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JAC Advance Access published online on July 26, 2006
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkl303
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© The Author 2006. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org
Received April 21, 2006
Revised June 29, 2006
Accepted July 5, 2006

Brief report

Prevention of rifampicin resistance in Acinetobacter baumannii in an experimental pneumonia murine model, using rifampicin associated with imipenem or sulbactam

María E. Pachón-Ibáñez 1, Felipe Fernández-Cuenca 2, Fernando Docobo-Pérez 1, Jerónimo Pachón 3 *, and Álvaro Pascual 4

1 Service of Infectious Diseases, Hospitales Universitarios Virgen del Rocío, Avda. Manuel Siurot s/n, 41013, Sevilla, Spain
2 Service of Microbiology, Hospital Universitario Virgen Macarena, Avda. Dr Fedriani s/n, 41009, Sevilla, Spain
3 Service of Infectious Diseases, Hospitales Universitarios Virgen del Rocío, Avda. Manuel Siurot s/n, 41013, Sevilla, Spain; Department of Medicine, University of Sevilla, Avda. Dr Fedriani s/n, 41009, Sevilla, Spain
4 Service of Microbiology, Hospital Universitario Virgen Macarena, Avda. Dr Fedriani s/n, 41009, Sevilla, Spain; Department of Microbiology, University of Sevilla, Avda. Sánchez Pizjuan s/n, 41009, Sevilla, Spain

* To whom correspondence should be addressed.
Jerónimo Pachón, E-mail: jeronimopachon{at}telefonica.net


  Abstract

Objectives: To examine the development of rifampicin resistance in multidrug-resistant Acinetobacter baumannii exposed to rifampicin and the prevention of the appearance of rifampicin-resistant mutants when rifampicin is used in association with imipenem or sulbactam.

Methods: A clinical strain of multidrug-resistant A. baumannii was used to examine the frequency of resistance to rifampicin in vivo, in a pneumonia model in immunocompetent C57BL/6 mice. The in vitro and in vivo prevention of the development of resistance to rifampicin was analysed using rifampicin alone or in association with imipenem or sulbactam, in time-kill studies and in the experimental murine pneumonia, respectively.

Results: Rifampicin-resistant mutants were found at 48 and 72 h, both in vitro and in vivo, when rifampicin was used alone, with the MIC increasing from 4 to ≥128 mg/L. The in vivo frequency of rifampicin-resistant mutants was 3 x 10-6. On the contrary, no resistant mutants appeared after 72 h, in vitro or in vivo, when rifampicin was employed in association with imipenem or sulbactam. After six daily passages in rifampicin-free agar plates the resistant mutants maintained the high resistance to rifampicin (≥128 mg/L).

Conclusions: These results suggest that rifampicin must not be used alone in the treatment of infections caused by multidrug-resistant A. baumannii. In these cases, rifampicin may be used in combination with imipenem or sulbactam, which prevent the development of resistance to rifampicin.

Keywords: resistant mutant; combined treatment; in vivo resistance.
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