Activity of Simulated Human Dosage Regimens of Meropenem and Vaborbactam against Carbapenem-Resistant Enterobacteriaceae in an In Vitro Hollow-Fiber Model

Abstract

The objective of these studies was to evaluate the exposures of meropenem and vaborbactam that would produce antibacterial activity and prevent resistance development in carbapenem-resistant carbapenemase (KPC)-producing strains when tested at an inoculum of 10 CFU/ml. Thirteen isolates, three isolates, and one isolate were examined in an hollow-fiber model over 32 h. Simulated dosage regimens of 1 to 2 g of meropenem with 1 to 2 g of vaborbactam, with meropenem administered every 8 h by a 3-h infusion based on phase 1 or phase 3 patient pharmacokinetic data, were studied in the model. A dosage of 2 g of meropenem in combination with 2 g of vaborbactam was bactericidal against ,, and strains, with meropenem-vaborbactam MICs of up to 8 mg/liter. When the vaborbactam exposure was adjusted to the levels observed in patients enrolled in phase 3 trials (24-h free AUC, ∼550 mg · h/liter, versus 320 mg · h/liter in the phase 1 studies), 2 g of meropenem with 2 g of vaborbactam was also bactericidal against strains with meropenem-vaborbactam MICs of 16 mg/liter. In addition, this level of vaborbactam also suppressed the development of resistance observed using phase 1 exposures. In this pharmacodynamic model, exposures similar to 2 g of meropenem in combination with 2 g of vaborbactam administered every 8 h by a 3-h infusion in phase 3 trials produced antibacterial activity and suppressed the development of resistance against carbapenem-resistant KPC-producing strains of.

Ceftazidime/Avibactam, Meropenem/Vaborbactam, or Both? Clinical and Formulary Considerations

“…Data from hollow fiber infection models support the low propensity for meropenem/vaborbactam to select for resistance at the labeled dose [27]. When simulating exposures of meropenem/vaborbactam at this dose using phase 1 pharmacokinetic data, resistance was suppressed in all isolates up to MICs of 8/8 mg/L.…”

“…Resistance to meropenem/vaborbactam in KPC-producing isolates is mediated by a combination of KPC production and mutations to OmpK35 and OmpK36 [27,28]. Encouragingly, the likelihood of resistance selection while receiving meropenem/vaborbactam appears to be decreased compared with ceftazidime/avibactam, particularly for isolates that are susceptible (MIC ≤4/8 mg/L).…”

Pharmacokinetics/Pharmacodynamics of Vaborbactam, a Novel Beta-Lactamase Inhibitor, in Combination with Meropenem

“…All strains produced KPC-2 or KPC-3 and had meropenem MICs of 8 mg/liter or greater. In addition, some strains had mutations in outer membrane porins OmpK35 and OmpK36, which have an impact on the uptake of carbapenems (16).…”

“…In vitro hollow-fiber pharmacokinetic parameters. All the targeted PK values were simulated on the basis of clinical studies and have been described previously (16). Briefly, meropenem levels were Ͼ8 mg/liter for 75% of the dosing interval and Ͼ16 mg/ liter for 40% to 50% of the dosing interval, and the vaborbactam 24-h AUCs ranged from 192 to 550 mg · h/liter.…”

“…Bioanalytical assays. The bioanalytical assays for meropenem and vaborbactam have been described previously (16,17). Briefly, standard curves were prepared in plasma or MHB.…”