Population Pharmacokinetic Comparison and Pharmacodynamic Breakpoints of Ceftazidime in Cystic Fibrosis Patients and Healthy Volunteers

Bulitta, Jürgen B.; Landersdorfer, Cornelia B.; Hüttner, S.; Drusano, George L.; Kinzig, Martina; Holzgrabe, Ulrike; Stephan, U; Sörgel, Fritz

doi:10.1128/aac.00936-09

Cited by 52 publications

(46 citation statements)

References 68 publications

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“…An analysis of PK/PD characteristics of ceftazidime in non-CF and CF patients resulted in an analogous outcome (228). These data suggest that PK/PD analysis and calculation of target attainment rates should be performed on a regional/local level by using "real-life" PK and PD data from the relevant patient group.…”

Section: Preclinical and Clinical Pk/pd Studies In Cf Patientsmentioning

confidence: 75%

Pharmacokinetics and Pharmacodynamics of Aerosolized Antibacterial Agents in Chronically Infected Cystic Fibrosis Patients

Dalhoff¹

2014

Clin Microbiol Rev

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SUMMARY Bacteria adapt to growth in lungs of patients with cystic fibrosis (CF) by selection of heterogeneously resistant variants that are not detected by conventional susceptibility testing but are selected for rapidly during antibacterial treatment. Therefore, total bacterial counts and antibiotic susceptibilities are misleading indicators of infection and are not helpful as guides for therapy decisions or efficacy endpoints. High drug concentrations delivered by aerosol may maximize efficacy, as decreased drug susceptibilities of the pathogens are compensated for by high target site concentrations. However, reductions of the bacterial load in sputum and improvements in lung function were within the same ranges following aerosolized and conventional therapies. Furthermore, the use of conventional pharmacokinetic/pharmacodynamic (PK/PD) surrogates correlating pharmacokinetics in serum with clinical cure and presumed or proven eradication of the pathogen as a basis for PK/PD investigations in CF patients is irrelevant, as minimization of systemic exposure is one of the main objectives of aerosolized therapy; in addition, bacterial pathogens cannot be eradicated, and chronic infection cannot be cured. Consequently, conventional PK/PD surrogates are not applicable to CF patients. It is nonetheless obvious that systemic exposure of patients, with all its sequelae, is minimized and that the burden of oral treatment for CF patients suffering from chronic infections is reduced.

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Section: Preclinical and Clinical Pk/pd Studies In Cf Patientsmentioning

confidence: 75%

Pharmacokinetics and Pharmacodynamics of Aerosolized Antibacterial Agents in Chronically Infected Cystic Fibrosis Patients

Dalhoff¹

2014

Clin Microbiol Rev

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“…A standard WT of 70 kg and standard LBM of 53 kg were used. Further details on these body size models have been presented previously (16)(17)(18).…”

Section: Subjectsmentioning

confidence: 99%

“…The residual unidentified variability was modeled by a combined additive and proportional error model for plasma concentrations and amounts in urine. We applied first-order conditional estimation using the interaction option in NONMEM VI level 1.2 software (8) and the importance sampling Monte-Carlo Parametric Expectation-Maximization method (pmethod ϭ 4) in S-ADAPT software (version 1.57 beta) (6) for population PK modeling as reported previously (16,18,19). The SADAPT-TRAN translator tool (14) was used to facilitate S-ADAPT analyses.…”

Section: Subjectsmentioning

confidence: 99%

“…To illustrate the benefits of prolonged and continuous infusion compared to short-term infusions, we calculated the expected PTA for specific MIC distributions (referred to here as the "PTA expectation value") as described previously (16,18). We used eight previously published MIC distributions for cefpirome activity against P. aeruginosa from non-CF patients ( …”

Section: Subjectsmentioning

confidence: 99%

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Comparable Population Pharmacokinetics and Pharmacodynamic Breakpoints of Cefpirome in Cystic Fibrosis Patients and Healthy Volunteers

Bulitta¹,

Kinzig²,

Landersdorfer³

et al. 2011

Antimicrob Agents Chemother

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Cystic fibrosis (CF) patients are often reported to have higher clearances and larger volumes of distribution per kilogram of total body weight (WT) for beta-lactams than healthy volunteers. As pharmacokinetic (PK) data on cefpirome from studies of CF patients are lacking, we systematically compared its population PK and pharmacodynamic breakpoints for CF patients and healthy volunteers of similar body size. Twelve adult CF patients (median lean body mass [LBM] ‫؍‬ 45.7 kg) and 12 healthy volunteers (LBM ‫؍‬ 50.0 kg) received a single 10-min intravenous infusion of 2 g cefpirome. Plasma and urine concentrations were determined by high-performance liquid chromatography (HPLC). Population PK and Monte Carlo simulations were performed using NONMEM and S-ADAPT and a duration of an unbound plasma concentration above the MIC > 65% of the dosing interval as a pharmacodynamic target. Unscaled clearances for CF patients were similar to those seen with healthy volunteers, and the volume of distribution was 6% lower for CF patients. Linear scaling of total clearance by WT resulted in clearance that was 20% higher (P < 0.001 [nonparametric bootstrap]) in CF patients. Allometric scaling by LBM explained the differences between the two subject groups with respect to average clearance and volume of distribution and reduced the unexplained between-subject variability of renal and nonrenal clearance by 10 to 14%. For the CF patients, robust (>90%) probabilities of target attainment (PTA) were achieved by the administration of a standard dose of 2 g/70 kg WT every 12 h (Q12h) given as 30-min infusions for MICs < 1.5 mg/liter. As alternative dosage regimens, a 5-h infusion of 1.33 g/70 kg WT Q8h achieved robust PTAs for MICs < 8 to 12 mg/liter and a continuous infusion of 4 g/day for MICs < 12 mg/liter. Prolonged infusion of cefpirome is expected to be superior to short-term infusions for MICs between 2 and 12 mg/liter.

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“…The pharmacodynamic property that predicts better clinical efficacy in vitro is the time during which the tissue concentration of the antibiotic is greater than the MIC of the organism (1,2). Critically ill patients with severe sepsis present wide intra-and interindividual variations in volume of distribution, thus altering the pharmacokinetics of the antibiotic (2)(3)(4). A number of elements plead in favor of continuous administration of ceftazidime, both for reasons of clinical efficacy and to preserve bacteriological mutation (2,5).…”

mentioning

confidence: 99%

Lung Concentrations of Ceftazidime Administered by Continuous versus Intermittent Infusion in Patients with Ventilator-Associated Pneumonia

Cousson

Floch²,

Guillard

et al. 2015

Antimicrob Agents Chemother

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e Ceftazidime is a beta-lactam compound that exerts a time-dependent bactericidal effect. Numerous arguments are in favor of continuous administration of ceftazidime, both for reasons of clinical efficacy and to preserve bacteriological mutation. We report a prospective, single-center, parallel-group, randomized, controlled trial comparing two modes of administration of ceftazidime, namely, continuous administration (loading dose of 20 mg/kg of body weight followed by 60 mg/kg/day) versus intermittent administration (20 mg/kg over 30 min every 8 h) in 34 patients with ventilator-associated pneumonia due to Gram-negative bacilli. The study was performed over 48 h with 13 and 18 assessments of serum ceftazidime in the continuous-infusion group (group A) and the intermittent-fusion group (group B), respectively. Bronchoalveolar lavage (BAL) was performed at steady state in both groups at 44 h to determine ceftazidime levels in the epithelial lining fluid. We chose a predefined threshold of 20 mg/liter for serum concentrations of ceftazidime because of ecological conditions in our center. The median time above 20 mg/ liter (T>20 mg) was 100% in group A versus 46% in group B. In group A, 14/17 patients had 100% T>20 mg, versus only 1/17 patients in group B. In the epithelial lining fluid, the median concentration of ceftazidime was 12 mg/liter in group A versus 6 mg/liter in group B. A threshold of 8 mg/liter in the epithelial lining fluid was achieved twice as often in group A as in group B. This study of ceftazidime concentrations in the epithelial lining fluid indicates that continuous infusion presents advantages in terms of pharmacodynamics and predictable efficacy in patients presenting ventilator-associated pneumonia. Ceftazidime is a third-generation cephalosporin that is frequently used in the treatment of ventilator-associated pneumonia (VAP) because of its efficacy against Pseudomonas aeruginosa. Ceftazidime is a beta-lactam compound that exerts a time-dependent bactericidal effect. The pharmacodynamic property that predicts better clinical efficacy in vitro is the time during which the tissue concentration of the antibiotic is greater than the MIC of the organism (1, 2). Critically ill patients with severe sepsis present wide intra-and interindividual variations in volume of distribution, thus altering the pharmacokinetics of the antibiotic (2-4). A number of elements plead in favor of continuous administration of ceftazidime, both for reasons of clinical efficacy and to preserve bacteriological mutation (2, 5). In view of local ecological conditions in our center (MIC of ceftazidime for Pseudomonas aeruginosa of Ͻ4 mg/liter), we aimed to achieve a minimum serum concentration of 20 mg/liter.The primary objective of this study was to show that continuous infusion of ceftazidime is superior to intermittent infusion, as assessed by the concentration of ceftazidime in the epithelial lining fluid (ELF), in patients with VAP due to Gram-negative bacilli. The secondary objective was to show that continuous infus...

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Population Pharmacokinetic Comparison and Pharmacodynamic Breakpoints of Ceftazidime in Cystic Fibrosis Patients and Healthy Volunteers

Cited by 52 publications

References 68 publications

Pharmacokinetics and Pharmacodynamics of Aerosolized Antibacterial Agents in Chronically Infected Cystic Fibrosis Patients

Pharmacokinetics and Pharmacodynamics of Aerosolized Antibacterial Agents in Chronically Infected Cystic Fibrosis Patients

Comparable Population Pharmacokinetics and Pharmacodynamic Breakpoints of Cefpirome in Cystic Fibrosis Patients and Healthy Volunteers

Lung Concentrations of Ceftazidime Administered by Continuous versus Intermittent Infusion in Patients with Ventilator-Associated Pneumonia

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