title: Efficacy of rifampin and its combinations with imipenem, sulbactam, and colistin in experimental models of infection caused by imipenem-resistant Acinetobacter baumannii.
abstract: There are currently no defined optimal therapies available for multidrug-resistant (MDR) Acinetobacter baumannii infections. We evaluated the efficacy of rifampin, imipenem, sulbactam, colistin, and their combinations against MDR A. baumannii in experimental pneumonia and meningitis models. The bactericidal in vitro activities of rifampin, imipenem, sulbactam, colistin, and their combinations were tested using time-kill curves. Murine pneumonia and rabbit meningitis models were evaluated using the A. baummnnii strain Ab1327 (with MICs for rifampin, imipenem, sulbactam, and colistin of 4, 32, 32, and 0.5 mg/liter, respectively). Mice were treated with the four antimicrobials and their combinations. For the meningitis model, the efficacies of colistin, rifampin and its combinations with imipenem, sulbactam, or colistin, and of imipenem plus sulbactam were assayed. In the pneumonia model, compared to the control group, (i) rifampin alone, (ii) rifampin along with imipenem, sulbactam, or colistin, (iii) colistin, or (iv) imipenem plus sulbactam significantly reduced lung bacterial concentrations (10.6 +/- 0.27 [controls] versus 3.05 +/- 1.91, 2.07 +/- 1.82, 2.41 +/- 1.37, 3.4 +/- 3.07, 6.82 +/- 3.4, and 4.22 +/- 2.72 log(10) CFU/g, respectively [means +/- standard deviations]), increased sterile blood cultures (0% versus 78.6%, 100%, 93.3%, 93.8%, 73.3%, and 50%), and improved survival (0% versus 71.4%, 60%, 46.7%, 43.8%, 40%, and 85.7%). In the meningitis model rifampin alone or rifampin plus colistin reduced cerebrospinal fluid bacterial counts (-2.6 and -4.4 log(10) CFU/ml). Rifampin in monotherapy or with imipenem, sulbactam, or colistin showed efficacy against MDR A. baumannii in experimental models of pneumonia and meningitis. Imipenem or sulbactam may be appropriate for combined treatment when using rifampin.
authors.affiliation: Service of Infectious Diseases, Instituto de Biomedicina de Sevilla, Hospitales Universitarios Virgen del Rocío, CSIC, Universidad de Sevilla, Seville, Spain. meniapi@hotmail.com
authors.forename: María E
authors.initials: ME
authors.lastname: Pachón-Ibáñez
authors.forename: Fernando
authors.initials: F
authors.lastname: Docobo-Pérez
authors.forename: Rafael
authors.initials: R
authors.lastname: López-Rojas
authors.forename: Juan
authors.initials: J
authors.lastname: Domínguez-Herrera
authors.forename: Manuel E
authors.initials: ME
authors.lastname: Jiménez-Mejias
authors.forename: Andrés
authors.initials: A
authors.lastname: García-Curiel
authors.forename: Cristina
authors.initials: C
authors.lastname: Pichardo
authors.forename: Luis
authors.initials: L
authors.lastname: Jiménez
authors.forename: Jerónimo
authors.initials: J
authors.lastname: Pachón
mesh_terms: D000151:Acinetobacter Infections / Q000188:drug therapy / Q000382:microbiology / Q000401:mortality; D040981:Acinetobacter baumannii / Q000187:drug effects* / Q000235:genetics; D000818:Animals; D003091:Colistin / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D024901:Drug Resistance, Multiple, Bacterial; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D015378:Imipenem / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D016920:Meningitis, Bacterial / Q000188:drug therapy / Q000382:microbiology / Q000401:mortality; D051379:Mice; D008810:Mice, Inbred C57BL; D008826:Microbial Sensitivity Tests; D018410:Pneumonia, Bacterial / Q000188:drug therapy / Q000382:microbiology / Q000401:mortality; D011817:Rabbits; D012293:Rifampin / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D013407:Sulbactam / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D015378:Imipenem; D013407:Sulbactam; D012293:Rifampin; D003091:Colistin