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

• Published in: Clinical microbiology and infection Vol. 11; no. 4; pp. 319 - 325
• Main Authors: Bernabeu-Wittel, M., Pichardo, C., García-Curiel, A., Pachón-Ibáñez, M.E., Ibáñez-Martínez, J., Jiménez-Mejías, M.E., Pachón, J.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Elsevier Ltd 01.04.2005; Blackwell Science Ltd; Blackwell
• Subjects: Acinetobacter baumannii; Acinetobacter baumannii - drug effects; Acinetobacter Infections - drug therapy; Acinetobacter Infections - metabolism; Acinetobacter Infections - microbiology; amikacin; Amikacin - pharmacology; Amikacin - therapeutic use; Animals; Anti-Bacterial Agents - pharmacology; Anti-Bacterial Agents - therapeutic use; Antibacterial agents; Antibiotics. Antiinfectious agents. Antiparasitic agents; Biological and medical sciences; Disease Models, Animal; Drug Resistance, Multiple, Bacterial; Drug Synergism; Drug Therapy, Combination; experimental pneumonia; Female; Guinea Pigs; imipenem; Imipenem - pharmacology; Imipenem - therapeutic use; Lung - drug effects; Lung - microbiology; Medical sciences; Microbial Sensitivity Tests; pharmacodynamics; pharmacokinetics; Pharmacology. Drug treatments; Pneumonia, Bacterial - drug therapy; Pneumonia, Bacterial - metabolism; Pneumonia, Bacterial - microbiology; pharmacokinetics; Acinetobacter baumannii; amikacin; experimental pneumonia; imipenem; pharmacodynamics; Lung disease; Drug combination; Pneumonia; Amikacin; Respiratory disease; β-Lactams; Neisseriaceae; Biological activity; Infection; In vivo; Carbapenem derivatives; Antibiotic; Treatment; Aminoglycoside; Multiple resistance; Bacteria; Micrococcales; Antibacterial agent; Pharmacokinetics; Imipenem
• ISSN: 1198-743X; 1469-0691
• DOI: 10.1111/j.1469-0691.2005.01095.x

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 Δt /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 Δt/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.