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Purpose: A series of iterative population pharmacokinetic (PK) modeling and probability of target attainment (PTA) analyses based on emerging data supported dose selection for aztreonam-avibactam, an investigational combination antibiotic for serious Gram-negative bacterial infections., Methods: Two iterations of PK models built from avibactam data in infected patients and aztreonam data in healthy subjects with "patient-like" assumptions were used in joint PTA analyses (primary target: aztreonam 60% fT > 8 mg/L, avibactam 50% fT > 2.5 mg/L) exploring patient variability, infusion durations, and adjustments for moderate (estimated creatinine clearance [CrCL] > 30 to ≤ 50 mL/min) and severe renal impairment (> 15 to ≤ 30 mL/min). Achievement of > 90% joint PTA and the impact of differential renal clearance were considerations in dose selection., Results: Iteration 1 simulations for Phase I/IIa dose selection/modification demonstrated that 3-h and continuous infusions provide comparable PTA; avibactam dose drives joint PTA within clinically relevant exposure targets; and loading doses support more rapid joint target attainment. An aztreonam/avibactam 500/137 mg 30-min loading dose and 1500/410 mg 3-h maintenance infusions q6h were selected for further evaluation. Iteration 2 simulations using expanded PK models supported an alteration to the regimen (500/167 mg loading; 1500/500 mg q6h maintenance 3-h infusions for CrCL > 50 mL/min) and selection of doses for renal impairment for Phase IIa/III clinical studies., Conclusion: A loading dose plus 3-h maintenance infusions of aztreonam-avibactam in a 3:1 fixed ratio q6h optimizes joint PTA. These analyses supported dose selection for the aztreonam-avibactam Phase III clinical program., Clinical Trial Registration: NCT01689207; NCT02655419; NCT03329092; NCT03580044., (© 2024. The Author(s).)

Aim: The aim of this study was to build and verify a preliminary physiologically based pharmacokinetic (PBPK) model of Chinese pregnant women. The model was used to predict maternal pharmacokinetics (PK) of 6 predominantly renally cleared drugs., Method: Based on SimCYP Caucasian pregnancy population dataset, the preliminary Chinese pregnant population was built by updating several key parameters and equations according to physiological parameters of Chinese (or Japanese) pregnant women. Drug-specific parameters of 6 renally cleared drugs were validated through PBPK modeling of Caucasian non-pregnant, Caucasian pregnant and Chinese non-pregnant population. The preliminary PBPK model of Chinese pregnant population was then developed by integrating the preliminary Chinese pregnant population and the drug-specific parameters. This model was verified by comparing the predicted maternal PK of these 6 drugs with the observed in vivo data from the literature., Results: The preliminary Chinese pregnant population PBPK model successfully predicted the PK of 6 target drugs for different pregnancy stages. The predicted plasma concentrations time profiles fitted the observed data well, and most predicted PK parameters were within 2-fold of observed data., Conclusions: The preliminary Chinese pregnant population PBPK model provided a useful tool to predict the maternal PK of 6 predominantly renally cleared drugs in Chinese pregnant women., (© 2020 John Wiley & Sons, Ltd.)

SPR741 is a novel polymyxin B derivative, with minimal intrinsic antibacterial activity and reduced nonclinical nephrotoxicity compared to levels with polymyxin B, that interacts with the outer membrane of Gram-negative bacteria, enhancing penetration of coadministered antibiotics. The safety, tolerability, and pharmacokinetics (PK) of SPR741 were evaluated in two studies, after single and multiple intravenous (i.v.) doses in healthy adult subjects and after coadministration with partner antibiotics. In the single and multiple ascending-dose study, SPR741 or placebo was administered as a 1-h infusion at single doses of 5 to 800 mg and in multiple doses of 50 to 600 mg every 8 h (q8h) for 14 days. In the drug-drug interaction study, a single 400-mg i.v. dose of SPR741 was administered alone and in combination with piperacillin-tazobactam, ceftazidime, and aztreonam. PK parameters for SPR741 and partner antibiotics were determined using noncompartmental analysis. After single doses, a dose-linear and proportional increase in mean maximum concentration in plasma ( C max ) and area under the concentration-time curve (AUC) was observed. At doses of 100 to 800 mg, >50% of the dose was excreted in the urine in the first 4 h postdose. After multiple doses, the mean half-life was 2.2 h on day 1 and up to 14.0 h on day 14, with no evidence of accumulation after 14 days of dosing up to 400 mg. The PK profile of SPR741 and partner antibiotics was unchanged with coadministration. SPR741 was generally well tolerated at doses up to 1,800 mg/day. These data support further clinical development of SPR741 for treating serious infections due to resistant bacteria. (These studies have been registered at ClinicalTrials.gov under identifiers NCT03022175 and NCT03376529.)., (Copyright © 2019 Eckburg et al.)

The purpose of this study was to investigate aztreonam (ATM) and avibactam (AVI) distribution in intraperitoneal fluid and muscle interstitial fluid by microdialysis in rats, with or without peritonitis, and to compare the unbound concentrations in tissue with the unbound concentrations in blood. Microdialysis probes were inserted into the jugular veins, hind leg muscles, and peritoneal cavities of control rats ( n = 5) and rats with intra-abdominal sepsis ( n = 9) induced by cecal ligation and punctures. ATM and AVI probe recoveries in each medium were determined for both molecules in each rat by retrodialysis by drug. ATM-AVI combination was administered as an intravenous bolus at a dose of 100-25 mg · kg -1 Microdialysis samples were collected over 120 min, and ATM-AVI concentrations were determined by liquid chromatography-tandem mass spectrometry. Noncompartmental pharmacokinetic analysis was conducted and nonparametric tests were used for statistical comparisons between groups (infected versus control) and medium. ATM and AVI distribution in intraperitoneal fluid and muscle was rapid and complete both in control rats and in rats with peritonitis, and the concentration profiles in blood, intraperitoneal fluid, and muscle were virtually superimposed, in control and infected animals, both for ATM and AVI. No statistically significant difference was observed between unbound tissue extracellular fluid and systemic areas under the curve for both molecules in control and infected animals. In the present study, intraperitoneal infection induced by cecal ligation and puncture had no apparent effect on ATM and AVI pharmacokinetics in rats., (Copyright © 2018 American Society for Microbiology.)

Background: A β-lactamase inhibitor (BLI) confers susceptibility of β-lactamase-expressing multidrug resistant (MDR) organisms to the partnering β-lactam (BL)., Aims: To discuss the experimental design and modelling strategies for two-drug combinations, using ceftazidime- and aztreonam-avibactam combinations, as examples., Sources: The information came from several publications on avibactam in vitro time-kill studies and corresponding pharmacodynamic models., Content: The experimental design to optimally gather crucial information from constant-concentration time-kill studies is to use an agile matrix of two-drug concentration combinations that cover 0.25- to 4-fold BL minimum inhibitory concentration (MIC) relative to the BLI concentrations to be tested against the particular isolate. This shifting agile design can save substantial costs and resources, without sacrificing crucial information needed for model development. The complex synergistic BL/BLI interaction is quantitatively explored using a semi-mechanistic pharmacokinetic-pharmacodynamic (PK/PD) mathematical model that accounts for antimicrobial activities in the combination, bacteria-mediated BL degradation and inhibition of BL degradation by BLI. A predictive mathematical formulation for the two-drug killing effects preserves the correlation between the model-derived EC 50 of BL and the BL MIC. The predictive value of PK/PD model is evaluated against external data that were not used for model development, including but not limited to in vitro hollow fibre and in vivo murine infection models., Implications: As a framework for translational predictions, the goal of this modelling strategy is to significantly decrease the decision-making time by running clinical trial simulations with MIC-substituted EC 50 function for isolates of comparable susceptibility through established correlation between BL MIC and EC 50 values., (Copyright © 2017 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Avibactam is a novel non-β-lactam β-lactamase inhibitor that has been approved in the United States and Europe for use in combination with ceftazidime. Combinations of avibactam with aztreonam or ceftaroline fosamil have also been clinically evaluated. Until recently, there has been very little precedence of which pharmacokinetic/pharmacodynamic (PK/PD) indices and magnitudes are appropriate to use for β-lactamase inhibitors in population PK modeling for analyzing potential doses and susceptibility breakpoints. For avibactam, several preclinical studies using different in vitro and in vivo models have been conducted to identify the PK/PD index of avibactam and the magnitude of exposure necessary for effect in combination with ceftazidime, aztreonam, or ceftaroline fosamil. The PD driver of avibactam critical for restoring the activity of all three partner β-lactams was found to be time dependent rather than concentration dependent and was defined as the time that the concentration of avibactam exceeded a critical concentration threshold (% f T>C T ). The magnitude of the C T and the time that this threshold needed to be exceeded to elicit particular PD endpoints varied depending on the model and the partner β-lactam. This review describes the preclinical studies used to determine the avibactam PK/PD target in combination with its β-lactam partners., (Copyright © 2018 American Society for Microbiology.)

Background: Concomitant use of oral azithromycin and inhaled tobramycin occurs in approximately half of US cystic fibrosis (CF) patients. Recent data suggest that this combination may be antagonistic., Methods: Test the hypothesis that azithromycin reduces the clinical benefits of tobramycin by analyses of clinical trial data, in vitro modeling of P. aeruginosa antibiotic killing, and regulation of the MexXY efflux pump., Results: Ongoing administration of azithromycin associates with reduced ability of inhaled tobramycin, as compared with aztreonam, to improve lung function and quality of life in a completed clinical trial. In users of azithromycin FEV 1 (L) increased 0.8% during a 4-week period of inhaled tobramycin and an additional 6.4% during a subsequent 4-week period of inhaled aztreonam (P<0.005). CFQ-R respiratory symptom score decreased 1.8 points during inhaled tobramycin and increased 8.3 points during subsequent inhaled aztreonam (P<0.001). A smaller number of trial participants not using azithromycin had similar improvement in lung function and quality of life scores during inhaled tobramycin and inhaled aztreonam. In vitro, azithromycin selectively reduced the bactericidal effects tobramycin in cultures of clinical strains of P. aeruginosa, while up regulating antibiotic resistance through MexXY efflux., Conclusions: Azithromycin appears capable of reducing the antimicrobial benefits of tobramycin by inducing adaptive bacterial stress responses in P. aeruginosa, suggesting that these medications together may not be optimal chronic therapy for at least some patients., (Copyright © 2016 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

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.)

Aztreonam is a monocyclic β-lactam antibiotic often used to treat infections caused by Enterobacteriaceae or Pseudomonas aeruginosa. Despite the long history of clinical use, population pharmacokinetic modeling of aztreonam in renally impaired patients is not yet available. The aims of this study were to assess the impact of renal impairment on aztreonam exposure and to evaluate dosing regimens for patients with renal impairment. A population model describing aztreonam pharmacokinetics following intravenous administration was developed using plasma concentrations from 42 healthy volunteers and renally impaired patients from 2 clinical studies. The final pharmacokinetic model was used to predict aztreonam plasma concentrations and evaluate the probability of pharmacodynamic target attainment (PTA) in patients with different levels of renal function. A 2-compartment model with first-order elimination adequately described aztreonam pharmacokinetics. The population mean estimates of aztreonam clearance, intercompartmental clearance, volume of distribution of the central compartment, and volume of distribution of the peripheral compartment were 4.93 L/h, 9.26 L/h, 7.43 L, and 6.44 L, respectively. Creatinine clearance and body weight were the most significant variables to explain patient variability in aztreonam clearance and volume of distribution, respectively. Simulations using the final pharmacokinetic model resulted in a clinical susceptibility break point of 4 and 8 mg/L, respectively, based on the clinical use of 1- and 2-g loading doses with the same or reduced maintenance dose every 8 hours for various renal deficiency patients. The population pharmacokinetic modeling and PTA estimation support adequate PTAs (>90% PTA) from the aztreonam label for dose adjustment of aztreonam in patients with moderate and severe renal impairment., (© 2016, The American College of Clinical Pharmacology.)

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.)

Background: Pseudomonas aeruginosa (Pa) infection is an important contributor to the progression of cystic fibrosis (CF) lung disease. The cornerstone treatment for Pa infection is the use of inhaled antibiotics. However, there is substantial lung disease heterogeneity within and between patients that likely impacts deposition patterns of inhaled antibiotics. Therefore, this may result in airways below the minimal inhibitory concentration of the inhaled agent. Very little is known about antibiotic concentrations in small airways, in particular the effect of structural lung abnormalities. We therefore aimed to develop a patient-specific airway model to predict concentrations of inhaled antibiotics and to study the impact of structural lung changes and breathing profile on local concentrations in airways of patients with CF., Methods: In- and expiratory CT-scans of children with CF (5-17 years) were scored (CF-CT score), segmented and reconstructed into 3D airway models. Computational fluid dynamic (CFD) simulations were performed on 40 airway models to predict local Aztreonam lysine for inhalation (AZLI) concentrations. Patient-specific lobar flow distribution and nebulization of 75 mg AZLI through a digital Pari eFlow model with mass median aerodynamic diameter range were used at the inlet of the airway model. AZLI concentrations for central and small airways were computed for different breathing patterns and airway surface liquid thicknesses., Results: In most simulated conditions, concentrations in both central and small airways were well above the minimal inhibitory concentration. However, small airways in more diseased lobes were likely to receive suboptimal AZLI. Structural lung disease and increased tidal volumes, respiratory rates and larger particle sizes greatly reduced small airway concentrations., Conclusions: CFD modeling showed that concentrations of inhaled antibiotic delivered to the small airways are highly patient specific and vary throughout the bronchial tree. These results suggest that anti-Pa treatment of especially the small airways can be improved.

Introduction: Chronic airway infection in cystic fibrosis (CF) is linked with progressive loss of pulmonary function and is the primary cause of mortality. Treatment regimens have generally focused on the use of chronic antibiotic therapy to target Pseudomonas aeruginosa (PA), a major pathogen associated with a decline in FEV1%. Specifically, inhaled antibiotic therapy provides high antibiotic sputum concentrations and decreases bacterial burden., Areas Covered: This article describes the pharmacology, pharmacodynamics/pharmacokinetics, clinical efficacy, microbiology and safety of aztreonam lysine (AZLI, Cayston), an inhaled antibiotic indicated for use in CF patients with PA. Articles were identified using MEDLINE (1966 - June 13, 2013) and EMBASE (1947 - June 13, 2013). Abstracts from the annual meeting (2011 - 2012) of the North American Cystic Fibrosis Conference were searched to identify additional publications., Expert Opinion: AZLI is an additional product that can be used in the management of CF and will likely play a major role in the suppression of PA. Clinical trials have demonstrated improvements in pulmonary function and patient reported symptoms. AZLI may therefore be used as an alternative to traditional inhaled antibiotics in patients with moderate-to-severe CF and PA colonization. Further investigation is warranted into use of AZLI in mild lung disease and for PA eradication.

Although a worldwide increasing incidence of bacterial infections with panresistant pathogens may need innovative antiinfective agents, no breakthrough developments can be expected in the near future. As a consequence, well-tried antibiotics like aztreonam, fosfomycin and colistin, are experiencing a clinical revival, particularly if they are used in an improved manner. Even penicillin G with its narrow spectrum of antimicrobial activity remains an important considerable agent of first choice in special indications compared to broad spectrum antiinfectives.

Background: Various inhaled antibiotics are currently used for treating chronic Pseudomonas aeruginosa lung infection in cystic fibrosis (CF) patients, however their relative efficacies are unclear. We compared the efficacy of the inhaled antibiotics tobramycin (TIP, TIS-T, TIS-B), colistimethate sodium (colistin) and aztreonam lysine for inhalation (AZLI) based on data from randomised controlled trials., Methods: In the base case, efficacies of antibiotics were compared using a network meta-analysis of seven trials including change from baseline in forced expiratory volume in 1 second (FEV(1)) % predicted, P. aeruginosa sputum density and acute exacerbations., Results: The tobramycin preparations, AZLI and colistin, showed comparable improvements in efficacy in terms of FEV1% predicted at 4 weeks; the difference in % change from baseline (95%CrI) for TIP was compared to TIS-T (-0.55, -3.5;2.4), TIS-B (-0.64, -7.1;5.7), AZLI (3.64, -1.0;8.3) and colistin (5.77, -1.2;12.8)., Conclusion: We conclude that all studied antibiotics have comparable efficacies for the treatment of chronic P. aeruginosa lung infection in CF., (Copyright © 2012 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Objective: To evaluate the pharmacology, clinical efficacy, and safety of aztreonam lysine for inhalation (AZLI) for cystic fibrosis (CF)-related signs and symptoms of pulmonary disease., Data Sources: Literature was searched in MEDLINE through PubMed and cross-referenced with EMBASE (1980-June 2012). The key search terms used were aztreonam lysine, nebulized, inhaled, and cystic fibrosis. Bibliographies of selected articles were used to identify additional references. Ongoing trials were identified through a review of Web site trial registries., Study Selection and Data Extraction: Articles were limited to those written in English about studies conducted in humans. Studies included in this review examined both adult and pediatric patients with CF., Data Synthesis: Aztreonam lysine is an inhaled monocyclic β-lactam antibiotic approved for use in the CF population. Four completed clinical trials with peer-reviewed published data were reviewed to assess the efficacy and safety of single-course AZLI; a fifth trial assessed the safety and efficacy of repeat courses of AZLI. None of these trials compared AZLI in a head-to-head manner with tobramycin for inhalation. In patients with moderate to severe pulmonary disease, AZLI administration improved forced expiratory volume in 1 second measurements, decreased sputum bacterial Pseudomonas aeruginosa density, and improved symptoms. Adverse effects in clinical trials were generally mild and similar to those with placebo., Conclusions: AZLI is safe and effective for management of pulmonary-related symptoms in patients with CF who are colonized with P. aeruginosa and have moderate to severe pulmonary disease. Additional trial data comparing AZLI with tobramycin are warranted to further establish the place of AZLI in therapy.

An aerosol form of aztreonam lysinate has recently been developed as a treatment for cystic fibrosis patients suffering from chronic Pseudomonas aeruginosa lung colonization. Local administration means the drug can reach mucus concentrations in the order of hundreds of times the MIC(50) of Pseudomonas associated with severe lung disease in cystic fibrosis, resulting in a significant reduction in airway bacterial density and a parallel improvement in lung function. These advantages are maintained over prolonged periods of treatments. Administration of the drug is optimized by the use of a specific eFlow(®) system, resulting in considerable reductions in treatment times when compared with conventional nebulizers. The drug has been proven safe and no concomitant induction of resistance to Pseudomonas was found during the clinical trial period of 18 months. Aztreonam lysinate has been shown to ameliorate pulmonary function in cystic fibrosis patients with chronic airway Pseudomonas infection and this is paralleled by a reduction in bacterial density in the lungs. The increased availability of new aerosolized antibiotics for cystic fibrosis will lead to new scenarios in the treatment of the disease.

Acquisition of Pseudomonas aeruginosa, the most prevalent organism isolated from cystic fibrosis (CF) airways, is associated with an accelerated clinical deterioration and reduced survival. Strategies to chronically suppress P. aeruginosa infections in individuals with CF have evolved over the last four decades and now largely focus on regular administration of aerosolized antibiotics. Aztreonam lysine (AZLI; Cayston, Gilead Pharmaceuticals [Foster City, CA, USA]), a novel formulation of the monobactam aztreonam suitable for aerosol delivery has recently been developed. AZLI is administered as 75 mg three-times daily for 28 days in 'on/off' cycles using the Altera/eFlow electronic nebulizer (PARI Innovative Manufacturers [Midlothian, VA, USA]). In individuals with CF chronically infected with P. aeruginosa, AZLI improved healthcare-associated quality-of-life scores, pulmonary function and weight, prolonged time to requirement of antibacterial therapy for symptoms of pulmonary exacerbation and reduced P. aeruginosa sputum burdens. These outcomes were durable over 18 months of cycled use. AZLI has been demonstrated to be safe and effective, and expands available chronic maintenance therapies in CF.

Importance of the Field: Chronic endobronchial infection in cystic fibrosis (CF) leads to progressive lung function loss and respiratory failure. Most adult CF patients are infected with Pseudomonas aeruginosa, an important predictor of mortality. Suppressing chronic P. aeruginosa infection with inhaled antibiotics is standard of care for CF patients., Areas Covered in This Review: This review describes the development (2003 - 2010) of aztreonam lysine 75 mg powder and solvent for nebulizer solution (AZLI; Cayston), an aerosolized formulation of the monobactam antibiotic aztreonam., What the Reader Will Gain: AZLI was studied in patients with CF and chronic P. aeruginosa airway infection. In placebo-controlled trials, AZLI improved respiratory symptoms, increased forced expiratory volume in 1 sec (FEV(1)), decreased sputum P. aeruginosa density, and was well tolerated. An open-label follow-on trial of nine 'on/off' courses showed that AZLI was safe and the effect durable with repeated administration. AZLI was recently approved for use in CF patients in Australia and the USA, and conditionally approved in Canada and the European Union. AZLI is given three times daily for 28 days (2 - 3 min/dose), followed by 28 days off-drug. AZLI is used only with the Altera Nebulizer System, which provides appropriate particle size and small airway deposition, and has excellent portability., Take Home Message: AZLI is a new therapy that is safe and effectively improves respiratory symptoms and FEV(1) in patients with CF.

In an in vitro pharmacodynamic model, linezolid attenuated the activity of aztreonam and ceftazidime against Escherichia coli. Conversely, synergy was detected at 24 and 48 h when daptomycin or vancomycin was added to aztreonam and ceftazidime. We conclude that significant yet underappreciated interactions may occur between gram-positive-spectrum and gram-negative-spectrum antibacterials.

Our objectives were to compare the pharmacokinetics (PK) of carumonam, a monobactam, between cystic fibrosis (CF) patients and healthy volunteers and assess its pharmacodynamic profile. We studied 10 adult CF patients and 18 healthy volunteers of similar body size (dose: 2.166 g of carumonam as 15-min intravenous infusion). High performance liquid chromatography with ultraviolet detection (HPLC-UV) was used for drug analysis and NONMEM (ICON, Ellicot City, MD) for population PK and Monte Carlo simulation with targets between > or =20% and 100% free time above MIC (fT > MIC). Unscaled renal clearance was 24% higher in CF patients. Lean body mass and creatinine clearance explained the difference in average clearance and volume of distribution between both subject groups. For a daily dose of 6 g per 70 kg of total body weight, 15-min infusions q8h achieved robust (>90%) probabilities of target attainment (PTAs) (target, 60% fT > MIC) for MICs < or =3 mg/L in CF patients and < or =6 mg/L in healthy volunteers. At the same dose, 4-h infusions q8h achieved robust PTAs up to markedly higher MICs < or =8 to 12 mg/L in CF patients and < or =16 mg/L in healthy volunteers.

Progressive respiratory failure due to Pseudomonas aeruginosa is the leading cause of morbidity and mortality in patients with cystic fibrosis. The pulmonary delivery of antimicrobial agents provides high concentrations of drug directly to the site of infection and attains pharmacokinetic-pharmacodynamic indices exceeding those which can be achieved with systemic dosing. MP-376 is a new formulation of levofloxacin that enables the safe aerosol delivery of high concentrations of drug to pulmonary tissues. In vivo studies were conducted to demonstrate the efficacy of MP-376 in models of mouse pulmonary infection. The superiority of aerosol dosing over systemic dosing was demonstrated in models of both acute and chronic lung infection. In a model of acute lung infection, aerosol treatment with MP-376 once or twice daily reduced the lung bacterial load to a greater extent than aerosol tobramycin or aztreonam did when they were administered at similar or higher doses. The bacterial killing by aerosol MP-376 observed in the lung in the model of acute pulmonary infection translated to improved survival (P < 0.05). In a model of chronic pulmonary infection, aerosol MP-376 had antimicrobial effects superior to those of aztreonam (P < 0.05) and effects similar to those of tobramycin (P > 0.05). In summary, these data show that aerosol MP-376 has in vivo activity when it is used to treat acute and chronic lung infections caused by P. aeruginosa.

This randomized crossover study in healthy participants assessed pharmacokinetic interactions between telavancin, aztreonam, and piperacillin/tazobactam. Part 1: 11 participants received telavancin 10 mg/kg, aztreonam 2 g, or a combination of telavancin 10 mg/kg+aztreonam 2 g intravenously on 3 separate days. Part 2: 12 participants received telavancin 10 mg/kg, piperacillin/tazobactam 4.5 g, or a combination of telavancin 10 mg/kg+piperacillin/tazobactam 4.5 g intravenously on 3 separate days. Blood and urine drug concentrations were measured up to 48 hours posttreatment. Drug interactions were assessed by equivalence analysis of noncompartmental pharmacokinetic parameters, focusing on area under plasma concentration-time curves (AUC), log transformed; if the antilog of the 90% confidence intervals (CIs) for the mean log AUC difference was within equivalence bounds (0.70, 1.43), the effect of coadministration on the pharmacokinetics of the respective drug was deemed not clinically significant. Plasma concentration-time curves for all treatment pairs were nearly superimposable with comparable values for pharmacokinetic parameter estimates. In equivalence analyses, 90% CI for the mean difference in log AUC in each comparison fell within the predefined clinical equivalence limits and bioequivalence limits (0.80, 1.25). Administration of aztreonam or piperacillin/tazobactam with telavancin had no clinically significant effect on the pharmacokinetic disposition of any of these drugs.

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.

Aztreonam (AZM) is a monobactam antibiotic with a high level of activity against gram-negative micro-organisms, including Pseudomonas aeruginosa. We evaluated AZM pharmacokinetics and pharmacokinetic-pharmacodynamic relationships in patients with cystic fibrosis (CF) and healthy subjects. Pharmacokinetic data in eight CF patients and healthy subjects that were matched for age, gender, weight, and height were obtained and analyzed by using the nonparametric adaptive grid algorithm. Probabilities of target attainment using percentages of time of unbound concentration above the MIC (fT>MIC) were obtained by using a Monte Carlo simulation. AZM total body clearance was significantly higher in CF patients (100.1 +/- 17.1 versus 76.2 +/- 7.4 ml/min in healthy subjects; P < 0.01). The pharmacokinetic parameter estimates for terminal half-life (1.54 +/- 0.17 h [mean +/- the standard deviation]) and volume of distribution (0.20 +/- 0.02 liters/kg in patients with CF patients were not different from those in healthy subjects. Monte Carlo simulations with a target of a fT>MIC of 50 to 60% at a dose of 1,000 mg every 8 h indicated a clinical breakpoint of 4 mg/liter and 1 to 2 mg/liter for healthy subjects and CF patients, respectively. This study using matched controls showed that AZM total body clearance and not the volume of distribution is higher in CF patients as a result of increased renal clearance. Pharmacokinetic parameter estimates in healthy subjects resulted in a clinical susceptibility breakpoint of < or =4 mg/liter for a dose of 1,000 mg every 8 h. Patients suspected of having high clearance rates, such as CF patients, should be monitored closely, with dosing regimens adjusted accordingly.

This study investigated the release of antibiotics in vivo, from an articulating polymethylmethacrylate (PMMA) spacer used in two-stage revision arthroplasty of infected hip implants. Forty-six patients who underwent two-stage revision hip arthroplasty for infections were managed with an interim PMMA spacer loaded with a high dose of vancomycin and aztreonam. Serum and aliquots of drainage collected after the first-stage surgery, and joint fluid obtained at the time of the second-stage surgery were analyzed for antibiotic concentrations by high performance liquid chromatography and bioactivity by tube dilution bioassay. Following implantation, the highest levels of antibiotics were measured in aliquots of drainage on the first day (vancomycin: 1538.0 +/- 243.6 microg/mL; aztreonam: 1003.5 +/- 323.5 microg/mL), decreasing to 571.9 +/- 169.4 microg/mL for vancomycin and 313.6 +/- 88.3 microg/mL for aztreonam after 7 days. Antibiotic concentrations in serum were very low (vancomycin: 0.58 +/- 0.2 microg/mL, range: 0.1-1.6 microg/mL; aztreonam: 0.46 +/- 0.3 microg/mL, range: 0.1-0.9 microg/mL at 24 h) and there was no systemic adverse effect. At a mean 107 days after the first-stage surgery, the concentrations of antibiotics in joint fluid were well above the minimal inhibitory concentration of most common microorganisms. The released antibiotics were bioactive against the test organisms. Based on the observed results, we confirmed the safety and effectiveness of in vivo drug delivery from antibiotic-impregnated PMMA hip spacers.

Background: Aztreonam lysinate for inhalation (AI) is a novel monobactam formulation being investigated for pulmonary Pseudomonas aeruginosa infections in patients with cystic fibrosis (CF)., Methods: Pre-clinical studies investigated the pre- and post-nebulization activity of AI and its activity in the presence of CF sputum. A double-blind, placebo-controlled, dose-escalation trial determined pharmacokinetics and tolerability of AI in subjects with CF. Single daily escalating doses of AI 75, 150, or 225 mg, or placebo were self-administered using an eFlow Electronic Nebulizer. Sputum samples were collected up to 4 hr and blood samples up to 8 hr post-dose., Results: AI activity against multiple CF isolates was retained after nebulization via eFlow, and activity was not inhibited by CF sputum. All 12 adult subjects and 11/12 adolescents tolerated all AI doses. One patient had an asymptomatic FEV1 decrease > 20% with the 150 mg dose. Median aztreonam sputum concentrations in adults 10 min after AI 75, 150, and 225 mg were 383, 879, and 985 microg/g, respectively. Median sputum concentrations in adolescents 10 min after AI 75, 150, and 225 mg were 324, 387, and 260 microg/g, respectively. Systemic exposure to AI was low. Plasma pharmacokinetics in adults receiving AI 75 mg were Cmax = 419 ng/g, Tmax = 0.99 hr, t1/2 = 2.1 hr. Aztreonam concentrations in sputum were at or above the MIC50 for at least 4 hr post-dose., Conclusion: These data support the continued development of AI for treatment of pulmonary infections in patients with CF.

This study evaluated the pharmacodynamics of continuous infusion beta-lactams against pulmonary isolates of Gram-negative bacteria from patients managed in intensive care units (ICUs) in the USA. Multiple 10,000-patient Monte Carlo simulations were performed by integrating pharmacokinetic data from healthy individuals with 2408 MICs from the 2002 Intensive Care Unit Surveillance System database. These pharmacodynamic simulations suggested that continuous infusion regimens of cefepime, aztreonam, ceftazidime and piperacillin-tazobactam 13.5 g have the greatest likelihood of achieving pharmacodynamic targets against isolates of Enterobacteriaceae in the ICU. Beta-lactams are unlikely to achieve pharmacodynamic targets against Pseudomonas aeruginosa or Acinetobacter baumannii when administered as monotherapy.

Aztreonam belongs to the monobactam group of naturally occurring antibiotic compounds characterized by a monocycling ring structure. Aztreonam is the first monobactam that has been approved for use in pediatric medicine by US FDA in the year 1998.

The common usage of extended spectrum beta-lactams co-administered with amikacin in everyday clinical practice for infections by multidrug-resistant isolates has created the need to search for pharmacokinetic interaction. Eighteen healthy volunteers were enrolled in the study; six were administered 1g of ceftazidime singly intravenously or combined with 0.5 g of amikacin; six received 0.5 g of imipenem singly or combined with 0.5 g of amikacin and six 1g of aztreonam singly or combined with 0.5 g of amikacin. Blood and urine samples were collected at regular time intervals and apparent serum levels were determined by a microbiological assay. Co-administration of ceftazidime and amikacin resulted in higher C(max) and AUC for amikacin than when administered alone. Co-administration of imipenem and amikacin resulted in higher C(max) for imipenem than when administered alone. The tested interactions did not affect plasma half-life (t(1/2)) and clearance rate of any antimicrobial compared with its single administration. All tested drugs were mainly eliminated by glomerular filtration. It is concluded that co-administration of ceftazidime, imipenem or aztreonam with amikacin in healthy volunteers might affect C(max) and AUC without influencing any other pharmacokinetic parameter. The probable clinical endpoint is that giving ceftazidime, imipenem or aztreonam with amikacin might result in a transient elevation of beta-lactam serum levels without further affecting the complete pharmacokinetic profile of each drug as obtained after administration of the drug alone.

Multidrug resistance (MDR) has been reported in both prokaryotes and eukaryotes, underscoring the challenge of design and screening of more efficacious new drugs. For instance, the efflux pump of Pseudomonas aeruginosa (gram-negative bacteria) can extrude a variety of structurally and functionally diverse substrates, which leads to MDR. In this study, we present a new platform that studies modes of action of antibiotics in living bacterial cells (P. aeruginosa), in real-time, at nanometer scale and single-cell resolution using nanoparticle optics and single living cell imaging. The color index of silver (Ag) nanoparticles (violet, blue, green, and red) is used as the sized index (30 +/- 10, 50 +/- 10, 70 +/- 10, and 90 +/- 10 nm) for real-time measurement of sized transformation of the cell wall and membrane permeability at the nanometer scale. We have demonstrated that the number of Ag nanoparticles accumulated in cells increases as the aztreonam (AZT) concentration increases and as incubation time increases, showing that AZT induces the sized transformation of membrane permeability and the disruption of the cell wall. The results demonstrate that nanoparticle optics assay can be used as a new powerful tool for real-time characterization of modes of action of antimicrobial agents in living cells at the nanometer scale. Furthermore, studies of mutants of WT bacteria (nalB-1 and DeltaABM), suggest that an efflux pump (MexA-MexB-OprM) effectively extrudes substrates (nanoparticles) out of the cells, indicating that the MDR mechanism involves the induction of changes in membrane permeability and the intrinsic pump machinery.

Objective: To evaluate whether the effect of acetazolamide on piperacillin's aqueous humor concentrations observed in animals exists also in humans for ceftazidime, cefotaxime, ceftriaxone and aztreonam., Methods: One hundred and eighty-eight patients undergoing eye cataract surgery were randomly allocated to receive intravenous ceftazidime, cefotaxime, aztreonam or ceftriaxone with (subgroup A) or without (subgroup B) concomitant oral administration of acetazolamide. Antibiotic concentrations in serum and the aqueous humor, simultaneously sampled during the operation, were measured using an agar well diffusion technique, and the ratios of the concentrations of aqueous humor to serum were calculated and compared. Statistical analysis was performed by using the paired t-test., Results: Mean aqueous humor ceftazidime concentrations at 2, 4 and 6 h were 24.65, 16.4 and 8.6 mg/L (subgroup A), and 4.26, 8.66 and 5.61 mg/L (subgroup B). Corresponding concentrations of cefotaxime were 1.75, 1.0 and 0.77 mg/L (subgroup A), and 1.11, 0.81 and 0.58 mg/L (subgroup B), and of aztreonam 6.9, 5.84 and 3.61 mg/L (subgroup A), and 3.38, 2.57 and 1.48 mg/L (subgroup B). Ceftriaxone concentrations at 2, 4, 6 and 12 h were 1.78, 1.49, 1.57 and 1.41 mg/L (subgroup A), and 1.35, 0.95, 1.08 and 0.85 mg/L (subgroup B). The differences in aqueous humor concentrations when acetazolamide was administered were statistically significant (P < 0.05), with the exception of ceftazidime 6 h, cefotaxime 6 h and ceftriaxone 2 h., Conclusions: Although acetazolamide resulted in statistically significant increases in the aqueous humor concentrations of all the antibiotics tested, this effect was most marked for ceftazidime.

Linezolid, a new oxazolidinone antimicrobial agent, has a spectrum of activity encompassing a wide variety of Grampositive bacteria. The purpose of this study was to evaluate the pharmacokinetics of linezolid and aztreonam, an antimicrobial agent with selective activity against Gram-negative bacteria, when given alone and in combination. Healthy subjects were randomized to receive single, 30-minute intravenous infusions of (1) linezolid 375 mg, (2) aztreonam 1000 mg, and (3) linezolid 375 mg plus aztreonam 1000 mg in an open-label, crossover manner. The only statistically significant differences observed with combination treatment relative to each drug alone were an increase in the maximum plasma concentration of linezolid (approximately 18%) and an approximate 7% decrease in the apparent elimination rate of aztreonam, neither of which are expected to be clinically significant. In healthy subjects, the combination of linezolid and aztreonam was safe and well tolerated compared with each agent used alone. Pharmacokinetic data demonstrate that coadministration of linezolid and aztreonam does not alter the disposition of either agent under single-dose conditions. Therefore, it is not expected that a dose alteration of either agent will be necessary in a clinical setting.

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.

An in vitro pharmacokinetic model was used to determine if aztreonam could enhance the pharmacodynamics of cefepime or ceftazidime against an isogenic panel of Pseudomonas aeruginosa 164, including wild-type (WT), partially derepressed (PD), and fully derepressed (FD) phenotypes. Logarithmic-phase cultures were exposed to peak concentrations achieved in serum with 1- or 2-g intravenous doses, elimination pharmacokinetics were simulated, and viable bacterial counts were measured over three 8-h dosing intervals. In studies with cefepime and cefepime-aztreonam against the PD strain, samples were also filter sterilized, assayed for active cefepime, and assayed for nitrocefin hydrolysis activity before and after overnight dialysis. Against WT strains, the cefepime-aztreonam combination was the most active regimen, but viable counts at 24 h were only 1 log below those in cefepime-treated cultures. Against PD and FD strains, the antibacterial activity of cefepime-aztreonam was significantly enhanced over that of each drug alone, with 3.5 logs of killing by 24 h. Hydrolysis and bioassay studies demonstrated that aztreonam was inhibiting the extracellular cephalosporinase that had accumulated and was thus protecting cefepime in the extracellular environment. In contrast to cefepime-aztreonam, the pharmacodynamics of ceftazidime-aztreonam were not enhanced over those of aztreonam alone. Further pharmacodynamic studies with five other P. aeruginosa strains producing increased levels of cephalosporinase demonstrated that the enhanced pharmacodynamics of cefepime-aztreonam were not unique to the isogenic panel. The results of these studies demonstrate that aztreonam can enhance the antibacterial activity of cefepime against derepressed mutants of P. aeruginosa producing increased levels of cephalosporinase. This positive interaction appears to be due in part to the ability of aztreonam to protect cefepime from extracellular cephalosporinase inactivation. Clinical evaluation of this combination 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.

The differential tissue distributions of aztreonam and ceftazidime within fibrin clots infected with Pseudomonas aeruginosa, Enterobacter cloacae, and Serratia marcescens, their efficacies, and the in vivo bacterial morphological changes induced by these drugs were evaluated. Rabbits were given intravenously a single dose of 100 mg of either agents/kg of body weight. In the cores of the clots, the peak levels of both drugs were much lower than those observed in the peripheries and in serum. Aztreonam's half-lives within the peripheries and in the cores of the fibrin clots were up to six times higher than observed in serum, while ceftazidime's half-lives in clots were twice that observed in serum. This resulted in a much greater penetration ratio for aztreonam than for ceftazidime. Both drugs controlled the growth of P. aeruginosa in vivo, but E. cloacae and S. marcescens responded better to ceftazidime. Morphological changes were more abundant in the peripheries than in the cores of the clots. In the control group, P. aeruginosa's morphology in the cores was different than that in the peripheries of the clots. Against P. aeruginosa, aztreonam did induce morphological changes in the cores while ceftazidime did not. Electron microscopic studies revealed that morphological changes associated with aztreonam seemed different than those of ceftazidime. Along with elongation of bacteria, more bow tie and herniated bacteria were observed with aztreonam. Though both agents selectively affect PBP 3, as manifested by elongated bacteria, they induce in the peripheries of the clots thickening, breaks, and detachment in bacterial cell walls, alterations which are generally associated with antibiotics affecting PBP 1a and 1b.

The MIC is the main microbiologic parameter used to predict the efficacies of antibiotics. However, it is well known that MICs may vary according to the inoculum size used (inoculum effect), especially with some beta-lactam antibiotics. In order to correlate the pharmacologic and microbiologic properties of some beta-lactams, an experimental model of intraperitoneal infection caused by Escherichia coli in nonneutropenic and neutro-penic mice was developed. The animals were treated with three different doses of either ampicillin, piperacillin, aztreonam, cefazolin, or cefotaxime. The linear regression analysis obtained in our model shows a better correlation between in vitro activity and efficacy when the MICs considered were those obtained with a large inoculum (ca. 1 x 10(8) CFU/ml) instead of the standard inoculum (5 x 10(5) CFU/ml). The correlations for the MICs obtained with the large inoculum were 0.78 for log2 maximum concentration of drug in serum (Cmax)/ MIC, 0.72 the time that the concentrations exceeded the MIC, and 0.79 for log2 area under the serum concentration-time curve (AUC)/MIC at 24 h in nonneutropenic mice. The corresponding values in neutropenic mice, also for the MICs obtained with the large inoculum, were 0.54, 0.68, and 0.64, respectively, at 24 h. A good correlation was also obtained for the same parameters in nonneutropenic mice at 48 h. The values of Cmax, AUC, and the time that the concentrations exceeded the MIC were parallel among the antibiotics studied, and our study confirms that the time that the levels in serum exceed the MIC is a significant parameter determining the efficacies of beta-lactam antibiotics, but the correlation is much better when the MICs obtained with the large inoculum instead of those obtained with the standard (low) inoculum are considered.

Amorphos injectable form of aztreonam (BIOKTAM) was prepared. It was shown that after intramuscular or intravenous administration there are not any considerable differences in the bioavailability of aztreonam from BIOKTAM and of the drug from AZACTAM.

Study Objective: To evaluate the pharmacokinetic profiles of aztreonam and imipenem in critically ill trauma patients with pneumonia., Methods: Trauma patients in intensive care units who were intubated within 3 days of hospital admission were eligible for the study. Patients with the clinical diagnosis of pneumonia were consecutively randomized to receive either aztreonam plus vancomycin or imipenem-cilastatin. Serial blood samples were taken and sputum was collected to determine aztreonam and imipenem concentrations after 2-3 days and 7-8 days of therapy. Pharmacokinetics of both agents were estimated and compared with estimates from healthy volunteers., Results: Twenty patients were enrolled in the study, 10 patients received imipenem-cilastatin, and 10 received aztreonam plus vancomycin. Steady-state volume of distribution (Vss) for aztreonam at 2-3 days and 7-8 days was significantly greater in patients than in historical controls, whereas the Vss for imipenem was greater at 2-3 days. The beta-half-life for aztreonam at both sampling periods was significantly greater in patients than in controls. No significant changes in pharmacokinetics occurred over time for either antibiotic. Sputum concentrations of aztreonam and imipenem were highly variable when sampled 2 hours after the infusion., Conclusion: Larger volumes of distribution were observed for both aztreonam and imipenem in trauma patients than in volunteers, suggesting that standard initial dosages of the antibiotics may result in lower concentrations in these critically ill patients. Both antibiotics penetrated into the sputum of most patients; however, the degree of penetration was highly variable in relation to serum concentrations.

Objective: To describe the pharmacokinetic profile of aztreonam and vancomycin hydrochloride in a clinically relevant experimental model of hemorrhagic shock and trauma., Methods: Ten mongrel pigs (mean +/- SD weight, 26.7 +/- 6.4 kg) were anesthetized with fentanyl citrate and ventilated, and an indwelling catheter was placed in the jugular vein. On day 3, all pigs were subjected to fentanyl administration, ventilation, soft-tissue injury, and an arterial hemorrhage (mean +/- SD, 40% +/- 8%). After a 1-hour shock period, baseline hemodynamics were restored by reinfusing shed blood plus twice the shed volume as lactated Ringer's solution. Aztreonam and vancomycin were infused on day 1, after resuscitation on day 3, and on days 4 and 8. Serial plasma samples were collected for 6 hours after treatment, and differences were compared with analysis of variance., Results: Aztreonam clearance initially decreased with trauma, but subsequently increased by 48% (P < .02) by day 8. Aztreonam steady-state volume decreased by 34% (P = .05, baseline value vs that on day 8). Vancomycin clearance was increased between 25% and 52% (P < .001) on days 3, 4, and 8 compared with the baseline value. Vancomycin steady-state volume initially increased with trauma (P = .009), but it subsequently decreased by 29% (P < .001) on day 8. These data cannot be explained by changes in plasma volume per se because levels of plasma sodium, potassium, chloride, and calcium were within normal reference ranges at all time points. Neither liver nor renal functions were severely impaired because levels of serum urea nitrogen, bilirubin, liver enzymes, creatinine, and plasma proteins were within normal reference ranges. Furthermore, our previous work demonstrated that systemic and splanchnic organ oxygen delivery and demand were near normal immediately after fluid resuscitation and for at least 3 days thereafter; thus, there were probably no major perfusion abnormalities in the liver or kidney., Conclusions: For at least 5 days after trauma, clearance and steady-state volume of aztreonam and vancomycin are altered. These changes suggest that the interval and magnitude of dosing should be adjusted, relative to the standard recommended dosages of each antibiotic, to maximize their efficacy. Similar studies should be done for other antibiotics.

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.

The monobactam antibiotic aztreonam (AZT) was administered by intravenous drip infusion to women with intrauterine infections at 6-hour intervals and its concentrations in the maternal blood, umbilical blood, and umbilical tissue were determined at parturition to evaluate its transport to the umbilicus and fetus, and this accumulation in the tissue. Further, umbilical tissue was cultured to detect bacteria and examined histologically to evaluate the efficacy of AZT its treatment of omphalitis. Neither maternal nor umbilical blood showed any signs of drug accumulation, and there was a correlation between maternal and umbilical blood levels of AZT and time lapsed after most recent administration. Umbilical tissue levels of AZT tended to increase with time for about 12 hours after the start of administration, but showed no tendency to further rise thereafter. The umbilical tissue cultures were negative for causative pathogens 12 hours or more after the initial dosing. Histological examination of umbilical tissue was negative for omphalitis 12 hours or more after the start of administration in all but one patient. After the administration of AZT to pregnant women with intrauterine infections, it was detected in the umbilicus and fetus in high concentrations at parturition without appreciable tissue accumulation, newborn infection or adverse reaction. The overall results suggest that AZT is clinical effective when used in the treatment of omphalitis.

Objective: To assess the impact of degradation of aztreonam, a beta-lactam antibiotic, during HPLC analysis on pharmacokinetic parameter estimates., Methods: The baseline (B) serum concentration-time data from a published pharmacokinetic study of aztreonam were degraded using first-order equations and a degradation rate constant (0.014 h-1) determined from a preliminary degradation study. Samples were mathematically degraded for autosampler run times of 8-13 h (D1) to approximate a normal work day and for autosampler run times of 16-17 h (D2) and compared with B data. It was assumed that B data were nondegraded and that changes in chromatography were the result of degradation of azetreonam and not to any changes in chromatographic conditions. A two-compartment model was used to fit the data and pharmacokinetic parameters were calculated using standard equations. Statistical significance between all pharmacokinetic parameters for B and D1 and B and D2 was determined using the paired, two-tailed Student's t-test., Results: Increased variability was noted for all pharmacokinetic parameters for D1 and D2 compared with B. Statistically significant differences were found for clearance (B < D1, p = 0.0095 and B < D2, p = 0.0194), steady-state volume of distribution (B < D2, p = 0.0392), and area under the serum concentration-time curve (B > D1, p = 0.0497)., Conclusions: Aztreonam degradation resulted in increased variability in pharmacokinetic parameter estimates. Investigators should be cognizant of this and preliminary studies should be performed to characterize degradation for the length of the expected autosampler run.

There were 73 evaluable patients entered into a prospective, double-blinded trial comparing aztreonam/clindamycin (A/C) to gentamicin/clindamycin (G/C) for the prevention of infection after penetrating abdominal trauma. Aztreonam was administered at a dosage of 2 g every 8 hours and gentamicin at 5 mg/kg for the first 24 hours and then adjusted by serum monitoring to a peak of 6 to 8 micrograms/mL and a trough of less than 2 micrograms/mL; all patients received 900 mg of clindamycin every 8 hours. Patients with colon wounds received 4 days of antibiotics, and the remaining patients received a 24-hour course. Gunshot wounds occurred in 69% of patients: 74% of all patients had some hollow viscus injury, and 26% had only solid viscus injury. The groups were well matched according to abdominal trauma index, percentage with colon injury, and transfusion requirements. Failures occurred in eight patients (11%): two wound infections, five intra-abdominal infections, and one case of necrotizing fasciitis. Seven infections occurred in 36 (19%) G/C patients compared with 1 in 37 (3%) A/C patients (p < 0.03). The hospital stay was 12 +/- 11 days for G/C patients and 8 +/- 7 for A/C patients (p < 0.12). The superiority of the A/C regimen may be partially attributable to relative underdosing of gentamicin (approximately half of the patients had inadequate levels after 24 hours) combined with a favorable pharmacokinetic profile (significantly prolonged half-life) of aztreonam in this clinical setting.

Plasma concentrations of aztreonam follow a 2-compartment open model with a distribution half-life of 0.20 hours after intravenous injection. The volume of distribution at steady-state (Vss) after intravenous and intramuscular injection is about 0.16 L/kg (0.42 L/kg for free drug). After intramuscular injection, absorption is almost complete. Absorption after intraperitoneal administration in patients with peritonitis is 92%. Over a large dosage range, plasma concentrations increase dose proportionally. In healthy individuals, about 56% of the drug is plasma protein bound. Diffusion into tissues is generally slow, and the ratio between mean tissue and plasma aztreonam concentration seems to depend mainly on tissue composition. Aztreonam penetrates into cerebrospinal fluid (CSF) more rapidly in patients with inflamed meninges than in those with noninflamed meninges. Diffusion through the placenta is poor, as is diffusion into breastmilk. Aztreonam is predominantly eliminated by the kidney, partly by active tubular excretion. Extrarenal clearance appears to be through hepatic excretion. Metabolism occurs to a very limited extent. Total plasma clearance (CLp) in healthy adults is about 5.6 L/h and the terminal elimination half-life is 1.7 to 2.0 hours. CLp is similar in both children and adults when expressed as a function of bodyweight. However, in neonates, especially in low birthweight infants, CLp is lower. In various disease states, the Vss of aztreonam is not appreciably different from that found in healthy individuals. However, patients with low serum albumin levels (e.g. burn patients, critically ill patients and those with cirrhosis of the liver) generally have an increased volume of distribution. The elimination half-life of the drug is dependent on renal function.(ABSTRACT TRUNCATED AT 250 WORDS)

Aztreonam is a monobactam exhibiting an antibacterial spectrum similar to that of the aminoglycosides, with activity against aerobic gram-negative bacilli, and is the only related drug that may be given to patients hypersensitive to beta-lactams. The pharmacokinetics of aztreonam were compared in two groups of healthy volunteers. The young group comprised 10 adults between the ages of 18 and 30 years, and the elderly group included 10 adults older than 65 years of age. The two groups each received two doses (1 and 2 g) aztreonam, separated by 1 week. Although the mean peak serum concentrations of aztreonam for the two groups were similar, there were differences in other pharmacokinetic parameters. For example, for the 2-g dose the mean half-life (1.8 +/- .51 versus 3.1 +/- .9 hour), and area under the curve (AUC) (294.42 +/- 64.08 versus 469.01 +/- 144.02 micrograms x hour/mL per 1.73 m2) were less for the younger group compared with the elderly group. The mean total body clearance of aztreonam was greater for the younger than the elderly group. The results were similar to the pharmacokinetic parameters derived from the 1-g dose. These results mirror the lower creatinine clearances and higher serum creatinine levels found in the elderly group. The data suggest that lower doses of aztreonam given at less frequent intervals may be appropriate in the elderly population.

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.