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 -