Article révisé par les pairs
Résumé : A drug combination, vancomycin (VAN) plus tetrahydrolipstatin (THL), has demon-strated an effective synergistic action in vitro againstMycobacterium tuberculosis(Mtb). The poor oral bioavailability of VAN and THL and the predominant tropism ofMtb infection to the lungs make their pulmonary administration very attractive. Toevaluate their local tolerability, bronchial cells, alveolar cells and monocytes wereexposed to concentrations around and above their minimal inhibitory concentration(MIC). The VAN had no inhibitory activity on the tested human cell lines, even at aconcentration 125 times higher than its MIC, whereas the THL, alone or in combina-tion with VAN, presented a cytostatic action. Monolayer epithelium showed no sig-nificant irreversible damage at concentrations up to 100 times the combination MIC.BALB/cAnNRj mice exposed to concentration of 50 times the combination MICdelivered endotracheally 3 times a week for 3 weeks showed no clinical signs or sig-nificant weight loss. The increase of proinflammatory biomarkers (i.e., IL-1, IL-6, TNF-αand proportion of inflammatory cells) and cytotoxicity in bronchoalveolar lavagefluid (BALF) were non-significant. Lung histopathology did not show significant tissuedamage. The VAN/THL combination at doses up to 50 times the combination MIC isfound to be thus well tolerated by pulmonary route. This study is a promising resultand encouraging further investigations of pulmonary administration of VAN/THLcombination as dry powder for anti-tuberculosis treatment.

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