Chemical formula: C₇H₁₁N₃O₆S Molecular mass: 265.24 g/mol PubChem compound: 9835049
Avibactam is a non β-lactam, β- lactamase inhibitor that acts by forming a covalent adduct with the enzyme that is stable to hydrolysis. It inhibits both Ambler class A and class C β-lactamases and some class D enzymes, including extended-spectrum β-lactamases (ESBLs), KPC and OXA-48 carbapenemases, and AmpC enzymes. Avibactam does not inhibit class B enzymes (metallo-β-lactamases) and is not able to inhibit many class D enzymes.
Bacterial resistance mechanisms that could potentially affect avibactam include mutant or acquired PBPs, decreased outer membrane permeability to either compound, active efflux of either compound, and β-lactamase enzymes refractory to inhibition by avibactam and able to hydrolyse ceftazidime.
No synergy or antagonism was demonstrated in in vitro drug combination studies with avibactam and metronidazole, tobramycin, levofloxacin, vancomycin, linezolid, colistin and tigecycline.
Minimum Inhibitory Concentration (MIC) breakpoints established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) for avibactam are as follows:
| Organisms | Susceptible | Resistant |
|---|---|---|
| Enterobacteriaceae | ≤8 mg/L | >8 mg/L |
| Pseudomonas aeruginosa | ≤8 mg/L | >8 mg/L |
For avibactam the PK-PD index is the percent time of the free drug concentration above a threshold concentration over the dose interval (% fT >CT).
The human protein binding of avibactam is approximately 8%. The steady-state volumes of distribution of avibactam were about 18 L, respectively in healthy adults following multiple doses of 500 mg avibactam infused over 2 hours every 8 hours. Avibactam penetrate into human bronchial epithelial lining fluid (ELF) to the same extent with concentrations around 30% of those in plasma. The concentration time profiles are similar for ELF and plasma.
Avibactam penetration of the blood brain barrier has not been studied clinically; however, in rabbits with inflamed meninges, CSF exposures of avibactam were 38% of plasma AUC, respectively.
No metabolism of avibactam was observed in human liver preparations (microsomes and hepatocytes). Unchanged avibactam was the major drug-related component in human plasma and urine following dosing with [14C]-avibactam.
The terminal half-life (t1⁄2) of avibactam is about 2 h after intravenous administration. Avibactam is excreted unchanged into the urine with a renal clearance of approximately 158 mL/min, suggesting active tubular secretion in addition to glomerular filtration. Approximately 97% of the avibactam dose is recovered in the urine, 95% within 12 h. Less than 0.25% of avibactam is excreted into faeces.
The pharmacokinetics of avibactam is approximately linear across the dose range studied (50 mg to 2000 mg) for a single intravenous administration. No appreciable accumulation of avibactam was observed following multiple intravenous infusions of 500 mg of avibactam administered every 8 hours for up to 11 days in healthy adults with normal renal function.
Renal impairment:
The average increases in avibactam AUC are 3.8-fold and 7-fold in subjects with moderate and severe renal impairment.
Hepatic impairment:
The pharmacokinetics of avibactam in patients with any degree of hepatic impairment has not been studied.
As avibactam do not appear to undergo significant hepatic metabolism, the systemic clearance of either active substance is not expected to be significantly altered by hepatic impairment.
Elderly patients (≥65 years):
Following a single intravenous administration of 500 mg avibactam as a 30-minute IV infusion, the elderly had a slower terminal half-life of avibactam, which may be attributed to age related decrease in renal clearance.
Gender and race:
The pharmacokinetics of avibactam is not significantly affected by gender or race.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity or genotoxicity. Carcinogenicity studies have not been conducted with avibactam.
In pregnant rabbits administered avibactam at 300 and 1000 mg/kg/day, there was a dose-related lower mean foetal weight and delayed ossification, potentially related to maternal toxicity. Plasma exposure levels at maternal and foetal NOAEL (100 mg/kg/day) indicate moderate to low margins of safety. In the rat, no adverse effects were observed on embryofetal development or fertility. Following administration of avibactam throughout pregnancy and lactation in the rat, there was no effect on pup survival, growth or development, however there was an increase in incidence of dilation of the renal pelvis and ureters in less than 10% of the rat pups at maternal exposures greater than or equal to approximately 1.5 times human therapeutic exposures.
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