Aerosolized Polymyxin B for Treatment of Respiratory Tract Infections: Determination of Pharmacokinetic-Pharmacodynamic Indices for Aerosolized Polymyxin B against Pseudomonas aeruginosa in a Mouse Lung Infection Model

Abstract

Pulmonary administration of polymyxins is increasingly used for the treatment of respiratory tract infections caused by multidrug-resistant Gram-negative bacteria, such as those in patients with cystic fibrosis. However, there is a lack of pharmacokinetics (PK), pharmacodynamics (PD), and toxicity data of aerosolized polymyxin B to inform rational dosage selection. The PK and PD of polymyxin B following pulmonary and intravenous dosing were examined in neutropenic infected mice, and the data were analyzed by a population PK model. Dose fractionation study was performed for total daily doses between 2.06 and 24.8 mg base/kg of weight against Pseudomonas aeruginosa ATCC 27853, PAO1, and FADDI-PA022 (MIC of 1 mg/liter for all three strains). Histopathological examination of the lung was undertaken at 24 h posttreatment in both healthy and neutropenic infected mice. A two-compartment PK model was required for both epithelial lining fluid (ELF) and plasma drug exposure. The model consisted of central and peripheral compartments and was described by bidirectional first-order distribution clearance. The ratio of the area under the curve to the MIC (AUC/MIC) was the most predictive PK/PD index to describe the antimicrobial efficacy of aerosolized polymyxin B in treating lung infections in mice (R 2 of 0.70 to 0.88 for ELF and 0.70 to 0.87 for plasma). The AUC/MIC targets associated with bacteriostasis against the three P. aeruginosa strains were 1,326 to 1,506 in ELF and 3.14 to 4.03 in plasma. Histopathological results showed that polymyxin B aerosols significantly reduced lung inflammation and preserved lung epithelial integrity. This study highlights the advantageous PK/PD characteristics of pulmonary delivery of polymyxin B over intravenous administration in achieving high drug exposure in ELF.

Proof-of-Principle Study in a Murine Lung Infection Model of Antipseudomonal Activity of Phage PEV20 in a Dry-Powder Formulation

“…In our experiments, the method achieved a delivery of 97.0% Ϯ 2.2% of the loaded sample, and the residual volume in the syringe after delivery was negligible. Recent studies by our group confirmed the suitability and consistencies in dose delivery using the intratracheal route, even for complex pharmacokinetic and pharmacodynamics studies (9,10). In the present study, the bacterial loads after inoculation in four mice were log 10 5.6, log 10 5.6, log 10 5.5, and log 10 5.5 CFU/lung, reflecting the tight control of dose given via the intratracheal route.…”

“…Luminescence imaging showed that bacteria had spread all over the body after 8 h, with heavy loads in the nose, lungs, and stomach. More recently, a number of groups have employed intratracheal instillation for bacteria and antibiotic administration to enable a direct and reproducible delivery to the lungs (8)(9)(10). Intratracheal administration using a MicroSprayer aerosolizer and a Dry powder insufflator enables noninvasive delivery; yet, this administration route is still underexplored.…”

Pharmacokinetic/Pharmacodynamic Evaluation of Solithromycin against Streptococcus pneumoniae Using Data from a Neutropenic Murine Lung Infection Model

“…Regardless of whether drug exposure was measured in plasma or in ELF, the AUC/MIC ratio was identified as the PK/PD index that best predicted solithromycin efficacy against S. pneumoniae. While investigators have measured drug exposure in plasma and ELF in separate cohorts of mice or modeled PK in plasma and ELF separately (15), it is more optimal to determine drug exposure simultaneously in murine plasma and ELF and comodel these data (16)(17)(18). The advantage of such an approach, as described herein, is the ability to estimate intercompartmental transfer rate constants and improve the precision of the PK parameter estimates.…”

Polymyxins Nebulization over Intravenous Injection: Pharmacokinetics and Pharmacodynamics-Based Therapeutic Evaluation

“…The same study also showed effective PK/PD characteristics attained by polymyxin B nebulization and achieved relatively higher drug concentration than intravenous polymyxin B [23]. The concentration of polymyxin B is affected by the route of administration and relatively higher concentration is attained by inhaling polymyxin B in mice [23].…”

“…The aerosolized dosing regimen of polymyxin B and colistin has not yet been globally established and in some places, recently this drug delivery system has been introduced as a secondary administrative option for treating serious infections of RTI. Due to the lack of PK/PD data on aerosolized polymyxin B, no specific dosing regimen has yet been developed [23]. In an 18month long ICU-based study, researchers found that polymyxin B nebulization in 2 mg/Kg of BW/ day in 2 equally divided doses showed promising therapeutic outcomes [13].…”