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

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: Ruta Petraitiene, Vidmantas Petraitis, Povilas Kavaliauskas, Bo Bo W Maung, Farehin Khan, Ethan Naing, Thein Aung, Vilma Zigmantaite, Ramune Grigaleviciute, Audrius Kucinskas, Rimantas Stakauskas, Benjamin N Georgiades, Chase A Mazur, Joshua A Hayden, Michael J Satlin, Thomas J Walsh
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 64 Issue 4 (03 24 2020) ISSN: 1098-6596 [Electronic] United States
• PMID: 32015048 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 American Society for Microbiology.

Chemical References

• Anti-Bacterial Agents
• Azabicyclo Compounds
• Bacterial Proteins
• Drug Combinations
• avibactam, ceftazidime drug combination
• beta-Lactamase Inhibitors
• Ceftazidime
• beta-Lactamases
• carbapenemase

Topics

• Animals
• Anti-Bacterial Agents (pharmacokinetics, therapeutic use)
• Azabicyclo Compounds (pharmacokinetics, therapeutic use)
• Bacteremia (drug therapy, microbiology)
• Bacterial Load (drug effects)
• Bacterial Proteins (metabolism)
• Carbapenem-Resistant Enterobacteriaceae (drug effects)
• Ceftazidime (pharmacokinetics, therapeutic use)
• Drug Combinations
• Drug Resistance, Multiple, Bacterial (genetics)
• Female
• Klebsiella Infections (drug therapy)
• Klebsiella pneumoniae (drug effects)
• Microbial Sensitivity Tests
• Neutropenia
• Pneumonia, Bacterial (drug therapy, microbiology)
• Rabbits
• beta-Lactamase Inhibitors (pharmacokinetics, therapeutic use)
• beta-Lactamases (metabolism)