazidime, carbapenems, and piperacillin-tazobactam as definitive treatment of P. aeruginosa bacteremia. Higher rates of resistant P. aeruginosa after patients were treated with carbapenems, along with the general preference for carbapenem-sparing regimens, suggests using ceftazidime or piperacillin-tazobactam for treating susceptible infection.

Pregnant travellers and their offspring are vulnerable to severe outcomes following a wide range of infections. Vaccine-preventable diseases can have a particularly severe course in pregnant women, but little is known about the safety of travel vaccines in pregnant women. We performed a systematic review of all published literature concerning the safety of vaccines frequently given to travellers such as yellow fever, MMR (mumps, measles and rubella), influenza, Tdap (tetanus, diphtheria and pertussis), meningococcus, hepatitis A and B, rabies, polio, typhoid fever, tick-borne encephalitis and Japanese encephalitis vaccines. We included case series, cohort studies and randomized controlled trials (RCTs). For the meta-analysis, we included only RCTs that compared the administration of a vaccine to placebo or to no vaccine. Outcome measures included severe systemic adverse events, maternal outcomes related to the course of pregnancy, neonatal outcomes and local adverse events. We calculated the risk ratio and its 95% confidence interval as the summary measure. The safety of influenza vaccine is supported by high-quality evidence. For Tdap vaccine, no evidence of any harm was found in the meta-analysis of RCTs. A slight increase in chorioamnionitis rate was reported in 3 out of 12 observational studies. However, this small possible risk is far outweighed by a much larger benefit in terms of infant morbidity and mortality. Meningococcal vaccines are probably safe during pregnancy, as supported by RCTs comparing meningococcal vaccines to other vaccines. Data from observational studies support the safety of hepatitis A, hepatitis B and rabies vaccines, as well as that of the live attenuated yellow fever vaccine. We found little or no data about the safety of polio, typhoid, Japanese encephalitis, tick-borne encephalitis and MMR vaccines during pregnancy.

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.