Pharmacokinetics and Efficacy of Ceftazidime-Avibactam in the Treatment of Experimental Pneumonia Caused by Klebsiella pneumoniae Carbapenemase-Producing K. pneumoniae in Persistently Neutropenic Rabbits
| Autor: | Joshua A Hayden, Vilma Zigmantaite, Chase A. Mazur, Ramune Grigaleviciute, Michael J. Satlin, Ruta Petraitiene, Thein Aung, Ethan Naing, Thomas J. Walsh, Vidmantas Petraitis, Audrius Kučinskas, Bo Bo Win Maung, Rimantas Stakauskas, Povilas Kavaliauskas, Benjamin Georgiades, Farehin Khan |
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| Rok vydání: | 2020 |
| Předmět: |
medicine.medical_specialty
Neutropenia Klebsiella pneumoniae Avibactam Ceftazidime Bacteremia Microbial Sensitivity Tests Loading dose Gastroenterology beta-Lactamases 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Bacterial Proteins Pharmacokinetics Drug Resistance Multiple Bacterial Internal medicine Pneumonia Bacterial medicine Animals Experimental Therapeutics Pharmacology (medical) 030212 general & internal medicine Pharmacology 0303 health sciences medicine.diagnostic_test biology 030306 microbiology business.industry Ceftazidime/avibactam biology.organism_classification medicine.disease Bacterial Load Anti-Bacterial Agents Klebsiella Infections Drug Combinations Pneumonia Carbapenem-Resistant Enterobacteriaceae Infectious Diseases Bronchoalveolar lavage chemistry Female Rabbits beta-Lactamase Inhibitors business Azabicyclo Compounds medicine.drug |
| Zdroj: | Antimicrob Agents Chemother |
| ISSN: | 1098-6596 0066-4804 |
| DOI: | 10.1128/aac.02157-19 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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