Dose selection for aztreonam-avibactam, including adjustments for renal impairment, for Phase IIa and Phase III evaluation.

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.

Preliminary physiologically based pharmacokinetic modeling of renally cleared drugs in Chinese pregnant women.

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.

Safety, Tolerability, Pharmacokinetics, and Drug Interaction Potential of SPR741, an Intravenous Potentiator, after Single and Multiple Ascending Doses and When Combined with ß-Lactam Antibiotics in Healthy Subjects.

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 (Cmax) 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.).

Avibactam Pharmacokinetic/Pharmacodynamic Targets.

Avibactam is a novel non-ß-lactam ß-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 ß-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 ß-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 (%fT>CT). The magnitude of the CT and the time that this threshold needed to be exceeded to elicit particular PD endpoints varied depending on the model and the partner ß-lactam. This review describes the preclinical studies used to determine the avibactam PK/PD target in combination with its ß-lactam partners.

Microdialysis Study of Aztreonam-Avibactam Distribution in Peritoneal Fluid and Muscle of Rats with or without Experimental Peritonitis.

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.

A review of the pharmacokinetics and pharmacodynamics of aztreonam.

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-ß-lactamases. Of particular interest are the pharmacokinetic and pharmacodynamic properties of aztreonam alone and in combination with ß-lactamase inhibitors. The choice of inhibitor may vary depending on the spectrum of ß-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 ß-lactamase inhibitors.

Pharmacokinetics/pharmacodynamics of a ß-lactam and ß-lactamase inhibitor combination: a novel approach for aztreonam/avibactam.

OBJECTIVES: The combination of aztreonam/avibactam has promising activity against MDR Gram-negative pathogens producing metallo-ß-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 ß-lactam/ß-lactamase inhibitor combinations.

Inhaled aztreonam lysine for cystic fibrosis pulmonary disease-related outcomes.

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 ß-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.

[Revival of selected well-tried antibiotics. Special features of the antiinfective agents penicillin G, fosfomycin, aztreonam and colistin]. / Altbewährte Antibiotika im neuen Licht. Sonderstellungen der Antiinfektiva Benzylpenicillin, Fosfomycin, Aztreonam und Colistin.

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.

Efficacy of aerosol MP-376, a levofloxacin inhalation solution, in models of mouse lung infection due to Pseudomonas aeruginosa.

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.

Evaluating aztreonam and ceftazidime pharmacodynamics with Escherichia coli in combination with daptomycin, linezolid, or vancomycin in an in vitro pharmacodynamic model.

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.

Lack of pharmacokinetic drug interactions following concomitant administration of telavancin with aztreonam or piperacillin/tazobactam in healthy participants.

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.

Experimental design and modelling approach to evaluate efficacy of ß-lactam/ß-lactamase inhibitor combinations.

BACKGROUND: A ß-lactamase inhibitor (BLI) confers susceptibility of ß-lactamase-expressing multidrug resistant (MDR) organisms to the partnering ß-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 EC50 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 EC50 function for isolates of comparable susceptibility through established correlation between BL MIC and EC50 values.

Evaluation of Aztreonam Dosing Regimens in Patients With Normal and Impaired Renal Function: A Population Pharmacokinetic Modeling and Monte Carlo Simulation Analysis.

Aztreonam is a monocyclic ß-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.

Effects of i.v. push administration on ß-lactam pharmacodynamics.

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.

Impact of azithromycin on the clinical and antimicrobial effectiveness of tobramycin in the treatment of cystic fibrosis.

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 FEV1 (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.

High concentration and bioactivity of vancomycin and aztreonam eluted from Simplex cement spacers in two-stage revision of infected hip implants: a study of 46 patients at an average follow-up of 107 days.

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.

Microbiology, safety, and pharmacokinetics of aztreonam lysinate for inhalation in patients with cystic fibrosis.

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.

Continuous infusion beta-lactams for intensive care unit pulmonary infections.

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.