Low-dose aerosol model of pneumococcal pneumonia in the mouse: utility for evaluation of antimicrobial efficacy

Current mouse models of pneumococcal infection have two disadvantages: (1) those that are not based on lung infections do not take into account the tissue pharmacokinetics of drugs in the lung parenchyma; and (2) those that are pneumonia models typically use large infectious doses to produce fulminant infections. The objective of this study was to determine the utility of a low-dose aerosol pneumonia model for evaluation of antimicrobial efficacy. Mice infected with penicillin-susceptible or non-susceptible pneumococci were left untreated or treated for 2.5 days with ertapenem in a range of doses. Efficacy was determined by the change in log10 colony-forming unit (CFU) counts and survival. Low-dose aerosol infection with the penicillin-susceptible strain 6303 produced an indolent pneumonia that was reliably lethal 1-2 weeks after infection. Ertapenem demonstrated bactericidal activity and prevented mortality over a range of doses after infection with strain 6303, but demonstrated only bacteriostatic activity at the highest doses used against the more resistant 1980 strain. A beneficial effect on survival was seen at doses approaching bioequivalence with the standard human dosage. The low-dose aerosol model of pneumococcal pneumonia in the mouse is a viable alternative model for the evaluation of antimicrobial efficacy. It may be particularly useful in the evaluation of drugs that concentrate in the alveolar epithelial lining fluid or lung parenchyma.