Use of a new mouse model of Acinetobacter baumannii pneumonia to evaluate the postantibiotic effect of imipenem

Abstract

Acinetobacter baumannii is responsible for severe nosocomial pneumonia. To evaluate new therapeutic regimens for infections due to multiresistant strains and to study the pharmacodynamic properties of various antibiotics, we developed an experimental mouse model of acute A. baumannii pneumonia. C3H/HeN mice rendered transiently neutropenic were infected intratracheally with 5 x 10(6) CFU of A. baumannii. The mean log10 CFU/g of lung homogenate (+/- the standard deviation) were 9 +/- 0.9, 9.4 +/- 0.8, 8.6 +/- 1.2, and 7.7 +/- 1.4 on days 1, 2, 3, and 4 postinoculation. The lung pathology was characterized by pneumonitis with edema and a patchy distribution of hemorrhages in the peribronchovascular spaces of both lungs. Abscesses formed on days 3 and 4. Four days after inoculation, subacute pneumonitis characterized by alveolar macrophage proliferation and areas of fibrosis was observed. The cumulative mortality on day 4 was 85%. This new model was used to study the effects of 1, 2, or 3 50-mg/kg doses of imipenem. Imipenem concentrations in lungs were above the MIC for 2 h after the last dose. The in vivo postantibiotic effect (PAE) was determined during the 9-h period following the last dose; it decreased in duration with the number of doses: 9.6, 6.4, and 4 h after 1, 2, and 3 50-mg/kg doses, respectively. In contrast, no in vitro PAE was observed. This model offers a reproducible acute course of A. baumannii pneumonia. The presence of a prolonged in vivo PAE supports the currently recommended dosing intervals of imipenem for the treatment of human infections due to A. baumannii, i.e., 15 mg/kg three times a day.

The Immune Response against Acinetobacter baumannii, an Emerging Pathogen in Nosocomial Infections

“…An initial indication about the protective role of neutrophils was the observation of high prevalence of infections caused by Acinetobacter in neutropenic patients (20). In agreement, early studies characterizing the therapeutic effect of imipenem against different strains of A. baumannii in a mouse model had to be performed in cyclophosphamide-treated neutropenic mice, due to the low susceptibility to A. baumannii shown by immunocompetent mice (21). Ten years later, van Faassen and colleagues directly evaluated the neutrophil role in pneumonia caused by A. baumannii .…”

Active and Passive Immunization Protects against Lethal, Extreme Drug Resistant-Acinetobacter baumannii Infection

“…However, A. baumannii bacteremia spontaneously clears in mice unless a host defect is present [39]. Similarly, in our initial pilot experiments, a lethal iv infectious inoculum could not be identified in normal Balb/c mice, unless inocula were so high that they induced overwhelming infection resulting in death within 24 h (e.g., ≥10 9 bacilli).…”

Efficacy of tigecycline/colistin combination in a pneumonia model caused by extensively drug-resistant Acinetobacter baumannii

“…In this model, results differ in accordance with inoculum density. In experimental models, A. baumannii leads to interstitial pneumonia [17,18]. Accordingly, in the current study the presence of interstitial pneumonia was demonstrated pathologically.…”

“…Increase in virulence of bacterial strains with porcine mucin or exacerbation of disease by creating neutropenia in animals were reported in various studies [1,8,19]. The virulence of A. baumannii does not differ among animals with or without neutropenia [18]. Most of the patients followed-up in our department are not neutropenic.…”