Lung Pharmacokinetics of Tobramycin by Intravenous and Nebulized Dosing in a Mechanically Ventilated Healthy Ovine Model

Abstract

Pseudomonasvaeruginosa and other Gram-negative organisms occurs frequently, 1 and is associated with significant morbidity and mortality. 2 Drugs from the aminoglycoside class, such as tobramycin, are recommended for the treatment of ventilator-associated pneumonia 3 and are effective against numerous Gram-negative organisms including P. aeruginosa, Klebsiella pneumoniae, and Acinetobacter baumanii. 4 Despite systemic antibiotic therapy, therapeutic failure is common. 5 One reason for this lack of effect could be poor lung penetration due to low lung epithelial lining aBStraCt Background: Nebulized antibiotics may be used to treat ventilator-associated pneumonia. In previous pharmacokinetic studies, lung interstitial space fluid concentrations have never been reported. The aim of the study was to compare intravenous and nebulized tobramycin concentrations in the lung interstitial space fluid, epithelial lining fluid, and plasma in mechanically ventilated sheep with healthy lungs. Methods: Ten anesthetized and mechanically ventilated healthy ewes underwent surgical insertion of microdialysis catheters in upper and lower lobes of both lungs and the jugular vein. Five ewes were given intravenous tobramycin 400 mg, and five were given nebulized tobramycin 400 mg. Microdialysis samples were collected every 20 min for 8 h. Bronchoalveolar lavage was performed at 1 and 6 h. results: The peak lung interstitial space fluid concentrations were lower with intravenous tobramycin 20.2 mg/l (interquartile range, 12 mg/l, 26.2 mg/l) versus the nebulized route 48.3 mg/l (interquartile range, 8.7 mg/l, 513 mg/l), P = 0.002. For nebulized tobramycin, the median epithelial lining fluid concentrations were higher than the interstitial space fluid concentrations at 1 h (1,637; interquartile range, 650, 1,781, vs. 16 mg/l, interquartile range, 7, 86, P < 0.001) and 6 h (48, interquartile range, 17, 93, vs. 4 mg/l, interquartile range, 2, 9, P < 0.001). For intravenous tobramycin, the median epithelial lining fluid concentrations were lower than the interstitial space fluid concentrations at 1 h (0.

Ventilator-associated pneumonia caused by multidrug-resistant Gram-negative bacteria: understanding nebulization of aminoglycosides and colistin

“…In healthy sheep, high and homogeneously distributed tobramycin pulmonary interstitial concentrations are observed 30 min after nebulization followed by a bi-compartmental decrease, and contrasting with low concentrations after intravenous administration [2]. In pneumonia, high antibiotic tissue concentrations are also observed but are heterogeneously distributed, and likely influenced by the aeration loss [6,7].…”

“…The main reason for nebulizing aminoglycosides and colistin in VAP is to bypass the alveolar-capillary barrier which offers a severe obstacle to lung penetration following intravenous administration. In comparison to intravenous route, nebulized aminoglycosides and colistin can achieve significantly higher lung tissue concentrations necessary for the effective treatment of VAP due to MDR GNB [1,2]. For colistin, this is achieved with minimal systemic toxicity compared to intravenous administration.…”

“…1e-i) [5]. Evidence of high lung tissue concentrations relies on microdialysis [2] or open lung biopsies [1] that can be performed exclusively in experimental studies.…”

“…1 Multidisciplinary Intensive Care Unit, Department of Anaesthesiology and Critical Care, La Pitié-Salpêtrière Hospital, Assistance Publique Hôpitaux de Paris, Medicine Sorbonne University, Paris, France. 2 Critical Care Department, Centre Hospitalo-Universtaire Vaudois, Lausanne, Switzerland. 3 Unitat Cures Intensives, Hospital Universitari de Vic, Barcelona, Spain.…”

Nebulized Antibiotics for Healthcare- and Ventilator-Associated Pneumonia

“…In a healthy sheep model, lung concentrations of tobramycin in the ELF obtained by BAL overestimated the interstitial concentrations measured by microdialysis by an average of approximately 10-fold. 31 However, nebulized tobramycin allowed higher antibiotic exposure in the interstitial fluid than the IV route, with peak concentrations more than twice as high, suggesting better efficacy for an antibiotic with concentration-dependent bactericidal effect.…”