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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. 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. 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). 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. EU AIDA grant Health-F3-2011-278348.

Gram-negative bacteremia is a major cause of morbidity and mortality in hospitalized patients. Data to guide the duration of antibiotic therapy are limited. 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%. 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. 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. NCT01737320.

There is a need for additional therapeutic options for serious infections caused by Gram-negative pathogens. In the phase 3, descriptive REVISIT study, we investigated the safety and efficacy of aztreonam–avibactam in the treatment of complicated intra-abdominal infections or hospital-acquired pneumonia or ventilator-associated pneumonia (HAP–VAP) caused, or suspected to be caused, by Gram-negative bacteria. This prospective, multinational, open-label, central assessor-masked study enrolled adults who were hospitalised with a complicated intra-abdominal infection or HAP–VAP. Patients were randomly allocated via block randomisation using interactive response technology stratified by infection type in a 2:1 ratio to aztreonam–avibactam (with metronidazole for complicated intra-abdominal infection) or meropenem with or without colistin for 5–14 days for complicated intra-abdominal infection or 7–14 days for HAP–VAP. The primary endpoint was clinical cure at the test-of-cure visit (within 3 days before or after day 28) in the intention-to-treat (ITT) population. Secondary endpoints included 28-day mortality in the ITT population and safety in patients in the ITT population who received study drug (safety analysis set). No formal hypothesis testing was planned. The study was registered with ClinicalTrials.gov (NCT03329092) and EudraCT (2017–002742–68) and is complete. Between April 5, 2018, and Feb 23, 2023, we screened 461 patients. 422 patients were enrolled and randomly allocated (282 in the aztreonam–avibactam group and 140 in the meropenem group, forming the ITT analysis set), of whom ten patients (seven in the aztreonam–avibactam group and three in the meropenem group) were randomly allocated but did not receive study treatment. 271 (64%) of 422 patients had at least one Gram-negative pathogen from an adequate specimen identified at baseline. The most frequent baseline pathogens were Enterobacterales (252 [93%] of 271). Overall, 19 (24%) of 80 isolates tested for carbapenemases were carbapenemase-positive (serine, metallo-β-lactamase, or both). 193 (68·4%) of 282 patients in the aztreonam–avibactam group and 92 (65·7%) of 140 in the meropenem group had clinical cure at the test-of-cure visit (treatment difference 2·7% [95% CI –6·6 to 12·4]). For patients with complicated intra-abdominal infection, the adjudicated clinical cure rate was 76·4% (159 of 208) for the aztreonam–avibactam group and 74·0% (77 of 104) for the meropenem group. Cure rates in patients with HAP–VAP were 45·9% (34 of 74) for aztreonam–avibactam and 41·7% (15 of 36) for meropenem. 28-day all-cause mortality rates were 4% (12 of 282) for aztreonam–avibactam and 7% (ten of 140) for meropenem; in patients with complicated intra-abdominal infection, mortality was 2% (four of 208) and 3% (three of 104) for aztreonam–avibactam and meropenem, respectively, and in patients with HAP–VAP, mortality was 11% (eight of 74) and 19% (seven of 36), respectively. Aztreonam–avibactam was generally well tolerated, and safety findings were consistent with the known safety profile of aztreonam monotherapy. There were no treatment-related serious adverse events in the aztreonam–avibactam group. These phase 3 efficacy and safety data provide support for aztreonam–avibactam as a potential therapeutic option for complicated intra-abdominal infection or HAP–VAP caused by Gram-negative bacteria. Pfizer.

Background Novel, rapid blood culture diagnostics can provide faster antibiotic susceptibility results (AST) compared to standard methods but their impact on clinical outcomes is unclear and not assessed in many prospective clinical trials. Methods This study is a two-arm, multicenter, multinational, prospective randomized controlled clinical trial conducted in countries with high antibiotic resistance rates including Greece, India, Israel, and Spain. Nine hundred hospitalized subjects who have blood cultures collected as part of routine clinical care with growth of Gram-negative bacilli (GNB) will be randomized 1:1 to blood culture evaluation using standard of care (SOC) AST vs. a rapid phenotypic AST method, VITEK REVEAL™ in addition to SOC AST. Subjects in both study arms will be reviewed by antibiotic stewardship clinicians who will recommend changes to antibiotic therapy, if indicated. The primary outcome is a composite three-category Desirability of Outcome Ranking (DOOR) defined using three ordered levels: alive without deleterious events, alive with at least one deleterious event, and death. Key secondary outcomes include mortality, length of stay, and time to antibiotic escalation or de-escalation within 3 days of randomization. Exploratory outcomes include a five-category DOOR, categorial agreement between VITEK REVEAL™ and SOC testing, clinician compliance with antibiotic stewardship recommendations, and desirability of treatment selection based on antibiotic spectrum, activity, and bloodstream isolate susceptibility profile (DOOR MAT). The primary analysis will be conducted on the modified intention-to-treat population. Discussion This trial will evaluate whether use of a rapid phenotypic AST method improves outcomes compared to use of conventional methods for patients with Gram-negative bloodstream infections in clinical settings with high antibiotic resistance rates. Trial registration ClinicalTrials.gov ID NCT06174649. Registered on Dec 18 2023. Protocol version Number 20-0021, version 5.0, 11-April-2024.

Whether antibiotic rotation strategies reduce prevalence of antibiotic-resistant, Gram-negative bacteria in intensive care units (ICUs) has not been accurately established. We aimed to assess whether cycling of antibiotics compared with a mixing strategy (changing antibiotic to an alternative class for each consecutive patient) would reduce the prevalence of antibiotic-resistant, Gram-negative bacteria in European intensive care units (ICUs). In a cluster-randomised crossover study, we randomly assigned ICUs to use one of three antibiotic groups (third-generation or fourth-generation cephalosporins, piperacillin–tazobactam, and carbapenems) as preferred empirical treatment during 6-week periods (cycling) or to change preference after every consecutively treated patient (mixing). Computer-based randomisation of intervention and rotated antibiotic sequence was done centrally. Cycling or mixing was applied for 9 months; then, following a washout period, the alternative strategy was implemented. We defined antibiotic-resistant, Gram-negative bacteria as Enterobacteriaceae with extended-spectrum β-lactamase production or piperacillin–tazobactam resistance, and Acinetobacter spp and Pseudomonas aeruginosa with piperacillin–tazobactam or carbapenem resistance. Data were collected for all admissions during the study. The primary endpoint was average, unit-wide, monthly point prevalence of antibiotic-resistant, Gram-negative bacteria in respiratory and perineal swabs with adjustment for potential confounders. This trial is registered with ClinicalTrials.gov, number NCT01293071. Eight ICUs (from Belgium, France, Germany, Portugal, and Slovenia) were randomly assigned and patients enrolled from June 27, 2011, to Feb 16, 2014. 4069 patients were admitted during the cycling periods in total and 4707 were admitted during the mixing periods. Of these, 745 patients during cycling and 853 patients during mixing were present during the monthly point-prevalence surveys, and were included in the main analysis. Mean prevalence of the composite primary endpoint was 23% (168/745) during cycling and 22% (184/853) during mixing (p=0·64), yielding an adjusted incidence rate ratio during mixing of 1·039 (95% CI 0·837–1·291; p=0·73). There was no difference in all-cause in-ICU mortality between intervention periods. Antibiotic cycling does not reduce the prevalence of carriage of antibiotic-resistant, Gram-negative bacteria in patients admitted to the ICU. European Union Seventh Framework Programme.

The risk of bacteremia is considered low in children with acute bronchiolitis. However the rate of occult bacteremia in infants with RSV infection is not well established. The aim was to determine the actual rate and predictive factors of bacteremia in children admitted to hospital due to confirmed RSV acute respiratory illness (ARI), using both conventional culture and molecular techniques. A prospective multicenter study (GENDRES-network) was conducted between 2011-2013 in children under the age of two admitted to hospital because of an ARI. Among those RSV-positive, bacterial presence in blood was assessed using PCR for Meningococcus, Streptococcus pneumoniae, Haemophilus influenzae, Streptococcus pyogenes, Klebsiella pneumoniae, Pseudomonas aeruginosa, Escherichia coli, and Staphylococcus aureus, in addition to conventional cultures. 66 children with positive RSV respiratory illness were included. In 10.6% patients, bacterial presence was detected: H. influenzae (n = 4) and S. pneumoniae (n = 2). In those patients with bacteremia, there was a previous suspicion of bacterial superinfection and had received empirical antibiotic treatment 6 out of 7 (85.7%) patients. There were significant differences in terms of severity between children with positive bacterial PCR and those with negative results: PICU admission (100% vs. 50%, P-value = 0.015); respiratory support necessity (100% vs. 18.6%, P-value < 0.001); Wood-Downes score (mean = 8.7 vs. 4.8 points, P-value < 0.001); GENVIP scale (mean = 17 vs. 10.1, P-value < 0.001); and length of hospitalization (mean = 12.1 vs. 7.5 days, P-value = 0.007). Bacteremia is not frequent in infants hospitalized with RSV respiratory infection, however, it should be considered in the most severe cases.

Infections caused by extended-spectrum beta-lactamases (ESBL) producing Gram-negative bacteria has emerge as a global threat in clinical practices. The treat is more serious in developing countries due to inappropriate use, poor adherence, use of counterfeit, sub-standard antibiotics and poor infection control practices. Data on ESBL producing Gram-negative bacteria are limited in developing countries including Ethiopia. The aim of this study was therefore, to describe the burden of ESBL producing Gram negative pathogens isolated from patients attending at Felege Hiwot Comprehensive Specialized Hospital, Bahir Dar, Amhara region. A total of 532 clinical samples of blood, urine, stool, wound, abscess, ear discharge, nasal discharge, cervical discharge and body fluid specimens were aseptically collected and bacteriologically processed. Identification of the bacterial species was performed using an automated system (Vitek-2 Compact 27530, USA) and antibiotic susceptibility test was determined by disk diffusion method and selection of antibiotics were in accordance with CLSI guidelines. The MDR pattern of the Gram-negative pathogens was assessed using phenotypic methods of ESBL and carbapenemase production following standard procedure. A total of 532 samples were processed and 263 pathogens were isolated. Of these, 185 (70.3%) were Gram-negative and 78 (29.7%) Gram-positive. Of the Gram-negative bacteria the high proportion of the isolates were identified from blood 146/185 (78.9%) and 29/185 (15.7%) were from urine cultures. The most common isolate in all clinical samples was Klebsiella pneumoniae 97/185 (52.4%) followed by Escherichia coli 23/185 (12.4%), Acinetobacter baumannii 15/185 (17.6%) and Enterobacter aerogenes 12/185(6.5%). Of the total Gram negatives, the prevalence of MDR was 148/185 (80.0%). Of the MDR isolates the prevalence of ESBL producers were, 127/148 (85.8%) and 24/148 (16.2%) were carbapenemase producers. Prevalence of MDR and ESBL producing Gram-negative pathogens in this hospital is alarmingly high. Therefore, continuous monitoring of the problem with effective infection prevention and careful selection of empirical therapy are warranted in the study area.

Carbapenem-resistant Gram-negative (CRGN) bacterial infections are an urgent health threat, especially in low-income and middle-income countries (LMICs), where they are rarely detected and might not be treated appropriately given inadequate health system capacity. To understand this treatment gap, we estimated the total number of CRGN bacterial infections requiring an active agent and the number of individuals potentially initiated on appropriate treatment in eight large LMICs. For eight selected countries (Bangladesh, Brazil, Egypt, India, Kenya, Mexico, Pakistan, and South Africa), we estimated deaths associated with CRGN bacterial infections (that were not susceptible to other antibiotics) in 2019 using data from the Global Burden of Disease 2021 study on antimicrobial resistance. We used estimates from the literature to establish infection type-specific case fatality rates and an overall case fatality rate for CRGN bacterial infections. The total number of CRGN bacterial infections requiring an active agent could then be calculated by dividing the total number of CRGN bacterial infection-related deaths by the overall case fatality rate. We estimated the treatment gap (ie, the number of individuals with CRGN bacterial infections who were not appropriately treated) by subtracting from the total number of infections the number of individuals who initiated appropriate treatment, which was estimated using 2019 IQVIA sales data for six antibiotics active against CRGN bacteria, corrected to account for IQVIA's partial data coverage for each country and dose-adjusted by age. In 2019, in the eight selected countries, we estimated that there were 1 496 219 CRGN bacterial infections (95% CI 1 365 392–1 627 047) but that only 103 647 treatment courses were procured. The resulting treatment gap (1 392 572 cases [95% CI 1 261 745–1 523 400]) meant that only 6·9% of patients were treated appropriately. The treatment gap persisted even when we used more restrictive assumptions. The most-procured antibiotic was tigecycline (intravenous; 47 531 [45·9%] of 103 647 courses). India procured most of the treatment courses (83 468 [80·5%] courses), with 7·8% of infections treated appropriately (treatment gap 982 848 cases [95% CI 909 291–1 056 405]). The rates of appropriate treatment coverage were highest in Mexico (5634 [5·4%] courses procured; treatment gap 32 141 cases [30 416–33 867]) and Egypt (7572 [7·3%] courses procured; treatment gap 43 258 cases [38 742–47 774]), both with 14·9% of infections treated appropriately. Infections caused by CRGN bacteria are likely to be significantly undertreated in LMICs. To close this treatment gap, improved access to diagnostics and antibiotics, strengthening of health systems, and research to identify gaps in the treatment pathway are needed. Global Antibiotic Research and Development Partnership, supported by the Governments of Canada, Germany, Japan, Monaco, the Netherlands, Switzerland, and the UK, and by the Canton of Geneva, the EU, the Bill & Melinda Gates Foundation, Global Health EDCTP3, GSK, the RIGHT Foundation, the South African Medical Research Council, and Wellcome.

Key Points Multidrug-resistant Gram-negative pathogens are rapidly emerging and spreading globally These multidrug-resistant pathogens are frequently associated with major pathologies, including urinary tract infections Routine urological practices are affected by multidrug-resistant pathogens Knowledge of the local epidemiology of multidrug-resistant Gram-negative bacteria is essential for determining empirical antimicrobial therapy Urinary tract infections (UTIs) are very common and are a major contributor to global antibiotic use and resistance. Without effective antibiotics active against common uropathogens, many urological procedures would carry excessive risk. In this article, Zowawi and coauthors describe the current global epidemiology of resistance in Gram-negative uropathogens and discuss the genetic and molecular mechanisms underlying the resistance of these phenotypes. They also examine the effect of resistance on common urological procedures and summarize various preventive and therapeutic options. Antibiotic resistance in Gram-negative uropathogens is a major global concern. Worldwide, the prevalence of Enterobacteriaceae that produce extended-spectrum β-lactamase or carbapenemase enzymes continues to increase at alarming rates. Likewise, resistance to other antimicrobial agents including aminoglycosides, sulphonamides and fluoroquinolones is also escalating rapidly. Bacterial resistance has major implications for urological practice, particularly in relation to catheter-associated urinary tract infections (UTIs) and infectious complications following transrectal-ultrasonography-guided biopsy of the prostate or urological surgery. Although some new drugs with activity against Gram-negative bacteria with highly resistant phenotypes will become available in the near future, the existence of a single agent with activity against the great diversity of resistance is unlikely. Responding to the challenges of Gram-negative resistance will require a multifaceted approach including considered use of current antimicrobial agents, improved diagnostics (including the rapid detection of resistance) and surveillance, better adherence to basic measures of infection prevention, development of new antibiotics and research into non-antibiotic treatment and preventive strategies.

Klebsiella pneumoniae, Acinetobacter species, and Pseudomonas aeruginosa are priority pathogens identified by the World Health Organization that have emerged as major causes of healthcare-associated infections. Their increasing resistance to multiple antimicrobial agents poses significant challenges to clinical management and infection control efforts. This study aimed to determine the prevalence, associated risk factors, antimicrobial resistance patterns, and carbapenemase production of K. pneumoniae, Acinetobacter spp., and P. aeruginosa among hospitalized patients with suspected bloodstream, urinary tract, and surgical site healthcare-associated infections at the University of Gondar Comprehensive Specialized Hospital, Northwest Ethiopia. A hospital-based cross-sectional study was conducted from August 2024 to June 2025 among 477 patients suspected of bloodstream, urinary tract, or surgical site healthcare-associated infections. Socio-demographic and clinical data were collected using a semi-structured questionnaire. Blood, urine, and wound/pus specimens were aseptically collected and inoculated on MacConkey, blood, and cysteine lactose electrolyte-deficient agar following standard microbiological techniques. Antimicrobial susceptibility testing was performed using the Kirby-Bauer disc diffusion method on Mueller-Hinton agar according to Clinical and Laboratory Standards Institute guidelines. Data were analyzed using SPSS version 27. Bivariate and multivariate logistic regression analyzes were used to identify factors associated with healthcare-associated infections. P value < 0.05 was considered statistically significant. Among the 477 patients, 118 (24.7%) developed healthcare-associated infections caused by K. pneumoniae, Acinetobacter spp., and P. aeruginosa, with culture positivity rates of 14.9%, 4.8%, and 5%, respectively. Significant associated factors included age under five (AOR = 13.260, p < 0.001) and 5-17 (AOR = 4.081, p < 0.025), prior hospital admission (AOR = 8.302, p < 0.001), prolonged hospital stay (AOR = 3.213, p < 0.001), and admission to the orthopedic ward (AOR = 6.071, p < 0.003). Multidrug resistance was detected in 94.4% of K. pneumoniae, 69.6% of Acinetobacter spp., and 58.3% of P. aeruginosa isolates. Carbapenemase production occurred in 92%, 77.8%, and 57.1% of these carbapenem-resistant isolates, respectively. Amikacin, meropenem, and ciprofloxacin were the most effective antimicrobials, whereas chloramphenicol was effective only against K. pneumoniae. This study showed high prevalence of multidrug resistance and carbapenemase production among K. pneumoniae, Acinetobacter spp., and P. aeruginosa in the study area, highlighting the urgent need to strengthen infection prevention and control measures and to promote antimicrobial stewardship programs.