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Antimicrobial Agents and Chemotherapy, April 2009, p. 1552-1560, Vol. 53, No. 4
0066-4804/09/$08.00+0     doi:10.1128/AAC.01264-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Azithromycin in Pseudomonas aeruginosa Biofilms: Bactericidal Activity and Selection of nfxB Mutants{triangledown}

Xavier Mulet, María D. Maciá, Ana Mena, Carlos Juan, José L. Pérez, and Antonio Oliver*

Servicio de Microbiología and Unidad de Investigación, Hospital Son Dureta, Instituto Universitario de Investigación en Ciencias de la Salud, Palma de Mallorca, Spain

Received 22 September 2008/ Accepted 24 January 2009

Azithromycin (AZM) has shown promising results in the treatment of Pseudomonas aeruginosa chronic lung infections such as those occurring in cystic fibrosis (CF) patients. We evaluated the effect of hypermutation and alginate hyperproduction on the bactericidal activity and resistance development to AZM in P. aeruginosa biofilms. Strains PAO1, its mucA mutant (PAOMA), and their respective mutS-deficient hypermutable derivatives (PAOMS and PAOMSA) were used. Biofilms were incubated with several AZM concentrations for 1, 2, 4, or 7 days, and the numbers of viable cells were determined. During the first 2 days, AZM showed bactericidal activity for all the strains, but in extended AZM incubation for strain PAOMS and especially strain PAOMSA, a marked increased in the number of viable cells was observed, particularly at 4 µg/ml. Biofilms formed by the lineages recovered from the 7-day experiments showed enhanced AZM resistance. Furthermore, most of the independent lineages studied, including those obtained from biofilms treated with AZM concentrations as low as 0.5 µg/ml, showed MexCD-OprJ hyperexpression and mutations in nfxB. The role of nfxB mutation in AZM resistance was further confirmed through the characterization of nfxB and mexD knockout mutants. Results from this work show that, although AZM exhibits bactericidal activity against P. aeruginosa biofilms, resistant mutants are readily selected and that, furthermore, they frequently show cross-resistance to other unrelated antipseudomonal agents such as ciprofloxacin or cefepime but hypersusceptibility to others such as imipenem or tobramycin. Therefore, these results should help guide the selection of appropriate antipseudomonal therapies in CF patients under AZM maintenance treatment.

* Corresponding author. Mailing address: Servicio de Microbiología and Unidad de Investigación, Hospital Son Dureta, C. Andrea Doria no. 55, 07014 Palma de Mallorca, Spain. Phone: 34 971 175 148. Fax: 34 971 175 185. E-mail: antonio.oliver{at}ssib.es

{triangledown} Published ahead of print on 2 February 2009.

Antimicrobial Agents and Chemotherapy, April 2009, p. 1552-1560, Vol. 53, No. 4
0066-4804/09/$08.00+0     doi:10.1128/AAC.01264-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Pena, C., Suarez, C., Tubau, F., Juan, C., Moya, B., Dominguez, M. A., Oliver, A., Pujol, M., Ariza, J. (2009). Nosocomial Outbreak of a Non-Cefepime-Susceptible Ceftazidime-Susceptible Pseudomonas aeruginosa Strain Overexpressing MexXY-OprM and Producing an Integron-Borne PSE-1 ss-Lactamase. J. Clin. Microbiol. 47: 2381-2387 [Abstract] [Full Text]  


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