Dataset Information

Pharmacokinetics and pharmacodynamics of aerosolized antibacterial agents in chronically infected cystic fibrosis patients.

ABSTRACT: 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.

SUBMITTER: Dalhoff A

PROVIDER: S-EPMC4187638 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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Pharmacokinetics and pharmacodynamics of aerosolized antibacterial agents in chronically infected cystic fibrosis patients.

Dalhoff Axel A

Clinical microbiology reviews 20141001 4

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 dec ...[more]

PMID: 25278574

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Project description:Adults with cystic fibrosis (CF) frequently harbor Staphylococcus aureus, which is increasingly antibiotic resistant. Telavancin is a once-daily rapidly bactericidal antibiotic active against methicillin-, linezolid-, and ceftaroline-resistant S. aureus Because CF patients experience alterations in pharmacokinetics, the optimal dose of telavancin in this population is unknown. Adult CF patients (n?=?18) admitted for exacerbations received 3 doses of telavancin 7.5?mg/kg of body weight (first 6 patients) or 10?mg/kg (final 12 patients) every 24?h (q24h). Population pharmacokinetic models with and without covariates were fitted using the nonparametric adaptive grid algorithm in Pmetrics. The final model was used to perform 5,000-patient Monte Carlo simulations for multiple telavancin doses. The best fit was a 2-compartment model describing the volume of distribution of the central compartment (Vc ) as a multiple of total body weight (TBW) and the volume of distribution of the central compartment scaled to total body weight (V ?) normalized by the median observed value (Vc ?=?V ??×?TBW/52.1) and total body clearance (CL) as a linear function of creatinine clearance (CRCL) (CL?=?CLNR?+?CL??×?CRCL), where CLNR represents nonrenal clearance and CL? represents the slope term on CRCL to estimate renal clearance. The mean population parameters were as follows: V ?, 4.92? ± 0.76 liters?·?kg-1; CLNR, 0.59? ± 0.30 liters?·?h-1; CL?, 5.97?×?10-3 ± 1.24?×?10-3; Vp (volume of the peripheral compartment), 3.77? ± 1.41 liters; Q (intercompartmental clearance), 4.08? ± 2.17 liters?·?h-1 The free area under the concentration-time curve (fAUC) values for 7.5 and 10?mg/kg were 30? ± 4.6 and 52? ± 12?mg?·?h/liter, respectively. Doses of 7.5?mg/kg and 10?mg/kg achieved 76.5% and 100% probability of target attainment (PTA) at a fAUC/MIC threshold of >215, respectively, for MIC of ?0.12?mg/liter. The probabilities of reaching the acute kidney injury (AKI) threshold AUC (763?mg?·?h?·?liter-1) for these doses were 0% and 0.96%, respectively. No serious adverse events occurred. Telavancin 10?mg/kg yielded optimal PTA and minimal risk of AKI, suggesting that this FDA-approved dose is appropriate to treat acute pulmonary exacerbations in CF adults. (The clinical trial discussed in this study has been registered at ClinicalTrials.gov under identifier NCT03172793.).

Dataset Information

Pharmacokinetics and pharmacodynamics of aerosolized antibacterial agents in chronically infected cystic fibrosis patients.

Publications

Pharmacokinetics and pharmacodynamics of aerosolized antibacterial agents in chronically infected cystic fibrosis patients.

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