Meropenem exerts bactericidal activity by inhibiting peptidoglycan cell wall synthesis as a result of binding to and inhibition of activity of essential penicillin-binding proteins (PBPs).
Vaborbactam is a non-beta-lactam inhibitor of class A and class C serine beta-lactamases, including Klebsiella pneumoniae carbapenemase, KPC. It acts by forming a covalent adduct with beta-lactamases and is stable to beta-lactamase-mediated hydrolysis. Vaborbactam does not inhibit class B enzymes (metallo-β-lactamases) or class D carbapenemases. Vaborbactam has no antibacterial activity.
Mechanisms of resistance in Gram-negative bacteria that are known to affect meropenem/vaborbactam include organisms that produce metallo-β-lactamases or oxacillinases with carbapenemase activity.
Mechanisms of bacterial resistance that could decrease the antibacterial activity of meropenem/vaborbactam include porin mutations affecting outer membrane permeability and overexpression of efflux pumps.
In vitro studies demonstrated no antagonism between meropenem/vaborbactam and levofloxacin, tigecycline, polymyxin, amikacin, vancomycin, azithromycin, daptomycin or linezolid.
Minimum inhibitory concentration (MIC) breakpoints established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST – Breakpoint tables for interpretation of MICs and zone diameters, version 1.0, 2021) are as follows:
| Organisms | Minimum Inhibitory Concentrations (mg/l) | |
|---|---|---|
| Susceptible | Resistant | |
| Enterobacteriaceae | ≤81 | >81 |
| Pseudomonas aeruginosa | ≤81 | >81 |
1 For susceptibility testing purposes, the concentration of vaborbactam is fixed at 8 mg/l.
The antimicrobial activity of meropenem has been shown to best correlate with the percent of the dosing interval during which the free meropenem concentrations in plasma exceed the meropenem minimum inhibitory concentration. For vaborbactam, the PK-PD index associated with antimicrobial activity is the ratio of free vaborbactam plasma AUC: meropenem/vaborbactam MIC.
The plasma protein binding of meropenem is approximately 2%. The plasma protein binding of vaborbactam is approximately 33%.
The steady-state volumes of distribution of meropenem and vaborbactam in patients were 20.2 L and 18.6 L, respectively, following doses of 2 g meropenem/2 g vaborbactam infused over 3 hours every 8 hours, indicating that both compounds distribute into a volume of distribution consistent with the extracellular fluid compartment.
Both meropenem and vaborbactam penetrate into human bronchial epithelial lining fluid (ELF) with concentrations around 65% and 79% of unbound plasma concentrations of meropenem and vaborbactam, respectively. The concentration time profiles are similar for ELF and plasma.
Meropenem is mostly eliminated unchanged. About 25% of the administered dose is eliminated as the inactive open ring form.
Vaborbactam does not undergo metabolism.
The terminal half-life (t½) is 2.30 hours and 2.25 hours for meropenem and vaborbactam, respectively.
Both meropenem and vaborbactam are primarily excreted via the kidneys. Approximately 40-60% of a meropenem dose is excreted unchanged within 24-48 hours with a further 25% recovered as the microbiologically inactive hydrolysis product. The elimination of meropenem by the kidneys resulted in high therapeutic concentrations in urine. The mean renal clearance for meropenem was 7.7 L/h. The mean non-renal clearance for meropenem was 4.8 L/h, which comprises both fecal elimination (~2% of the dose) and degradation due to hydrolysis.
Approximately 75 to 95% of vaborbactam is excreted unchanged in the urine over a 24-48 hour period. The elimination of vaborbactam by the kidneys resulted in high concentrations in the urine. The mean renal clearance for vaborbactam was 10.5 L/h.
The Cmax and AUC of meropenem and vaborbactam are linear across the dose range studied (1 g to 2 g for meropenem and 0.25 g to 2 g for vaborbactam) when administered as a single 3-hour intravenous infusion. There is no accumulation of meropenem or vaborbactam following multiple intravenous infusions administered every 8 hours for 7 days in subjects with normal renal function.
Neither meropenem nor vaborbactam inhibit CYP450 enzymes in vitro at pharmacologically relevant concentrations.
Both meropenem and vaborbactam do not inhibit renal or hepatic transporters at pharmacologically relevant concentrations.
Pharmacokinetic studies with meropenem and vaborbactam in patients with renal impairment have shown that the plasma clearance of both meropenem and vaborbactam correlates with creatinine clearance.
As meropenem/vaborbactam does not undergo hepatic metabolism, the systemic clearance of meropenem/vaborbactam is not expected to be affected by hepatic impairment.
Pharmacokinetic data from a population pharmacokinetic analysis showed a reduction in plasma clearance of meropenem/vaborbactam that correlates with age-associated reduction in creatinine clearance.
In a population pharmacokinetic analysis there was no effect of gender or race on the pharmacokinetics of meropenem and vaborbactam.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, reproduction toxicity or genotoxicity. Carcinogenicity studies have not been conducted with meropenem.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, reproduction toxicity or genotoxicity. Carcinogenicity studies have not been conducted with vaborbactam.
In repeat dose toxicity studies in dogs, minimal hepatic inflammation was observed after 14 days and 28 days of exposure to vaborbactam alone or combined meropenem/vaborbactam.
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