Integration of individual preclinical and clinical anti-infective PKPD data to predict clinical study outcomes.

The AIDA randomized clinical trial found no significant difference in clinical failure or survival between colistin monotherapy and colistin-meropenem combination therapy in carbapenem-resistant Gram-negative infections. The aim of this reverse translational study was to integrate all individual preclinical and clinical pharmacokinetic-pharmacodynamic (PKPD) data from the AIDA trial in a pharmacometric framework to explore whether individualized predictions of bacterial burden were associated with the trial outcomes. The compiled dataset included for each of the 207 patients was (i) information on the infecting Acinetobacter baumannii isolate (minimum inhibitory concentration, checkerboard assay data, and fitness in a murine model), (ii) colistin plasma concentrations and colistin and meropenem dosing history, and (iii) disease scores and demographics. The individual information was integrated into PKPD models, and the predicted change in bacterial count at 24 h for each patient, as well as patient characteristics, was correlated with clinical outcomes using logistic regression. The in vivo fitness was the most important factor for change in bacterial count. A model-predicted growth at 24 h of ≥2-log10 (164/207) correlated positively with clinical failure (adjusted odds ratio, aOR = 2.01). The aOR for one unit increase of other significant predictors were 1.24 for SOFA score, 1.19 for Charlson comorbidity index, and 1.01 for age. This study exemplifies how preclinical and clinical anti-infective PKPD data can be integrated through pharmacodynamic modeling and identify patient- and pathogen-specific factors related to clinical outcomes - an approach that may improve understanding of study outcomes.

Medical cannabis and its effect on oncological outcomes in patients with ovarian cancer treated with PARP inhibitors.

BACKGROUND: Poly (ADP-ribose) polymerase inhibitors (PARPi) play a pivotal role in ovarian cancer management. With medical cannabis emerging as a novel component of supportive care, this study investigated the impact of medical cannabis use on oncological outcomes in patients with ovarian cancer undergoing PARPi therapy. METHODS: The study included patients from a single institution database treated for ovarian cancer between January 2014 and January 2020 who received PARPi maintenance therapy in a first-line or recurrent disease setting after a confirmed response to platinum-based treatment. The study categorized patients as cannabis users and cannabis-naïve. Univariate and multivariate Cox regression analysis and the Kaplan-Meier method were used to assess the effects of medical cannabis use on the duration of PARPi therapy, progression-free survival, and overall survival. RESULTS: Among the eligible patients (n=93), most were cannabis-naïve (69%, n=64) while the rest used medical cannabis (31%, n=29). Medical cannabis use rates were comparable for patients receiving PARPi therapy post-primary treatment or for recurrence (42%, n=9, vs 27%, n=20; p=0.1). Both groups exhibited similar median duration for PARPi therapy (12.1 vs 9.5 months; p=0.89) and progression-free survival (20 vs 21 months; p=0.83). Kaplan-Meier analysis detected no differences in progression-free survival associated with cannabis use. Although cannabis users had an extended overall survival compared with the cannabis-naïve group (129.3 vs 99 months; p=0.03), cannabis use was insignificant for overall survival on multivariate analysis (p=0.10). Multivariate analysis showed stage IV at diagnosis (p=0.02) to be the sole factor associated with progression-free survival (p=0.02). CONCLUSION: Medical cannabis usage in patients receiving PARPi treatment showed no association with duration of PARPi therapy, progression-free survival, or overall survival.

Active surveillance for carbapenem-resistant Acinetobacter baumannii (CRAB) carriage.

IMPORTANCE: Our study's results provide promising evidence for the incorporation of a high-sensitivity carbapenem-resistant Acinetobacter baumannii (CRAB) screening method in healthcare settings. Such an approach could prove beneficial in enhancing infection prevention and control measures, leading to improved patient outcomes and potentially alleviating the burden of CRAB in healthcare systems.

Utilizing Ceftazidime/Avibactam Therapeutic Drug Monitoring in the Treatment of Neurosurgical Meningitis Caused by Difficult-to-Treat Resistant Pseudomonas aeruginosa and KPC-Producing Enterobacterales.

Background: Central nervous system (CNS) infections caused by Klebsiella pneumoniae carbapenemase (KPC)-producing Enterobacterales and difficult-to-treat resistant (DTR) Pseudomonas aeruginosa represent a formidable clinical challenge. Antimicrobial regimens that efficiently penetrate the cerebrospinal fluid (CSF) and achieve sufficient concentrations associated with microbiologic and clinical cure are limited. We evaluated therapy with ceftazidime-avibactam (CAZ-AVI) in order to guide precise dosing in the treatment of CNS infections. Methods: Therapeutic drug monitoring (TDM) was performed in 3 patients with health care-associated ventriculitis and meningitis (HAVM) using CAZ-AVI 2.5 g infused intravenously every 8 hours as standard and extended infusion. Simultaneous CSF and plasma samples were obtained throughout the dosing interval in each patient. Concentrations of CAZ and AVI were determined by liquid chromatography/mass spectrometry. Results: Bacterial identification revealed KPC-producing Klebsiella pneumoniae (KPC-Kp), DTR Pseudomonas aeruginosa, and KPC-producing Enterobacter cloacae (KPC-Ent.c). All isolates were resistant to carbapenems. The minimum inhibitory concentrations (MICs) of CAZ-AVI were 0.25/4, 4/4, and 0.25/4 µg/mL, respectively. CAZ and AVI concentrations were determined in CSF samples ranging from 29.0 to 15.0 µg/mL (CAZ component) and 4.20 to 0.92 µg/mL (AVI component), respectively. AVI achieved concentrations ≥1 µg/mL in 11 out of 12 CSF samples collected throughout the dosing interval. Clinical and microbiologic cure were attained in all patients. Conclusions: Postinfusion concentrations of CAZ-AVI were measured in plasma and CSF samples obtained from 3 patients with complicated CNS infections caused by antimicrobial-resistant isolates. The measured concentrations revealed that standard CAZ and AVI exposures sufficiently attained values correlating to 50% fT > MIC, which are associated with efficient bacterial killing.

Acinetobacter baumannii Bloodstream Infections: A Nationwide Study in Israel.

Acinetobacter baumannii (Ab) bloodstream infections (BSIs) are a major public health concern and associated with high mortality. We describe the nationwide incidence, antimicrobial resistance, and mortality of Ab-BSI in Israel using laboratory-based BSI surveillance data from January 2018 to December 2019. During the study period, there were 971 Ab-BSI events (508 in 2018 and 463 in 2019), with an average annual incidence of 8.08/100,000 population. The median age of patients was 72 (IQR 62-83), and 56.4% were males. Two-thirds of Ab-BSI events were hospital-onset (HO), with median day of onset 16 (IQR 9-30). HO-BSI incidence was 0.62/10,000 patient-days (rate per 10,000 patient-days: 2.78, 1.17, and 0.2 for intensive care, medical, and surgical wards, respectively). Carbapenem susceptibility was 23.4%; 41.4% and 14.9% in community and HO events, respectively. The 14-day, 30-day, and 1-year mortality were 51.2%, 59.3%, and 81.4%, respectively. Carbapenem-resistant Ab-BSI were associated with a significantly higher 14-day, 30-day, and 1-year mortality (p < 0.001 for all). In the multivariable model, age (aHR 1.02) and carbapenem resistance (aHR 3.21) were independent predictors of 30-day mortality. In conclusion, Ab-BSIs pose a significant burden with high mortality, especially associated with antimicrobial resistance. Attention should be focused on prevention and improving treatment.

Prevalence and Clinical Consequences of Colistin Heteroresistance and Evolution into Full Resistance in Carbapenem-Resistant Acinetobacter baumannii.

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.

Hospital-acquired bacterial infections in coronavirus disease 2019 (COVID-19) patients in Israel.

BACKGROUND: We sought to determine incidence of common hospital-acquired bacteria among coronavirus disease 2019 (COVID-19) patients in Israeli general hospitals during the first year of the pandemic. METHODS: We analyzed routinely collected incidence data to determine hospital acquisition of the following sentinel bacteria: Klebsiella pneumoniae, Escherichia coli, Staphylococcus aureus, Enterococcus faecalis, Enterococcus faecium, Pseudomonas aeruginosa, Acinetobacter baumannii, and Clostridioides difficile. We examined 3 acquisition measures: (1) sentinel bacteria, (2) sentinel bacteremia, and (3) antimicrobial-resistant sentinel bacteremia. The study period was March 1, 2020, through January 31, 2021. RESULTS: Analysis of pooled data from the 26 hospitals surveyed revealed that rates were higher for all 3 acquisition measures among COVID-19 patients than they were among patients on general medical wards in 2019, but lower than those among patients in intensive care units in 2019. The incidence rate was highest during the first COVID-19 wave, despite a lower proportion of severe COVID-19 cases among total hospitalized during this wave. Wide variation in incidence was evident between hospitals. CONCLUSIONS: Hospitalized COVID-19 patients experienced nosocomial bacterial infection at rates higher than those of patients on pre-pandemic general medical wards, adding to the complexity of their care. Lower rates of nosocomial infection after the first wave, despite higher proportions of severely ill patients, suggest that healthcare worker practices, rather than patient-related factors, were responsible for most of these infections.

Effect of temperature on Escherichia coli bloodstream infection in a nationwide population-based study of incidence and resistance.

BACKGROUND: The incidence of Escherichia coli bloodstream infections (BSI) is high and increasing. We aimed to describe the effect of season and temperature on the incidence of E. coli BSI and antibiotic-resistant E. coli BSI and to determine differences by place of BSI onset. METHODS: All E. coli BSI in adult Israeli residents between January 1, 2018 and December 19, 2019 were included. We used the national database of mandatory BSI reports and outdoor temperature data. Monthly incidence and resistance were studied using multivariable negative binomial regressions with season (July-October vs. other) and temperature as covariates. RESULTS: We included 10,583 events, 9012 (85%) community onset (CO) and 1571 (15%) hospital onset (HO). For CO events, for each average monthly temperature increase of 5.5 °C, the monthly number of events increased by 6.2% (95% CI 1.6-11.1%, p = 0.008) and the monthly number of multidrug-resistant events increased by 4.9% (95% CI 0.3-9.7%, p = 0.04). The effect of season was not significant. For HO events, incidence of BSI and resistant BSI were not associated with temperature or season. CONCLUSION: Temperature increases the incidence of CO E. coli BSI and CO antibiotic-resistant E. coli BSI. Global warming threatens to increase the incidence of E. coli BSI.

Current state of antimicrobial stewardship in solid organ transplantation in Israel.

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.

One-year mortality and years of potential life lost following bloodstream infection among adults: A nation-wide population based study.

Background: Limited data exist on long-term consequences of bloodstream infections (BSIs). We aimed to examine incidence, 1-year mortality, and years of potential life lost (YPLL) following BSI. We estimated the relative contribution of hospital-onset BSI (HO-BSI) and antibiotic-resistant BSI to incidence, mortality and YPLL. Methods: We used data from Israel's national BSI surveillance system (covering eight sentinel bacteria, comprising 70% of all BSIs) and the national death registry. Adults with BSI between January 2018 and December 2019 were included. The outcomes were all-cause 30-day and 1-year mortality, with no adjustment for co-morbidities. We calculated the age-standardized mortality rate and YPLL using the Global Burden of Disease reference population and life expectancy tables. Findings: In total, 25,376 BSIs occurred over 2 years (mean adult population: 6,068,580). The annual incidence was 209·1 BSIs (95% CI 206·5-211·7) per 100,000 population. The case fatality rate was 25·6% (95% CI 25·0-26·2) at 30 days and 46·4% (95% CI 45·5-47·2) at 1 year. The hazard of death increased by 30% for each decade of age (HR=1·3 [95% CI 1·2-1·3]). The annual age-standardized mortality rate and YPLL per 100,000 were 50·8 (95% CI 49·7-51·9) and 1,012·6 (95% CI 986·9-1,038·3), respectively. HO-BSI (6,962 events) represented 27·4% (95% CI 26·9-28·0) of BSIs, 33·9% (95% CI 32·6-35·0) of deaths and 39·9% (95% CI 39·5-40·2) of YPLL. HO-BSI by drug-resistant bacteria (3,072 events) represented 12·1% (95% CI 11·7-12·5) of BSIs, 15·6% (95% CI 14·7-16·5) of deaths, and 18·4% (95% CI 18·1-18·7) of YPLL. Interpretation: One-year mortality following BSI is high. The burden of BSI is similar to that of ischemic stroke. HO-BSI and drug-resistant BSI contribute disproportionately to BSI mortality and YPLL. Funding: None.

Hospital-Onset Bloodstream Infections Caused by Eight Sentinel Bacteria: A Nationwide Study in Israel, 2018-2019.

Nationwide studies on hospital-onset bloodstream infections (HO-BSIs) are scarce. To describe incidence, mortality and antimicrobial resistance (AMR) of HO-BSI caused by eight sentinel bacteria in Israel, we used laboratory-based BSI surveillance data from 1 January 2018 to 31 December 2019. All hospitals reported positive blood cultures growing Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Acinetobacter baumannii, Streptococcus pneumoniae, Staphylococcus aureus, Enterococcus faecalis and Enterococcus faecium. We calculated HO-BSI incidence and 14-day, 30-day and 1-year mortality in adults. We performed multivariable logistic regression to identify predictors of 30-day mortality. The study included 6752 HO-BSI events: K. pneumoniae (1659, 22.1%), E. coli (1491, 19.8%), S. aureus (1315, 17.5%), P. aeruginosa (1175, 15.6%), E. faecalis (778, 10.4%), A. baumannii (654, 8.7%), E. faecium (405, 5.4%) and S. pneumoniae (43, 0.6%). Overall incidence was 2.84/1000 admissions (95% CI: 2.77-2.91) and 6.88/10,000 patient-days (95% CI: 6.72-7.05). AMR isolates accounted for 44.2% of events. Fourteen-day, thirty-day and one-year mortality were 30.6% (95% CI: 28.5%-32.8%), 40.2% (95% CI: 38.2%-42.1%) and 66.5% (95% CI: 64.7%-68.3%), respectively. Organisms with highest risk for 30-day mortality (compared with E. coli) were A. baumannii (OR 2.85; 95% CI: 2.3-3.55), E. faecium (OR 2.16; 95% CI: 1.66-2.79) and S. pneumoniae (OR 2.36; 95% CI: 1.21-4.59). Mortality was higher in AMR isolates (OR 1.57; 95% CI: 1.4-1.77). This study highlights the incidence, associated high mortality and important role of antibiotic resistance in HO-BSI.

Large-scale WGS of carbapenem-resistant Acinetobacter baumannii isolates reveals patterns of dissemination of ST clades associated with antibiotic resistance.

OBJECTIVES: To describe the population genetics and antibiotic resistance gene distribution of carbapenem-resistant Acinetobacter baumannii (CRAB) isolates causing infections in three Mediterranean countries. METHODS: Isolates were collected during the 2013-17 AIDA clinical trial in six hospitals in Israel, Greece and Italy. WGS, bioinformatic characterization and antibiotic resistance profiling were performed. RESULTS: In the 247 CRAB isolates characterized in this study, ST distribution varied by country: 29/31 (93.5%) Greek isolates, 34/41 (82.9%) Italian isolates and 70/175 (40.0%) Israeli isolates belonged to ST2. The identified ST2 isolates included eight distinct clades: 2C, 2D and 2H were significantly more common in Italy, while 2F was unique to Greece. The uncommon ST3 was not present among Greek isolates and constituted only 5/41 (12%) Italian isolates. On the other hand, it was much more common among Israeli isolates: 78/175 (44.6%) belonged to ST3. The vast majority of isolates, 240/247 (97.2%), were found to harbour acquired carbapenemases, primarily blaOXA-23. The chromosomal oxaAb (blaOXA-51-like) and ampC genes characteristic of this organism were also ubiquitous. Most (96.4%) ST3 isolates carried a broad-host-range plasmid IncP1α. CONCLUSIONS: The geographical differences in CRAB populations support the theory that clonal spread of CRAB leads to endemicity in hospitals and regions. The close association between antibiotic resistance genes and clades, and between plasmids and STs, suggest that de novo creation of MDR A. baumannii is rare. The clustering of antibiotic resistance genes and plasmids that is unique to each clade/ST, and nearly uniform within clades/STs, suggests that horizontal transmission is rare but crucial to the clade's/ST's success.

In vivo fitness of carbapenem-resistant Acinetobacter baumannii strains in murine infection is associated with treatment failure in human infections.

OBJECTIVES: Mortality among patients with carbapenem-resistant Acinetobacter baumannii (CRAB) infections varies between studies. We examined whether in vivo fitness of CRAB strains is associated with clinical outcomes in patients with CRAB infections. METHODS: Isolates were collected from patients enrolled in the AIDA trial with hospital-acquired pneumonia, bloodstream infections and/or urinary tract infections caused by CRAB. The primary outcome was 14-day clinical failure, defined as failure to meet all criteria: alive; haemodynamically stable; improved or stable Sequential Organ Failure Assessment (SOFA) score; improved or stable oxygenation; and microbiological cure of bacteraemia. The secondary outcome was 14-day mortality. We tested in vivo growth using a neutropenic murine thigh infection model. Fitness was defined based on the CFU count 24 hours after injection of an inoculum of 105 CFU. We used mixed-effects logistic regression to test the association between fitness and the two outcomes. RESULTS: The sample included 266 patients; 215 (80.8%) experienced clinical failure. CRAB fitness ranged from 5.23 to 10.08 log CFU/g. The odds of clinical failure increased by 62% for every 1-log CFU/g increase in fitness (OR 1.62, 95% CI 1.04-2.52). After adjusting for age, Charlson score, SOFA score and acquisition in the intensive care unit, fitness remained significant (adjusted OR 1.63, 95% CI 1.03-2.59). CRAB fitness had a similar effect on 14-day mortailty, although the association was not statistically significant (OR 1.56, 95% CI 0.95-2.57). It became significant after adjusting for age, Charlson score, SOFA score and recent surgery (adjusted OR 1.88, 95% CI 1.09-3.25). CONCLUSIONS: In vivo CRAB fitness was associated with clinical failure in patients with CRAB infection.

A nationwide population-based study of Escherichia coli bloodstream infections: incidence, antimicrobial resistance and mortality.

OBJECTIVES: Escherichia coli is the leading cause of bloodstream infection (BSI). The incidence of E. coli BSI caused by antibiotic-resistant strains is increasing. We aimed to describe the nationwide incidence and resistance profile of E. coli BSI in Israel and its impact on mortality, to compare E. coli BSI mortality with all-cause mortality, and community-onset with hospital-onset E. coli BSIs. METHODS: We used mandatory BSI surveillance reports submitted by all Israeli hospitals to the Ministry of Health and the national death registry. All E. coli BSIs from 1 January 2018 to 31 December 31 2019 in patients aged 18 and over were included. RESULTS: A total of 11 113 E. coli BSIs occurred in 10 218 patients; 85% (9012/10 583) were community onset. Median age was 76 (IQR 65-85), and 57% (6304/11 113) of cases occurred in women. The annual incidence was 92.5 per 100 000 population. Antibiotic resistance was frequent and significantly more common in hospital-onset than in community-onset BSI; 65% (1021/1571) vs. 45% (4049/9012) were multidrug-resistant (MDR) (p < 0.001). The case fatality rate (CFR) was higher following hospital-onset BSI than community-onset: 23% (276/1214) vs. 12% (926/7620) at 14 days, 31% (378/1214) vs. 16% (1244/7620) at 30 days, and 55% (418/766) vs. 34% (1645/4903) at 1 year (p < 0.001 for all comparisons). The 1-year CFR was 47% (1258/2707) for MDR vs. 28% (928/3281) for non-MDR (p < 0.001). The annual mortality rate was 31.0 per 100 000 population, comprising 4.2% (31.0/734.8) of all causes of deaths. DISCUSSION: E. coli BSI carries a high burden, with a large proportion of MDR isolates, which are associated with increased incidence and CFR.

New evidence for managing Gram-negative bloodstream infections.

PURPOSE OF REVIEW: Gram-negative bloodstream infections (GNBSI) are common and carry considerable mortality. Treatment is complicated by increasing antimicrobial resistance, posing a challenge for timely appropriate antibiotics and limiting the choices of effective definitive therapy. The present review aims to summarize recent studies addressing the management of GNBSI. RECENT FINDINGS: New rapid diagnostic tests (RDT) for pathogen identification and antibiotic susceptibility are associated with improved antimicrobial stewardship and reduced length of stay. No mortality benefit or patient-related outcomes are reported. Data regarding the use of new beta-lactam beta-lactamase inhibitors (BLBLIs) for treating multidrug resistance Gram-negative bacteria is supportive, though questions regarding combinations, optimal dosing, mode of administration, and resistance emergence remain to be clarified. Current data regarding cefiderocol necessitates further studies in order to support its use in GNBSI. Shortened (≤7 days) duration of therapy and early oral step down for GNBSI are supported by the literature. The role of repeated blood cultures should be further defined. SUMMARY: RDTs should be implemented to improve antibiotic stewardship. Clinical implications on patient-related outcomes should be evaluated. New BLBLIs show promise in the treatment of GNBSI. Additional data are needed regarding the use of cefiderocol. Antibiotic therapy should be shortened and early oral step down should be considered.

Sero-Prevalence and Sero-Incidence of Antibodies to SARS-CoV-2 in Health Care Workers in Israel, Prior to Mass COVID-19 Vaccination.

Objectives: This study aims to examine the prevalence and risk factors of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sero-positivity in health care workers (HCWs), a main risk group, and assess the sero-incidence of SARS-CoV-2 infection between the first and second waves of coronavirus disease 2019 (COVID-19) in Israel. Methods: A longitudinal study was conducted among 874 HCWs from nine hospitals. Demographics, health information, and blood samples were obtained at baseline (first wave-April-May 2020) and at follow-up (n = 373) (second wave-September-November 2020). Sero-positivity was determined based on the detection of total antibodies to the nucleocapsid antigen of SARS-CoV-2, using electro-chemiluminescence immunoassay (Elecsys® Anti-SARS-CoV-2, Roche Diagnostics, Rotkreuz, Switzerland). Results: The sero-prevalence of SARS-CoV-2 antibodies was 1.1% [95% confidence intervals (CI) 0.6-2.1] at baseline and 8.3% (95% CI 5.9-11.6) at follow-up. The sero-conversion of SARS-CoV-2 serum antibody was 6.9% (95% CI 4.7-9.9) during the study period. The increase in SARS-CoV-2 sero-prevalence paralleled the rise in PCR-confirmed SARS-CoV-2 infections among the HCWs across the country. The likelihood of SARS-CoV-2 sero-prevalence was higher in males vs. females [odds ratio (OR) 2.52 (95% CI 1.05-6.06)] and in nurses vs. physicians [OR 4.26 (95% CI 1.08-16.77)] and was associated with being quarantined due to exposure to COVID-19 patients [OR 3.54 (95% CI 1.58-7.89)] and having a positive PCR result [OR 109.5 (95% CI 23.88-502.12)]. Conclusions: A significant increase in the risk of SARS-CoV-2 infection was found among HCWs between the first and second waves of COVID-19 in Israel. Nonetheless, the sero-prevalence of SARS-CoV-2 antibodies remains low, similar to the general population. Our findings reinforce the rigorous infection control policy, including quarantine, and utilization of personal protective equipment that should be continued together with COVID-19 immunization in HCWs and the general population.

An outbreak of carbapenem-resistant Acinetobacter baumannii in a COVID-19 dedicated hospital.

We describe an outbreak of carbapenem-resistant Acinetobacter baumannii (CRAB) in a COVID-19 dedicated hospital. The suspected mechanism of transfer was an environmental source that persisted despite evacuation and terminal cleaning of the entire hospital, and transmitted through healthcare workers' hands or equipment. This outbreak demonstrates that practices to prevent the spread of multidrug-resistant organisms must not be neglected during the COVID-19 pandemic.

The Israeli national policy for discontinuation of isolation of carbapenem-resistant Enterobacterales carriers by carbapenemase type: a retrospective cohort study.

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.

Excluded versus included patients in a randomized controlled trial of infections caused by carbapenem-resistant Gram-negative bacteria: relevance to external validity.

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.

Surgical antibiotic prophylaxis in patients colonized with multidrug-resistant Gram-negative bacteria: practical and conceptual aspects.

Antibiotic resistance threatens the effectiveness of surgical antibiotic prophylaxis (SAP) regimens aimed at preventing surgical site infection (SSI). With a focus on procedures in which Gram-negative bacteria (GNB) are the main pathogens causing SSI, this review summarizes the evidence and describes how SAP must evolve in response to carriage of MDR GNB among surgical patients. Randomized controlled trials of SAP for carriers of resistant GNB require prohibitively large sample sizes. No professional guidelines address the topic of adapting SAP for known carriers of resistant GNB. For patients whose carrier status is unknown, the effects of different SAP strategies have been studied for transrectal ultrasound-guided prostate biopsy and colorectal surgery. The four possible strategies for SAP in the era of antibiotic resistance are: no SAP; universal standard SAP; pre-surgical screening for carriage of antibiotic-resistant pathogens before surgery and targeted SAP (i.e. broad-spectrum antibiotics only for those who screen positive); and universal broad-spectrum SAP. The prevalence of carriage determines the efficiency of each strategy. Decolonization is a potential adjunct to SAP.