In vivo efficacy of combination of colistin with fosfomycin or minocycline in a mouse model of multidrug-resistant Acinetobacter baumannii pneumonia

Abstract

Unfortunately, the options for treating multidrug-resistant (MDR) Acinetobacter baumannii (A. baumannii) infections are extremely limited. Recently, fosfomycin and minocycline were newly introduced as a treatment option for MDR A. baumannii infection. Therefore, we investigated the efficacy of the combination of colistin with fosfomycin and minocycline, respectively, as therapeutic options in MDR A. baumannii pneumonia. We examined a carbapenem-resistant A. baumannii isolated from clinical specimens at Severance Hospital, Seoul, Korea. The effect of colistin with fosfomycin, and colistin with minocycline on the bacterial counts in lung tissue was investigated in a mouse model of pneumonia caused by MDR A. baumannii. In vivo, colistin with fosfomycin or minocycline significantly (p < 0.05) reduced the bacterial load in the lungs compared with the controls at 24 and 48 h. In the combination groups, the bacterial loads differed significantly (p < 0.05) from that with the more active antimicrobial alone. Moreover, the combination regimens of colistin with fosfomycin and colistin with minocycline showed bactericidal and synergistic effects compared with the more active antimicrobial alone at 24 and 48 h. This study demonstrated the synergistic effects of combination regimens of colistin with fosfomycin and minocycline, respectively, as therapeutic options in pneumonia caused by MDR A. baumannii.

Figure 1

Time-kill curves. Colistin/fosfomycin and colistin/minocycline combinations showed bactericidal effects, with >3 log₁₀ reductions in CFU at 4, 8, and 24 h. The combination regimens showed synergistic effects, with ≥2 log₁₀ decreases in CFU compared with the monotherapy regimens (0.5 × MIC). (C: colistin; F: fosfomycin; M: minocycline).

Figure 2

Histopathology of the lung tissues of mice at 4 (A), 24 (B), and 48 h (C) after inoculation with A. baumannii (H&E; bar = 100 µm). (A) At 4 h after inoculation, no significant lesion was present in the alveoli, bronchioles, or bronchi, except for minimal edema in the alveolar cavity. (B) At 24 h after inoculation, moderate numbers of neutrophils (dark triangle) and macrophages (blue triangle) had infiltrated the alveoli; moderate edema was present, and bacterial colonization (dark arrow) was observed in the alveolar cavities. (C) At 48 h after inoculation, large numbers of neutrophils (dark triangle) and macrophages (blue triangle) had infiltrated the alveoli.