Probability of Target Attainment of Tobramycin Treatment in Acute and Chronic Pseudomonas aeruginosa Lung Infection Based on Preclinical Population Pharmacokinetic Modeling

Abstract

Biofilms and infectious process may alter free antimicrobial concentrations at the site of infection. Tobramycin (TOB), an aminoglycoside used to treat lung infections caused by Pseudomonas aeruginosa, binds to alginate present in biofilm extracellular matrix increasing its minimum inhibitory concentration (MIC). This work aimed to investigate the impact of biofilm-forming P. aeruginosa infection on TOB lung and epithelial lining fluid (ELF) penetration, using microdialysis, and to develop a population pharmacokinetic (popPK) model to evaluate the probability of therapeutic target attainment of current dosing regimens employed in fibrocystic and non-fibrocystic patients. The popPK model developed has three compartments including the lung. The ELF concentrations were described by a penetration factor derived from the lung compartment. Infection was a covariate in lung volume (V3) and only chronic infection was a covariate in central volume (V1) and total clearance (CL). Simulations of the recommended treatments for acute and chronic infection achieved >90% probability of target attainment (PTA) in the lung with 4.5 mg/kg q24h and 11 mg/kg q24h, respectively, for the most prevalent P. aeruginosa MIC (0.5 mg/mL). The popPK model was successfully applied to evaluate the PTA of current TOB dosing regimens used in the clinic, indicating the need to investigate alternative posology.

Tobramycin-loaded nanoparticles of thiolated chitosan for ocular drug delivery: Preparation, mucoadhesion and pharmacokinetic evaluation

“…However, the positive charge was not the only factor that affected the bioadhesion of TCS. The presence of free -NH2 and –OH groups from TCS molecules, which form hydrogen bonds with the mucin on the surface of the eye, may have further encouraged it [ 42 ]. In pharmacokinetics, a p -value of less than 0.05 indicates that the results are statistically significant.…”

Clinical recommendations for the inpatient management of lower respiratory tract infections in children and adolescents with severe neurological impairment in Germany

“…All options are intended to offer an alternative treatment choice alongside the use of carbapenems for non-critically ill patients. Inhaled ABT, especially with tobramycin, can support acute treatment [ 73 – 75 ].…”

Lung microdialysis and in vivo PK/PD integration of cefquinome against Actinobacillus pleuropneumoniae in a porcine experimental lung infection model

“…Additionally, due to the uncertainty of the dilution factor between bronchoalveolar lavage fluid and the actual interstitial or epithelial lining fluid concentrations within the lungs, PK characteristics are often described based on total drug content rather than the free drug concentration (22)(23)(24). Microdialysis has been applied to measure the concentration of antimicrobial drugs in the fluid and provide preclinical drug development and clinical PK/PD data for antimicrobial drugs (25,26). Therefore, this study employed microdialysis to investigate the PK characteristics of unbound cefquinome in the lung and evaluate the in vivo antibacterial effect of cefquinome against A. pleuropneumoniae.…”