Journal of Antimicrobial Chemotherapy (2002) 49, 697-698
© 2002 The British Society for Antimicrobial Chemotherapy
Correspondence |
Effect of an efflux pump inhibitor on the MIC of nalidixic acid for Acinetobacter baumannii and Stenotrophomonas maltophilia clinical isolates
Servei de Microbiologia. Institut Clinic d'Infeccions i Immunologia, Hospital Clínic, IDIBAPS, Facultat de Medicina, Universitat de Barcelona, Villarroel 170, 08036 Barcelona, Spain
Sir,
Both Acinetobacter baumannii and Stenotrophomonas maltophilia are opportunistic nosocomial pathogens found mostly in intensive care units.1 These microorganisms are known to be resistant to many commonly used antimicrobial agents including the quinolones. Thus, MICs of ciprofloxacin ranging from 4 to 256 mg/L are found among many of the clinical isolates of both microorganisms2 (J. Vila, A. Ribera, F. Marco, J. Ruiz, J. Mensa, J. Chaves, G. Hernandez & M. T. Jimenez de Anta, unpublished results).
The main mechanisms of resistance to these antimicrobial agents are mutations in the quinolone target genes or a decrease in quinolone accumulation due either to changes in permeability of the outer membrane or to overexpression of an efflux system(s).3 Contrary to what has been described in Enterobacteriaceae, the lowest MICs of most quinolones for the susceptible strains of the non-fermentative bacteria without mutations in the gyrA or parC genes, range from 0.125 to 1 mg/L, compared with 0.006–0.01 mg/L in Enterobacteriaceae.3 This suggests the possibility that this difference in the basal level of quinolone resistance between the two types of bacteria may be due to a decrease in quinolone accumulation. In fact, some studies have recently demonstrated the involvement of efflux mechanisms in acquiring multidrug resistance in S. maltophilia.2,4 Moreover, other studies suggest the presence of efflux systems in A. baumannii (J. Vila, A. Ribera, F. Marco, J. Ruiz, J. Mensa, J. Chaves, G. Hernandez & M. T. Jimenez de Anta, unpublished results).
In this study, the MICs of nalidixic acid and ciprofloxacin were analysed in the presence and absence of an efflux pump inhibitor (MC 207,110) in 22 clinical isolates of A. baumannii and 17 epidemiologically unrelated clinical isolates of S. maltophilia. This inhibitor is reported to inhibit Mex-type pumps in Pseudomonas aeruginosa,5 and AcrAB in Escherichia coli.6
Briefly, the MICs of ciprofloxacin (Bayer, Leverkusen, Germany) and nalidixic acid (Sigma, St Louis, MO, USA) were determined by using broth microdilution tests, in either the presence or absence of MC 207,110 (purchased from Sigma as Phe-Arg-ß-naphthylamide) at a concentration of 20 mg/L, in accordance with the guidelines established by the NCCLS.7 The breakpoints used for ciprofloxacin and nalidixic acid were also those proposed by the NCCLS.
The results show that this inhibitor only affects the MIC of nalidixic acid, while the MIC of ciprofloxacin did not change. In 45% of the A. baumannii clinical isolates the MIC of nalidixic acid decreased at least eight-fold in the presence of this compound, while the MIC decreased in only 18% of the S. maltophilia clinical isolates (Table
).
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The results obtained show that this efflux pump inhibitor affects A. baumannii such that the only MIC changes observed were those of nalidixic acid. The prevalence of strains of S. maltophilia in which the MIC of nalidixic acid was affected by this inhibitor was very low in comparison with A. baumannii. As well as these two quinolones, we tested the MIC of norfloxacin for some strains of the two species, in the presence and the absence of MC 207,110, and did not find any change in the MIC of this fluoroquinolone for any of the strains tested. These results indicate that A. baumannii possesses an efflux pump that is inhibited by MC 207,110 and able to pump nalidixic acid out of the cell, whereas only a few strains of S. maltophilia seem to have this resistance mechanism.
To support this idea we have to take into account previous results obtained with another efflux pump inhibitor, reserpine, tested in both microorganisms2 (J. Vila, A. Ribera, F. Marco, J. Ruiz, J. Mensa, J. Chaves, G. Hernandez & M. T. Jimenez de Anta, unpublished results). In contrast to MC 207,110, we found that reserpine decreased the MIC not only of nalidixic acid, but also of some other quinolones such as ciprofloxacin and norfloxacin. Moreover, the strains affected by reserpine were not affected by MC 207,110, with the exception of one strain, 167 (R). This suggests the possibility that the two inhibitors act on different efflux pumps.
It is known that efflux-mediated resistance is widespread in clinical settings. In order to avoid this resistance, compounds that eliminate the effect of efflux pumps need to be developed to provide alternative therapies.
Notes
* Corresponding author. Tel: +34-93-2275522; Fax: +34-93-2275454; E-mail: vila{at}medicina.ub.es 
References
1 . Gales, A. C., Jones, R. N., Forward, K. R., Liñares, J., Sader, H. S. & Verhoef, J. (2001). Emerging importance of multidrug-resistant Acinetobacter species and Stenotrophomonas maltophilia as pathogens in seriously ill patients: geographic patterns, epidemiological features, and trends in the SENTRY antimicrobial surveillance program (1997–1999). Clinical Infectious Diseases 32, Suppl., 104–13.
2 . Ribera, A., Jurado, A., Ruiz, J., Marco, F., Valle, O., Mensa, J. et al. (2002). In vitro activity of clinafloxacin with other quinolones against Stenotrophomonas maltophilia clinical isolates in the presence and absence of reserpine. Diagnostic Microbiology and Infectious Disease, in press.
3 . Vila, J., Ruiz, J. & Navia, M. (1999). Molecular bases of quinolone resistance acquisition in gram-negative bacteria. Recent Research Development of Antimicrobial Agents and Chemotherapy 3, 323–44.
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Alonso, A. & Martinez, J. L. (2000). Cloning and characterization of SmeDEF, a novel multidrug efflux pump from Stenotrophomonas maltophilia. Antimicrobial Agents and Chemotherapy 44, 3079–86.
5 . Renau, T. E., Leger, R., Flamme, E. M., Sangalang, J., She, M. W., Yen, R. et al. (1999). Inhibitors of efflux pumps in Pseudomonas aeruginosa potentiate the activity of the fluoroquinolone antibacterial levofloxacin. Journal of Medical Chemistry 42, 4928–31.
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Mazzariol, A., Tokue, Y., Kanegawa, T. M., Cornaglia, G. & Nikaido, H. (2000). High-level fluoroquinolone-resistant clinical isolates of Escherichia coli overproduce multidrug efflux protein AcrA. Antimicrobial Agents and Chemotherapy 44, 3441–3.
7 . National Committee for Clinical Laboratory Standards. (2000). Methods for Dilution Antimicrobial Susceptibility Tests for Bacterial that Grow Aerobically: Approved Standard M7-A5. NCCLS, Wayne, PA.
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