Antimicrobial resistance in Enterobacterales infections among children in sub-Saharan Africa: a systematic review and meta-analysis.

Background: The burden of antimicrobial resistance (AMR) has been estimated to be the highest in sub-Saharan Africa (SSA). The current study estimated the proportion of drug-resistant Enterobacterales causing infections in SSA children. Methods: We searched MEDLINE/PubMed, Embase and the Cochrane Library to identify retrospective and prospective studies published from 01/01/2005 to 01/06/2022 reporting AMR of Enterobacterales causing infections in sub-Saharan children (0-18 years old). Studies were excluded if they had unclear documentation of antimicrobial susceptibility testing methods or fewer than ten observations per bacteria. Data extraction and quality appraisal were conducted by two authors independently. The primary outcome was the proportion of Enterobacterales resistant to antibiotics commonly used in paediatrics. Proportions were combined across studies using mixed-effects logistic regression models per bacteria and per antibiotic. Between-study heterogeneity was assessed using the I2 statistic. The protocol was registered with PROSPERO (CRD42021260157). Findings: After screening 1111 records, 122 relevant studies were included, providing data on more than 30,000 blood, urine and stool isolates. Escherichia coli and Klebsiella spp. were the predominant species, both presenting high proportions of resistance to third-generation cephalosporins, especially in blood cultures: 40.6% (95% CI: 27.7%-55%; I2: 85.7%, number of isolates (n): 1032) and 84.9% (72.8%-92.2%; I2: 94.1%, n: 2067), respectively. High proportions of resistance to other commonly used antibiotics were also observed. E. coli had high proportions of resistance, especially for ampicillin (92.5%; 95% CI: 76.4%-97.9%; I2: 89.8%, n: 888) and gentamicin (42.7%; 95% CI: 30%-56.5%; I2: 71.9%, n: 968). Gentamicin-resistant Klebsiella spp. were also frequently reported (77.6%; 95% CI: 65.5%-86.3%; I2: 91.6%, n: 1886). Interpretation: High proportions of resistance to antibiotics commonly used for empirical treatment of infectious syndromes were found for Enterobacterales in sub-Saharan children. There is a critical need to better identify local patterns of AMR to inform and update clinical guidelines for better treatment outcomes. Funding: No funding was received.

Excess resource use and cost of drug-resistant infections for six key pathogens in Europe: a systematic review and Bayesian meta-analysis.

BACKGROUND: Quantifying the resource use and cost of antimicrobial resistance establishes the magnitude of the problem and drives action. OBJECTIVES: Assessment of resource use and cost associated with infections with six key drug-resistant pathogens in Europe. METHODS: A systematic review and Bayesian meta-analysis. DATA SOURCES: MEDLINE (Ovid), Embase (Ovid), Econlit databases, and grey literature for the period 1 January 1990, to 21 June 2022. STUDY ELIGIBILITY CRITERIA: Resource use and cost outcomes (including excess length of stay, overall costs, and other excess in or outpatient costs) were compared between patients with defined antibiotic-resistant infections caused by carbapenem-resistant (CR) Pseudomonas aeruginosa and Acinetobacter baumannii, CR or third-generation cephalosporin Escherichia coli (3GCREC) and Klebsiella pneumoniae, methicillin-resistant Staphylococcus aureus, and vancomycin-resistant Enterococcus faecium, and patients with drug-susceptible or no infection. PARTICIPANTS: All patients diagnosed with drug-resistant bloodstream infections (BSIs). INTERVENTIONS: NA. ASSESSMENT OF RISK OF BIAS: An adapted version of the Joanna Briggs Institute assessment tool, incorporating case-control, cohort, and economic assessment frameworks. METHODS OF DATA SYNTHESIS: Hierarchical Bayesian meta-analyses were used to assess pathogen-specific resource use estimates. RESULTS: Of 5969 screened publications, 37 were included in the review. Data were sparse and heterogeneous. Most studies estimated the attributable burden by, comparing resistant and susceptible pathogens (32/37). Four studies analysed the excess cost of hospitalization attributable to 3GCREC BSIs, ranging from -€ 2465.50 to € 6402.81. Eight studies presented adjusted excess length of hospital stay estimates for methicillin-resistant S. aureus and 3GCREC BSIs (4 each) allowing for Bayesian hierarchical analysis, estimating means of 1.26 (95% credible interval [CrI], -0.72 to 4.17) and 1.78 (95% CrI, -0.02 to 3.38) days, respectively. CONCLUSIONS: Evidence on most cost and resource use outcomes and across most pathogen-resistance combinations was severely lacking. Given the importance of this evidence for rational policymaking, further research is urgently needed.

Clinical significance and burden of carbapenem-resistant Enterobacterales (CRE) colonization acquisition in hospitalized patients.

BACKGROUND: Carbapenem-resistant Enterobacterales (CRE) infections have a significant morbidity and mortality toll. The clinical significance and associated burden of CRE colonization rather than infection state are not frequently investigated. We aimed to assess the outcomes of CRE colonized patients compared to matched controls. METHODS: A secondary analysis of a 1:2 matched case-control study at a tertiary hospital in northern Israel (January-2014 to June-2017). Cases were adults who newly acquired CRE colonization during hospitalization. Controls were inpatients negatively screened for CRE, matched by age, hospitalization division and total days of hospitalization 90 days prior to screening. Our primary outcome was 1-year all-cause mortality. Secondary outcomes included 30-day mortality, diagnosis of any clinical infection, overall days of hospital stay and bloodstream infections all in 1-year follow-up. We estimated crude and propensity score weighted estimates for study outcomes. RESULTS: We included a total of 1019 patients: 340 CRE colonized and 679 non-colonized controls. After adjustment, CRE colonization was not associated with increased 1-year mortality (weighted OR 0.98, 95% CI 0.64-1.50, p = 0.936). CRE colonized patients had 1.7 times the odds of clinical infection of any cause (weighted odds ratio (OR) 1.65, 95% CI 1.06-2.56, p = 0.025). CRE colonized patients had increased length of hospital stay compared to controls (weighted OR 1.52, 95%CI 1.10-2.10, p < 0.001) among 1-year survivors. CONCLUSIONS: CRE colonization may not be independently associated with mortality but with higher risk of clinical infections and longer hospital stays. Infection prevention and antimicrobial stewardship are of utmost importance to prevent acquisition and infections in colonized patients.

Frequency of bloodstream infections caused by six key antibiotic-resistant pathogens for prioritization of research and discovery of new therapies in Europe: a systematic review.

BACKGROUND: To prioritize healthcare investments, ranking of infections caused by antibiotic-resistant bacteria should be based on accurate incidence data. OBJECTIVES: We performed a systematic review to estimate frequency measures of antimicrobial resistance for six key bacteria causing bloodstream infections (BSI) in European countries. DATA SOURCES: We searched PubMed, Web of Science, Embase databases, and the ECRAID-Base Epidemiological-Network platform. STUDY ELIGIBILITY CRITERIA: We included studies and surveillance systems assessing resistance-percentage, prevalence, or incidence-density of BSI because of carbapenem-resistant Pseudomonas aeruginosa, Acinetobacter baumannii, Klebsiella pneumoniae, and Escherichia coli, third-generation cephalosporins-resistant E. coli and K. pneumoniae, vancomycin-resistant Enterococcus faecium, and methicillin-resistant Staphylococcus aureus. METHODS: Reviewers independently assessed published data and evaluated study quality with the modified Joanna Briggs Institute critical appraisal tool. Pooled estimates were determined using random effects meta-analysis. Consistency of data was assessed using random effects meta-regression (Wald test, p > 0.05). RESULTS: We identified 271 studies and 52 surveillance systems from 32 European countries. Forty-five studies (16%) reported on BSI, including 180 frequency measures most commonly as resistance-percentage (88, 48.9%). Among 309 frequency measures extracted from 24 (46%) surveillance systems, 278 (89%) were resistance-percentages. Frequency measures of methicillin-resistant S. aureus and vancomycin-resistant E. faecium BSI were more frequently reported from Southern Europe and Western Europe (80%), whereas carbapenem-resistant P. aeruginosa BSI from Northern Europe and Western Europe (88%). Highest resistance-percentages were detected for carbapenem-resistant A. baumannii (66% in Central Eastern Europe) and carbapenem-resistant K. pneumoniae (62.8% in Southern Europe). Pooled estimates showed lower resistance-percentages in community versus healthcare-associated infections and in children versus adults. Estimates from studies and surveillance systems were mostly consistent among European regions. The included data was of medium quality. DISCUSSION: Pathogen-specific frequency measures of antimicrobial resistance in BSI are insufficient to inform antibiotic stewardship and research and development strategies. Improving data collection and standardization of frequency measures is urgently needed.

A systematic review on the excess health risk of antibiotic-resistant bloodstream infections for six key pathogens in Europe.

BACKGROUND: Antimicrobial resistance is a global threat, which requires novel intervention strategies, for which priority pathogens and settings need to be determined. OBJECTIVES: We evaluated pathogen-specific excess health burden of drug-resistant bloodstream infections (BSIs) in Europe. METHODS: A systematic review and meta-analysis. DATA SOURCES: MEDLINE, Embase, and grey literature for the period January 1990 to May 2022. STUDY ELIGIBILITY CRITERIA: Studies that reported burden data for six key drug-resistant pathogens: carbapenem-resistant (CR) Pseudomonas aeruginosa and Acinetobacter baumannii, third-generation cephalosporin or CR Escherichia coli and Klebsiella pneumoniae, methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecium. Excess health outcomes compared with drug-susceptible BSIs or uninfected patients. For MRSA and third-generation cephalosporin E. coli and K. pneumoniae BSIs, five or more European studies were identified. For all others, the search was extended to high-income countries. PARTICIPANTS: Paediatric and adult patients diagnosed with drug-resistant BSI. INTERVENTIONS: Not applicable. ASSESSMENT OF RISK OF BIAS: An adapted version of the Joanna-Briggs Institute assessment tool. METHODS OF DATA SYNTHESIS: Random-effect models were used to pool pathogen-specific burden estimates. RESULTS: We screened 7154 titles, 1078 full-texts and found 56 studies on BSIs. Most studies compared outcomes of drug-resistant to drug-susceptible BSIs (46/56, 82.1%), and reported mortality (55/56 studies, 98.6%). The pooled crude estimate for excess all-cause mortality of drug-resistant versus drug-susceptible BSIs ranged from OR 1.31 (95% CI 1.03-1.68) for CR P. aeruginosa to OR 3.44 (95% CI 1.62-7.32) for CR K. pneumoniae. Pooled crude estimates comparing mortality to uninfected patients were available for vancomycin-resistant Enterococcus and MRSA BSIs (OR of 11.19 [95% CI 6.92-18.09] and OR 6.18 [95% CI 2.10-18.17], respectively). CONCLUSIONS: Drug-resistant BSIs are associated with increased mortality, with the magnitude of the effect influenced by pathogen type and comparator. Future research should address crucial knowledge gaps in pathogen- and infection-specific burdens to guide development of novel interventions.

Risk factors for acquisition of carbapenemase-producing versus non-carbapenemase-producing enterobacterales: a case-control study.

OBJECTIVES: We aimed to assess the association between carbapenem-resistant Enterobacterales (CRE) colonization pressure and carbapenem exposure and acquisition of carbapenemase-producing Enterobacterales (CPE) and non-carbapenemase-producing carbapenem-resistant Enterobacterales (non-CP-CRE). METHODS: We conducted a parallel 1:2 matched case-control study at Rambam Health Care Campus, Israel, from January 2014 to June 2017. The cases included all adults who acquired CPE or non-CP-CRE in hospital. The controls were hospitalized patients who were negative for CRE on screening and matched by age, hospitalization division and the number of hospitalization days 90 days prior to CRE screening. The exposures of interest were high CRE colonization pressure, defined as a higher-than-median proportion of CRE carriers in the concurrent patient's department before acquisition, and carbapenem exposure, assessed as days of treatment. Conditional logistic regression was used for analyses of CPE and non-CP-CRE. RESULTS: In total, 1058 patients were included: 278 CPE and 75 non-CP-CRE cases, matched to 556 and 149 controls, respectively. High CRE colonization pressure was associated with CPE acquisition (adjusted odds ratio [aOR], 2.6; 95% CI, 1.69-4.02); however, the duration of carbapenem treatment was not (aOR, 1.004; 95% CI, 0.98-1.03; 1-day increment). The duration of carbapenem treatment was significantly associated with non-CP-CRE acquisition (aOR per day, 1.07; 95% CI, 1.03-1.11). A source patient was identified significantly more frequently in epidemiological acquisition investigations of CPE than in those of non-CP-CRE (107/240, 44.6% vs. 18/64, 28.1%, respectively; p 0.017). CONCLUSIONS: CPE acquisition was associated with horizontal transmission, whereas non-CP-CRE was associated with carbapenem exposure. Differences in the drivers of acquisition mandate tailored infection prevention efforts.

External Validity of a Randomized Controlled Trial on Duration of Antibiotics for the Treatment of Gram-Negative Bacteremia.

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.

EMBRACE-WATERS statement: Recommendations for reporting of studies on antimicrobial resistance in wastewater and related aquatic environments.

BACKGROUND: A One Health approach requires integrative research to elucidate antimicrobial resistance (AMR) in the environment and the risks it poses to human health. Research on this topic involves experts from diverse backgrounds and professions. Shortcomings exist in terms of consistent, complete, and transparent reporting in many environmental studies. Standardized reporting will improve the quality of scientific papers, enable meta-analyses and enhance the communication among different experts. In this study, we aimed to generate a consensus of reporting standards for AMR research in wastewater and related aquatic environments. METHODS: Based on a risk of bias assessment of the literature in a systematic review, we proposed a set of study quality indicators. We then used a multistep modified Delphi consensus to develop the EMBRACE-WATERS statement (rEporting antiMicroBial ResistAnCE in WATERS), a checklist of recommendations for reporting in studies of AMR in wastewater and related aquatic environments. FINDINGS: Consensus was achieved among a multidisciplinary panel of twenty-one experts in three steps. The developed EMBRACE-WATERS statement incorporates 21 items. Each item contains essential elements of high-quality reporting and is followed by an explanation of their rationale and a reporting-example. The EMBRACE-WATERS statement is primarily intended to be used by investigators to ensure transparent and comprehensive reporting of their studies. It can also guide peer-reviewers and editors in evaluation of manuscripts on AMR in the aquatic environment. This statement is not intended to be used to guide investigators on the methodology of their research. INTERPRETATION: We are hopeful that this statement will improve the reporting quality of future studies of AMR in wastewater and related aquatic environments. Its uptake would generate a common language to be used among researchers from different disciplines, thus advancing the One Health approach towards understanding AMR spread across aquatic environments. Similar initiatives are needed in other areas of One Health research.

The Effect of ß-Blockers for Burn Patients on Clinical Outcomes: Systematic Review and Meta-Analysis.

OBJECTIVES: To assess the effects and safety of ß-blockers in hospitalized patients with burns. METHODS: A systematic review and meta-analysis of the literature. A broad search was conducted to identify all randomized controlled trials (RCTs) comparing ß-blockers to control in hospitalized patients with burns. The primary outcome was 3-month all-cause mortality. Secondary outcomes were clinical patient-relevant end points. We subgrouped results by children/adults and burn severity. Risk of bias was assessed using the individual domain approach. RESULTS: Four RCTs reported in 11 publications were included. Primary outcome of mortality was assessed in children (2 trials, n = 424) and adults (2 trials, n = 148) with severe burns. No significant difference was found between propranolol and control for mortality (risk ratio [RR] = 0.82, 95% CI = 0.48-1.39, 4 trials with broad confidence intervals in adults and children), sepsis (RR = 0.81, 95% CI = 0.46-1.43, 2 trials), and survivors' length of stay (absolute mean difference = 2.53, 95% CI = -2.58-7.63, 3 trials). There was no significant difference in bradycardia (RR = 1.33, 95% CI = 0.77-2.3, 2 trials), hypotension (RR = 1.26, 95% CI = 0.73-2.17, 3 trials), or cardiac arrhythmia (RR: 2.97, 95% CI: 0.12-71.87, 1 trial). The evidence was graded as very low certainty, due to trial's internal risk of bias, imprecision, and possible selective reporting. CONCLUSIONS: No sufficient evidence was found to support or refute an advantage for ß-blocker use in children or adults after burns. Additional studies are needed to create a consensus and formulate practice guidelines on the optimal ß-blocker to use, indications for initiation, and duration of treatment.

Comparison of antibiotic-resistant bacteria and antibiotic resistance genes abundance in hospital and community wastewater: A systematic review.

Antibiotic-resistant bacteria (ARB) and antibiotic-resistance genes (ARGs) are constantly shed into the aquatic environment, with hospital wastewater potentially acting as an important source for resistance spread into the environment. A systematic review was conducted aiming to investigate the role of hospital wastewater on dissemination of antimicrobial resistance in the aquatic environment. Studies included in the review compared the prevalence of ARB and/or ARGs in hospital versus community wastewater. Data were extracted on ARB and/or ARG prevalence. Data on sampling techniques, microbiological methodology and risk of bias of included studies were recorded. Thirty-seven studies were included. Higher frequencies of antibiotic resistance determinants were found in hospital wastewater compared to community sources in 30/37 (81%) of included studies. However, trends for specific multi-drug-resistant bacteria differed. Antibiotic-resistant Gram-negative were more prevalent in hospital compared to community wastewaters, with higher concentrations of extended-spectrum-beta-lactamase-producing pathogens and carbapenemase-producing Enterobacteriaceae in hospital sources in 9/9 studies and 6/7 studies, respectively. Hospitals did not contribute consistently to the abundance of vancomycin-resistant Enterococci (VRE); 5/10 studies found higher abundance of VRE in hospital compared to community wastewaters. Reporting on sampling methods, wastewater treatment processes and statistical analysis were at high risk of bias. Extreme heterogeneity in study methods and outcome reporting precluded meta-analysis. Current evidence concurs that hospital wastewater is an important source for antibiotic resistance in aquatic environments, mainly multidrug-resistant Gram-negative bacteria. Future research is needed to assess the effect of wastewater treatment processes on overall antibiotic resistance in the aquatic environment.

"Risk factors for ventilator-associated pneumonia following cardiac surgery: case-control study".

BACKGROUND: Ventilator-associated pneumonia (VAP) following cardiac surgery is a preventable complication associated with adverse outcomes. AIMS: We aimed to assess risk factors and outcomes of VAP following cardiac surgery. METHODS: A matched 1:3 case:control study, including adult patients undergoing cardiac surgery through sternotomy between Sep-2014 to Mar-2017 was conducted in a tertiary-care hospital in Israel. Cases included all patients developing VAP within 30 days after surgery, defined using consensus criteria. Controls were matched for age, gender and surgery type. Operative data were collected prospectively, other data were collected retrospectively. Cox regression was used for adjusted analysis of matched data. FINDINGS: Out of 946 operated patients, we identified 57 patients with VAP after cardiac surgery (17.7 episodes per 1000 ventilator-days) matched to 149 controls. Significant independent risk factors for VAP included congestive heart failure (OR 2.357 95%CI 1.052-5.281), Chest re-exploration in ICU (OR 10.213 95%CI: 2.235-46.678), preoperative glucose levels (OR 1.1010 per 1 mg/dl increase 95%CI: 1.004-1.019) intraoperative red blood cell transfusions (OR 1.542 per 1 unit 95%CI: 1.109-2.094) and pulmonary hypertension (OR 2.261 95%CI 1.048-6.554). VAP was most commonly caused by Gram-negative pathogens. VAP was associated with higher mortality, longer length of stay, longer need for ventilator support and longer stay in ICU setting. CONCLUSIONS: Postoperative VAP in cardiac surgery patients is associated with severe clinical outcomes. We identified risk factors that can aid in preventive measures implementation for high risk patients.

Risk factors for limb surgical site infection following coronary artery bypass graft using open great saphenous vein harvesting: a retrospective cohort study.

OBJECTIVES: Our goal was to define risk factors for limb (leg) surgical site infections (SSIs) following coronary artery bypass grafting (CABG) with open saphenous vein grafting and to estimate their consequences for patients. METHODS: We performed a retrospective cohort study in a primary and tertiary hospital in Israel that included all adult patients undergoing CABG with open saphenous vein harvesting (November 2014-August 2016). Patients were followed perioperatively from admission until 90 days postoperatively, including post-discharge follow-up. Operative data were collected prospectively. We analysed risk factors for leg SSIs using univariate and multivariate methods. RESULTS: Thirty-six of 351 (10.3%) patients developed leg SSI. Median time to detection was 14 days (interquartile range 11-24) and 25/36 (69.4%) patients were diagnosed after discharge. Independent risk factors for SSI included female sex [odds ratio (OR) 4.08, 95% confidence interval (CI) 1.79-9.28], body mass index >30 (OR 2.12, 95% CI 1.01-4.48), peripheral vascular disease (OR 3.33, 95% CI 1.48-7.49) and use of more than 1 saphenous vein graft (OR 2.08, 95% CI 0.88-4.96). Infected patients had longer hospitalizations after surgery [7 days (5-12) vs 6 days (5-7), P = 0.002], higher antibiotic consumption (P = 0.002) and higher readmission rates of 24/36 (66.7%) vs 59/262 (22.5%) (P < 0.001) than non-infected controls. CONCLUSIONS: Leg SSIs following coronary artery bypass surgery are common and associated with morbidity. We suggest reconsidering open saphenous vein harvesting in obese female patients with peripheral vascular disease.

The use of patch tests in the diagnosis of delayed hypersensitivity drug eruptions.

BACKGROUND: Adverse drug reactions (ADRs) are common. In the absence of a sufficiently sensitive and specific laboratory test, identification of the culprit drug remains a diagnostic challenge. Patch tests have recently been advocated as a means of detecting drug sensitivity. OBJECTIVE: To further elucidate the usefulness of patch tests in revealing the causative drugs of cutaneous ADRs (CADRs). MATERIALS AND METHODS: We conducted a non-blinded, prospective, controlled clinical trial. Twenty-five patients with a history of CADRs were patch tested, and 25 healthy subjects who had never experienced CADRs served as controls. RESULTS: A morbilliform eruption was the most frequent skin reaction. Patch tests were positive in eight of the 25 patients with CADR (32%). Specifically, five of the 13 patients with morbilliform drug eruption (38.4%) tested positive, as did one of the four patients with erythema multiforme/Stevens-Johnson syndrome (25%), and one of the two patients with the drug reaction with eosinophilia and systemic symptoms syndrome. Antibiotics and anticonvulsants resulted in positive patch tests most often. Patch test sensitivity was 32%, specificity was 92%, and negative and positive predictive values were 57.5% and 80%, respectively. Significant correlation was found between the patch test result and the clinical probability of a CADR according to the imputability score of the drug. CONCLUSIONS: Patch testing for drugs causing ADRs shows high specificity rates even though the sensitivity is low. Such tests may therefore be useful in supporting the diagnosis of delayed-type CADRs, particularly when antibiotics or anticonvulsants are involved and the cutaneous reaction is a morbilliform rash.