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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.

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.

Advanced age is an important factor affecting Clostridioides difficile infection (CDI) risk and outcome. While fever and leukocytosis are prominent findings in young individuals with CDI, they are usually blunted in the elderly. Furthermore, chronic kidney disease often exists among this population prior to the CDI episode onset. We aimed to examine whether the accepted definition of severe CDI (leukocytosis ≥ 15,000 cells/μl or serum creatinine > 1.5 mg/dl) predicts poor outcomes in the elderly. All CDI hospitalized individuals between January-2013 and May-2020 were included. The study population was dichotomized into older group (≥ 65 years) and younger group (

AIMS: To assess the short-term immunogenicity to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccine in a population of heart transplant (HTx) recipients. A prospective single-centre cohort study of HTx recipients who received a two-dose SARS-CoV-2 mRNA vaccine (BNT162b2, Pfizer-BioNTech). METHODS AND RESULTS: Whole blood for anti-spike IgG (S-IgG) antibodies was drawn at days 21-26 and at days 35-40 after the first vaccine dose. Geometric mean titres (GMT) ≥50 AU/mL were interpreted positive. Included were 42 HTx recipients at a median age of 61 [interquartile range (IQR) 44-69] years. Median time from HTx to the first vaccine dose was 9.1 (IQR 2.6-14) years. Only 15% of HTx recipients demonstrated the presence of positive S-IgG antibody titres in response to the first vaccine dose [GMT 90 (IQR 54-229) AU/mL]. Overall, 49% of HTx recipients induced S-IgG antibodies in response to either the first or the full two-dose vaccine schedule [GMT 426 (IQR 106-884) AU/mL]. Older age [68 (IQR 59-70) years vs. 46 (IQR 34-63) years, P = 0.034] and anti-metabolite-based immunosuppression protocols (89% vs. 44%, P = 0.011) were associated with low immunogenicity. Importantly, 36% of HTx recipients who were non-responders to the first vaccine dose became S-IgG seropositive in response to the second vaccine dose. Approximately a half of HTx recipients did not generate S-IgG antibodies following SARS-CoV-2 two-dose vaccine. CONCLUSIONS: The generally achieved protection from SARS-CoV-2 mRNA vaccination should be regarded with caution in the population of HTx recipients. The possible benefit of additive vaccine should be further studied.

Complicated urinary tract infection (cUTI) is a frequent cause of morbidity. In this multinational retrospective cohort study, we aimed to demonstrate risk factors for enterococcal UTI. Univariate and multivariate analyses of risk factors for enterococcal infection were performed. Among 791 hospitalized patients with cUTI, enterococci accounted for approximately 10% of cases (78/791). Risk factors for enterococcal UTI in multivariable analysis were male gender, age range of 55-75 years, catheter-associated UTI, and urinary retention. This information may assist treating physicians in their decision-making on prescribing empiric anti-enterococcus treatment to hospitalized patients presenting with cUTI and thus improve clinical outcomes.

Background: 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.Methods: 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.Results: 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].Conclusions: 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.

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.

Pseudocirrhosis is the occurrence of capsular retraction in patients with metastatic liver disease, usually of breast origin. It usually appears in these patients following chemotherapy and may result from shrinkage of the tumor, with scarring and nodular regeneration. In this article, we describe the first case of pseudocirrhosis, following treatment of transitional cell carcinoma metastatic to the liver. Portal vein thrombosis, a rare complication in pseudocirrhosis, was also detected in this patient.

BackgroundAge/frailty are strong predictors of COVID-19 mortality. After the second BNT162b2 dose, immunity wanes faster in older (≥65 years) versus younger adults. The durability of response after the third vaccine is unclear.MethodsThis prospective cohort study included healthcare workers/family members≥60 years who received a third BNT162b2 dose. Blood samples were drawn immediately before (T0), 10□19 (T1), and 74□103 (T2) days after the third dose. Anti-spike IgG titers were determined using a commercial assay, seropositivity was defined as≥50 AU/mL. Neutralising antibody titres were determined at T2. Adverse events, COVID-19 infections, and clinical frailty scale (CFS) levels were documented.FindingsThe analysis included 97 participants (median age, 70 years [IQR, 66□74], 58% CFS level 2). IgG titres, which increased significantly from T0 to T1 (medians, 440 AU/mL [IQR, 294□923] and 25,429 [14203□36114] AU/mL, respectively; pvs T1). In a multivariable analysis, only time from the first vaccine was significantly associated with lower IgG levels at T2 (p=0·004). At T2, 60 patients were evaluated for neutralising antibodies; all were seropositive (median, 1294 antibody titre [IQR, 848□2072]). Neutralising antibody and anti-spike IgG levels were correlated (R=0·6, pInterpretationAnti-spike IgG and neutralising antibody levels remain adequate 3 months after the third BNT162b2 vaccine in healthy adults≥60 years, although the decline in IgG is concerning. A third vaccine dose in this population should be top priority.FundingNo external funding.Research in contextEvidence before this studyWe searched PubMed on Aug 1, 2021, for published research articles with no date restrictions, using the search terms of “SARS-Cov-2”, “COVID-19”, “vaccine”, “dose”, “antibody response”, and “adults” with English as a filter. Several studies were identified that investigated waning of immunity in healthy adults. It is well established through epidemiology and serology studies that in healthy adults, the protection conferred by the BNT162b2 messenger RNA (mRNA) vaccine (Pfizer/BioNtech) wanes significantly after several months. Studies have also shown that the immune response to the vaccine varies with age, and that after the second dose of the BNT162b2 vaccine, the older adult population (65-85 years of age) typically has a lower immune response (as reflected in an analysis of anti-spike IgG antibodies and neutralising antibody titres), than younger adults (18-55 years of age), and that the immunity wanes in all age groups within several months.Added value of this studyThis is, to our knowledge, the first study that examined anti-spike IgG and neutralising antibody titres three months after the third BNT162b2 vaccine dose. The study has demonstrated that three months after that dose, participants, who were healthy adults aged 60 years and older, remained anti-spike IgG seropositive, although a significant decrease in anti-spike IgG titres was observed (compared to two weeks after the third dose). In addition, a statistically significant correlation was observed between the neutralising antibody titres and the anti-spike IgG titres, and all participants were seropositive for neutralising antibodies three months after the third dose. Also, no major adverse events or COVID-19 infections were reported.Implications of all the available evidenceAs our data suggest that a third dose of the BNT162b2 vaccine is effective in maintaining adequate immune response against COVID-19 for at least several months in healthy adults aged 60 years and older, and as it is well established that older adults are at higher risk of severe COVID-19 disease and COVID-19 mortality, providing a third dose to this population should be a top priority. Our data also highlight that understanding the waning of the immune response in other age groups is key for making evidence-based policies regarding booster vaccinations for the population at large.

BackgroundCoronavirus disease 2019 was first diagnosed in Israel at the end of February 2020. By the end of June 2021, there were 842 536 confirmed cases and 6428 deaths. Our aim in this multicenter, retrospective, cohort study is to describe the demographic and clinical characteristics of hospitalized patients and compare the pandemic waves before immunization.MethodsOf 22 302 patients hospitalized in general medical centers, we randomly selected 6329 for the study. Of these, 3582 and 1106 were eligible for the study in the first period (first and second waves) and in the second period (third wave), respectively.ResultsThirty-day mortality was higher in the second period than in the first period, 25.20% vs 13.68% (P ConclusionsInvasive ventilation, use of ECMO, and mortality rate were 1.5 to 2 times higher in the second period than in the first period. In the second period, patients had a more severe presentation and higher mortality than those in the first period.

This study assesses antispike (anti-S) IgG antibody titers before and after a third BNT162b2 dose (booster) in individuals aged 60 years and older in Israel.

Purpose Immunogenicity of Covid-19 vaccines may be negatively impacted by anti-cancer treatment. The management of primary brain tumor (PBT) patients routinely includes temozolomide and steroids, which are immune-suppressive. In this study, we aimed to determine the rate of seropositivity in PBT patients following receipt of two doses of the BNT162b2 vaccine. Methods We prospectively evaluated IgG antibody levels against SARS-CoV-2 spike protein in 17 PBT patients following two doses of the BNT162b2 mRNA vaccine. IgG levels were collected at two time points: T1 - after a median of 44 days from the second vaccine dose and T2 - after a median of 130 days from the second dose. Titers were compared against a group of healthy controls (HC) comprised of patients’ family members/caregivers. Results At T1, 88.2% (15/17) of PBT patients achieved seroconversion, compared with 100% (12/12) of HCs. Median IgG titer was significantly lower in the PBT group compared to the HC group (1,908 AU/mL vs 8,198 AU/mL, respectively; p=0.002). At T2, 80% (12/15) of PBT achieved seroconversion, compared to 100% (10/10) of the HCs. Median IgG titer remained significantly lower in the PBT group (410 vs 1687; p=0.002). All three PBT patients who failed to seroconvert at T2 had been treated with corticosteroids during vaccination. In a univariate analysis, steroid use was negatively associated with antibody titer. Conclusion Most PBT patients achieve seroconversion after receiving the BNT162b2 vaccine, but with lower IgG titer compared to HCs. Steroid use during the vaccination period is associated with lower titer.

OBJECTIVES The immunogenicity of two-dose severe acute respiratory syndrome coronavirus 2 vaccine is lower among heart transplant (HTx) recipients, compared with the general population. Our aim was to assess the immunogenicity of a third-dose vaccine in HTx recipients. METHODS This is a prospective cohort study of HTx recipients who received a third dose of the BNT162b2 vaccine. Immunogenicity was assessed by serum levels of anti-spike immunoglobulin G (S-IgG), taken at baseline and 14–28 days after the third dose. Titres above 50 U/ml were interpreted positive. RESULTS We Included 42 HTx recipients at a median age of 65 years [interquartile range (IQR) 58–70]. At baseline, the median of 27 days (IQR 13–42) before the third dose and the median titre of the whole group was 18 U/ml (IQR 4–130). Only 14 patients (33%) were S-IgG seropositive. After the third dose, the proportion of seropositive patients increased significantly to 57% (P = 0.05) and the median titre increased significantly to 633 U/ml (IQR 7–6104, P < 0.0001). Younger age at HTx (OR per 1-year decrease 1.07, P = 0.05), low tacrolimus serum level (OR per 1-unit decrease 2.28, P = 0.02), mammalian target of rapamycin use (OR 13.3, P = 0.003), lack of oral steroids use (OR 4.17, P = 0.04) and lack of calcineurin inhibitor use (71% of responders vs 100% non-responders received calcineurin inhibitors, P = 0.01) were predictors of seropositive result after the third dose. However, no significant association was detected following adjustment for baseline S-IgG titre. CONCLUSIONS Third-dose booster of BNT162b2 vaccine significantly increased immunogenicity among HTx recipients who previously received a two-dose vaccine.

Background Stratification by clinical scores of patients suspected of infection can be used to support decisions on treatment and diagnostic workup. Seven clinical scores, SepsisFinder (SF), National Early Warning Score (NEWS), Sequential Orgen Failure Assessment (SOFA), Mortality in Emergency Department Sepsis (MEDS), quick SOFA (qSOFA), Shapiro Decision Rule (SDR) and Systemic Inflammatory Response Syndrome (SIRS), were evaluated for their ability to predict 30-day mortality and bacteraemia and for their ability to identify a low risk group, where blood culture may not be cost-effective and a high risk group where direct-from-blood PCR (dfbPCR) may be cost effective. Methods Retrospective data from two Danish and an Israeli hospital with a total of 1816 patients were used to calculate the seven scores. Results SF had higher Area Under the Receiver Operating curve than the clinical scores for prediction of mortality and bacteraemia, significantly so for MEDS, qSOFA and SIRS. For mortality predictions SF also had significantly higher area under the curve than SDR. In a low risk group identified by SF, consisting of 33% of the patients only 1.7% had bacteraemia and mortality was 4.2%, giving a cost of € 1976 for one positive result by blood culture. This was higher than the cost of € 502 of one positive dfbPCR from a high risk group consisting of 10% of the patients, where 25.3% had bacteraemia and mortality was 24.2%. Conclusion This may motivate a health economic study of whether resources spent on low risk blood cultures might be better spent on high risk dfbPCR.

Advanced age is an important factor affecting Clostridioides difficile infection (CDI) risk and outcome. While fever and leukocytosis are prominent findings in young individuals with CDI, they are usually blunted in the elderly. Furthermore, chronic kidney disease often exists among this population prior to the CDI episode onset.We aimed to examine whether the accepted definition of severe CDI (leukocytosis ≥ 15,000 cells/μl or serum creatinine 1.5 mg/dl) predicts poor outcomes in the elderly.All CDI hospitalized individuals between January-2013 and May-2020 were included. The study population was dichotomized into older group (≥ 65 years) and younger group ( 65 years). Primary composite outcome was 30-day mortality, colectomy due to severe colitis, or intensive care unit admission. The older group was divided according to the primary outcome to evaluate the effect of CDI severity criteria.The study included 853 patients. Of them, 571 were in the older group and 282 in the younger one. The primary outcome was significantly more common in the older group (93/571, 16% vs. 31/282, 11%; p = 0.04). Ninety days mortality was significantly higher in the older group [116/571, 20% vs. 30/282, 11%; p 0.01]. In multivariate analysis, accepted CDI severity criteria were not significantly associated with poor outcomes (odds ratio [OR] = 1.2, 95% confidence interval [CI] 0.7-2.2, p = 0.5). Advanced dementia and low serum albumin were significant predictors of poor outcomes (OR = 3, 95%CI 1.5-6, p = 0.002 and OR = 3.1, 95%CI 1.7-5.8, p 0.01).The accepted definition of CDI severity was not useful in predicting CDI poor outcomes in older adults. In this population, we suggest advanced dementia and low albumin among others as CDI severity markers.

Objectives The rise in carbapenem resistance among Gram-negative bacteria has renewed interest in colistin. Recently, the EUCAST-CLSI Polymyxin Breakpoints Working Group declared that broth microdilution (BMD) is the only valid method for colistin susceptibility testing. BMD is not easily incorporated into the routine work of clinical laboratories, and usually this test is incorporated serially, resulting in delayed susceptibility reporting. We tested a strategy of combining VITEK® 2 with a 2 μg/mL colistin agar dilution (VITEK® 2/AD) screening plate to improve performance and time to reporting of colistin susceptibility. Methods Colistin susceptibility for 364 clinical isolates was determined by VITEK® 2/AD and compared with the reference standard BMD according to the ISO 20776-1:2007 and CLSI guidelines. The EUCAST colistin susceptibility breakpoint of ≤2 μg/mL was used. Escherichia coli NCTC 13846 served as quality control strain. Agreement, very major error (VME) and major error rates were determined using ISO 20776-2:2007. Results The VME rate for VITEK® 2 alone was 30.6% (15/49, 95% CI 18.3–45.4%), and was reduced to 10.2% (5/49, 95% CI 3.4–22.2%) using the VITEK® 2/AD combined testing. The combined testing had categorical agreement with BMD of 97% (354/364, 95% CI 95.0–98.7%), and a major error (ME) rate of 1.6% (5/315, 95% CI 0.5–3.7%). Using the combined testing, even against challenging strains, 349 (95.8%, 95% CI 93.3–97.7%) colistin susceptibility results could be reported, and only 15 isolates required further analysis by BMD. Discussion Our method is simple to apply and allows rapid reporting of colistin susceptibility.

BackgroundGram-negative bacteremia is a major cause of morbidity and mortality in hospitalized patients. Data to guide the duration of antibiotic therapy are limited.MethodsThis 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%.ResultsWe 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.ConclusionsIn 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 RegistrationNCT01737320.

Background We evaluated the association between mortality and colistin resistance in Acinetobacter baumannii infections and the interaction with antibiotic therapy. Methods This is a secondary analysis of a randomized controlled trial of patients with carbapenem-resistant gram-negative bacterial infections treated with colistin or colistin-meropenem combination. We evaluated patients with infection caused by carbapenem-resistant A. baumannii (CRAB) identified as colistin susceptible (CoS) at the time of treatment and compared patients in which the isolate was confirmed as CoS with those whose isolates were retrospectively identified as colistin resistant (CoR) when tested by broth microdilution (BMD). The primary outcome was 28-day mortality. Results Data were available for 266 patients (214 CoS and 52 CoR isolates). Patients with CoR isolates had higher baseline functional capacity and lower rates of mechanical ventilation than patients with CoS isolates. All-cause 28-day mortality was 42.3% (22/52) among patients with CoR strains and 52.8% (113/214) among patients with CoS isolates (P = .174). After adjusting for variables associated with mortality, the mortality rate was lower among patients with CoR isolates (odds ratio [OR], 0.285 [95% confidence interval {CI}, .118–.686]). This difference was associated with treatment arm: Mortality rates among patients with CoR isolates were higher in those randomized to colistin-meropenem combination therapy compared to colistin monotherapy (OR, 3.065 [95% CI, 1.021–9.202]). Conclusions Colistin resistance determined by BMD was associated with lower mortality among patients with severe CRAB infections. Among patients with CoR isolates, colistin monotherapy was associated with a better outcome compared to colistin-meropenem combination therapy. Clinical Trials Registration NCT01732250

Hospital readmissions following severe infections are a major economic burden on the health care system and have a negative influence on patients' quality of life. Understanding the risk factors for readmission, particularly the extent to which they could be prevented, is of a great importance. In this study we evaluated potentially preventable risk factors for 60-day readmission in patients surviving hospitalization for complicated urinary tract infection (cUTI). This was a multinational, multicentre retrospective cohort study conducted in Europe and the Middle East. Our cohort included survivors of hospitalization due to cUTI during the years 2013–2014. The primary outcome was 60-day readmission following index hospitalization. Patient characteristics that could have influenced readmission: demographics, infection presentation and management, microbiological and clinical data; were collected via computerized medical records from infection onset up to 60 days after hospital discharge. Overall, 742 patients were included. The cohort median age was 68 years (interquartile range, (IQR) 55–80) and 43.3% (321/742) of patients were males. The all-cause 60-day readmission rate was 20.1% (149/742) and more than half were readmitted for infection [57.1%, (80/140)]. Recurrent cUTI was the most frequent cause for readmission [46.4% (65/140)]. Statistically significant risk factors associated with 60-day readmission in multivariable analysis were: older age (odds ratio (OR) 1.02 for an one-year increment, confidence interval (CI) 1.005–1.03), diabetes mellitus (OR 1.63, 95% CI 1.04–2.55), cancer (OR 1.7, 95% CI 1.05–2.77), previous urinary tract infection (UTI) in the last year (OR 1.8, 95% CI: 1.14–2.83), insertion of an indwelling bladder catheter (OR 1.62, 95% CI 1.07–2.45) and insertion of percutaneous nephrostomy (OR 3.68, 95% CI 1.67–8.13). In conclusion, patients surviving hospitalization for cUTI are frequently re-hospitalized, mostly for recurrent urinary infections associated with a medical condition that necessitated urinary interventions. Interventions to avoid re-admissions should target these patients.

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.

Burden of COVID-19 on Hospitals across the globe is enormous and has clinical and economic implications. In this retrospective study including consecutive adult patients with confirmed SARS-CoV-2 who were admitted between 3/2020 and 30/9/20, we aimed to identify post-discharge outcomes and risk factors for re-admission among COVID-19 hospitalized patients. Mortality and re-admissions were documented for a median post discharge follow up of 59 days (interquartile range 28,161). Univariate and multivariate analyses of risk factors for re-admission were performed. Overall, 618 hospitalized COVID-19 patients were included. Of the 544 patient who were discharged, 10 patients (1.83%) died following discharge and 50 patients (9.2%) were re-admitted. Median time to re-admission was 7 days (interquartile range 3, 24). Oxygen saturation or treatment prior to discharge were not associated with re-admissions. Risk factors for re-admission in multivariate analysis included solid organ transplantation (hazard ratio [HR] 3.37, 95% confidence interval [CI] 2.73–7.5, p = 0.0028) and higher Charlson comorbidity index (HR 1.34, 95% CI 1.23–1.46, p

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.

Complicated urinary tract infection (cUTI) is a frequent cause of morbidity. In this multinational retrospective cohort study, we aimed to demonstrate risk factors for enterococcal UTI. Univariate and multivariate analyses of risk factors for enterococcal infection were performed. Among 791 hospitalized patients with cUTI, enterococci accounted for approximately 10% of cases (78/791). Risk factors for enterococcal UTI in multivariable analysis were male gender, age range of 55-75 years, catheter-associated UTI, and urinary retention. This information may assist treating physicians in their decision-making on prescribing empiric anti-enterococcus treatment to hospitalized patients presenting with cUTI and thus improve clinical outcomes.

Objectives In vitro models showing synergism between polymyxins and carbapenems support combination treatment for carbapenem-resistant Gram-negative (CRGN) infections. We tested the association between the presence of in vitro synergism and clinical outcomes in patients treated with colistin plus meropenem. Methods This was a secondary analysis of AIDA, a randomized controlled trial comparing colistin with colistin–meropenem for severe CRGN infections. We tested in vitro synergism using a checkerboard assay. Based on the fractional inhibitory concentration (ΣFIC) index for each colistin–meropenem combination, we categorized results as synergistic, antagonistic or additive/indifferent. The primary outcome was clinical failure at 14 days. Secondary outcomes were 14- and 28-day mortality and microbiological failure. Results The sample included 171 patients with infections caused by carbapenem-resistant Acinetobacter baumannii (n = 131), Enterobacteriaceae (n = 37) and Pseudomonas aeuruginosa (n = 3). In vitro testing showed synergism for 73 isolates, antagonism for 20 and additivism/indifference for 78. In patients who received any colistin plus meropenem, clinical failure at 14 days was 59/78 (75.6%) in the additivism/indifference group (reference category), 54/73 (74.0%) in the synergism group (adjusted odds ratio (aOR) 0.76, 95% CI 0.31–1.83), and 11/20 (55%) in the antagonism group (aOR 0.77, 95% CI 0.22–2.73). There was no significant difference between groups for any secondary outcome. Comparing the synergism group to patients treated with colistin monotherapy, synergism was not protective against 14-day clinical failure (aOR 0.52, 95% CI 0.26–1.04) or 14-day mortality (aOR1.09, 95% CI 0.60–1.96). Discussion In vitro synergism between colistin and meropenem via checkerboard method did not translate into clinical benefit.

Objectives: The aim was to analyse the population pharmacokinetics of colistin and to explore the relationship between colistin exposure and time to death. Methods: Patients included in the AIDA randomized controlled trial were treated with colistin for severe infections caused by carbapenem-resistant Gram-negative bacteria. All subjects received a 9 million units (MU) loading dose, followed by a 4.5 MU twice daily maintenance dose, with dose reduction if creatinine clearance (CrCL) < 50 mL/min. Individual colistin exposures were estimated from the developed population pharmacokinetic model and an optimized two-sample per patient sampling design. Time to death was evaluated in a parametric survival analysis. Results: Out of 406 randomized patients, 349 contributed pharmacokinetic data. The median (90% range) colistin plasma concentration was 0.44 (0.14–1.59) mg/L at 15 minutes after the end of first infusion. In samples drawn 10 hr after a maintenance dose, concentrations were >2 mg/L in 94% (195/208) and 44% (38/87) of patients with CrCL ≤120 mL/min, and >120 mL/min, respectively. Colistin methanesulfonate sodium (CMS) and colistin clearances were strongly dependent on CrCL. High colistin exposure to MIC ratio was associated with increased hazard of death in the multivariate analysis (adjusted hazard ratio (95% CI): 1.07 (1.03–1.12)). Other significant predictors included SOFA score at baseline (HR 1.24 (1.19–1.30) per score increase), age and Acinetobacter or Pseudomonas as index pathogen. Discussion: The population pharmacokinetic model predicted that >90% of the patients had colistin concentrations >2 mg/L at steady state, but only 66% at 4 hr after start of treatment. High colistin exposure was associated with poor kidney function, and was not related to a prolonged survival.

Summary 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.

Ureteral stents are routinely used in renal transplant and are associated with reduced urological complications but increased urinary tract infections (UTIs). There is no agreement on the preferred time to removal of stents after transplantation. We performed a systematic review and meta-analysis of all randomized controlled trials (RCTs) comparing stent duration of =14 days. Electronic databases were searched to identify RCTs that compared early vs late stent removal. Primary outcome was urinary tract infections. Secondary outcomes included various urological complications. No significant difference in UTI rates was demonstrated between short and long stent duration (relative risk (RR) 0.85, 95% confidence interval (CI) 0.44-1.64), with significant heterogeneity (I2 = 86%). Sensitivity analysis evaluating studies with low risk of bias for allocation concealment demonstrated statistically significant lower rates of UTI with short stent duration (RR 0.48, 95% CI 0.32-0.71) with no heterogeneity. No significant difference was demonstrated for the outcome of major urological complications (RR 0.72, 95% CI 0.50-1.05), without heterogeneity. Ureteral stenosis rates were significantly lower in the short duration arm (RR 0.42, 95% CI 0.18-0.98). Early removal of ureteral stents after renal transplant may be associated with reduced rates of UTI and ureteral stenosis. Additional RCTs are needed.

Prediction of both the likelihood of bacteraemia and of death within 30 days allows for prudent decisions to be made regarding the diagnostic workup and therapy of patients with suspected sepsis. In this paper, we combine two predictive models and perform machine learning to tune the new model’s ability to predict both bacteraemia and 30-day mortality. The model was then validated on three independent datasets. There was no difference in the discriminatory ability of the model compared to each of the predecessors. For bacteraemia prediction, the new model had an AUC = 0.71 for the training data, and AUC = 0.73, 0.74 and 0.79 for the validation data. For mortality prediction, the model had an AUC = 0.81 for the training data and AUC = 0.76, 0.84 and 0.80 for the validation data.