Chemical formula: C₁₃H₁₇N₅O₈S₂ Molecular mass: 435.433 g/mol PubChem compound: 5742832
Aztreonam is a monocyclic beta-lactam antibiotic with potent bactericidal activity against a wide spectrum of Gram-negative aerobic pathogens.
Unlike the majority of beta-lactam antibiotics, it is not an inducer in vitro of beta-lactamase activity. Aztreonam is usually active in vitro against those resistant aerobic organisms whose beta-lactamases hydrolyse other antibiotics.
Aztreonam exhibits activity in vitro against gram-negative aerobic pathogens, including P. aeruginosa. Aztreonam binds to penicillin-binding proteins of susceptible bacteria, which leads to inhibition of bacterial cell wall synthesis, followed by filamentation and cell lysis.
Loss of susceptibility to aztreonam in CF patients with P. aeruginosa occurs either through selection of strains with mutations located on the chromosome or rarely through acquisition of plasmid/integron mediated genes.
Known mechanisms of resistance to aztreonam mediated by mutation of chromosomal genes include: hyperexpression of the Class C beta-lactamase AmpC and up-regulation of the efflux pump MexAB-OprM. The known mechanism of resistance to aztreonam mediated by acquisition of genes involves acquisition of extended spectrum beta-lactam enzymes (ESBLs) that hydrolyse the four-member, nitrogen-containing ring of aztreonam.
ESBLs from Class A, B and D beta-lactamases may have activity against aztreonam. Class A beta-lactamases reported to hydrolyse aztreonam include the VEB type (primarily Southeast Asia), PER type (Turkey), and GES and IBC types (France, Greece, and S. Africa). There are rare reports of organisms with metallo-beta-lactamases (MBLs), Class B, that are resistant to aztreonam, VIM-5 (K. pneumoniae and P. aeruginosa – Turkey), VIM-6 (P. putida – Singapore) and VIM-7 (P. aeruginosa – United States), however, it is possible that these organisms were expressing multiple resistance mechanisms and thus a MBL was not responsible for the observed resistance to aztreonam. There are rare reports of Class D beta-lactamases from clinical isolates of P. aeruginosa, OXA-11 (Turkey) and OXA-45 (United States) that hydrolyse aztreonam.
Sputum concentrations:
Individual patients' sputum aztreonam concentrations exhibited considerable variability. For the combined Phase 3 placebo-controlled studies, ten minutes following a single dose of 75 mg inhaled aztreonamon Days 0, 14, and 28, the mean sputum concentrations in 195 patients with CF were 726 μg/g, 711 μg/g, and 715 μg/g, respectively, indicating no increased accumulation of aztreonam following repeated dosing.
Plasma concentrations:
Individual patients' plasma aztreonam concentrations exhibited considerable variability.
One hour following a single dose of 75 mg inhaled aztreonam (at approximately peak plasma concentration), the mean plasma level in patients with CF was 0.59 μg/ml. Mean peak plasma levels at Days 0, 14, and 28 of a course with 75 mg inhaled aztreonam 3 times a day were 0.55 μg/ml, 0.67 μg/ml, and 0.65 μg/ml, respectively, indicating no systemic accumulation of aztreonam following 3 times a day dosing. In contrast, the serum concentration of aztreonam following administration of aztreonam for injection (500 mg) is approximately 54 μg/ml.
Plasma aztreonam concentrations in paediatric patients aged 3 months to <6 years are comparable to those observed for children >6 years, adolescents and adults.
Single 30-minute i.v. infusions of 0.5 g, 1.0 g and 2.0 g in healthy volunteers produced peak serum levels of 54, 90 and 204 mg/L, and single 3-minute i.v. injections of the same doses produced peak levels of 58, 125 and 242 mg/L. Peak levels of aztreonam are achieved at about one hour after i.m. administration. After identical single i.m. or i.v. doses, the serum concentrations are comparable at 1 hour (1.5 hours from the start of i.v. infusion), with similar slopes of serum concentrations thereafter.
The serum half-life of aztreonam averaged 1.7 hours in subjects with normal renal function, independent of the dose and route. In healthy subjects 60-70% of a single i.m. or i.v. dose was recovered in the urine by 8 hours, and urinary excretion was essentially complete by 12 hours.
The protein binding of aztreonam in plasma is approximately 77% at clinically relevant plasma concentrations.
Aztreonam is not extensively metabolised. The principal metabolite (SQ26,992) 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.
The elimination half-life of aztreonam from serum is approximately 2.1 hours for inhalation administration, similar to what has been reported for aztreonam for injection. Approximately 10% of the total inhaled aztreonamdose is excreted in the urine as unchanged drug, as compared to 60-65% following intravenous administration of aztreonam for injection. Systemically absorbed aztreonam is eliminated about equally by active tubular secretion and glomerular filtration.
There was no clinically relevant effect of age or sex on the pharmacokinetics of aztreonam.
Pharmacokinetic studies have not been performed in patients with renal or hepatic impairment.
Peak levels of aztreonam are achieved at about one hour after i.m. administration. After identical single i.m. or i.v. doses, the serum concentrations are comparable at 1 hour (1.5 hours from the start of i.v. infusion), with similar slopes of serum concentrations thereafter. The serum half-life of aztreonam averaged 1.7 hours in subjects with normal renal function, independent of the dose and route. In healthy subjects 60-70% of a single i.m. or i.v. dose was recovered in the urine by 8 hours, and urinary excretion was essentially complete by 12 hours.
The Phase 2 and 3 placebo-controlled, registrational studies permitted comparison of plasma concentrations 1 hour post dose of aztreonam by age (6 to 12 years, 13 to 17 years, and ≥18 years). Data from these studies revealed minimal differences in mean plasma aztreonam concentrations between age groups in patients receiving aztreonam 3 times a day.
Pooled sputum concentration data from the Phase 2 and 3 registrational studies revealed some evidence of lower mean sputum concentrations in patients aged 13 to 17 years following one dose of aztreonam 3 times a day. However, all mean sputum concentration values were associated with relatively large standard deviations.
A 104-week rat inhalation toxicology study to assess the carcinogenic potential of ascending doses of aztreonamdemonstrated no drug-related increase in malignant tumours.
Genotoxicity (Chromosomal aberration and mouse lymphoma mutation assay) studies with aztreonam were negative.
Aztreonam was well tolerated in a comprehensive series of preclinical toxicity and safety studies.
Fertility, teratology, perinatal and postnatal studies were conducted with aztreonam for i.v. injection in rats at daily doses up to 750 mg/kg without adverse effects. The survival rate during the lactation period was slightly reduced in the offspring of rats that received the highest dose.
© 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.
