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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.
Petraitiene, Ruta; Petraitis, Vidmantas; Kavaliauskas, Povilas; Maung, Bo Bo W; Khan, Farehin; Naing, Ethan; Aung, Thein; Zigmantaite, Vilma; Grigaleviciute, Ramune; Kucinskas, Audrius; Stakauskas, Rimantas; Georgiades, Benjamin N; Mazur, Chase A; Hayden, Joshua A; Satlin, Michael J; Walsh, Thomas J.
Afiliação
  • Petraitiene R; 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.
  • Petraitis V; Institute of Infectious Disease and Pathogenic Microbiology, Prienai, Lithuania.
  • Kavaliauskas P; Transplantation-Oncology Infectious Diseases Program, Division of Infectious Diseases, Department of Medicine, Weill Cornell Medicine of Cornell University, New York, New York, USA.
  • Maung BBW; Institute of Infectious Disease and Pathogenic Microbiology, Prienai, Lithuania.
  • Khan F; Lithuanian University of Health Sciences, Biological Research Center, Kaunas, Lithuania.
  • Naing E; Transplantation-Oncology Infectious Diseases Program, Division of Infectious Diseases, Department of Medicine, Weill Cornell Medicine of Cornell University, New York, New York, USA.
  • Aung T; Institute of Infectious Disease and Pathogenic Microbiology, Prienai, Lithuania.
  • Zigmantaite V; Lithuanian University of Health Sciences, Biological Research Center, Kaunas, Lithuania.
  • Grigaleviciute R; Transplantation-Oncology Infectious Diseases Program, Division of Infectious Diseases, Department of Medicine, Weill Cornell Medicine of Cornell University, New York, New York, USA.
  • Kucinskas A; Transplantation-Oncology Infectious Diseases Program, Division of Infectious Diseases, Department of Medicine, Weill Cornell Medicine of Cornell University, New York, New York, USA.
  • Stakauskas R; Transplantation-Oncology Infectious Diseases Program, Division of Infectious Diseases, Department of Medicine, Weill Cornell Medicine of Cornell University, New York, New York, USA.
  • Georgiades BN; Transplantation-Oncology Infectious Diseases Program, Division of Infectious Diseases, Department of Medicine, Weill Cornell Medicine of Cornell University, New York, New York, USA.
  • Mazur CA; Lithuanian University of Health Sciences, Biological Research Center, Kaunas, Lithuania.
  • Hayden JA; Lithuanian University of Health Sciences, Biological Research Center, Kaunas, Lithuania.
  • Satlin MJ; Lithuanian University of Health Sciences, Biological Research Center, Kaunas, Lithuania.
  • Walsh TJ; Lithuanian University of Health Sciences, Biological Research Center, Kaunas, Lithuania.
Article em En | MEDLINE | ID: mdl-32015048
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.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Infecções por Klebsiella / Ceftazidima / Compostos Azabicíclicos / Inibidores de beta-Lactamases / Klebsiella pneumoniae / Antibacterianos Idioma: En Ano de publicação: 2020 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Infecções por Klebsiella / Ceftazidima / Compostos Azabicíclicos / Inibidores de beta-Lactamases / Klebsiella pneumoniae / Antibacterianos Idioma: En Ano de publicação: 2020 Tipo de documento: Article