Pharmacokinetic/pharmacodynamic assessment of the in-vivo efficacy of imipenem alone or in combination with amikacin for the treatment of experimental multiresistant Acinetobacter baumannii pneumonia

Abstract

A guinea-pig pneumonia model involving imipenem-susceptible and imipenem-resistant strains of Acinetobacter baumannii was developed to assess the in-vitro and in-vivo activities of imipenem, alone or in combination with amikacin, and the pharmacokinetic and pharmacodynamic parameters. Serum levels were measured by bioassay (imipenem) or immunoassay (amikacin), followed by calculation of pharmacokinetic and pharmacodynamic parameters (Cmax, AUC, t1/2, Cmax/MIC, AUC/MIC, and Deltat/MIC). In-vivo efficacy was evaluated by comparing bacterial counts in the lungs of treatment groups with end-of-therapy controls by anova and post-hoc tests. Decreases in the Cmax (13.4%), AUC (13%), t1/2 (25%) and Deltat/MIC (11.8-32.2%) of imipenem were observed when it was administered with amikacin, compared with administration of imipenem alone. Similarly, decreases in the Cmax (34.5%), AUC (11.6%), Cmax/MIC (34.5%) and AUC/MIC (11.7%) of amikacin were observed when it was administered with imipenem. Bacterial counts in lungs were reduced by imipenem (p 0.004) with the imipenem-susceptible strain, and by amikacin (p 0.001) with the imipenem-resistant strain. The combination of imipenem plus amikacin was inferior to imipenem alone with the imipenem-susceptible strain (p 0.01), despite their in-vitro synergy, and was inferior to amikacin alone with the imipenem-resistant strain (p < 0.0001). In summary, combined use of imipenem with amikacin was less efficacious than monotherapy, probably because of a drug-drug interaction that resulted in decreased pharmacokinetic and pharmacodynamic parameters for both antimicrobial agents.

Therapeutic options forAcinetobacter baumanniiinfections: an update

“…Likewise in an experimental pneumonia model in guinea pigs, Bernabeu-Wittel et al [108] showed that the combination of amikacin with imipenem was not as effective as monotherapy with imipenem in reducing the bacterial concentration in the lungs, probably because of an in vivo chemical drug--drug interaction, resulting in decreased pharmacokinetics/pharmacodynamics parameters for both antibacterial agents. In summary, neither study supports the addition of amikacin to imipenem in the treatment of A. baumannii pneumonia.…”

Rat Pneumonia and Soft-Tissue Infection Models for the Study of Acinetobacter baumannii Biology

“…In contrast, bacteria are often cleared in murine pneumonia models. Therefore, in the majority of Acinetobacter murine pneumonia models reported on to date, the animals received porcine mucin with the bacterial challenge (4,25,26,34,36) or were rendered neutropenic (20, 21), permutations FIG. 9.…”

Innate Immune Responses to Systemic Acinetobacter baumannii Infection in Mice: Neutrophils, but Not Interleukin-17, Mediate Host Resistance

“…However, antibiograms performed on these strains showed a rough correlation between virulence and degree of antibiotic resistance, a relationship that has not previously been investigated. The tendency for A. baumannii strains to exhibit a high level of antibiotic resistance is well established in the literature (1,2,6,7,18,20,22,27,28,33,39,49,59). Resistance is due both to chromosomally encoded resistance genes and to ones found on plasmids and transposons (12).…”