title: A Robust Pneumonia Model in Immunocompetent Rodents to Evaluate Antibacterial Efficacy against S. pneumoniae, H. influenzae, K. pneumoniae, P. aeruginosa or A. baumannii.
abstract: Efficacy of candidate antibacterial treatments must be demonstrated in animal models of infection as part of the discovery and development process, preferably in models which mimic the intended clinical indication. A method for inducing robust lung infections in immunocompetent rats and mice is described which allows for the assessment of treatments in a model of serious pneumonia caused by S. pneumoniae, H. influenzae, P. aeruginosa, K. pneumoniae or A. baumannii. Animals are anesthetized, and an agar-based inoculum is deposited deep into the lung via nonsurgical intratracheal intubation. The resulting infection is consistent, reproducible, and stable for at least 48 h and up to 96 h for most isolates. Studies with marketed antibacterials have demonstrated good correlation between in vivo efficacy and in vitro susceptibility, and concordance between pharmacokinetic/pharmacodynamic targets determined in this model and clinically accepted targets has been observed. Although there is an initial time investment when learning the technique, it can be performed quickly and efficiently once proficiency is achieved. Benefits of the model include elimination of the neutropenic requirement, increased robustness and reproducibility, ability to study more pathogens and isolates, improved flexibility in study design and establishment of a challenging infection in an immunocompetent host.
authors.affiliation: Antibacterial Discovery Performance Unit, GlaxoSmithKline; Jennifer.L.Hoover@gsk.com.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Hoover
authors.affiliation: Antibacterial Discovery Performance Unit, GlaxoSmithKline.
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Lewandowski
authors.affiliation: Antibacterial Discovery Performance Unit, GlaxoSmithKline.
authors.forename: Cindy L
authors.initials: CL
authors.lastname: Mininger
authors.affiliation: Antibacterial Discovery Performance Unit, GlaxoSmithKline.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Singley
authors.affiliation: Antibacterial Discovery Performance Unit, GlaxoSmithKline.
authors.forename: Scott
authors.initials: S
authors.lastname: Sucoloski
authors.affiliation: Antibacterial Discovery Performance Unit, GlaxoSmithKline.
authors.forename: Stephen
authors.initials: S
authors.lastname: Rittenhouse
mesh_terms: D000151:Acinetobacter Infections / Q000188:drug therapy / Q000382:microbiology; D040981:Acinetobacter baumannii / Q000472:pathogenicity; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D004195:Disease Models, Animal; D006192:Haemophilus Infections / Q000188:drug therapy; D006193:Haemophilus influenzae / Q000472:pathogenicity; D007710:Klebsiella Infections / Q000188:drug therapy; D007711:Klebsiella pneumoniae / Q000472:pathogenicity; D008297:Male; D051379:Mice; D018410:Pneumonia, Bacterial / Q000188:drug therapy* / Q000382:microbiology; D011018:Pneumonia, Pneumococcal / Q000188:drug therapy / Q000382:microbiology; D011552:Pseudomonas Infections / Q000188:drug therapy / Q000382:microbiology; D011550:Pseudomonas aeruginosa / Q000472:pathogenicity; D017207:Rats, Sprague-Dawley; D015203:Reproducibility of Results; D013296:Streptococcus pneumoniae / Q000472:pathogenicity
chemical_list: D000900:Anti-Bacterial Agents