title: In Vitro Activities of Novel Antimicrobial Combinations against Extensively Drug-Resistant Acinetobacter baumannii.
abstract: Extensively drug-resistant (XDR) Acinetobacter spp. have emerged as a cause of nosocomial infections, especially under conditions of intensive care. Unfortunately, resistance to colistin is increasing and there is a need for new therapeutic options. We aimed to study the effect of some novel combinations against XDR Acinetobacter baumannii in an in vitro pharmacokinetics-pharmacodynamics (PK/PD) model. Three nonrelated clinical strains of XDR A. baumannii were investigated. Antibiotic-simulated regimens were colistin at 3 MU every 8 h (q8h) (first dose, 6 MU), daptomycin at 10 mg/kg of body weight q24h, imipenem at 1 g q8h, and ertapenem at 1 g q24h. Combination regimens included colistin plus daptomycin, colistin plus imipenem, and imipenem plus ertapenem. Samples were obtained at 0, 1, 2, 4, 8, and 24 h. Among the single-agent regimens, only the colistin regimen resulted in significant reductions in log10 CFU per milliliter compared to the control for all the strains tested. Although colistin achieved bactericidal activity at 4 h, it was not able to reach the limit of detection (1 log10 CFU/ml). One strain had significant regrowth at 24 h without the emergence of resistance. Daptomycin-colistin combinations led to a significant reduction in levels of log10 CFU per milliliter that were better than those achieved with colistin as a single-agent regimen, reaching the limit of detection at 24 h against all the strains. The combination of imipenem plus ertapenem outperformed the colistin regimen, although the results did not reach the limit of detection, with significant regrowth at 24 h. Similarly, colistin-plus-imipenem combinations reduced the levels of log10 CFU per milliliter at 8 h, with significant regrowth at 24 h but with development of resistance to colistin. We have shown some potentially useful alternatives for the treatment of extensively drug-resistant A. baumannii. Among them, the daptomycin-colistin combination was the most effective and should be investigated in future studies.
authors.affiliation: Laboratorio de Investigación Antimicrobiana Hospital Universitario San Cecilio, Granada, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Córdoba
authors.affiliation: Laboratorio de Investigación Antimicrobiana Hospital Universitario San Cecilio, Granada, Spain.
authors.forename: N M
authors.initials: NM
authors.lastname: Coronado-Álvarez
authors.affiliation: Laboratorio de Investigación Antimicrobiana Hospital Universitario San Cecilio, Granada, Spain.
authors.forename: D
authors.initials: D
authors.lastname: Parra
authors.affiliation: Laboratorio de Investigación Antimicrobiana Hospital Universitario San Cecilio, Granada, Spain Servicio de Enfermedades Infecciosas, Hospital Universitario San Cecilio, Granada, Spain arrapj@gmail.com.
authors.forename: J
authors.initials: J
authors.lastname: Parra-Ruiz
mesh_terms: D000151:Acinetobacter Infections / Q000188:drug therapy / Q000382:microbiology; D040981:Acinetobacter baumannii / Q000187:drug effects* / Q000254:growth & development; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics* / Q000494:pharmacology; D019540:Area Under Curve; D003091:Colistin / Q000493:pharmacokinetics* / Q000494:pharmacology; D015169:Colony Count, Microbial; D017576:Daptomycin / Q000493:pharmacokinetics* / Q000494:pharmacology; D004334:Drug Administration Schedule; D004338:Drug Combinations; D024901:Drug Resistance, Multiple, Bacterial; D000077727:Ertapenem; D006801:Humans; D015378:Imipenem / Q000493:pharmacokinetics / Q000494:pharmacology; D057230:Limit of Detection; D008826:Microbial Sensitivity Tests; D008954:Models, Biological; D015233:Models, Statistical; D047090:beta-Lactams / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D004338:Drug Combinations; D047090:beta-Lactams; D015378:Imipenem; D000077727:Ertapenem; D017576:Daptomycin; D003091:Colistin