Estimating amoxicillin influx/efflux in chinchilla middle ear fluid and simultaneous measurement of antibacterial effect.
Huang Y, Yang Z, Cartier L, Cheung B, Sawchuk RJ.
Understanding the transport process and the factors that control the influx/efflux of antibiotics between plasma and middle ear fluid is essential in optimizing the antimicrobial efficacy in the treatment of acute otitis media. In this study, an experimental chinchilla model with the application of a microdialysis technique was utilized to evaluate amoxicillin middle ear distribution kinetics. Amoxicillin solutions at various doses were instilled into the middle ear with a simultaneous intravenous bolus dose. Unbound amoxicillin levels were monitored by microdialysis in both ears. Serial phlebotomy provided samples for the measurement of unbound amoxicillin concentration in plasma ultrafiltrates. In infected chinchillas, discrete middle ear fluid samples were plated and cultured to characterize Streptococcus pneumoniae growth-kill kinetics. Noncompartmental analysis was used to estimate distributional and elimination clearances assuming linear pharmacokinetics. A nonlinear Michaelis-Menten equation was also used to determine the efflux clearance (from middle ear fluid to plasma) in a mammillary compartment model. No difference was observed in amoxicillin pharmacokinetics between control and infected chinchillas. Influx clearance was (4.6 +/- 2.4) x 10(-3) ml/min-kg and significantly lower than the efflux clearance estimated as (19.2 +/- 9.7) x 10(-3) ml/min-kg (P < 0.002). Nonlinear kinetics was observed in the locally dosed ear. The microdialysis procedure did not interfere with the bacterial growth-kill profile, thereby enabling pharmacokinetic and pharmacodynamic evaluation concurrently. In conclusion, the results suggested that the distribution equilibrium of amoxicillin in the middle ear favors efflux to plasma over influx. An active transport mechanism across middle ear mucosal epithelium may be involved in amoxicillin distribution.