This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Schmitz, F.-J. Articles by Fluit, A. C. Search for Related Content PubMed PubMed Citation Articles by Schmitz, F.-J. Articles by Fluit, A. C.

 Previous Article  |  Next Article 

Antimicrobial Agents and Chemotherapy, September 2001, p. 2666-2667, Vol. 45, No. 9
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.9.2666-2667.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

LETTERS TO THE EDITOR

Propensity of Fluoroquinolones with Different Moieties at Position 8 to Cause Resistance Development in Clinical Isolates of Streptococcus pneumoniae

	LETTER

In a recent study, we exposed Streptococcus pneumoniae isolates to subinhibitory concentrations of six fluoroquinolones (FQs) (1). This subculturing led to resistance development. None of the FQs, however, was associated with a clearly lower potential to cause resistance development, measured as an increase in MIC-doubling dilutions. However, based on the limited data available, i.e., six isolates, further studies were needed to clarify whether resistance development is strain dependent or dichotomous due to differences in the FQ composition.

Thus, we repeatedly exposed 70 clinical S. pneumoniae strains for 6 days to ciprofloxacin (CIP), gatifloxacin (GAT), gemifloxacin (GEM), levofloxacin (LEV), and moxifloxacin (MOX) (1). Mean MICs (in micrograms per milliliter) for the original isolates were as follows: GEM, 0.017; MOX, 0.091; GAT, 0.175; LEV, 0.707; CIP, 0.788.

In order to analyze the rate of resistance development, we converted the MICs for all clinical strains and selected mutant isolates to a log scale (base 2). Initial values at time zero (original MICs) were subtracted from MICs on days 1 through 6. The slope of the MIC increase over the 6-day period was computed by linear regression and compared by analysis of variance with the Student-Newman-Keuls posthoc test; differences were considered statistically significant if P was <0.05. Judging from the squared correlation coefficients R² (means ± standard errors: CIP, 0.916 ± 0.007; GAT, 0.754 ± 0.018; GEM, 0.926 ± 0.008; LEV, 0.899 ± 0.009; MOX, 0.755 ± 0.019), the linearity of the individual lines was good, meaning that the regression coefficients were a reasonable measure of the resistance development rate. The relatively low R² values of GAT and MOX reflect low slope values rather than lack of linearity.

Nearly identical lines were found for CIP and GEM, both reaching rather high log₂ MIC increases after 6 days (4.6 ± 0.14 and 4.3 ± 0.15 µg/ml), while much lower increases were measured for LEV (2.99 ± 0.14 µg/ml), MOX (2.20 ± 0.11 µg/ml), and GAT (2.16 ± 0.11 µg/ml). The rates of resistance development are statistically different between the drugs tested (Fig. 1). These differences, measured on the log scale, correspond to x-fold increases in the initial MICs per day: GAT, 1.30-fold; MOX, 1.30-fold; LEV, 1.52-fold; GEM, 1.68-fold; CIP, 1.78-fold. Thus, GAT and MOX, the two FQs with a methoxy moiety at the C-8 position, displayed the lowest propensity for causing resistance development.

View larger version (31K): [in this window] [in a new window]   FIG. 1.   The rate of resistance development as measured by the slopes of individual time-dependent increases in MICs of five FQs. The data are means with standard errors (n = 70 strains). GAT exhibits the lowest MIC increase, with a mean rate of <0.4 log2 units per day (corresponding to a 1.30-fold increase per day), while CIP shows the highest mean slope, with >0.8 log2 units per day (corresponding to a 1.78-fold increase per day).

Our data are supported by reports from the laboratory of Drlica and coworkers, who showed that GAT was less affected by changes in either DNA gyrase or topoisomerase IV (2, 5-8). Similar results were reported by A. Dalhoff for MOX (8th Int. Cong. Infect. Dis., poster 47.003, 1998; 37th Annu. Meet. Infect. Dis. Soc. Am., poster 102, 1999; 1st Int. Symp. Resist. Gram-Positive Infect., 2000). Data reported by other authors demonstrate that the molecular entity selected for the C-8 position of an FQ can enhance the drug's antibacterial activity (3, 4). In summary, the clinical relevance of a potentially lower propensity of an FQ with the C-8-methoxy moiety to develop resistance should be analyzed in animal studies as well as in surveillance studies to investigate FQ MIC increases for S. pneumoniae in combination with the use of different FQs.

	FOOTNOTES

^* Phone and fax: 49-2132-72040

E-mail: schmitfj{at}uni-duesseldorf.de

	REFERENCES

1.	Boos, M., S. Mayer, A. Fischer, K. Köhrer, S. Scheuring, P. Heisig, J. Verhoef, A. C. Fluit, and F.-J. Schmitz. 2001. In-vitro development of resistance to six quinolones in Streptococcus pneumoniae, Streptococcus pyogenes, and Staphylococcus aureus. Antimicrob. Agents Chemother. 45:938-942[Abstract/Free Full Text].
2.	Dong, Y., C. Xu, X. Zhao, J. Domagala, and K. Drlica. 1998. Fluoroquinolone action against mycobacteria: effects of C-8 substituents on growth, survival, and resistance. Antimicrob. Agents Chemother. 42:2978-2984[Abstract/Free Full Text].
3.	Ito, T., M. Matsumoto, and T. Nishino. 1995. Improved bactericidal activity of Q-35 against quinolone-resistant staphylococci. Antimicrob. Agents Chemother. 39:1522-1525[Abstract].
4.	Kitamura, A., K. Hoshino, Y. Kimura, I. Hayakawa, and K. Sato. 1995. Contribution of the C-8 substituent of DU-6859a, a new potent fluoroquinolone, to its activity against DNA gyrase mutants of Pseudomonas aeruginosa. Antimicrob. Agents Chemother. 39:1467-1471[Abstract].
5.	Lu, T., X. Zhao, and K. Drlica. 1999. Gatifloxacin activity against quinolone-resistant gyrase: allele-specific enhancement of bacteriostatic and bactericidal activities by the C-8-methoxy group. Antimicrob. Agents Chemother. 43:2969-2974[Abstract/Free Full Text].
6.	Zhao, B. Y., R. Pine, J. Domagala, and K. Drlica. 1999. Fluoroquinolone action against clinical isolates of Mycobacterium tuberculosis: effects of a C-8 methoxyl group on survival in liquid media and in human macrophages. Antimicrob. Agents Chemother. 43:661-666[Abstract/Free Full Text].
7.	Zhao, X., J. Y. Wang, C. Xu, Y. Dong, J. Zhou, J. Domagala, and K. Drlica. 1998. Killing of Staphylococcus aureus by C-8-methoxy fluoroquinolones. Antimicrob. Agents Chemother. 42:956-958[Abstract/Free Full Text].
8.	Zhao, X., C. Xu, J. Domagala, and K. Drlica. 1997. DNA topoisomerase targets of the fluoroquinolones: a strategy for avoiding bacterial resistance. Proc. Natl. Acad. Sci. USA 94:13991-13996[Abstract/Free Full Text].

					F.-J. Schmitz* Mechthild Boos Susanne Mayer Institute for Medical Microbiology and Virology Heinrich-Heine-Universität Düsseldorf Universitatsstrasse 1, Geb. 22.21 D-40225 Düsseldorf, Germany
					Dieter Hafner Harold Jagusch Institute for Pharmacology and Clinical Pharmacology Heinrich-Heine-Universität Düsseldorf Düsseldorf, Germany
					Jan Verhoef Ad C. Fluit University Medical Center Utrecht Utrecht, The Netherlands

This article has been cited by other articles:

• Croisier, D., Etienne, M., Bergoin, E., Charles, P.-E., Lequeu, C., Piroth, L., Portier, H., Chavanet, P. (2004). Mutant Selection Window in Levofloxacin and Moxifloxacin Treatments of Experimental Pneumococcal Pneumonia in a Rabbit Model of Human Therapy. Antimicrob. Agents Chemother. 48: 1699-1707 [Abstract] [Full Text]  
• Jonas, D., Engels, I., Hartung, D., Beyersmann, J., Frank, U., Daschner, F. D. (2003). Development and mechanism of fluoroquinolone resistance in Legionella pneumophila. J Antimicrob Chemother 51: 275-280 [Abstract] [Full Text]  
• Hansen, G. T., Metzler, K., Drlica, K., Blondeau, J. M. (2003). Mutant Prevention Concentration of Gemifloxacin for Clinical Isolates of Streptococcus pneumoniae. Antimicrob. Agents Chemother. 47: 440-441 [Full Text]  

This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Schmitz, F.-J. Articles by Fluit, A. C. Search for Related Content PubMed PubMed Citation Articles by Schmitz, F.-J. Articles by Fluit, A. C.