Pleun Joppe van Duijn1, Walter Verbrugghe2, Philippe Germaine Jorens2, Fabian Spöhr3, Dirk Schedler3, Maria Deja4, Andreas Rothbart5, Djillali Annane6, Christine Lawrence7, Jean-Claude Nguyen Van8, Benoit Misset9, Matjaz Jereb10, Katja Seme11, Franc Šifrer12, Viktorija Tomiç13, Francisco Estevez14, Jandira Carneiro14, Stephan Harbarth15, Marinus Johannes Cornelis Eijkemans16, Marc Bonten17. 1. Department of Epidemiology, Julius Center for Health Sciences and Primary Care, Utrecht, Netherlands. Electronic address: joppe.vanduijn@gmail.com. 2. Department of Critical Care Medicine, Antwerp University Hospital, Antwerp, Belgium. 3. Klinik für Anästhesiologie und Operative Intensivmedizin, Uniklinik Köln, Cologne, Germany. 4. Klinik für Anästhesiologie und Intensivmedizin, Universitätsklinikum Schleswig-Holstein, Lübeck, Germany. 5. Department of Anesthesiology and Operative Intensive Care Medicine (CCM, CVK), Charité Universitätsmedizin, Berlin, Germany. 6. General Intensive Care Unit, Raymond-Poincaré Hospital, Garches, France. 7. Microbiology Unit, Raymond-Poincaré Hospital, Garches, France. 8. Unité de Microbiologie Clinique, Groupe Hospitalier Paris Saint Joseph, Paris, France. 9. Intensive Care Unit, Charles Nicolle University Hospital, Rouen, France. 10. Department of Infectious Diseases, University Medical Centre, Ljubljana, Slovenia. 11. Faculty of Medicine, Institute of Microbiology and Immunology, University of Ljubljana, Ljubljana, Slovenia. 12. Department of Intensive Care Medicine, Klinika Golnik, Golnik, Slovenia. 13. Department of Medical Microbiology, Klinika Golnik, Golnik, Slovenia. 14. Intensive Care Unit and Emergency Department, Centro Hospitalar Trás-os-Montes e Alto Douro, Vila Real, Portugal. 15. Infection Control Program, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland. 16. Department of Biostatistics and Research Support, Julius Center for Health Sciences and Primary Care, Utrecht, Netherlands. 17. Department of Epidemiology, Julius Center for Health Sciences and Primary Care, Utrecht, Netherlands; Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, Netherlands.
Abstract
BACKGROUND: 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). METHODS: 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. FINDINGS: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. INTERPRETATION: Antibiotic cycling does not reduce the prevalence of carriage of antibiotic-resistant, Gram-negative bacteria in patients admitted to the ICU. FUNDING: European Union Seventh Framework Programme.
RCT Entities:
BACKGROUND: 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). METHODS: 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. FINDINGS: 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. INTERPRETATION: Antibiotic cycling does not reduce the prevalence of carriage of antibiotic-resistant, Gram-negative bacteria in patients admitted to the ICU. FUNDING: European Union Seventh Framework Programme.
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