Aztreonam inhibits bacterial peptidoglycan cell wall synthesis following binding to penicillin-binding proteins (PBPs), which leads to bacterial cell lysis and death. Aztreonam is generally stable to hydrolysis by class B enzymes (metallo-β-lactamases).
Avibactam is a non β-lactam, β-lactamase inhibitor that acts by forming a covalent adduct with the enzyme that is stable to hydrolysis. Avibactam inhibits both Ambler class A and class C β-lactamases and some class D enzymes, including extended-spectrum β-lactamases (ESBLs), Klebsiella pneumoniae carbapenemase (KPC) and OXA-48 carbapenemases, and AmpC enzymes. Avibactam does not inhibit class B enzymes and is not able to inhibit many class D enzymes.
Bacterial resistance mechanisms that could potentially affect aztreonam-avibactam include β-lactamase enzymes refractory to inhibition by avibactam and able to hydrolyse aztreonam, mutant or acquired PBPs, decreased outer membrane permeability to either compound, and active efflux of either compound.
No synergy or antagonism was demonstrated in in vitro drug combination studies with aztreonam-avibactam and amikacin, ciprofloxacin, colistin, daptomycin, gentamicin, levofloxacin, linezolid, metronidazole, tigecycline, tobramycin, and vancomycin.
The aztreonam and avibactam geometric mean (CV%) steady-state maximum plasma concentration (Cmax,ss) and area under the concentration-time curve over 24 hours (AUC24,ss) in Phase 3 patients with normal renal function (n=127) after multiple 3-hour infusions of 1.5 g aztreonam/0.5 g avibactam administered every 6 hours were 54.2 mg/L (40.8) and 11.0 mg/L (44.9), respectively, and 833 mg*h/L (45.8) and 161 mg*h/L (47.5), respectively. Pharmacokinetic parameters of aztreonam and avibactam following single- and multiple-dose administration of aztreonam-avibactam in combination were similar to those determined when aztreonam or avibactam were administered alone.
The human protein binding of avibactam and aztreonam is concentration independent and low, approximately 8% and 38%, respectively. The steady-state volumes of distribution of aztreonam and avibactam were comparable, about 20 L and 24 L, respectively, in patients with complicated intra-abdominal infections following multiple doses of 1.5 g/0.5 g aztreonam-avibactam every 6 hours infused over 3 hours.
Aztreonam crosses the placenta and is excreted in the breast milk.
Penetration of aztreonam into pulmonary epithelial lining fluid (ELF) has not been studied clinically; a mean ratio of concentration in bronchial secretions to concentration in serum of 21% to 60% has been reported in intubated patients at 2 to 8 hours after a single aztreonam 2 g intravenous dose.
Avibactam penetrates into human bronchial ELF with concentrations around 30% that of plasma, and a similar concentration time profile between ELF and plasma. Avibactam penetrates into the subcutaneous tissue at the site of skin infections, with tissue concentrations approximately equal to free drug concentrations in plasma.
Penetration of aztreonam into the intact blood-brain barrier is limited, resulting in low levels of aztreonam in the cerebrospinal fluid (CSF) in the absence of inflammation; however, concentrations in CSF are increased when the meninges are inflamed.
Aztreonam is not extensively metabolised. The principal metabolite is inactive and is formed by opening of the beta-lactam ring due to hydrolysis. Recovery data indicate that about 10% of the dose is excreted as this metabolite. 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-lives (t½) of both aztreonam and avibactam are approximately 2 to 3 hours after intravenous administration.
Aztreonam is excreted in the urine by active tubular secretion and glomerular filtration. Approximately 75% to 80% of an intravenous or intramuscular dose was recovered in the urine. The components of urinary radioactivity were unchanged aztreonam (approximately 65% recovered within 8 hours), the inactive β-lactam ring hydrolysis product of aztreonam (approximately 7%) and unknown metabolites (approximately 3%). Approximately 12% of aztreonam is excreted into faeces.
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. The percentage unchanged drug excreted in urine was independent of administered dose and accounted for 83.8% to 100% of the avibactam dose at steady-state. Less than 0.25% of avibactam is excreted into faeces.
The pharmacokinetics of both aztreonam and avibactam are approximately linear across the dose range studied (1500 mg to 2000 mg aztreonam; 375 mg to 600 mg avibactam). No appreciable accumulation of aztreonam or avibactam was observed following multiple intravenous infusions of 1500 mg/500 mg of aztreonam-avibactam administered every 6 hours for up to 11 days in healthy adults with normal renal function.
Elimination of aztreonam and avibactam is decreased in patients with renal impairment. The average increases in avibactam AUC are 2.6-fold, 3.8-fold, 7-fold and 19.5-fold in subjects with mild (here defined as CrCL 50 to 79 mL/min), moderate (here defined as CrCL 30 to 49 mL/min), severe renal impairment (CrCL <30 mL/min, not requiring dialysis) and end-stage renal disease, respectively, compared to subjects with normal renal function (here defined as CrCL >80 mL/min). Dose adjustment is needed in patients with estimated CrCL ≤50 mL/min.
The pharmacokinetics of avibactam in patients with any degree of hepatic impairment has not been studied. As aztreonam and 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.
Mean elimination half-life of both aztreonam and avibactam is increased, and plasma clearance decreased in the elderly, consistent with age-related reduction in renal clearance of aztreonam and avibactam.
The pharmacokinetics of aztreonam-avibactam have not been evaluated in paediatric patients.
The pharmacokinetics of aztreonam-avibactam is not significantly affected by gender or race. In a population pharmacokinetic analysis of aztreonam-avibactam, no clinically relevant differences in exposures were observed in adult patients with body mass index (BMI) ≥30 kg/m² compared to adult patients with BMI <30 kg/m².
Aztreonam non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, or toxicity to reproduction. Carcinogenicity studies have not been conducted with aztreonam by the intravenous route.
Avibactam 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.
A 28-day combination toxicology study in rats indicated that avibactam did not alter the safety profile of aztreonam when given in combination.
Animal studies with aztreonam do not indicate direct or indirect harmful effects with respect to fertility, pregnancy, embryonal/foetal development, parturition or postnatal development.
In pregnant rabbits administered avibactam at 300 and 1 000 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 embryofoetal 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 2.8 times human therapeutic exposures.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
