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Pharmacokinetics and Efficacy of Ceftazidime-Avibactam in the Treatment of Experimental Pneumonia Caused by Klebsiella pneumoniae Carbapenemase-Producing K. pneumoniae in Persistently Neutropenic Rabbits.
Antimicrob Agents Chemother. 2020 03 24; 64(4)AA

Abstract

Klebsiella pneumoniae carbapenemase-producing Klebsiella pneumoniae (KPC-Kp) is an emerging global public health threat that causes life-threatening pneumonia and bacteremia. Ceftazidime-avibactam (CZA) represents a promising advance for the treatment of serious infections caused by KPC-Kp We investigated the pharmacokinetics and efficacy of ceftazidime-avibactam in the treatment of experimental KPC-Kp pneumonia in persistently neutropenic rabbits. For single-dose and multidose (administration every 8 h) pharmacokinetics, rabbits received ceftazidime-avibactam intravenous infusions at 60/15, 90/22.5, and 120/30 mg/kg of body weight. Ceftazidime mean area under the concentration-time curves (AUCs) ranged from 287 to 608 μg·h/ml for a single dose and from 300 to 781 μg·h/ml for multiple doses. Avibactam AUCs ranged from 21 to 48 μg·h/ml for a single dose and from 26 to 48 μg·h/ml for multiple doses. KPC-Kp pneumonia was established by direct endotracheal inoculation. Treatments consisted of ceftazidime-avibactam at 120/30 mg/kg every 6 h, a polymyxin B (PMB) loading dose of 2.5 mg/kg followed by 1.5 mg/kg every 12 h q12h, or no treatment (untreated controls [UC]). There were significant reductions in the residual bacterial burden, lung weights, and pulmonary hemorrhage scores in CZA- and PMB-treated rabbits for a 7-day or a 14-day (P ≤ 0.01) course in comparison with those in the UC. These results corresponded to significant decreases in the bacterial burden in bronchoalveolar lavage fluid after a 7-day or a 14-day treatment (P ≤ 0.01). The outcomes demonstrated an improved response at 14 days versus that at 7 days. There was significantly prolonged survival in rabbits treated with CZA for 14 days in comparison with that in the PMB-treated or UC rabbits (P ≤ 0.05). This study demonstrates that ceftazidime-avibactam displays linear dose-proportional exposures simulating those seen from human plasma pharmacokinetic profiles, is active for the treatment of experimental KPC-Kp pneumonia in persistently neutropenic rabbits, and provides an experimental foundation for the treatment of severely immunocompromised patients with this life-threatening infection.

Authors+Show Affiliations

Transplantation-Oncology Infectious Diseases Program, Division of Infectious Diseases, Department of Medicine, Weill Cornell Medicine of Cornell University, New York, New York, USA rop2016@med.cornell.edu. Institute of Infectious Disease and Pathogenic Microbiology, Prienai, Lithuania.Transplantation-Oncology Infectious Diseases Program, Division of Infectious Diseases, Department of Medicine, Weill Cornell Medicine of Cornell University, New York, New York, USA. Institute of Infectious Disease and Pathogenic Microbiology, Prienai, Lithuania. Lithuanian University of Health Sciences, Biological Research Center, Kaunas, Lithuania.Transplantation-Oncology Infectious Diseases Program, Division of Infectious Diseases, Department of Medicine, Weill Cornell Medicine of Cornell University, New York, New York, USA. Institute of Infectious Disease and Pathogenic Microbiology, Prienai, Lithuania. Lithuanian University of Health Sciences, Biological Research Center, Kaunas, Lithuania.Transplantation-Oncology Infectious Diseases Program, Division of Infectious Diseases, Department of Medicine, Weill Cornell Medicine of Cornell University, New York, New York, USA.Transplantation-Oncology Infectious Diseases Program, Division of Infectious Diseases, Department of Medicine, Weill Cornell Medicine of Cornell University, New York, New York, USA.Transplantation-Oncology Infectious Diseases Program, Division of Infectious Diseases, Department of Medicine, Weill Cornell Medicine of Cornell University, New York, New York, USA.Transplantation-Oncology Infectious Diseases Program, Division of Infectious Diseases, Department of Medicine, Weill Cornell Medicine of Cornell University, New York, New York, USA.Lithuanian University of Health Sciences, Biological Research Center, Kaunas, Lithuania.Lithuanian University of Health Sciences, Biological Research Center, Kaunas, Lithuania.Lithuanian University of Health Sciences, Biological Research Center, Kaunas, Lithuania.Lithuanian University of Health Sciences, Biological Research Center, Kaunas, Lithuania.Allergan Inc., Irvine, California, USA.Department of Pathology and Laboratory Medicine, Weill Cornell Medicine of Cornell University, New York, New York, USA.Department of Pathology and Laboratory Medicine, Weill Cornell Medicine of Cornell University, New York, New York, USA.Transplantation-Oncology Infectious Diseases Program, Division of Infectious Diseases, Department of Medicine, Weill Cornell Medicine of Cornell University, New York, New York, USA.Transplantation-Oncology Infectious Diseases Program, Division of Infectious Diseases, Department of Medicine, Weill Cornell Medicine of Cornell University, New York, New York, USA. Department of Pediatrics, Weill Cornell Medicine of Cornell University, New York, New York, USA. Department of Microbiology & Immunology, Weill Cornell Medicine of Cornell University, New York, New York, USA.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

32015048

Citation

Petraitiene, Ruta, et al. "Pharmacokinetics and Efficacy of Ceftazidime-Avibactam in the Treatment of Experimental Pneumonia Caused By Klebsiella Pneumoniae Carbapenemase-Producing K. Pneumoniae in Persistently Neutropenic Rabbits." Antimicrobial Agents and Chemotherapy, vol. 64, no. 4, 2020.
Petraitiene R, Petraitis V, Kavaliauskas P, et al. Pharmacokinetics and Efficacy of Ceftazidime-Avibactam in the Treatment of Experimental Pneumonia Caused by Klebsiella pneumoniae Carbapenemase-Producing K. pneumoniae in Persistently Neutropenic Rabbits. Antimicrob Agents Chemother. 2020;64(4).
Petraitiene, R., Petraitis, V., Kavaliauskas, P., Maung, B. B. W., Khan, F., Naing, E., Aung, T., Zigmantaite, V., Grigaleviciute, R., Kucinskas, A., Stakauskas, R., Georgiades, B. N., Mazur, C. A., Hayden, J. A., Satlin, M. J., & Walsh, T. J. (2020). Pharmacokinetics and Efficacy of Ceftazidime-Avibactam in the Treatment of Experimental Pneumonia Caused by Klebsiella pneumoniae Carbapenemase-Producing K. pneumoniae in Persistently Neutropenic Rabbits. Antimicrobial Agents and Chemotherapy, 64(4). https://doi.org/10.1128/AAC.02157-19
Petraitiene R, et al. Pharmacokinetics and Efficacy of Ceftazidime-Avibactam in the Treatment of Experimental Pneumonia Caused By Klebsiella Pneumoniae Carbapenemase-Producing K. Pneumoniae in Persistently Neutropenic Rabbits. Antimicrob Agents Chemother. 2020 03 24;64(4) PubMed PMID: 32015048.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Pharmacokinetics and Efficacy of Ceftazidime-Avibactam in the Treatment of Experimental Pneumonia Caused by Klebsiella pneumoniae Carbapenemase-Producing K. pneumoniae in Persistently Neutropenic Rabbits. AU - Petraitiene,Ruta, AU - Petraitis,Vidmantas, AU - Kavaliauskas,Povilas, AU - Maung,Bo Bo W, AU - Khan,Farehin, AU - Naing,Ethan, AU - Aung,Thein, AU - Zigmantaite,Vilma, AU - Grigaleviciute,Ramune, AU - Kucinskas,Audrius, AU - Stakauskas,Rimantas, AU - Georgiades,Benjamin N, AU - Mazur,Chase A, AU - Hayden,Joshua A, AU - Satlin,Michael J, AU - Walsh,Thomas J, Y1 - 2020/03/24/ PY - 2019/10/25/received PY - 2020/01/24/accepted PY - 2020/2/6/pubmed PY - 2021/1/29/medline PY - 2020/2/5/entrez KW - Klebsiella pneumoniae carbapenemase-producing Klebsiella pneumoniae (KPC-Kp) KW - ceftazidime-avibactam (CZA) KW - pharmacokinetics KW - pneumonia KW - rabbits JF - Antimicrobial agents and chemotherapy JO - Antimicrob Agents Chemother VL - 64 IS - 4 N2 - Klebsiella pneumoniae carbapenemase-producing Klebsiella pneumoniae (KPC-Kp) is an emerging global public health threat that causes life-threatening pneumonia and bacteremia. Ceftazidime-avibactam (CZA) represents a promising advance for the treatment of serious infections caused by KPC-Kp We investigated the pharmacokinetics and efficacy of ceftazidime-avibactam in the treatment of experimental KPC-Kp pneumonia in persistently neutropenic rabbits. For single-dose and multidose (administration every 8 h) pharmacokinetics, rabbits received ceftazidime-avibactam intravenous infusions at 60/15, 90/22.5, and 120/30 mg/kg of body weight. Ceftazidime mean area under the concentration-time curves (AUCs) ranged from 287 to 608 μg·h/ml for a single dose and from 300 to 781 μg·h/ml for multiple doses. Avibactam AUCs ranged from 21 to 48 μg·h/ml for a single dose and from 26 to 48 μg·h/ml for multiple doses. KPC-Kp pneumonia was established by direct endotracheal inoculation. Treatments consisted of ceftazidime-avibactam at 120/30 mg/kg every 6 h, a polymyxin B (PMB) loading dose of 2.5 mg/kg followed by 1.5 mg/kg every 12 h q12h, or no treatment (untreated controls [UC]). There were significant reductions in the residual bacterial burden, lung weights, and pulmonary hemorrhage scores in CZA- and PMB-treated rabbits for a 7-day or a 14-day (P ≤ 0.01) course in comparison with those in the UC. These results corresponded to significant decreases in the bacterial burden in bronchoalveolar lavage fluid after a 7-day or a 14-day treatment (P ≤ 0.01). The outcomes demonstrated an improved response at 14 days versus that at 7 days. There was significantly prolonged survival in rabbits treated with CZA for 14 days in comparison with that in the PMB-treated or UC rabbits (P ≤ 0.05). This study demonstrates that ceftazidime-avibactam displays linear dose-proportional exposures simulating those seen from human plasma pharmacokinetic profiles, is active for the treatment of experimental KPC-Kp pneumonia in persistently neutropenic rabbits, and provides an experimental foundation for the treatment of severely immunocompromised patients with this life-threatening infection. SN - 1098-6596 UR - https://www.unboundmedicine.com/medline/citation/32015048/Pharmacokinetics_and_Efficacy_of_Ceftazidime_Avibactam_in_the_Treatment_of_Experimental_Pneumonia_Caused_by_Klebsiella_pneumoniae_Carbapenemase_Producing_K__pneumoniae_in_Persistently_Neutropenic_Rabbits_ L2 - http://aac.asm.org/cgi/pmidlookup?view=long&pmid=32015048 DB - PRIME DP - Unbound Medicine ER -