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The monobactam aztreonam is currently being re-examined as a therapeutic agent in light of the global spread of carbapenem resistance in aerobic Gram-negative bacilli and aztreonam's stability to Ambler class B metallo-β-lactamases. Of particular interest are the pharmacokinetic and pharmacodynamic properties of aztreonam alone and in combination with β-lactamase inhibitors. The choice of inhibitor may vary depending on the spectrum of β-lactamases produced by Enterobacteriaceae. The monobactam ring is also being used to produce new developmental monobactams. Thus, a greater understanding of aztreonam pharmacokinetics and dynamics is of great relevance in drug development. This review summarizes the pharmacokinetic profile of aztreonam in man and its pharmacodynamics in human and pre-clinical studies when studied alone and with β-lactamase inhibitors., (© The Author 2016. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

During 6 years, 2000 to 2006, we looked for evolution of antimicrobial resistance to beta-lactams of clinical isolates from patients with Gram negative infections. In vitro susceptibilities to piperacillin+tazobactam, ceftazidime, and aztreonam were followed along the period. Enterobacteriaceae of group 1 to 3 represent 24,884 strains and Pseudomonas spp. 11601. The global sensitivity of aztreonam was 85%, 87.1% for ceftazidime and 88.8% for pieracilline-tazobactam. Of course, aztreonam spectrum of activity is dedicated to Gram negative bacteria only but it is known to have a great penetration ratio in tissues and a half-live observed up to 6 times higher than in serum in experimental models. Antimicrobial rotation strategy is recommended in the prudent use of antibiotics. It seems that in our hospital a consistent increase of the use of aztreonam might be possible and proposed without increasing risk for infection control practices according to the microbiological laboratory results.

The pharmacodynamic parameter that appears to correlate best with a successful therapeutic outcome with beta-lactam antibiotics is the length of time the serum antibiotic concentration remains above the minimum inhibitory concentration (MIC) for the infecting pathogen. By maximizing this parameter, continuous administration of beta-lactam and related antibiotics by intravenous infusion could represent the optimal mode of drug administration. The pharmacokinetic and pharmacodynamic properties of ceftazidime administered by continuous intravenous infusion have been evaluated previously. Aztreonam is a monobactam antibiotic with similar pharmacokinetic and microbiologic activity to that of ceftazidime. This study evaluated the pharmacokinetic and pharmacodynamic characteristics of aztreonam administered as a continuous intravenous infusion in healthy volunteers against multiple clinical isolates. Five men and 3 women received 6 g of aztreonam administered by continuous intravenous infusion over 24 hours. Blood samples were collected before the infusion and at 0.5, 1 through 8, 12, 18, and 24 hours after the start of the infusion. Pharmacokinetic parameters were determined by standard equations. In vitro susceptibility testing was performed using National Committee for Clinical Laboratory Standards guidelines for 4 clinical isolates of gram-negative bacteria (2 each of Escherichia coli and Pseudomonas aeruginosa). Serum inhibitory titers (SITs) were determined in duplicate for each clinical isolate at 0 and 24 hours. The subjects' mean (+/- SD) age was 29.3+/-4.4 years; mean weight, 74.6+/-14.0 kg; and calculated mean creatinine clearance, 107+/-13 mL/min. For the pharmacokinetic parameters, mean (+/- SD) values were as follows: steady-state serum concentration, 40.9+/-8.8 microg/L; half-life, 1.5+/-0.4 hours; elimination rate constant, 0.50+/-0.13 hours(-1); steady-state volume of distribution, 0.18+/-0.04 L/kg; and total body clearance, 6.1+/-1.2 L/h. The MICs were 0.0625 and 0.125 microg/mL against the 2 E coli isolates and 4 microg/mL against both P aeruginosa isolates. The median SITs against the E. coli isolates were 1:256 and 1:512, and against the P. aeruginosa isolates were 1:8 and 1:16. At steady state, II subjects had serum concentrations of aztreonam > or =4 times the MIC for each organism. These findings suggest that further clinical study of the administration of aztreonam by continuous intravenous infusion is warranted.

The pharmacokinetics of aztreonam in critically ill surgical patients with serious gram-negative infections were studied. Blood samples were taken before and at 30 minutes, 2.5 hours, and 5 hours after a dose of aztreonam 2 g i.v. every six hours. All patients had received at least two aztreonam doses before the dosage interval being studied. Aztreonam concentrations were measured by high-performance liquid chromatography. Aztreonam's pharmacokinetics, the severity of illness, and patient outcomes were examined. A total of 28 patients with 111 serum aztreonam concentrations were included in the analysis. The patients were young (mean age, 35 years) and predominantly male. The mean APACHE II score was 19.3, and 22 patients had sepsis. Four patients died. The mean volume of distribution (V) of 0.35 L/ kg was nearly twice the previously reported steady-state value for healthy volunteers (0.18 L/kg) and was highly variable. A slightly higher than normal mean V, 0.22 L/ kg, was seen in a subset of six patients whose infection occurred earlier in their intensive care and who had lower APACHE II scores. While with some antibiotics the elevated V would imply difficulty in achieving therapeutic drug levels, 99 (89%) of the 111 concentrations were at or above the in vitro susceptibility breakpoint of 8 micrograms/mL. Despite observations of markedly increased and highly variable V in critically ill surgical patients, a standard dosage of aztreonam was usually sufficient to maintain adequate serum drug levels.

Aztreonam is a monocyclic beta-lactam antibiotic that is active exclusively against the aerobic gram-negative bacilli. It is not ototoxic or nephrotoxic and so is used as an alternative to aminoglycosides in a variety of clinical situations. In polymicrobial infections or when used for empiric therapy, aztreonam must be combined with other antimicrobial agents active against gram-positive and anaerobic species. Aztreonam is often effective against resistant strains of gram-negative organisms, which are often involved in nosocomial infections. Overuse of aztreonam should be avoided to prevent the emergence of resistant P. aeruginosa strains. Except in the treatment of P. aeruginosa infections, aztreonam should not be added to beta-lactam regimens for additional gram-negative coverage.

Aztreonam is the first monobactam and is unique among beta-lactam antibiotics for its spectrum of activity that is exclusively active against gram-negative aerobic bacteria. Broad clinical experience with this agent supports its use in the treatment of adults with severe or complicated urologic infections. Aztreonam may be safely used in patients with penicillin allergy. With a spectrum of activity that is comparable to the aminoglycosides but without the potential for ototoxicity or nephrotoxicity, aztreonam represents a rational choice of therapy for treatment of systemic urinary tract infections due to susceptible organisms.

Aztreonam is the first synthetic monobactam used in practical medicine. It is effective in Gram-negative aerobe infections. It inhibits the growth of most Enterobacteriaceae in concentrations below 2 mg/ml, and of Pseudomonas aeruginosa below 16 mg/ml. It shows a widespread, distribution achieving effective therapeutic concentration there, where infections are seen most frequently. The half-life is from 1.6 to 2.0 hours. It can be administered to patients every 8 and 12 hours in single parenteral doses of 0.5, 1.0, and 2.0 g. Aztreonam is a non-toxic antibiotic, a weak hapten with slight allergenicity. It has found therapeutic use together with the antibiotics directed against aerobic and anaerobic bacterial Gram-positive flora, and it is used in the therapy directed against infections with Gram-negative aerobes. It is an effective antibiotic in nosocomial infections, in oncological patients with neutropenia, and in elderly patients.