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Purpose: The effects of i.v. push administration on the pharmacodynamic exposures of meropenem, cefepime, and aztreonam were evaluated., Methods: Pharmacokinetic and pharmacodynamic analyses were conducted using previously published pharmacokinetic data for meropenem, cefepime, and aztreonam. The probability of target attainment (PTA) was assessed using Monte Carlo simulations for 30-minute and 5-minute infusions of approved dosing regimens and alternative dosing schemes often used in clinical practice, including 500 mg every 6 hours and 1 g every 8 hours for meropenem, 1 g every 6 hours and 2 g every 8 hours for cefepime, and 2 g every 8 hours for aztreonam. For each regimen examined, means and standard deviations for the percentage of the dosing interval that the free drug concentration remained above the minimum inhibitory concentration (MIC) were calculated and reported., Results: No or only minor differences were noted between 30-minute and 5-minute infusions. The largest differences were observed at an MIC of 4 mg/L for meropenem and an MIC of 16 mg/L for aztreonam. At an MIC of 4 mg/L, meropenem 500 mg every 6 hours as a 30-minute infusion had an 8% greater PTA compared with the 5-minute infusion. At an MIC of 16 mg/L, a 30-minute infusion of aztreonam 2 g every 8 hours had a 12% greater PTA compared with the 5-minute infusion., Conclusion: Simulations of meropenem, cefepime, and aztreonam by i.v. push over 5 minutes indicated that there would be minimal or no effect on pharmacodynamic exposures compared with the effect when administered by 30-minute infusions., (Copyright © 2017 by the American Society of Health-System Pharmacists, Inc. All rights reserved.)

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.)

Objectives: The combination of aztreonam/avibactam has promising activity against MDR Gram-negative pathogens producing metallo-β-lactamases (MBLs), such as New Delhi MBL-1. Pharmacokinetic (PK)/pharmacodynamic (PD) understanding of this combination is critical for optimal clinical dose selection. This study focuses on the determination of an integrated PK/PD approach for aztreonam/avibactam across multiple clinical Enterobacteriaceae strains., Methods: Six clinical Enterobacteriaceae isolates expressing MBLs and ESBLs were studied in an in vitro hollow-fibre infection model (HFIM) using various dosing regimens simulating human-like PK for aztreonam/avibactam. The neutropenic murine thigh infection model was used for in vivo validation against two bacterial strains., Results: MIC values of aztreonam/avibactam for the isolates ranged from 0.125 to 8 mg/L. Using a constant infusion of avibactam at 4 mg/L, the aztreonam PK/PD index was observed as % fT >MIC. Studies performed in the presence of a fixed dose of aztreonam revealed that the efficacy of avibactam correlates best with percentage of time above a critical threshold concentration of 2-2.5 mg/L. These conclusions translated well to the efficacy observed in the murine thigh model, demonstrating in vivo validation of the in vitro PK/PD target., Conclusions: PK/PD evaluations for aztreonam/avibactam in HFIM yielded a single target across strains with a wide MIC range. This integrated approach could be easily applied for forecasting clinically efficacious doses for β-lactam/β-lactamase inhibitor combinations., (© The Author 2015. 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.)

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.

The pharmacokinetics of aztreonam were studied in six healthy male subjects (group I) and 12 male patients with post-hepatitis liver cirrhosis and ascites. Patients were allocated into two groups according to serum creatinine; group II included nine patients with serum creatinine. < or = 15 mg/L while group III included three patients with serum creatinine > 15 mg/L. Aztreonam 1 g was given as iv bolus injection. Aztreonam reached a peak concentration in the ascitic fluid (AF) of 6.2 +/- 2.3 mg/L at 4 h, and of 8.7 +/- 4.4 mg/L at 6 h in groups II and III respectively. The level of the drug in AF 24 h post-dosing was still higher than MIC90 for Enterobacteriaceae in most patients. The half-life of elimination from serum increased significantly (P > 0.001) from 1.82 +/- 0.14 h in group I to 6.6 +/- 2.1 h and to 8.87 +/- 0.2 h in groups II and III, respectively. Both the central and the terminal volumes of distribution were higher in cirrhotic patients than in healthy volunteers. Liver cirrhosis and ascites resulted in a significant increase (P < 0.001) of the total body clearance (Cl) of aztreonam from 84 +/- 8 mL/h/kg in group I to 209 +/- 87 mL/h/kg in group II. However, the concomitant association of mild renal impairment in group III abolished this increase; Cl in group III was 122 +/- 50 mL/h/kg. The AUC0-infinity serum was 137.5 +/- 12.2, 78.5 +/- 24.9 and 151 +/- 42 mg.h/L in groups I, II and II, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

The pharmacokinetics of aztreonam and vancomycin were studied in six adult patients who developed peritonitis during Continuous Ambulatory Peritoneal Dialysis. Aztreonam 3 g was added to the first exchange in each 24 h period with vancomycin 500 mg on the first day and 250 mg on each subsequent day (provided the pre-dose serum vancomycin concentration was less than 10 mg/l) for a total of ten days. Aztreonam and vancomycin concentrations were measured in the serum and dialysate at 1, 2, 6, 12, 18 and 24 h after the initial dose and pre-dose on days 5 and 10. By the end of the ten day study all patients had recovered clinically and had a normal dialysate. For aztreonam, the mean peak serum concentration was 84.3 mg/l (range 59.6-102.8), the mean 24 h pre-dose serum concentration was 23.0 mg/l (range 8.6-39.2) and the mean 24 h pre-dose dialysate concentration was 15.5 mg/l (range 5.0-32.0). For vancomycin, the mean peak serum concentration was 10.2 mg/l (range 8.1-12.6), the mean 24 h pre-dose concentration was 5.5 mg/l (range 3.6-6.4), and the mean 24 h pre-dose dialysate concentration was 3.4 mg/l (range 2.4-4.6). In the treatment of CAPD peritonitis, once daily intra-peritoneal administration of aztreonam 3 g with vancomycin 500 mg initially and 250 mg on subsequent days (serum concentrations permitting) provides concentrations of antibiotic in both the serum and dialysate throughout the 24 h period in excess of the inhibitory concentrations of those organisms most frequently encountered in this condition.

Steady-state pharmacokinetics of carumonam were investigated in twelve healthy adult male volunteers after 20 min intravenous infusions of three consecutive carumonam dosage regimens: 1 g every 8 h (3 g/day) from 0-72 h, 2 g every 8 h (6 g/day) from 88-120 h and 2 g every 6 h (8 g/day) from 132-216 h. Serial plasma samples were collected after the first dose of the first regimen and the last dose of all three regimens and were analysed for carumonam by a specific HPLC method. The overall mean maximal plasma concentrations were 108 and 211 mg/l at the end of infusion of 1 and 2 g, respectively. The steady-state pharmacokinetic parameters and plasma concentration-time profiles of carumonam when adjusted for dose were similar for the three regimens. The overall terminal elimination half-life was 1.4 h (range 1.1-1.8 h), the apparent volume of distribution at steady state reached 11.5 l (range 8.7-15.5 l) and the total systemic clearance amounted to 118 ml/min (range 83-158 ml/min). Considering the frequency of dosing relative to the elimination half-life, accumulation of the drug in plasma was not expected and none was found from any of the three regimens. Carumonam was well tolerated up to 8 g/day and exhibited dose-independent pharmacokinetics which were not altered upon multiple dosing.

The pharmacokinetics of aztreonam were studied in ten critically ill intubated patients with lower respiratory tract infections. Serum and urinary concentrations of the drug and its penetration into bronchial secretions after a 2-g intravenous bolus were measured. Using a two-compartment linear model a terminal half-life of 1.87 + 0.46 h was determined. No interpatient differences were found for half-life values, AUC or volume of distribution, except in the case of one obese patient. The greatest variability was observed in the clearance values, and in particular the extrarenal clearance which ranged from 0.3 to 9.6 1/h. Maximum concentrations in bronchial secretions were reached very quickly in the 2 h after drug administration, with a range of 4.8-18.7 mg/l. No accumulation of aztreonam after repeated doses was detected.

We have studied the penetration of aztreonam into pus with a low mortality intra-abdominal abscess model in the Wistar rat. The mean peak serum concentration (standard error) of aztreonam was 74.6 +/- 9.88 mg/l at 30 min falling to 2.31 +/- 1.28 mg/l at 8 h. The mean concentration in pus was 17.04 +/- 2.01 mg/l at 2 h and was 14.47 +/- 2.23 mg/l at 8 h. These concentrations are in excess of the MICs of most Gram-negative aerobic bacilli commonly isolated from intra-abdominal abscesses.