Association between BNT162b2 vaccination and health-related quality of life up to 18 months post-SARS-CoV-2 infection in Israel.

We determined whether COVID-19 vaccination was associated with Quality of Life (QoL) changes among individuals previously infected with SARS-CoV-2 in Israel. Using a validated questionnaire, we collected information about socio-demographics, SARS-CoV-2 infection, COVID-19 vaccination and QoL (using the EQ-5D-5L tool) 3-18 months post-infection among adults tested for SARS-CoV-2 by polymerase chain reaction in Northern Israel between March 2020-June 2022. We compared post-COVID QoL between those vaccinated against COVID-19 at the time of infection and those not, using an adjusted linear regression model, stratified by time elapsed since infection. Of 951 participants, mean EQ-5D Utility Index (EQ-5D UI) was 0.82 (SD = 0.26) and 0.83 (SD = 0.25) among the 227 double and 250 triple vaccinated respectively, compared to 0.76 (SD = 0.33) among those who received 0 dose (n = 243). The size of the effect of vaccination was small (Cohen's d = 0.2). In the adjusted model, previously infected individuals vaccinated with two or more doses reported a QoL score post- infection 0.05 points higher (CI = 0.01-0.10, p = 0.02) compared with those unvaccinated when infected. No association between vaccination and QoL was detected beyond 12 months post-infection. Vaccination with two or more doses of COVID19 vaccine, or at least the BNT162b2 vaccine, may modestly mitigate QoL losses associated with post-acute COVID-19 symptoms, at least in the first 12 months post-infection.

Changes in Quality of Life Following SARS-CoV-2 Infection Among Jewish and Arab Populations in Israel: A Cross-Sectional Study.

Objectives: The long-term impact of COVID-19 on health inequalities is under-researched. We investigated changes in health-related inequalities following SARS-CoV-2 infection between the Jewish majority and the Arab/Druze minority in Israel. Methods: Patients with a positive SARS-CoV-2 RT-PCR test processed from one of the Northern-Israeli government hospitals between 03/2021 and 05/2022 were invited to participate. We collected socio-demographic, COVID-19-related, and health-related quality of life (HRQoL) information using a validated questionnaire. We compared pre- and post COVID-19 HRQoL changes between Jews and Arabs/Druze, up to 12+ months post-infection using an adjusted linear regression model. Results: Among the 881 included participants the average post-COVID HRQoL score was lower among Arabs/Druze than Jews (0.83 vs. 0.88; p = 0.005). Until 12 months post-infection, HRQoL changes were similar for Arabs/Druze and Jews. After 12 months, HRQoL dropped significantly more among Arabs/Druze than among Jews (0.11 points difference between the groups; p = 0.014), despite adjusting for socioeconomic variables. Conclusion: 12 months post-infection, COVID-19 affected the HRQoL of Arabs/Druze more than Jews, with the gap not fully explained by socio-economic differences. The COVID-19 pandemic may widen pre-existing long-term health inequalities.

The Relationship between Body Mass Index and In-Hospital Mortality in Bacteremic Sepsis.

BACKGROUND: The association between Body Mass Index (BMI) and clinical outcomes following sepsis continues to be debated. We aimed to investigate the relationship between BMI and in-hospital clinical course and mortality in patients hospitalized with bacteremic sepsis using real-world data. METHODS: A sampled cohort of patients hospitalized with bacteremic sepsis between October 2015 and December 2016 was identified in the National Inpatient Sample (NIS) database. In-hospital mortality and length of stay were defined as the relevant outcomes. Patients were divided into 6 BMI (kg/m2) subgroups; (1) underweight ≤ 19, (2) normal-weight 20-25, (3) over-weight 26-30, (4) obese I 31-35, (5) obese II 36-39, and (6) obese stage III ≥ 40. A multivariable logistic regression model was used to find predictors of mortality, and a linear regression model was used to find predictors of an extended length of stay (LOS). RESULTS: An estimated total of 90,760 hospitalizations for bacteremic sepsis across the U.S. were analyzed. The data showed a reverse-J-shaped relationship between BMI and study population outcomes, with the underweight patients (BMI ≤ 19 kg/m2) suffering from higher mortality and longer LOS as did the normal-weight patients (BMI 20-25 kg/m2) when compared to the higher BMI groups. The seemingly protective effect of a higher BMI diminished in the highest BMI group (BMI ≥ 40 kg/m2). In the multivariable regression model, BMI subgroups of ≤19 kg/m2 and ≥40 kg/m2 were found to be independent predictors of mortality. CONCLUSIONS: A reverse-J-shaped relationship between BMI and mortality was documented, confirming the "obesity paradox" in the real-world setting in patients hospitalized for sepsis and bacteremia.

Associations between reported post-COVID-19 symptoms and subjective well-being, Israel, July 2021 - April 2022.

The impact of individual symptoms reported post-COVID-19 on subjective well-being (SWB) is unknown. We described associations between SWB and selected reported symptoms following SARS-CoV-2 infection. We analysed reported symptoms and subjective well being from 2295 participants (of which 576 reporting previous infection) in an ongoing longitudinal cohort study taking place in Israel. We estimated changes in SWB associated with reported selected symptoms at three follow-up time points (3-6, 6-12 and 12-18 months post infection) among participants reporting previous SARS-CoV-2 infection, adjusted for key demographic variables, using linear regression. Our results suggest that the biggest and most sustained changes in SWB stems from non-specific symptoms (fatigue -7.7 percentage points (pp), confusion/ lack of concentration -10.7 pp, and sleep disorders -11.5pp, P < 0.005), whereas the effect of system-specific symptoms, such as musculoskeletal symptoms (weakness in muscles and muscle pain) on SWB, are less profound and more transient. Taking a similar approach for other symptoms and following individuals over time to describe trends in SWB changes attributable to specific symptoms will help understand the post-acute phase of COVID-19 and how it should be defined and better managed. Post-acute COVID19 symptoms were associated with a significant decrease in subjective well being up to 18 months after initial infection.

Assessing the impact of a positive Biofire® FilmArray® Meningitis/Encephalitis Panel result on clinical management and outcomes.

A rapid and accurate diagnosis of meningitis/encephalitis (ME) is required for early and effective intervention or adjustment of empirical treatment. This study retrospectively analyzed 485 records of patients hospitalized at the Padeh Poriya Medical Center during 2016-2020, due to a suspicion of ME. Pathogen distribution in cerebrospinal fluid samples, as determined using the BioFire® FilmArray ME Panel (MEP), is presented, as well as comparison of demographic and clinical characteristics, clinical management and outcomes of MEP+ (105) vs MEP- (380) patients. Pathogen distribution correlated with that reported in the literature, with Enterovirus (62%) being the most common causative agent. MEP+ patients were significantly younger than MEP- patients. Antibiotics use prior to lumbar puncture was significantly higher among MEP+ patients. MEP+ was associated with more frequent antibiotic change, compared to MEP-. While MEP+ contributed to early treatment adjustment or cessation, it did not necessarily impact the length of stay or patient outcomes.

Association between BNT162b2 vaccination and reported incidence of post-COVID-19 symptoms: cross-sectional study 2020-21, Israel.

The effectiveness of Coronavirus disease 2019 (COVID-19) vaccines against the long-term COVID-19 symptoms expressed by a substantial proportion of patients is not well understood. We determined whether vaccination with the BNT162b2 mRNA vaccine was associated with incidence of reporting long-term symptoms post-SARS-CoV-2 infection. We invited individuals PCR-tested for SARS-CoV-2 infection at participating hospitals between March 2020 and November 2021 to fill an online questionnaire that included information about demographics, acute COVID-19 episode and symptoms they were currently experiencing. Using binomial regression, we compared vaccinated individuals with those unvaccinated and those uninfected, in terms of post-acute self-reported symptoms. Of the 951 infected, 637(67%) were vaccinated. In the study population, the most prevalent symptoms were: fatigue (22%), headache (20%), weakness of limbs (13%), and persistent muscle pain (10%). After adjusting for age, time from beginning of symptoms to responding to the survey, and baseline symptoms, those who received two vaccine doses were less likely than unvaccinated individuals to report any of these symptoms (fatigue, headache, weakness of limbs, persistent muscle pain) by 62%, 50%, 62%, and 66% respectively, (Risk ratios 0.38, 0.50, 0.38, 0.34, p < 0.04 in the listed sequence). Compared to the 2447 included individuals who never reported SARS-CoV-2 infection, double-vaccinated participants were no more likely to report any of the mentioned symptoms. Vaccination with 2+ doses of BNT162b2 was associated with a reduced risk of reporting most of the common post-acute COVID-19 symptoms. Our results suggest that BNT162b2 vaccination may have a protective effect against longer term COVID-19 symptoms.

Hospitalised patients with breakthrough COVID-19 following vaccination during two distinct waves in Israel, January to August 2021: a multicentre comparative cohort study.

BackgroundChanging patterns of vaccine breakthrough can clarify vaccine effectiveness.AimTo compare breakthrough infections during a SARS-CoV-2 Delta wave vs unvaccinated inpatients, and an earlier Alpha wave.MethodsIn an observational multicentre cohort study in Israel, hospitalised COVID-19 patients were divided into three cohorts: breakthrough infections in Comirnaty-vaccinated patients (VD; Jun-Aug 2021) and unvaccinated cases during the Delta wave (ND) and breakthrough infections during an earlier Alpha wave (VA; Jan-Apr 2021). Primary outcome was death or ventilation.ResultsWe included 343 VD, 162 ND and 172 VA patients. VD were more likely older (OR: 1.06; 95% CI: 1.05-1.08), men (OR: 1.6; 95% CI: 1.0-2.5) and immunosuppressed (OR: 2.5; 95% CI: 1.1-5.5) vs ND. Median time between second vaccine dose and admission was 179 days (IQR: 166-187) in VD vs 41 days (IQR: 28-57.5) in VA. VD patients were less likely to be men (OR: 0.6; 95% CI: 0.4-0.9), immunosuppressed (OR: 0.3; 95% CI: 0.2-0.5) or have congestive heart failure (OR: 0.6; 95% CI: 0.3-0.9) vs VA. The outcome was similar between all cohorts and affected by age and immunosuppression and not by vaccination, variant or time from vaccination.ConclusionsVaccination was protective during the Delta variant wave, as suggested by older age and greater immunosuppression in vaccinated breakthrough vs unvaccinated inpatients. Nevertheless, compared with an earlier post-vaccination period, breakthrough infections 6 months post-vaccination occurred in healthier patients. Thus, waning immunity increased vulnerability during the Delta wave, which suggests boosters as a countermeasure.

Assessment of dry eye disease in N95 versus surgical face mask wearers during COVID-19.

Purpose: Investigating the effect of different face masks on dry eye disease (DED) among healthcare workers during the COVID-19 pandemic. Methods: This was a comparative, cross-sectional study. Participants were included into two groups: group 1 (n = 30) wore surgical masks, and group 2 (n = 30) wore N95 masks with face shields. Demographic and ocular surface disease index questionnaires (OSDI) were performed. In addition, Tear break-up time (TBUT), corneal and conjunctival fluorescein staining, and meibography to assess meibomian gland loss (MGL) were performed on all participants. Independent T-test was used to compare continuous parameters and Chi-square test for categorical variables. The relationship between continuous variables was tested using bivariate Pearson correlation. Results: Sixty healthcare workers participated in this study (36 females and 24 males). The mean (±SD) age of the surgical mask and N95 groups was 35.33 (±14.94) and 36.63 (±10.64) years, respectively. Both masks caused dryness according to TBUT, MGL, and OSDI scores. DED per DEWS II definition was observed in 14 (46.7%) and 16 (53.3%) patients in groups 1 and 2, respectively. Comparing the two groups, N95 mask caused significantly more dryness according to TBUT (P = 0.042) and fluorescein staining (P = 0.038 for the right eye and P = 0.015 for the left eye). Conclusion: Physicians should be aware of the potential dry eye signs secondary to face mask wear during the COVID-19 pandemic. Further attention should be taken in patients who suffer from preexisting dry eye syndrome and in patients who undergo intraocular operations.

Clinical management of severe infections caused by carbapenem-resistant gram-negative bacteria: a worldwide cross-sectional survey addressing the use of antibiotic combinations.

OBJECTIVES: Optimal treatment of carbapenem-resistant Gram-negative bacteria (CR-GNB) infections is uncertain because of the lack of good-quality evidence and the limited effectiveness of available antibiotics. The aim of this survey was to investigate clinicians' prescribing strategies for treating CR-GNB infections worldwide. METHODS: A 36-item questionnaire was developed addressing the following aspects of antibiotic prescribing: respondent's background, diagnostic and therapeutic availability, preferred antibiotic strategies and rationale for selecting combination therapy. Prescribers were recruited following the snowball sampling approach, and a post-stratification correction with inverse proportional weights was used to adjust the sample's representativeness. RESULTS: A total of 1012 respondents from 95 countries participated in the survey. Overall, 298 (30%) of the respondents had local guidelines for treating CR-GNB at their facility and 702 (71%) had access to Infectious Diseases consultation, with significant discrepancies according to country economic status: 85% (390/502) in high-income countries versus 59% (194/283) in upper-medium-income countries and 30% (118/196) in lower-middle-income countries/lower-income-countries). Targeted regimens varied widely, ranging from 40 regimens for CR-Acinetobacter spp. to more than 100 regimens for CR-Enterobacteriaceae. Although the majority of respondents acknowledged the lack of evidence behind this choice, dual combination was the preferred treatment scheme and carbapenem-polymyxin was the most prescribed regimen, irrespective of pathogen and infection source. Respondents noticeably disagreed around the meaning of 'combination therapy' with 20% (150/783) indicating the simple addition of multiple compounds, 42% (321/783) requiring the presence of in vitro activity and 38% (290/783) requiring in vitro synergism. CONCLUSIONS: Management of CR-GNB infections is far from being standardized. Strategic public health focused randomized controlled trials are urgently required to inform evidence-based treatment guidelines.

Risk factors for functional decline among survivors of Gram-negative bloodstream infection: A prospective cohort study.

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.

BNT162b2 vaccine breakthrough: clinical characteristics of 152 fully vaccinated hospitalized COVID-19 patients in Israel.

OBJECTIVES: The mRNA coronavirus disease 2019 (COVID-19) vaccines have shown high effectiveness in the prevention of symptomatic COVID-19, hospitalization, severe disease and death. Nevertheless, a minority of vaccinated individuals might become infected and experience significant morbidity. Characteristics of vaccine breakthrough infections have not been studied. We sought to portray the population of Israeli patients, who were hospitalized with COVID-19 despite full vaccination. METHODS: A retrospective multicentre cohort study of 17 hospitals included patients fully vaccinated with Pfizer/BioNTech's BNT162b2 vaccine who developed COVID-19 more than 7 days after the second vaccine dose and required hospitalization. The risk for poor outcome, defined as a composite of mechanical ventilation or death, was assessed. RESULTS: A total of 152 patients were included, accounting for half of hospitalized fully vaccinated patients in Israel. Poor outcome was noted in 38 patients and mortality rate reached 22% (34/152). Notably, the cohort was characterized by a high rate of co-morbidities predisposing to severe COVID-19, including hypertension (108; 71%), diabetes (73; 48%), congestive heart failure (41; 27%), chronic kidney and lung diseases (37; 24% each), dementia (29; 19%) and cancer (36; 24%), and only six (4%) had no co-morbidities. Sixty (40%) of the patients were immunocompromised. Higher viral load was associated with a significant risk for poor outcome. Risk also appeared higher in patients receiving anti-CD20 treatment and in patients with low titres of anti-Spike IgG, but these differences did not reach statistical significance. CONCLUSIONS: We found that severe COVID-19 infection, associated with a high mortality rate, might develop in a minority of fully vaccinated individuals with multiple co-morbidities. Our patients had a higher rate of co-morbidities and immunosuppression compared with previously reported non-vaccinated hospitalized individuals with COVID-19. Further characterization of this vulnerable population may help to develop guidance to augment their protection, either by continued social distancing, or by additional active or passive vaccinations.

Spotted Fever Group Rickettsioses in Israel, 2010-2019.

In a multicenter, nationwide, retrospective study of patients hospitalized with spotted fever group rickettsiosis in Israel during 2010-2019, we identified 42 cases, of which 36 were autochthonous. The most prevalent species was the Rickettsia conorii Israeli tick typhus strain (n = 33, 79%); infection with this species necessitated intensive care for 52% of patients and was associated with a 30% fatality rate. A history of tick bite was rare, found for only 5% of patients; eschar was found in 12%; and leukocytosis was more common than leukopenia. Most (72%) patients resided along the Mediterranean shoreline. For 3 patients, a new Rickettsia variant was identified and had been acquired in eastern, mountainous parts of Israel. One patient had prolonged fever before admission and clinical signs resembling tickborne lymphadenopathy. Our findings suggest that a broad range of Rickettsia species cause spotted fever group rickettsiosis in Israel.

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.

Clinical and Demographic Characteristics of Patients With a New Diagnosis of Carriage or Clinical Infection With Carbapenemase-Producing Enterobacterales: A Retrospective Study.

Background: To examine the clinical, demographic, and microbiologic characteristics of new rectal carbapenemase-producing carbapenem-resistant Enterobacterales (CP-CRE) carriers vs. those with a clinical infection, hospitalized at Padeh-Poriya Medical Center between 2014 and 2017 and to examine the susceptibility profiles of isolates from clinical infections. Methods: In this retrospective, chart analysis, demographic and clinical data were collected from medical charts of 175 adult patients with either new- onset carbapenemase-producing Enterobacterales (CPE) carriage or clinical CPE infection. Collected data included age, ethnic group, place of residence, hospitalizations in the past 90 days, and 30-day mortality. Microbiological analyses considered bacterial genus, molecular resistance mechanism and antibiotic susceptibility. Results: A significantly higher percentage (42.4%) of CPE carriers were long-term care facility residents, and had been recently hospitalized (56.3%), as compared to patients with clinical CPE infection (29.2 and 45.9%, respectively). Additionally, we noted a high (58.3%) acquision of CPE in our hospital. The most common bacterial isolate was K. pneumoniae and the most common resistance mechanism was Klebsiella pneumoniae (K. pneumoniae) carbapenemases (KPC). High susceptibility rates to amikacin and chloramphenicol were also noted. Conclusions: This study reaffirmed the importance of CPE screening and infection control measures. The observed antibiotic susceptibility profile suggests amikacin and chloramphenicol as potential treatments for CPE infection.

New Spotted Fever Group Rickettsia Isolate, Identified by Sequence Analysis of Conserved Genomic Regions.

The clinical features of spotted fever group (SFG) Rickettsia induced disease range from a mild to severe illness. The clinical complexity is even greater due to the fact that the disease can be caused by different species with varying degrees of virulence. Current knowledge asserts that the Israeli SFG (ISF) strain Rickettsia conorii israelensis is the only human pathogenic SFG member in Israel. Current diagnostic procedures distinguish between SFG and the typhus group rickettsiosis, assuming all SFG-positive clinical samples positive for ISF. Molecular studies on questing ticks over the past decade have uncovered the existence of other SFG strains besides ISF in Israel and the region. This study describes the first documented analysis of SFG-positive samples from Israeli patients with the goal of distinguishing between ISF and non-ISF SFG strains. We managed to identify a new Rickettsia isolate from three independent clinical samples in Israel which was shown to be an as-yet unknown SFG member, showing no absolute identity with any known Rickettsia species present in the NCBI database.

[ANTIBIOTIC PRESCRIPTION ERRORS IN PATIENTS HOSPITALIZED IN INTERNAL MEDICINE DEPARTMENTS - A PROSPECTIVE COHORT STUDY].

AIMS: To examine the prevalence of antibiotic prescription errors in three medical departments. BACKGROUND: Prescription errors are common and associated with significant adverse drug events (ADEs), morbidity and mortality, and health care expenditures. METHODS: A prospective observational cohort study was conducted in three medical departments, including consecutive patients with suspected or proven infections, and/or antibiotic prescriptions. The primary outcome was the proportion of prescription errors, defined as: contraindications, inadequate dose regimen, and unnecessary antibiotic treatment. Secondary outcomes included incidence of ADEs, proportion of potential drug-drug interactions (DDIs) with clinical relevance, and prevalence of inadequate monitoring for ADEs and therapeutic drug monitoring (TDM). RESULTS: We identified 327 patient-episodes in 295 patients. The most common infectious diagnoses were urinary tract infection and pneumonia. Among 633 prescriptions, 113 (18%) contained errors in 87 (27%) patient-episodes. The most common types of error were inappropriate dose adjustment for renal function and unnecessary treatment. There were 6 prescriptions with contraindications (0.9%). Laboratory monitoring was required in 259 patient-episodes but inadequate in 40 (15%). TDM was required in 40 patient-episodes, but was not performed in 25 (63%). There were 69 ADEs in 61 patient-episodes (19%). Compared to patients without ADEs, patients who developed ADEs had more prescription errors (p=0.055), more potential DDIs (p=0.012), and received more often antibiotics that needed monitoring and TDM. CONCLUSIONS: Antibiotic prescription errors in medical departments are common and may be associated with significant ADEs. Our findings may help in prioritizing the customization of prescription computer decision support systems to improve antibiotic prescription.

Risk factors for meningitis in neurosurgical patients with cerebrospinal fluid drains: prospective observational cohort study.

BACKGROUND: Cerebrospinal fluid (CSF) drainage or intracranial pressure (ICP) monitoring devices are life-saving devices. We examined the risk factors for infections related to them and assessed the effect of an infection control (IC) intervention. METHODS: A prospective observational study was conducted in the Neurosurgical Department of our hospital between 2014 and 2017. We included all consecutive patients undergoing CSF catheter insertions, including external ventricular drainage (EVD), lumbar drainage (LD), and ICP catheters. An IC intervention was implemented between March and August 2016. We examined risk factors for meningitis or ventriculitis, defined according to Healthcare-associated infections surveillance definitions, on univariate and multivariate analysis. RESULTS: A total of 232 patients with 437 drains (212 EVDs, 92 LDs, and 133 ICPs) were included. On univariate and multivariate analysis, the infection incidence was 13.7 per 1000 drain days (17.3/1000 before IC intervention, 7.9/1000 during, and 9.2/1000 after the intervention). Most episodes were caused by Gram-negative bacteria, and the most common pathogen was Acinetobacter baumanii. Risk factors for infection per patient included diabetes mellitus (p = 0.017), CSF leak (p = 0.032), drain opening (p = 0.027), and the duration of the drain in days (p = 0.035). Risk factors per catheter included drain opening (p < 0.001), drain days (p = 0.001), and the IC intervention period compared to before the intervention period (p = 0.037). When restricting the analysis to EVDs, drain days (p = 0.001) was the only significant risk factor. CONCLUSIONS: Strict adherence to IC, shortening drain duration, and avoiding unnecessary opening and manipulation of the drains are crucial to preventing neurosurgical drain infections.

Seven Versus 14 Days of Antibiotic Therapy for Uncomplicated Gram-negative Bacteremia: A Noninferiority Randomized Controlled Trial.

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.

Colistin alone versus colistin plus meropenem for treatment of severe infections caused by carbapenem-resistant Gram-negative bacteria: an open-label, randomised controlled trial.

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.

Revival of old antibiotics: needs, the state of evidence and expectations.

The gap between the emergence of antibiotic resistance and new antibiotic development has drawn attention to old antibiotics whose spectrum of coverage frequently comprises highly resistant bacteria. However, these antibiotics have frequently not undergone the structured process of antibiotic development of modern antibiotics, from pharmacokinetic/pharmacodynamic (PK/PD) studies establishing safe and effective dosing, establishment of susceptibility breakpoints, to clinical trials establishing clinical safety and effectiveness. In this review, we highlight the gaps for which we need old antibiotics in community- and hospital-acquired infections. Reviewing recently published and ongoing randomised controlled trials (RCTs) shows advances in our understanding of the efficacy and effectiveness of oral fosfomycin, mecillinam and nitrofurantoin for cystitis, and of trimethoprim/sulfamethoxazole for complicated skin infections caused by methicillin-resistant Staphylococcus aureus (MRSA) in the community. Summarising older evidence shows the inferiority of chloramphenicol versus modern antibiotics for severe infections. We lack studies on severe infections caused by carbapenem-resistant Gram-negative bacteria and other multidrug-resistant (MDR) bacteria in hospitalised and critically ill patients; ongoing studies assessing colistin and intravenous fosfomycin might fill in some gaps. In the re-development process of old antibiotics, we mandate modern PK/PD studies comprising special populations as well as RCTs addressing the target population of patients in need of these antibiotics powered to examine patient-relevant outcomes. Structured antibiotic re-development from the laboratory to evidence-based treatment recommendations requires public funding, multidisciplinary collaboration, international co-ordination, and methods to streamline the recruitment of critically ill patients infected by MDR bacteria.