Pharmacodynamics of β-Lactamase Inhibition by NXL104 in Combination with Ceftaroline: Examining Organisms with Multiple Types of β-Lactamases

Abstract

New broad-spectrum ␤-lactamases such as KPC enzymes and CTX-M-15 enzymes threaten to markedly reduce the utility of our armamentarium of ␤-lactam agents, even our most potent drugs, such as carbapenems. NXL104 is a broad-spectrum non-␤-lactam ␤-lactamase inhibitor. In this evaluation, we examined organisms carrying defined ␤-lactamases and identified doses and schedules of NXL104 in combination with the new cephalosporin ceftaroline, which would maintain good bacterial cell kill and suppress resistance emergence for a clinically relevant period of 10 days in our hollow-fiber infection model. We examined three strains of Klebsiella pneumoniae and one isolate of Enterobacter cloacae. K. pneumoniae 27-908M carried KPC-2, SHV-27, and TEM-1 ␤-lactamases. Its isogenic mutant, K. pneumoniae 4207J, was "cured" of the plasmid expressing the KPC-2 enzyme. K. pneumoniae 24-1318A carried a CTX-M-15 enzyme, and E. cloacae 2-77C expressed a stably derepressed AmpC chromosomal ␤-lactamase. Dose-ranging experiments for NXL104 administered as a continuous infusion with ceftaroline at 600 mg every 8 h allowed identification of a 24-h area under the concentration-time curve (AUC) for NXL104 that mediated bactericidal activity and resistance suppression. Dose fractionation experiments identified that "time > threshold" was the pharmacodynamic index linked to cell kill and resistance suppression. Given these results, we conclude that NXL104 combined with ceftaroline on an 8-hourly administration schedule would be optimal for circumstances in which highly resistant pathogens are likely to be encountered. This combination dosing regimen should allow for optimal bacterial cell kill (highest likelihood of successful clinical outcome) and the suppression of resistance emergence.

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

“…In a few of the studies reported here, the growth suppression window was smaller for the avibactam bolus dose than for the avibactam infusion, consistent with the findings of Louie et al (32) Tables 3 and 4), regrowth was clearly occurring when avibactam dropped below a critical C T . In the present studies, the avibactam C T was Յ0.3 g/ml (Table 2) and the C T Q8 (in the background of ceftazidime PK representative of the human dose of 2 g) was Ͻ0.5 g/ml, demonstrating good agreement.…”

“…We infer that there must be some C T of avibactam below which the inhibitor is unable to protect the ␤-lactam from hydrolysis. On the basis of hollow-fiber experiments, Louie et al (32) reported that time above the C T was the avibactam variable dynamically linked with cell killing and resistance suppression when combined with the cephalosporin ceftaroline against ␤-lactamase-producing E. cloacae and K. pneumoniae. That would fit with the observation in the present study that avibactam, when not replenished by repeated dosing (or continuous infusion), appears to allow the return of ␤-lactamase activity and growth in the presence of "unprotected" ceftazidime ( Fig.…”

Relationship between Ceftolozane-Tazobactam Exposure and Selection for Pseudomonas aeruginosa Resistance in a Hollow-Fiber Infection Model

“…The hollow-fiber infection model has been used extensively for the examination of resistance prevention and was described previously (9,10). In brief, this pharmacodynamic system allows pathogens to grow in a peripheral chamber of the hollow-fiber cartridge.…”

Pharmacokinetics-Pharmacodynamics of a Novel β-Lactamase Inhibitor, CB-618, in Combination with Meropenem in an In Vitro Infection Model

“…Relationships between change from baseline in log 10 CFU/ml at 24 h and the ratio of the CB-618 area under the concentration-time curve over 24 h (AUC 0 -24 ), maximum CB-618 concentration (C max ), and percentage of the dosing interval that CB-618 concentrations remained above a given threshold (%TimeϾthreshold) were characterized. The CB-618 concentration threshold was identified through an iterative process previously described (16). In brief, a range of candidate CB-618 concentration thresholds (0.5 to 4 mg/liter) were evaluated.…”

“…One-compartment and hollow-fiber in vitro infection models have emerged as important tools for evaluating the adequacy of candidate ␤-lactam-␤-lactamase inhibitor dosing regimens (16,17,18,19,20). These models allow for evaluation of the relationship between ␤-lactamase inhibitor exposure in the context of a given ␤-lactam exposure and change in bacterial burden (17,18).…”