JAC Advance Access originally published online on July 15, 2003
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Journal of Antimicrobial Chemotherapy (2003) 52, 313-314
© 2003 The British Society for Antimicrobial Chemotherapy
Correspondence |
Reply
1 Health Sciences Centre, Clinical Microbiology, Winnipeg, Manitoba; 2 University of Manitoba, Medical Microbiology, Winnipeg, Manitoba; 3 Health Sciences Centre, Medicine, Winnipeg, Manitoba, Canada
Keywords: Streptococcus pneumoniae, DNA gyrase, topoisomerase IV, dual activity, fluoroquinolone
Sir,
The continued correspondence with Fisher et al.1–3 regarding our recent review of the dual activity of fluoroquinolones4 highlights controversial and important aspects of this topic. The serious issue of increasing worldwide antibiotic resistance has generated significant interest in dual-active fluoroquinolones. Dual-active fluoroquinolones demonstrate comparable activity in both cellular targets: DNA gyrase and topoisomerase IV.5 As we have previously stated,4 and Fisher et al.1,3 have reiterated, a fluoroquinolone demonstrates dual activity if a single mutation in gyrA or parC has a minimal (two-fold) effect on the MIC, and that it requires mutations in both gyrA and parC to generate substantially increased MICs (
4-fold). Based on this definition, clinafloxacin can be considered a dual-active fluoroquinolone.6
Conversely, we do not believe that the current data on gatifloxacin, gemifloxacin and moxifloxacin indicate that these agents are dual-active fluoroquinolones. The basis of this belief is results from clinical strains7,8 and our current work-in-progress laboratory strains. Fisher et al.1,3 state that results based on clinical and laboratory strains are problematic, and only well-defined isogenic laboratory strains should be used for dual-activity studies. Ideally, all research would be carried out with well-defined laboratory strains. However, results can only be applied in the context in which they were created and should not be extrapolated beyond those limitations. It is thus essential to evaluate the activity of fluoroquinolones on clinical isolates, as those are the results which are truly indicative of the situation in which the fluoroquinolones are to be employed.
Fisher et al.1,3 indicate that the crucial issue surrounding the dual activity of fluoroquinolones is whether parC or gyrA mutations will have little effect on the MIC, or whether mutants are recovered only at, or near, the MIC at low frequency. Based on these ideas, our laboratory mutants demonstrate that gatifloxacin, gemifloxacin and moxifloxacin are not dual active.9 Significant strain variability is apparent, and has resulted in the intermittent recovery of mutants at significantly increased MICs (8–16-fold).9 These mutants appeared at frequencies of 10–5 and 10–6.9 Sequencing of quinolone-resistance determining regions (QRDRs) of parC and gyrA was carried out subsequently with these mutants. The mutants that were recovered with high frequency at fluoroquinolone concentrations significantly elevated from their initial MIC had only single mutations in parC or gyrA.9 Thus, mutations in both parC and gyrA are not required to develop an elevated MIC.
In response to the second disagreement of Fisher et al.,1,3 as the clinical isolates were collected from the clinical environment in which fluoroquinolones are used, we feel data based on these isolates are highly significant and persuasive. In addition to sequencing the QRDRs of parC and gyrA, the clinical isolates on which we based our conclusions that parC mutations increase the MICs of gatifloxacin and moxifloxacin and that single gyrA mutations dramatically increase the MIC were also serotyped, genotyped and evaluated for efflux mechanisms.8 These are well-characterized clinical isolates. It is imperative that dual-active fluoroquinolones be evaluated with clinical isolates in order minimize treatment failures. If a single parC mutation had little effect on the MIC of dual-active fluoroquinolones then these agents could be used to treat infecting organisms with a single mutation. This is not the case, and no fluoroquinolone should be used for an S. pneumoniae infection with a known parC mutation.10 It is vital that prescribing physicians are not misled into believing that supposed dual-active fluoroquinolones can be used to treat intermediate- or low-level resistant organisms containing a single mutation.10 Davidson et al.11 recently published a report on fluoroquinolone treatment failure that resulted from the administration of levofloxacin for the treatment of an organism with a parC mutation. There are no data to suggest that gatifloxacin or moxifloxacin would have resulted in bacteriological cures in this case. To infer that they would be bacteriologically effective is misleading, and microbiologically and clinically unproven.
We agree that well-defined laboratory strains are essential in the evaluation of quinolone action and activity. However, it is essential that dual activity be studied in the clinical setting in order to find out how the fluoroquinolone will function in a true treatment situation.
Footnotes
* Corresponding author. Tel: +1-204-787-4684; Fax: +1-204-787-4699: E-mail: smithhj14{at}hotmail.com 
References
1
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Fisher, L. M. & Heaton, V. J. (2003). Dual activity of fluoroquinolones against Streptococcus pneumoniae. Journal of Antimicrobial Chemotherapy 51, 463–4.
2
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Smith, H. J., Nichol, K. A., Hoban, D. J. et al. (2003). Dual activity of fluoroquinolones against Streptococcus pneumoniae: Reply. Journal of Antimicrobial Chemotherapy 51, 464–5.
3 . Fisher, L. M., Gould, K. A., Pan, X.-S. et al. (2003). Analysis of dual active fluoroquinolones in Streptococcus pneumoniae. Journal of Antimicrobial Chemotherapy 52, DOI: 10.1093/jac/dkg329.
4
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Smith, H. J., Nichol, K. A., Hoban, D. J. et al. (2002). Dual activity of fluoroquinolones against Streptococcus pneumoniae: the facts behind the claims. Journal of Antimicrobial Chemotherapy 49, 893–5.
5
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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, and in vivo target preference for gyrase, and enhanced stabilization of cleavable complexes in vitro. Antimicrobial Agents and Chemotherapy 44, 3112–7.
6
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Pan, X.-S. & Fisher, L. M. (1998). DNA gyrase and topoisomerase IV are dual targets of clinafloxacin action in Streptococcus pneumoniae. Antimicrobial Agents and Chemotherapy 42, 2810–6.
7
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Brueggemann, A. B., Coffman, S. L., Rhomberg, P. et al. (2002). Fluoroquinolone resistance in Streptococcus pneumoniae in United States since 1994–1995. Antimicrobial Agents and Chemotherapy 46, 680–8.
8 . Zhanel, G. G., Walkty, A., Nichol, K. et al. (2003). Molecular characterization of fluoroquinolone resistant Streptococcus pneumoniae clinical isolates obtained from across Canada. Diagnostic Microbiology and Infectious Disease 45, 63–7.[CrossRef][Web of Science][Medline]
9 . Smith, H. J., Nichol, K. A., Walkty, A. et al. (2002). Different contribution of efflux to fluoroquinolone resistance in clinical isolates and laboratory-created mutants of Streptococcus pneumoniae. In Programs and Abstracts of the Hundred and Second American Society for Microbiology General Meeting, Salt Lake City, UT, 2002. Abstract A-18, p.43. American Society for Microbiology, Washington, DC, USA.
10 . Zhanel, G. G., Hoban D. J. & Chan C. K. (2002). Resistance to levofloxacin and failure of treatment of pneumococcal pneumonia. New England Journal of Medicine 347, 66.
11
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Davidson, R., Cavalcanti, R., Brunton J. L. et al. (2002). Resistance to levofloxacin and failure of treatment of pneumococcal pneumonia. New England Journal of Medicine 346, 747–50.
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