Pharmacokinetics and Efficacy of Ceftazidime-Avibactam in the Treatment of Experimental Pneumonia Caused by Klebsiella pneumoniae Carbapenemase-Producing K. pneumoniae in Persistently Neutropenic Rabbits

• Published in: Antimicrobial agents and chemotherapy Vol. 64; no. 4
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States American Society for Microbiology 24.03.2020
• Subjects: Animals; Anti-Bacterial Agents - pharmacokinetics; Anti-Bacterial Agents - therapeutic use; Azabicyclo Compounds - pharmacokinetics; Azabicyclo Compounds - therapeutic use; Bacteremia - drug therapy; Bacteremia - microbiology; Bacterial Load - drug effects; Bacterial Proteins - metabolism; beta-Lactamase Inhibitors - pharmacokinetics; beta-Lactamase Inhibitors - therapeutic use; beta-Lactamases - metabolism; Carbapenem-Resistant Enterobacteriaceae - drug effects; Ceftazidime - pharmacokinetics; Ceftazidime - therapeutic use; Drug Combinations; Drug Resistance, Multiple, Bacterial - genetics; Experimental Therapeutics; Female; Klebsiella Infections - drug therapy; Klebsiella pneumoniae - drug effects; Microbial Sensitivity Tests; Neutropenia; Pneumonia, Bacterial - drug therapy; Pneumonia, Bacterial - microbiology; Rabbits; pharmacokinetics; pneumonia; ceftazidime-avibactam (CZA); rabbits; Klebsiella pneumoniae carbapenemase-producing Klebsiella pneumoniae (KPC-Kp)
• ISSN: 0066-4804; 1098-6596
• DOI: 10.1128/AAC.02157-19

carbapenemase-producing (KPC- ) 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- We investigated the pharmacokinetics and efficacy of ceftazidime-avibactam in the treatment of experimental KPC- 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- 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 (  ≤ 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 (  ≤ 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 (  ≤ 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- pneumonia in persistently neutropenic rabbits, and provides an experimental foundation for the treatment of severely immunocompromised patients with this life-threatening infection.