The Pharmacokinetics/Pharmacodynamic Relationship of Durlobactam in Combination With Sulbactam in In Vitro and In Vivo Infection Model Systems Versus Acinetobacter baumannii-calcoaceticus Complex

被引:21
作者
O'Donnell, John P. [1 ,3 ]
Bhavnani, Sujata M. [2 ,4 ]
机构
[1] Entasis Therapeut, Dept Drug Metab & Pharmacokinet, Waltham, MA USA
[2] Inst Clin Pharmacodynam, Schenectady, NY USA
[3] Entasis Therapeut, 35 Gatehouse Dr, Waltham, MA 02451 USA
[4] Inst Clin Pharmacodynam, 242 Broadway, Schenectady, NY 12305 USA
关键词
pharmacokinetics; pharmacodynamics; Acinetobacter; sulbactam; durlobactam; diazabicyclooctane; BETA-LACTAMASE INHIBITORS; NOSOCOMIAL INFECTIONS; AMPICILLIN-SULBACTAM; RESISTANCE; PHARMACODYNAMICS; TAZOBACTAM; EMERGENCE; EFFICACY; COVALENT; KINETICS;
D O I
10.1093/cid/ciad096
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Sulbactam-durlobactam is a beta-lactam/beta-lactamase inhibitor combination currently in development for the treatment of infections caused by Acinetobacter, including multidrug-resistant (MDR) isolates. Although sulbactam is a beta-lactamase inhibitor of a subset of Ambler class A enzymes, it also demonstrates intrinsic antibacterial activity against a limited number of bacterial species, including Acinetobacter, and has been used effectively in the treatment of susceptible Acinetobacter-associated infections. Increasing prevalence of beta-lactamase-mediated resistance, however, has eroded the effectiveness of sulbactam in the treatment of this pathogen. Durlobactam is a rationally designed beta-lactamase inhibitor within the diazabicyclooctane (DBO) class. The compound demonstrates a broad spectrum of inhibition of serine beta-lactamase activity with particularly potent activity against class D enzymes, an attribute which differentiates it from other DBO inhibitors. When combined with sulbactam, durlobactam effectively restores the susceptibility of resistant isolates through beta-lactamase inhibition. The present review describes the pharmacokinetic/pharmacodynamic (PK/PD) relationship associated with the activity of sulbactam and durlobactam established in nonclinical infection models with MDR Acinetobacter baumannii isolates. This information aids in the determination of PK/PD targets for efficacy, which can be used to forecast efficacious dose regimens of the combination in humans.
引用
收藏
页码:S202 / S209
页数:8
相关论文
共 38 条
[1]   β-Lactamase inhibitors: what you really need to know [J].
Ambrose, Paul G. ;
Lomovskaya, Olga ;
Griffith, David C. ;
Dudley, Michael N. ;
VanScoy, Brian .
CURRENT OPINION IN PHARMACOLOGY, 2017, 36 :86-93
[2]   Antibacterial drug development program successes and failures: a pharmacometric explanation [J].
Ambrose, Paul G. .
CURRENT OPINION IN PHARMACOLOGY, 2017, 36 :1-7
[3]  
Barnes MD, 2019, MBIO, V10, DOI [10.1128/mbio.00159-19, 10.1128/mBio.00159-19]
[4]   High-dose ampicillin-sulbactam as an alternative treatment of late-onset VAP from multidrug-resistant Acinetobacter baumannii [J].
Betrosian, Alex P. ;
Frantzeskaki, Frantzeska ;
Xanthaki, Anna ;
Georgiadis, George .
SCANDINAVIAN JOURNAL OF INFECTIOUS DISEASES, 2007, 39 (01) :38-43
[5]   A translational pharmacokinetic/pharmacodynamic model to characterize bacterial kill in the presence of imipenem-relebactam [J].
Bhagunde, Pratik ;
Zhang, Zufei ;
Racine, Fred ;
Carr, Donna ;
Wu, Jin ;
Young, Katherine ;
Rizk, Matthew L. .
INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES, 2019, 89 :55-61
[6]  
Bhavnani SM., 2022, IDWEEK 2022
[7]   Discovery of MK-7655, a β-lactamase inhibitor for combination with Primaxin® [J].
Blizzard, Timothy A. ;
Chen, Helen ;
Kim, Seongkon ;
Wu, Jane ;
Bodner, Rena ;
Gude, Candido ;
Imbriglio, Jason ;
Young, Katherine ;
Park, Young-Whan ;
Ogawa, Aimie ;
Raghoobar, Susan ;
Hairston, Nichelle ;
Painter, Ronald E. ;
Wisniewski, Doug ;
Scapin, Giovanna ;
Fitzgerald, Paula ;
Sharma, Nandini ;
Lu, Jun ;
Ha, Sookhee ;
Hermes, Jeff ;
Hammond, Milton L. .
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2014, 24 (03) :780-785
[8]  
Bulik C., 2013, 53 INT C ANT AG CHEM
[9]  
Bulitta JB, 2019, ANTIMICROB AGENTS CH, V63, DOI [10.1128/aac.02307-18, 10.1128/AAC.02307-18]
[10]  
Cai Bin, 2017, Open Forum Infect Dis, V4, pofx176, DOI 10.1093/ofid/ofx176