title: Low-dose aerosol model of pneumococcal pneumonia in the mouse: utility for evaluation of antimicrobial efficacy.
abstract: 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.
authors.affiliation: Division of Infectious Diseases, Department of Medicine, 1503 E. Jefferson St., Baltimore, MD 21231, USA. enuermb@jhmi.edu
authors.forename: Eric
authors.initials: E
authors.lastname: Nuermberger
authors.forename: Kris
authors.initials: K
authors.lastname: Helke
authors.forename: William R
authors.initials: WR
authors.lastname: Bishai
mesh_terms: D000336:Aerosols; D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D004195:Disease Models, Animal; D024881:Drug Resistance, Bacterial; D000077727:Ertapenem; D005260:Female; D051379:Mice; D008808:Mice, Inbred CBA; D010406:Penicillins / Q000494:pharmacology; D011018:Pneumonia, Pneumococcal / Q000188:drug therapy*; D013296:Streptococcus pneumoniae / Q000187:drug effects; D047090:beta-Lactams / Q000627:therapeutic use*
chemical_list: D000336:Aerosols; D000900:Anti-Bacterial Agents; D010406:Penicillins; D047090:beta-Lactams; D000077727:Ertapenem