In vivo fitness of carbapenem-resistant Acinetobacter baumannii strains in murine infection is associated with treatment failure in human infections.
Amir Nutman, Elizabeth Temkin, Jonathan Lellouche, Nadya Rakovitsky, Amichay Hameir, George Daikos, Emanuele Durante-Mangoni, Ioannis Pavleas, Yael Dishon, Neta Petersiel, Dafna Yahav, Noa Eliakim, Mariano Bernardo, Domenico Iossa, Lena E Friberg, Ursula Theuretzbacher, Leonard Leibovici, Mical Paul, Yehuda Carmeli, AIDA Study Group
Author Information
Amir Nutman: Division of Epidemiology and Preventive Medicine, Tel Aviv Sourasky Medical Centre, Tel Aviv, Israel; National Institute for Antibiotic Resistance and Infection Control, Israel Ministry of Health, Tel Aviv, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. Electronic address: amirn@tlvmc.gov.il.
Elizabeth Temkin: Division of Epidemiology and Preventive Medicine, Tel Aviv Sourasky Medical Centre, Tel Aviv, Israel; National Institute for Antibiotic Resistance and Infection Control, Israel Ministry of Health, Tel Aviv, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
Jonathan Lellouche: National Institute for Antibiotic Resistance and Infection Control, Israel Ministry of Health, Tel Aviv, Israel.
Nadya Rakovitsky: National Institute for Antibiotic Resistance and Infection Control, Israel Ministry of Health, Tel Aviv, Israel.
Amichay Hameir: National Institute for Antibiotic Resistance and Infection Control, Israel Ministry of Health, Tel Aviv, Israel.
George Daikos: First Department of Medicine, Laikon General Hospital, National and Kapodistrian University of Athens, Athens, Greece.
Emanuele Durante-Mangoni: Department of Precision Medicine, University of Campania "Luigi Vanvitelli", AORN Dei Colli-Monaldi Hospital, Napoli, Italy.
Ioannis Pavleas: Intensive Care Unit, Laikon General Hospital, Athens, Greece.
Yael Dishon: Institute of Infectious Diseases, Rambam Health Care Campus, Haifa, Israel; The Cheryl Spencer Institute for Nursing Research, University of Haifa, Haifa, Israel.
Neta Petersiel: Institute of Infectious Diseases, Rambam Health Care Campus, Haifa, Israel.
Dafna Yahav: Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; Infectious Diseases Unit, Rabin Medical Centre, Beilinson Hospital, Petah Tikva, Israel.
Noa Eliakim: Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; Department of Medicine E, Rabin Medical Centre, Beilinson Hospital, Petah Tikva, Israel.
Mariano Bernardo: Department of Precision Medicine, University of Campania "Luigi Vanvitelli", AORN Dei Colli-Monaldi Hospital, Napoli, Italy.
Domenico Iossa: Department of Precision Medicine, University of Campania "Luigi Vanvitelli", AORN Dei Colli-Monaldi Hospital, Napoli, Italy.
Lena E Friberg: Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
Ursula Theuretzbacher: Centre for Anti-Infective Agents, Vienna, Austria.
Leonard Leibovici: Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; Department of Medicine E, Rabin Medical Centre, Beilinson Hospital, Petah Tikva, Israel.
Mical Paul: Institute of Infectious Diseases, Rambam Health Care Campus, Haifa, Israel; The Ruth and Bruce Rappaport Faculty of Medicine, Techion - Israel Institute of Technology, Haifa, Israel.
Yehuda Carmeli: Division of Epidemiology and Preventive Medicine, Tel Aviv Sourasky Medical Centre, Tel Aviv, Israel; National Institute for Antibiotic Resistance and Infection Control, Israel Ministry of Health, Tel Aviv, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
OBJECTIVES: Mortality among patients with carbapenem-resistant Acinetobacter baumannii (CRAB) infections varies between studies. We examined whether in vivo fitness of CRAB strains is associated with clinical outcomes in patients with CRAB infections. METHODS: Isolates were collected from patients enrolled in the AIDA trial with hospital-acquired pneumonia, bloodstream infections and/or urinary tract infections caused by CRAB. The primary outcome was 14-day clinical failure, defined as failure to meet all criteria: alive; haemodynamically stable; improved or stable Sequential Organ Failure Assessment (SOFA) score; improved or stable oxygenation; and microbiological cure of bacteraemia. The secondary outcome was 14-day mortality. We tested in vivo growth using a neutropenic murine thigh infection model. Fitness was defined based on the CFU count 24 hours after injection of an inoculum of 10 CFU. We used mixed-effects logistic regression to test the association between fitness and the two outcomes. RESULTS: The sample included 266 patients; 215 (80.8%) experienced clinical failure. CRAB fitness ranged from 5.23 to 10.08 log CFU/g. The odds of clinical failure increased by 62% for every 1-log CFU/g increase in fitness (OR 1.62, 95% CI 1.04-2.52). After adjusting for age, Charlson score, SOFA score and acquisition in the intensive care unit, fitness remained significant (adjusted OR 1.63, 95% CI 1.03-2.59). CRAB fitness had a similar effect on 14-day mortailty, although the association was not statistically significant (OR 1.56, 95% CI 0.95-2.57). It became significant after adjusting for age, Charlson score, SOFA score and recent surgery (adjusted OR 1.88, 95% CI 1.09-3.25). CONCLUSIONS: In vivo CRAB fitness was associated with clinical failure in patients with CRAB infection.
