Activities of Ceftazidime and Avibactam against β-Lactamase-Producing Enterobacteriaceae in a Hollow-Fiber Pharmacodynamic Model

Abstract

Avibactam is a novel non-␤-lactam ␤-lactamase inhibitor that is currently undergoing phase 3 clinical trials in combination with ceftazidime. Ceftazidime is hydrolyzed by a broad range of ␤-lactamases, but avibactam is able to inhibit the majority of these enzymes. The studies described here attempt to provide insight into the amount of avibactam required to suppress bacterial growth in an environment where the concentrations of both agents are varying as they would when administered to humans. Following the simulation of a single intravenous dose of the drug, ceftazidime alone had no effect on any test organism, but a ceftazidime-avibactam combination resulted in rapid killing of all of the strains, with growth suppressed for the 8 h of the study. For seven of eight strains, this was achieved with a 1-g-250-mg profile, but a 2-g-500-mg profile was necessary to completely suppress a high-level-AmpC-producing isolate. When ceftazidime was infused continuously for 24 h with a single bolus dose of avibactam, rapid killing of all of the strains was again observed, with growth suppressed for 10 to >24 h. Regrowth appeared to commence once the avibactam concentration dropped below a critical concentration of approximately 0.3 g/ml. In a third series of studies, ceftazidime was administered every 8 h for 24 h with avibactam administered at fixed concentrations for short periods during each ceftazidime dose profile. Simulating a 1-g dose of ceftazidime, an avibactam pulse of >0.25 and <0.5 g/ml was required to suppress growth for 24 h. A vibactam, formerly NXL104 or AVE1330A, is the first of a new class of non-␤-lactam ␤-lactamase inhibitors, referred to as diazabicyclooctanes (1). It displays a broad spectrum of inhibitory activity against both class A and class C ␤-lactamases, including Klebsiella pneumoniae carbapenemase (KPC) enzymes (2), the AmpC ␤-lactamase of Pseudomonas aeruginosa (3), and extendedspectrum ␤-lactamases such as TEM, SHV, and CTX-M variants (4, 5). In studies with isolated enzymes, avibactam inactivates ␤-lactamases at low 50% inhibitory concentrations and with low turnover numbers (6, 7). It also inhibits some class D ␤-lactamases, OXA-48, for example (8). Avibactam has little intrinsic antibacterial activity but efficiently protects ␤-lactams from ␤-lactamase-catalyzed hydrolysis in a range of members of the family Enterobacteriaceae and in P. aeruginosa (3-5, 9). That a combination of ceftazidime and avibactam protects against bacterial infections by ␤-lactamase-producing bacteria has been demonstrated in animal models (10, 11), and two successful phase 2 human studies have been reported (12,13).Like the pharmacodynamic (PD) indices of other cephalosporins (14) and ␤-lactams generally (15), that of ceftazidime is the time during which its free (non-protein-bound) concentration exceeds the MIC for the infecting pathogen (fTϾMIC) (14-19). However, little is known about ␤-lactam-␤-lactamase-inhibitor pharmacokinetic (PK)-PD relationships (20)(21)(22), which is a prerequisite for the optimum design...

Pharmacokinetics and Dialytic Clearance of Ceftazidime-Avibactam in a Critically Ill Patient on Continuous Venovenous Hemofiltration

“…The pharmacodynamic parameter most closely associated with efficacy of the ␤-lactam inhibitors, including avibactam, appears to be the time during which the free drug concentration is above a threshold concentration required to inhibit ␤-lactamases throughout the dosing interval. For avibactam, this threshold has been shown to be 1 mg/liter for bactericidal activity and the target proportion of time above that threshold to be 30 to 50% for bactericidal activity (13,14). Using this endpoint and assuming 7% protein binding, the avibactam concentrations were also above this target for 100% of the dosing interval.…”

Efficacy of a Ceftazidime-Avibactam Combination in a Murine Model of Septicemia Caused by Enterobacteriaceae Species Producing AmpC or Extended-Spectrum β-Lactamases

“…In these preclinical studies, the septicemia model did not show any significant differences between the 4:1 and 8:1 ratios of ceftazidime-avibactam. Ultimately, a 4:1 ratio of ceftazidime-avibactam was selected for clinical development based on a number of fac- tors, including in vitro, in vivo, and the hollow-fiber infection model data (8,9,12,13,20,21,(23)(24)(25)(26)34).…”

In Vitro-In Vivo Discordance with Humanized Piperacillin-Tazobactam Exposures against Piperacillin-Tazobactam-Resistant/Pan-β-Lactam-Susceptible Klebsiella pneumoniae Strains

“…While the observation of in vitro/in vivo discordance has been reported among carbapenemaseproducing Klebsiella pneumoniae and Pseudomonas aeruginosa strains for the ␤-lactams, the exact mechanism(s) remain elusive (11)(12)(13)(14). One potential explanation is the abnormal enzyme accumulation in vitro, and given the potential role of TEM-1 ␤-lactamase in our Enterobacteriaceae isolates, it appears viable, although likely incomplete, in light of the known porin mutations in E. coli (3,4,(11)(12)(13)(14)(15). Alternatively, the discordance may be attributed in part to reduced resistance expression in vivo, as the addition of genetic virulence factors was shown to decrease the overall fitness of K. pneumoniae (16).…”