TY - JOUR
T1 - Short-term effects of appropriate empirical antimicrobial treatment with ceftolozane/tazobactam in a swine model of nosocomial pneumonia
AU - Motos, Ana
AU - Li Bassi, Gianluigi
AU - Pagliara, Francesco
AU - Fernandez-Barat, Laia
AU - Yang, Hua
AU - Xiol, Eli Aguilera
AU - Senussi, Tarek
AU - Idone, Francesco A.
AU - Travierso, Chiara
AU - Chiurazzi, Chiara
AU - Amaro, Rosanel
AU - Yang, Minlan
AU - Bobi, Joaquim
AU - Rigol, Montserrat
AU - Nicolau, David P.
AU - Frigola, Gerard
AU - Cabrera, Roberto
AU - Ramirez, Jose
AU - Pelosi, Paolo
AU - Blasi, Francesco
AU - Antonelli, Massimo
AU - Artigas, Antonio
AU - Vila, Jordi
AU - Kollef, Marin
AU - Torres, Antoni
N1 - Funding Information:
Financial support was provided by the Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomedica En Red-Enfermedades Respi-ratorias (CIBERES). A.M. is the recipient of a long-term research fellowship (LTRF 2017-01-00073) from the European Respiratory Society (ERS) and the Spanish Society of Pulmonology and Thoracic Surgery (SEPAR). G.L.B. is the recipient of a postdoctoral grant from the Strategic Plan for Research and Innovation in Health (PERIS) 2017–2021. A.T. was awarded with an ICREA academy grant (2019 to 2023).
Funding Information:
We thank Christina Sutherland of the Center of Anti-Infective Research & Development (Hartford, CT, USA) and Pure Honey Technologies (Billerica, MA, USA) for her technical assistance with the mass spectrometry- high-pressure liquid chromatography (MS-HPLC) assays. We are in debt to Laura Mu?oz for her support with the matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF) analysis. A.T. and G.L.B. received an unrestricted grant from Merck & Co, Kenilworth, NJ, USA, through their affiliated institution. Merck was not involved in the conduct of the study, data collection and management, analysis, interpretation of data, or preparation of the manuscript. Merck reviewed the final manuscript. The remaining authors have disclosed that they do not have any conflicts of interest. Financial support was provided by the Institut d'Investigacions Biom?diques August Pi i Sunyer (IDIBAPS), Centro de Investigaci?n Biomedica En Red-Enfermedades Respiratorias (CIBERES). A.M. is the recipient of a long-term research fellowship (LTRF 2017-01-00073) from the European Respiratory Society (ERS) and the Spanish Society of Pulmonology and Thoracic Surgery (SEPAR). G.L.B. is the recipient of a postdoctoral grant from the Strategic Plan for Research and Innovation in Health (PERIS) 2017-2021. A.T. was awarded with an ICREA academy grant (2019 to 2023). A.M., G.L.B., and A.T. participated in protocol development, study design, study management, statistical analysis, and data interpretation and wrote the first draft of the report. F.P., L.F.-B., H.Y., E.A.X., T.S., F.A.I., C.T., C.C., R.A., M.Y., J.B., M.R., G.F., R.C., and J.R. participated in data collection and interpretation and critically reviewed the first draft of the report. D.P.N., P.P., F.B., M.A., J.V., and M.K. participated in the study design and reviewed the report. An abstract of this study was presented at the 2017 American Thoracic Society Conference in Washington in June 2017. An abstract of this study was presented at the 2019 European Respiratory Society Conference in Madrid, September 2019.
Publisher Copyright:
Copyright © 2021 American Society for Microbiology. All Rights Reserved.
PY - 2021/2
Y1 - 2021/2
N2 - The rising frequency of multidrug-resistant and extensively drug-resistant (MDR/XDR) pathogens is making more frequent the inappropriate empirical antimicrobial therapy (IEAT) in nosocomial pneumonia, which is associated with increased mortality. We aim to determine the short-term benefits of appropriate empirical antimicrobial treatment (AEAT) with ceftolozane/tazobactam (C/T) compared with IEAT with piperacillin/tazobactam (TZP) in MDR Pseudomonas aeruginosa pneumonia. Twenty-one pigs with pneumonia caused by an XDR P. aeruginosa strain (susceptible to C/T but resistant to TZP) were ventilated for up to 72 h. Twenty-four hours after bacterial challenge, animals were randomized to receive 2-day treatment with either intravenous saline (untreated) or 25 to 50 mg of C/T per kg body weight (AEAT) or 200 to 225 mg of TZP per kg (IEAT) every 8 h. The primary outcome was the P. aeruginosa burden in lung tissue and the histopathology injury. P. aeruginosa burden in tracheal secretions and bronchoalveolar lavage (BAL) fluid, the development of antibiotic resistance, and inflammatory markers were secondary outcomes. Overall, P. aeruginosa lung burden was 5.30 (range, 4.00 to 6.30), 4.04 (3.64 to 4.51), and 4.04 (3.05 to 4.88) log10CFU/g in the untreated, AEAT, and IEAT groups, respectively (P = 0.299), without histopathological differences (P = 0.556). In contrast, in tracheal secretions (P < 0.001) and BAL fluid (P = 0.002), bactericidal efficacy was higher in the AEAT group. An increased MIC to TZP was found in 3 animals, while resistance to C/T did not develop. Interleukin-1β (IL-1β) was significantly downregulated by AEAT in comparison to other groups (P = 0.031). In a mechanically ventilated swine model of XDR P. aeruginosa pneumonia, appropriate initial treatment with C/T decreased respiratory secretions' bacterial burden, prevented development of resistance, achieved the pharmacodynamic target, and may have reduced systemic inflammation. However, after only 2 days of treatment, P. aeruginosa tissue concentrations were moderately affected.
AB - The rising frequency of multidrug-resistant and extensively drug-resistant (MDR/XDR) pathogens is making more frequent the inappropriate empirical antimicrobial therapy (IEAT) in nosocomial pneumonia, which is associated with increased mortality. We aim to determine the short-term benefits of appropriate empirical antimicrobial treatment (AEAT) with ceftolozane/tazobactam (C/T) compared with IEAT with piperacillin/tazobactam (TZP) in MDR Pseudomonas aeruginosa pneumonia. Twenty-one pigs with pneumonia caused by an XDR P. aeruginosa strain (susceptible to C/T but resistant to TZP) were ventilated for up to 72 h. Twenty-four hours after bacterial challenge, animals were randomized to receive 2-day treatment with either intravenous saline (untreated) or 25 to 50 mg of C/T per kg body weight (AEAT) or 200 to 225 mg of TZP per kg (IEAT) every 8 h. The primary outcome was the P. aeruginosa burden in lung tissue and the histopathology injury. P. aeruginosa burden in tracheal secretions and bronchoalveolar lavage (BAL) fluid, the development of antibiotic resistance, and inflammatory markers were secondary outcomes. Overall, P. aeruginosa lung burden was 5.30 (range, 4.00 to 6.30), 4.04 (3.64 to 4.51), and 4.04 (3.05 to 4.88) log10CFU/g in the untreated, AEAT, and IEAT groups, respectively (P = 0.299), without histopathological differences (P = 0.556). In contrast, in tracheal secretions (P < 0.001) and BAL fluid (P = 0.002), bactericidal efficacy was higher in the AEAT group. An increased MIC to TZP was found in 3 animals, while resistance to C/T did not develop. Interleukin-1β (IL-1β) was significantly downregulated by AEAT in comparison to other groups (P = 0.031). In a mechanically ventilated swine model of XDR P. aeruginosa pneumonia, appropriate initial treatment with C/T decreased respiratory secretions' bacterial burden, prevented development of resistance, achieved the pharmacodynamic target, and may have reduced systemic inflammation. However, after only 2 days of treatment, P. aeruginosa tissue concentrations were moderately affected.
KW - Animal models
KW - Appropriate empirical antimicrobial treatment
KW - Mechanical ventilation
KW - Pneumonia
KW - Pseudomonas aeruginosa
UR - http://www.scopus.com/inward/record.url?scp=85099915336&partnerID=8YFLogxK
U2 - 10.1128/AAC.01899-20
DO - 10.1128/AAC.01899-20
M3 - Article
C2 - 33168605
AN - SCOPUS:85099915336
VL - 65
JO - Antimicrobial Agents and Chemotherapy
JF - Antimicrobial Agents and Chemotherapy
SN - 0066-4804
IS - 2
M1 - e01899-20
ER -