Belén Gutiérrez-Gutiérrez1, Elena Salamanca1, Marina de Cueto1, Po-Ren Hsueh2, Pierluigi Viale3, José Ramón Paño-Pardo4, Mario Venditti5, Mario Tumbarello6, George Daikos7, Rafael Cantón8, Yohei Doi9, Felipe Francisco Tuon10, Ilias Karaiskos11, Elena Pérez-Nadales12, Mitchell J Schwaber13, Özlem Kurt Azap14, Maria Souli15, Emmanuel Roilides16, Spyros Pournaras17, Murat Akova18, Federico Pérez19, Joaquín Bermejo20, Antonio Oliver21, Manel Almela22, Warren Lowman23, Benito Almirante24, Robert A Bonomo25, Yehuda Carmeli13, David L Paterson26, Alvaro Pascual27, Jesús Rodríguez-Baño28. 1. Unidad Clínica de Enfermedades Infecciosas y Microbiología, Hospital Universitario Virgen Macarena, Instituto de Biomedicina de Sevilla, Universidad de Sevilla, Seville, Spain. 2. National Taiwan University Hospital, Zhongzheng District, Taipei City, Taiwan. 3. Teaching Hospital Policlinico S Orsola Malpighi, Bologna, Italy. 4. Hospital Universitario La Paz-Instituto de Investigación Hospital Universitario La Paz, Madrid, Spain; Hospital Clínico Universitario "Lozano Blesa"-Instituto de Investigación Sanitaria Aragón, Zaragoza, Spain. 5. Policlinico Umberto I, University of Rome La Sapienza, Rome, Italy. 6. Infectious Diseases Department, Catholic University of the Sacred Heart, Rome, Italy. 7. Laikon General Hospital, National and Kapodistrian University of Athens, Athens, Greece. 8. Hospital Ramón y Cajal, Madrid, Spain. 9. Infectious Diseases Division, University of Pittsburgh, Pittsburgh, PA, USA. 10. Hospital da Universidade Federal do Parana, Curitiba, Brazil. 11. Hygeia General Hospital, Athens, Greece. 12. Hospital Universitario Reina Sofía-Instituto Maimónides de Investigación Biomédica de Córdoba, Córdoba, Spain; Unidad Clínica de Enfermedades Infecciosas, University of Córdoba, Córdoba, Spain. 13. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; National Center for Infection Control, Israel Ministry of Health, Tel Aviv, Israel. 14. Baskent University Faculty of Medicine, Ankara, Turkey. 15. University General Hospital Attikon, Chaidiri, Greece. 16. Hippokration Hospital Thessaloniki, Thessaloniki, Greece. 17. Medical School, National and Kapodistrian University of Athens, Athens, Greece. 18. Hacettepe University School of Medicine, Ankara, Turkey. 19. Research Service, Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, OH, USA. 20. Hospital Español, Rosario, Argentina. 21. Hospital Universitario Son Espases, Palma de Mallorca, Spain. 22. Hospital Clinic, Barcelona, Spain. 23. Wits Donald Gordon Medical Centre, Johannesburg, South Africa. 24. Hospital Vall d'Hebrón, Barcelona, Spain. 25. Research Service, Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, OH, USA; Department of Medicine, Department of Pharmacology, Department of Biochemistry, and Department of Molecular Biology and Microbiology, Case Western Reserve University School of Medicine, Cleveland, OH, USA. 26. University of Queensland Centre for Clinical Research, University of Queensland, Herston, Brisbane, QLD, Australia. 27. Unidad Clínica de Enfermedades Infecciosas y Microbiología, Hospital Universitario Virgen Macarena, Instituto de Biomedicina de Sevilla, Universidad de Sevilla, Seville, Spain; Departamento de Microbiología, Universidad de Sevilla, Seville, Spain. 28. Unidad Clínica de Enfermedades Infecciosas y Microbiología, Hospital Universitario Virgen Macarena, Instituto de Biomedicina de Sevilla, Universidad de Sevilla, Seville, Spain; Departamento de Medicina, Universidad de Sevilla, Seville, Spain. Electronic address: jesusrb@us.es.
Abstract
BACKGROUND: The best available treatment against carbapenemase-producing Enterobacteriaceae (CPE) is unknown. The objective of this study was to investigate the effect of appropriate therapy and of appropriate combination therapy on mortality of patients with bloodstream infections (BSIs) due to CPE. METHODS: In this retrospective cohort study, we included patients with clinically significant monomicrobial BSIs due to CPE from the INCREMENT cohort, recruited from 26 tertiary hospitals in ten countries. Exclusion criteria were missing key data, death sooner than 24 h after the index date, therapy with an active antibiotic for at least 2 days when blood cultures were taken, and subsequent episodes in the same patient. We compared 30 day all-cause mortality between patients receiving appropriate (including an active drug against the blood isolate and started in the first 5 days after infection) or inappropriate therapy, and for patients receiving appropriate therapy, between those receiving active monotherapy (only one active drug) or combination therapy (more than one). We used a propensity score for receiving combination therapy and a validated mortality score (INCREMENT-CPE mortality score) to control for confounders in Cox regression analyses. We stratified analyses of combination therapy according to INCREMENT-CPE mortality score (0-7 [low mortality score] vs 8-15 [high mortality score]). INCREMENT is registered with ClinicalTrials.gov, number NCT01764490. FINDINGS: Between Jan 1, 2004, and Dec 31, 2013, 480 patients with BSIs due to CPE were enrolled in the INCREMENT cohort, of whom we included 437 (91%) in this study. 343 (78%) patients received appropriate therapy compared with 94 (22%) who received inappropriate therapy. The most frequent organism was Klebsiella pneumoniae (375 [86%] of 437; 291 [85%] of 343 patients receiving appropriate therapy vs 84 [89%] of 94 receiving inappropriate therapy) and the most frequent carbapenemase was K pneumoniae carbapenemase (329 [75%]; 253 [74%] vs 76 [81%]). Appropriate therapy was associated with lower mortality than was inappropriate therapy (132 [38·5%] of 343 patients died vs 57 [60·6%] of 94; absolute difference 22·1% [95% CI 11·0-33·3]; adjusted hazard ratio [HR] 0·45 [95% CI 0·33-0·62]; p<0·0001). Among those receiving appropriate therapy, 135 (39%) received combination therapy and 208 (61%) received monotherapy. Overall mortality was not different between those receiving combination therapy or monotherapy (47 [35%] of 135 vs 85 [41%] of 208; adjusted HR 1·63 [95% CI 0·67-3·91]; p=0·28). However, combination therapy was associated with lower mortality than was monotherapy in the high-mortality-score stratum (30 [48%] of 63 vs 64 [62%] of 103; adjusted HR 0·56 [0·34-0·91]; p=0·02), but not in the low-mortality-score stratum (17 [24%] of 72 vs 21 [20%] of 105; adjusted odds ratio 1·21 [0·56-2·56]; p=0·62). INTERPRETATION: Appropriate therapy was associated with a protective effect on mortality among patients with BSIs due to CPE. Combination therapy was associated with improved survival only in patients with a high mortality score. Patients with BSIs due to CPE should receive active therapy as soon as they are diagnosed, and monotherapy should be considered for those in the low-mortality-score stratum. FUNDING: Spanish Network for Research in Infectious Diseases, European Development Regional Fund, Instituto de Salud Carlos III, and Innovative Medicines Initiative.
BACKGROUND: The best available treatment against carbapenemase-producing Enterobacteriaceae (CPE) is unknown. The objective of this study was to investigate the effect of appropriate therapy and of appropriate combination therapy on mortality of patients with bloodstream infections (BSIs) due to CPE. METHODS: In this retrospective cohort study, we included patients with clinically significant monomicrobial BSIs due to CPE from the INCREMENT cohort, recruited from 26 tertiary hospitals in ten countries. Exclusion criteria were missing key data, death sooner than 24 h after the index date, therapy with an active antibiotic for at least 2 days when blood cultures were taken, and subsequent episodes in the same patient. We compared 30 day all-cause mortality between patients receiving appropriate (including an active drug against the blood isolate and started in the first 5 days after infection) or inappropriate therapy, and for patients receiving appropriate therapy, between those receiving active monotherapy (only one active drug) or combination therapy (more than one). We used a propensity score for receiving combination therapy and a validated mortality score (INCREMENT-CPE mortality score) to control for confounders in Cox regression analyses. We stratified analyses of combination therapy according to INCREMENT-CPE mortality score (0-7 [low mortality score] vs 8-15 [high mortality score]). INCREMENT is registered with ClinicalTrials.gov, number NCT01764490. FINDINGS: Between Jan 1, 2004, and Dec 31, 2013, 480 patients with BSIs due to CPE were enrolled in the INCREMENT cohort, of whom we included 437 (91%) in this study. 343 (78%) patients received appropriate therapy compared with 94 (22%) who received inappropriate therapy. The most frequent organism was Klebsiella pneumoniae (375 [86%] of 437; 291 [85%] of 343 patients receiving appropriate therapy vs 84 [89%] of 94 receiving inappropriate therapy) and the most frequent carbapenemase was K pneumoniae carbapenemase (329 [75%]; 253 [74%] vs 76 [81%]). Appropriate therapy was associated with lower mortality than was inappropriate therapy (132 [38·5%] of 343 patients died vs 57 [60·6%] of 94; absolute difference 22·1% [95% CI 11·0-33·3]; adjusted hazard ratio [HR] 0·45 [95% CI 0·33-0·62]; p<0·0001). Among those receiving appropriate therapy, 135 (39%) received combination therapy and 208 (61%) received monotherapy. Overall mortality was not different between those receiving combination therapy or monotherapy (47 [35%] of 135 vs 85 [41%] of 208; adjusted HR 1·63 [95% CI 0·67-3·91]; p=0·28). However, combination therapy was associated with lower mortality than was monotherapy in the high-mortality-score stratum (30 [48%] of 63 vs 64 [62%] of 103; adjusted HR 0·56 [0·34-0·91]; p=0·02), but not in the low-mortality-score stratum (17 [24%] of 72 vs 21 [20%] of 105; adjusted odds ratio 1·21 [0·56-2·56]; p=0·62). INTERPRETATION: Appropriate therapy was associated with a protective effect on mortality among patients with BSIs due to CPE. Combination therapy was associated with improved survival only in patients with a high mortality score. Patients with BSIs due to CPE should receive active therapy as soon as they are diagnosed, and monotherapy should be considered for those in the low-mortality-score stratum. FUNDING: Spanish Network for Research in Infectious Diseases, European Development Regional Fund, Instituto de Salud Carlos III, and Innovative Medicines Initiative.
Authors: D C Richter; T Brenner; A Brinkmann; B Grabein; M Hochreiter; A Heininger; D Störzinger; J Briegel; M Pletz; M A Weigand; C Lichtenstern Journal: Anaesthesist Date: 2019-10 Impact factor: 1.041
Authors: Marco Falcone; Giusy Tiseo; Emanuele Durante-Mangoni; Veronica Ravasio; Francesco Barbaro; Maria Paola Ursi; Maria Bruna Pasticci; Matteo Bassetti; Paolo Grossi; Mario Venditti; Marco Rizzi Journal: Antimicrob Agents Chemother Date: 2018-03-27 Impact factor: 5.191