Amir Nutman1, Jonathan Lellouche2, Elizabeth Temkin2, George Daikos3, Anna Skiada3, Emanuele Durante-Mangoni4, Yael Dishon-Benattar5, Roni Bitterman6, Dafna Yahav7, Vered Daitch7, Mariano Bernardo4, Domenico Iossa4, Oren Zusman8, Lena E Friberg9, Johan W Mouton10, Ursula Theuretzbacher11, Leonard Leibovici12, Mical Paul13, Yehuda Carmeli14. 1. National Institute for Infection Control and Antibiotic Resistance, Tel Aviv Medical Centre, Tel-Aviv, Israel; Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel. Electronic address: amirn@tlvmc.gov.il. 2. National Institute for Infection Control and Antibiotic Resistance, Tel Aviv Medical Centre, Tel-Aviv, Israel. 3. First Department of Medicine, Laikon General Hospital, Athens, Greece; National and Kapodistrian University of Athens, Athens, Greece. 4. Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy; AORN dei Colli-Monaldi Hospital, Naples, Italy. 5. Institute of Infectious Diseases, Rambam Health Care Campus, Haifa, Israel; The Cheryl Spencer Institute for Nursing Research, University of Haifa, Haifa, Israel. 6. Institute of Infectious Diseases, Rambam Health Care Campus, Haifa, Israel. 7. Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel; Infectious Diseases Unit, Rabin Medical Centre, Beilinson Hospital, Petah Tikva, Israel. 8. Department of Medicine E, Rabin Medical Centre, Beilinson Hospital, Peta Tikva, Israel. 9. Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden. 10. Department of Medical Microbiology and Infectious Diseases, Erasmus MC, Rotterdam, Netherlands. 11. Centre for Anti-Infective Agents, Vienna, Austria. 12. Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel; Department of Medicine E, Rabin Medical Centre, Beilinson Hospital, Peta Tikva, Israel. 13. 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. 14. National Institute for Infection Control and Antibiotic Resistance, Tel Aviv Medical Centre, Tel-Aviv, Israel; Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
Abstract
OBJECTIVES: In vitro models showing synergism between polymyxins and carbapenems support combination treatment for carbapenem-resistant Gram-negative (CRGN) infections. We tested the association between the presence of in vitro synergism and clinical outcomes in patients treated withcolistin plus meropenem. METHODS: This was a secondary analysis of AIDA, a randomized controlled trial comparing colistin with colistin-meropenem for severe CRGN infections. We tested in vitro synergism using a checkerboard assay. Based on the fractional inhibitory concentration (ΣFIC) index for each colistin-meropenem combination, we categorized results as synergistic, antagonistic or additive/indifferent. The primary outcome was clinical failure at 14 days. Secondary outcomes were 14- and 28-day mortality and microbiological failure. RESULTS: The sample included 171 patients with infections caused by carbapenem-resistant Acinetobacter baumannii (n = 131), Enterobacteriaceae (n = 37) and Pseudomonas aeuruginosa (n = 3). In vitro testing showed synergism for 73 isolates, antagonism for 20 and additivism/indifference for 78. In patients who received any colistin plus meropenem, clinical failure at 14 days was 59/78 (75.6%) in the additivism/indifference group (reference category), 54/73 (74.0%) in the synergism group (adjusted odds ratio (aOR) 0.76, 95% CI 0.31-1.83), and 11/20 (55%) in the antagonism group (aOR 0.77, 95% CI 0.22-2.73). There was no significant difference between groups for any secondary outcome. Comparing the synergism group to patients treated with colistin monotherapy, synergism was not protective against 14-day clinical failure (aOR 0.52, 95% CI 0.26-1.04) or 14-day mortality (aOR1.09, 95% CI 0.60-1.96). DISCUSSION: In vitro synergism between colistin and meropenem via checkerboard method did not translate into clinical benefit.
RCT Entities:
OBJECTIVES: In vitro models showing synergism between polymyxins and carbapenems support combination treatment for carbapenem-resistant Gram-negative (CRGN) infections. We tested the association between the presence of in vitro synergism and clinical outcomes in patients treated with colistin plus meropenem. METHODS: This was a secondary analysis of AIDA, a randomized controlled trial comparing colistin with colistin-meropenem for severe CRGN infections. We tested in vitro synergism using a checkerboard assay. Based on the fractional inhibitory concentration (ΣFIC) index for each colistin-meropenem combination, we categorized results as synergistic, antagonistic or additive/indifferent. The primary outcome was clinical failure at 14 days. Secondary outcomes were 14- and 28-day mortality and microbiological failure. RESULTS: The sample included 171 patients with infections caused by carbapenem-resistant Acinetobacter baumannii (n = 131), Enterobacteriaceae (n = 37) and Pseudomonas aeuruginosa (n = 3). In vitro testing showed synergism for 73 isolates, antagonism for 20 and additivism/indifference for 78. In patients who received any colistin plus meropenem, clinical failure at 14 days was 59/78 (75.6%) in the additivism/indifference group (reference category), 54/73 (74.0%) in the synergism group (adjusted odds ratio (aOR) 0.76, 95% CI 0.31-1.83), and 11/20 (55%) in the antagonism group (aOR 0.77, 95% CI 0.22-2.73). There was no significant difference between groups for any secondary outcome. Comparing the synergism group to patients treated with colistin monotherapy, synergism was not protective against 14-day clinical failure (aOR 0.52, 95% CI 0.26-1.04) or 14-day mortality (aOR1.09, 95% CI 0.60-1.96). DISCUSSION: In vitro synergism between colistin and meropenem via checkerboard method did not translate into clinical benefit.
Authors: Fabrício Rodrigues Torres de Carvalho; João Paulo Telles; Felipe Francisco Bodan Tuon; Roberto Rabello Filho; Pedro Caruso; Thiago Domingos Correa Journal: Antibiotics (Basel) Date: 2022-03-12