Department of Medical Microbiology, Faculties of 1 Medicine and 3 Pharmacy, University of Manitoba, Manitoba; Departments of 2 Clinical Microbiology and 4 Medicine, Health Sciences Centre, Winnipeg, Manitoba, Canada
Keywords: dual activity, fluoroquinolones
Sir,
The letter by Fisher & Heaton1 discusses many important considerations in the study of dual activity in fluoroquinolones, i.e. that enzymic and genetic studies evaluate different components in the activity of fluoroquinolones and that only proper understanding and use of fluoroquinolones will limit the emergence of clinical resistance. As Fisher & Heaton1 emphasize and as we clearly state in Dual activity of fluoroquinolones against Streptococcus pneumoniae: the facts behind the claims,2 enzymic studies only evaluate the binding affinities of fluoroquinolones to either DNA gyrase or topoisomerase IV. These studies are unable to evaluate intracellular accumulation and conditions, efflux and the events leading to lethality following drugenzyme binding;36 however, the differential strength of binding of the quinolones to their target enzymes is important for understanding the scientific basis underlying quinolones antibacterial action.
We agree that the genetic studies are very important for identifying dual-active fluoroquinolones. Fisher & Heaton1 suggest that with clinafloxacin, gatifloxacin, gemifloxacin and moxifloxacin there is no increase in MIC observed with S. pneumoniae isolates that have either a parC or gyrA mutation alone. We have created laboratory mutants of S. pneumoniae resistant to ciprofloxacin, gatifloxacin, gemifloxacin, levofloxacin and moxifloxacin. In order to have generated the mutants resistant to gatifloxacin, gemifloxacin and moxifloxacin, Fisher & Heaton1 suggest that the mutants must have mutations in both gyrA and parC. In fact, we observed mutations in gyrA alone for the gatifloxacin and moxifloxacin high-level resistant mutants and parC alone for those created resistant to gemifloxacin (H. J. Smith, M. Walters, D. J. Hoban and G. G. Zhanel, unpublished results).
The most important method for evaluating resistance mutations is to observe how they occur in the clinical setting. In clinical isolates, the MICs of all fluoroquinolones are low in the absence of mutations in gyrA and parC.7,8 All fluoroquinolones display increased MICs in the presence of a parC mutation.7,8 A spread of MICs is observed for gatifloxacin, levofloxacin and moxifloxacin when isolates have mutations in parC.7 Therefore, parC mutations do increase the MICs of gatifloxacin and moxifloxacin in some strains.7,8 The presence of a gyrA mutation, without a parC mutation, in clinical isolates results in dramatic MIC increases of gatifloxacin, levofloxacin and moxifloxacin.7 These data demonstrate that organisms do become less susceptible with a mutation in either parC or gyrA and not solely in the presence of mutations in both parC and gyrA. Thus, these fluoroquinolones are not dual-active.4 We do, however, agree that once mutations occur in both enzymes, one must assume that the organisms will be highly resistant to all fluoroquinolones and may result in bacteriological failure.9
Based on genetic studies and clinical isolates studied in our laboratory and others, we believe that our statement that clinically available, safe and effective dual-activity fluoroquinolones have yet to be created remains correct. Indeed, limiting the emergence of clinical resistance will result from a proper understanding of fluoroquinolone activity and appropriate use of fluoroquinolones in the clinical setting.
Footnotes
* Correspondence address. Clinical Microbiology, Health Sciences Centre, MS673-820 Sherbrook Street, Winnipeg, Manitoba, Canada R3A 1R9. Tel: +1-204-787-4684; Fax: +1-204-787-4699; E-mail: smithhj14{at}hotmail.com
References
1
.
Fisher, L. M. & Heaton, V. J. (2003). Dual activity of fluoroquinolones against Streptococcus pneumoniae. Journal of Antimicrobial Chemotherapy 51, 4634.
2
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Smith, H. J., Nichol, K. A., Hoban, D. J. & Zhanel, G. G. (2002). Dual activity of fluoroquinolones against Streptococcus pneumoniae: the facts behind the claims. Journal of Antimicrobial Chemotherapy 49, 8935.
3 . Bush, K. & Goldschmidt, R. (2000). Effectiveness of fluoroquinolones against Gram-positive bacteria. Current Opinion in Investigational Drugs 1, 2230.[Medline]
4
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Heaton, V. J., Ambler, J. E. & Fisher, L. M. (2000). Potent anti-pneumococcal activity of gemifloxacin is associated with dual targeting of gyrase and topoisomerase IV, an in vivo target preference for gyrase, and enhanced stabilization of cleavable complexes in vitro. Antimicrobial Agents and Chemotherapy 44, 31127.
5
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Morrisey, I. & George, J. T. (2000). Purification of pneumococcal type II topoisomerases and inhibition by gemifloxacin and other quinolones. Journal of Antimicrobial Chemotherapy 45, Suppl. S1, 1016.
6
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Pan, X. & Fisher, L. M. (1999). Streptococcus pneumoniae DNA gyrase and topoisomerase IV: overexpression, purification, and differential inhibition by fluoroquinolones. Antimicrobial Agents and Chemotherapy 43, 112936.
7
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Brueggemann, A. B., Coffman, S. L., Rhomberg, P., Huynh, H., Almer, L., Nilius, A. et al. (2002). Fluoroquinolone resistance in Streptococcus pneumoniae in United States since 19941995. Antimicrobial Agents and Chemotherapy 46, 6808.
8 . Zhanel, G. G., Walkty, A., Nichol, K., Smith, H., Noreddin, A. & Hoban, D. J. (2002). Molecular characterization of fluoroquinolone resistant Streptococcus pneumoniae clinical isolates obtained from across Canada. Diagnostic Microbiology and Infectious Disease, in press.
9
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Davidson, R., Cavalcanti, R., Brunton, J. L., Bast, D. J., deAzavedo, J. C. S., Kisbey, P. et al. (2002). Resistance to levofloxacin and failure of treatment of pneumococcal pneumonia. New England Journal of Medicine 346, 74750.