Dataset Information

Pharmacokinetics/pharmacodynamics of systemically administered polymyxin B against Klebsiella pneumoniae in mouse thigh and lung infection models.

ABSTRACT:

Background

The pharmacokinetic/pharmacodynamic (PK/PD) relationship for polymyxin B against Klebsiella pneumoniae infections is not known.

Methods

Dose-fractionation studies with subcutaneous polymyxin B were conducted in neutropenic mice in which infection with three strains of K. pneumoniae had been produced in thighs or lungs. Dosing (thigh infection 0.5-120?mg/kg/day; lung infection 5-120?mg/kg/day) commenced 2?h after inoculation, and bacterial burden was measured 24?h later. Plasma exposure measures for unbound polymyxin B were from population pharmacokinetic analysis of single doses and plasma protein binding by ultracentrifugation. The inhibitory sigmoid dose-effect model was employed to determine the relationship between exposure and efficacy. Antibacterial activities of polymyxin B and colistin against thigh infection were compared at equimolar doses generating exposures resulting in maximal antibacterial activity.

Results

The pharmacokinetics of polymyxin B were well described by a model comprising parallel linear and saturable pathways for absorption and elimination. Plasma binding of polymyxin B was constant (P?>?0.05) over the range ?0.9-37?mg/L; average (±SD) percentage bound was 91.4?±?1.65. In thigh infection, antibacterial effect was well correlated with fAUC/MIC (R2?=?0.89). Target values of fAUC/MIC for stasis and 1?log10 kill were 1.22-13.5 and 3.72-28.0, respectively; 2?log10 kill was not achieved for any strain, even at the highest tolerated dose. There was no difference (P?>?0.05) in antibacterial activity between polymyxin B and colistin with equimolar doses. It was not possible to achieve stasis in lung infection, even at the highest dose tolerated by mice.

Conclusions

The results will assist in the design of optimized dosage regimens of polymyxin B.

SUBMITTER: Landersdorfer CB

PROVIDER: S-EPMC5890666 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Publications

Pharmacokinetics/pharmacodynamics of systemically administered polymyxin B against Klebsiella pneumoniae in mouse thigh and lung infection models.

Landersdorfer Cornelia B CB Wang Jiping J Wirth Veronika V Chen Ke K Kaye Keith S KS Tsuji Brian T BT Li Jian J Nation Roger L RL

The Journal of antimicrobial chemotherapy 20180201 2

<h4>Background</h4>The pharmacokinetic/pharmacodynamic (PK/PD) relationship for polymyxin B against Klebsiella pneumoniae infections is not known.<h4>Methods</h4>Dose-fractionation studies with subcutaneous polymyxin B were conducted in neutropenic mice in which infection with three strains of K. pneumoniae had been produced in thighs or lungs. Dosing (thigh infection 0.5-120 mg/kg/day; lung infection 5-120 mg/kg/day) commenced 2 h after inoculation, and bacterial burden was measured 24 h later. ...[more]

PMID: 29149294

Similar Datasets

Project description:Resistance to polymyxin antibiotics is increasing. Without new antibiotic classes, combination therapy is often required. We systematically investigated bacterial killing with polymyxin-based combinations against multidrug-resistant (including polymyxin-resistant), carbapenemase-producing Klebsiella pneumoniae Monotherapies and double- and triple-combination therapies were compared to identify the most efficacious treatment using static time-kill studies (24 h, six isolates), an in vitro pharmacokinetic/pharmacodynamic model (IVM; 48 h, two isolates), and the mouse thigh infection model (24 h, six isolates). In static time-kill studies, all monotherapies (polymyxin B, rifampin, amikacin, meropenem, or minocycline) were ineffective. Initial bacterial killing was enhanced with various polymyxin B-containing double combinations; however, substantial regrowth occurred in most cases by 24 h. Most polymyxin B-containing triple combinations provided greater and more sustained killing than double combinations. Standard dosage regimens of polymyxin B (2.5 mg/kg of body weight/day), rifampin (600 mg every 12 h), and amikacin (7.5 mg/kg every 12 h) were simulated in the IVM. Against isolate ATH 16, no viable bacteria were detected across 5 to 25 h with triple therapy, with regrowth to ∼2-log10 CFU/ml occurring at 48 h. Against isolate BD 32, rapid initial killing of ∼3.5-log10 CFU/ml at 5 h was followed by a slow decline to ∼2-log10 CFU/ml at 48 h. In infected mice, polymyxin B monotherapy (60 mg/kg/day) generally was ineffective. With triple therapy (polymyxin B at 60 mg/kg/day, rifampin at 120 mg/kg/day, and amikacin at 300 mg/kg/day), at 24 h there was an ∼1.7-log10 CFU/thigh reduction compared to the starting inoculum for all six isolates. Our results demonstrate that the polymyxin B-rifampin-amikacin combination significantly enhanced in vitro and in vivo bacterial killing, providing important information for the optimization of polymyxin-based combinations in patients.

Dataset Information

Pharmacokinetics/pharmacodynamics of systemically administered polymyxin B against Klebsiella pneumoniae in mouse thigh and lung infection models.

Background

Methods

Results

Conclusions

Publications

Pharmacokinetics/pharmacodynamics of systemically administered polymyxin B against Klebsiella pneumoniae in mouse thigh and lung infection models.

Similar Datasets

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