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Antimicrobial Agents and Chemotherapy, March 2001, p. 938-942, Vol. 45, No. 3
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.3.938-942.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

In Vitro Development of Resistance to Six Quinolones in Streptococcus pneumoniae, Streptococcus pyogenes, and Staphylococcus aureus

Mechthild Boos,1 Susanne Mayer,1 Ansgar Fischer,1 Karl Köhrer,1 Sibylle Scheuring,1 Peter Heisig,2 Jan Verhoef,3 Ad C. Fluit,3 and F.-J. Schmitz1,3,*

Institute for Medical Microbiology and Virology, Heinrich-Heine Universität Düsseldorf, Düsseldorf,1 and Institute of Pharmaceutical Microbiology, University of Bonn, Bonn,2 Germany, and Eijkman-Winkler Institute for Medical Microbiology, University Medical Center Utrecht, Utrecht, The Netherlands3

Received 24 July 2000/Returned for modification 11 September 2000/Accepted 27 November 2000


    ABSTRACT
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Streptococcus pneumoniae, Streptococcus pyogenes, and Staphylococcus aureus isolates were exposed to subinhibitory MICs of ciprofloxacin, sparfloxacin, gatifloxacin, moxifloxacin, clinafloxacin, and gemifloxacin during a 10-day period. Subculturing led to resistance development, regardless of the initial potencies of the quinolones. None of the quinolones was associated with a significantly slower rate of resistance development.


    TEXT
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Fluoroquinolone resistance in gram-positive cocci is related to mutations in the DNA gyrase and topoisomerase IV genes (8-12, 16, 23) and the active efflux of agents (1, 3, 13, 21-25, 31, 44). Because fluoroquinolones differ in both their target affinity (8, 16, 33-36, 39) and their activation of efflux pumps (7, 13, 21, 22, 24, 25, 31, 42), one can speculate that the phenotypic expression of quinolone resistance will also differ. Studies have shown that fluoroquinolone resistance can be selected for in pneumococci and staphylococci (5, 6, 37).

In order to analyze the ability of newer fluoroquinolones to cause resistance development in Streptococcus pneumoniae, Streptococcus pyogenes, and Staphylococcus aureus, we repeatedly exposed six clinical strains of each species to ciprofloxacin, sparfloxacin, gatifloxacin, moxifloxacin, clinafloxacin, and gemifloxacin.

Approximately 5 × 107 CFU of each of the 18 strains was added to tubes containing 9.9 ml of appropriate broth containing antibiotic concentrations ranging from 3 doubling dilutions above to 3 doubling dilutions below the MIC of each of the six agents. The tubes were then incubated for 24 h at 37°C. Aliquots from the test tubes containing the highest drug concentration that permitted visible growth were used following a 1:100 dilution to inoculate a second set of serial drug dilutions. After overnight incubation, the bacteria were transferred again. Finally, after 10 serial transfers, the bacteria for which the MICs were the highest were collected, stored, and also subcultured on quinolone-free agar for 10 days to assess the stability of resistance.

MICs were determined by the microdilution methodology according to NCCLS guidelines (29, 30). Ciprofloxacin MIC determinations were conducted in the presence and absence of reserpine (20 µg/ml; tests were repeated three times) for all of the original isolates (n = 18) as well as for all of the selected mutants (n = 108) (7).

S. pneumoniae and S. aureus isolates were analyzed before and after transfers for mutations in the quinolone-resistance determining regions (QRDRs) of parC or grlA and gyrA, respectively (19, 40, 41).

The MIC results from subculturing as well as the mutations in the QRDRs of S. pneumoniae and S. aureus are summarized in the Tables 1 to 3. Subculturing with newer quinolones led to resistance development in all three species. This is in line with previous reports with regard to cephalosporins, macrolides, and older quinolones in pneumococci (5, 6, 37).

                              
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  		TABLE 1.   Resistance selection results for S. pneumoniaea


                              
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  		TABLE 2.   Resistance selection results for S. pyogenesa


                              
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  		TABLE 3.   Resistance selection for S. aureusa

Resistance was stable in all cases; i.e., the MICs for the 108 selected mutants remained within 1 doubling dilution after 10 transfers on quinolone-free agar. Similar results were reported by Davies et al. (5) for S. pneumoniae.

Gemifloxacin and clinafloxacin exhibited the best in vitro activities against all original isolates, followed by moxifloxacin and gatifloxacin. Ciprofloxacin showed the lowest in vitro activities (Tables 1 to 3). On the basis of a breakpoint of <= 1 µg/ml, 88 of the 108 selected mutants were inhibited by clinafloxacin, 65 were inhibited by gemifloxacin, 46 were inhibited by moxifloxacin, 32 were inhibited by gatifloxacin, 20 were inhibited by sparfloxacin, and 3 were inhibited by ciprofloxacin. This rank order of activity is in parallel with previous findings (2, 4, 7, 19, 20, 26).

On the basis of the results presented in Tables 1 to 3, none of the quinolones was associated with a clearly lower potential for resistance development, measured as an increase in MIC doubling dilutions, compared with the potential for resistance development of the other quinolones tested. On the basis of the limited available data, one must be cautious in drawing broad conclusions. Further studies will be needed to clarify whether resistance development is strain dependent or dichotomous, especially for the 8-methoxyfluoroquinolones (gatifloxacin, moxifloxacin) compared with the other compounds.

For five of the six original S. pneumoniae strains tested, ciprofloxacin MICs were 1 to 3 doubling dilutions lower in the presence of reserpine. After 10 serial passages in ciprofloxacin-containing medium, the ciprofloxacin MICs for the same five of the six S. pneumoniae mutants were again 1 to 3 doubling dilutions lower in the presence of reserpine than in its absence. The MICs for five of six of the mutants selected with moxifloxacin or clinafloxacin were 1 to 2 doubling dilutions lower, the MICs for five of six of the mutants selected with sparfloxacin or gatifloxacin were 1 to 3 doubling dilutions lower, and finally, the MICs for five of six of the mutants selected with gemifloxacin were 2 to 4 doubling dilutions lower.

Ciprofloxacin MICs for none of the six original S. pyogenes strains tested were lower in the presence of reserpine. After 10 serial passages, the ciprofloxacin MICs for only one mutant selected with gemifloxacin were decreased by 3 doubling dilutions.

Ciprofloxacin MICs for none of the six original S. aureus strains tested were lower in the presence of reserpine. After 10 serial passages, ciprofloxacin MICs for six of six mutants selected with ciprofloxacin were 2 to 3 doubling dilutions lower in the presence of reserpine, MICs for four of six mutants selected with sparfloxacin or gatifloxacin were 1 doubling dilution lower, MICs for three of six mutants selected with clinafloxacin were 2 doubling dilutions lower, and, finally, MICs for six of six mutants selected with gemifloxacin were 2 to 4 doubling dilutions lower.

These results illustrate the importance of efflux as an additional factor for the development of quinolone resistance in S. aureus, followed by S. pneumoniae, while efflux seems not to play a significant role in the process of quinolone resistance development in S. pyogenes. Furthermore, our data indicate that some of the newer fluoroquinolones, especially gemifloxacin, selected mutants which had reserpine-sensitive phenotypes for ciprofloxacin resistance. This phenomenon must be kept in mind during therapy with newer quinolones.

Mainly classical alterations in ParC (a Ser-79right-arrowPhe or Tyr or Asp-83right-arrowAsp) and GyrA (a Ser-81right-arrowPhe or Tyr) contributed to the resistance seen in most S. pneumoniae mutants (Table 1). These results confirm those from previous investigations (12, 15, 17, 19, 20, 27, 32, 38, 43).

In addition, mainly classical alterations in GrlA (a Ser-80right-arrowPhe or Tyr, a Glu-84right-arrowLys) and GyrA (a Ser-84right-arrowLeu or Lys and a Glu-88right-arrowLys or Val) contributed to the resistance in most S. aureus mutants (Table 3). These results are in line with previous observations (14, 18, 28, 40, 41).

In summary, sequential subculture in the presence of subinhibitory concentrations of newer fluoroquinolones led to resistance development in S. pneumoniae, S. pyogenes, and S. aureus. None of the quinolones tested was associated with a clearly lower potential of resistance development.


    FOOTNOTES

* Corresponding author. Mailing address: Institute for Medical Microbiology and Virology, Heinrich-Heine-Universität Düsseldorf, Universitätsstraße 1, Geb. 22.21, 40225 Düsseldorf, Germany. Phone and fax: 0049-2132-72040. E-mail: schmitfj{at}uni-duesseldorf.de.


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Antimicrobial Agents and Chemotherapy, March 2001, p. 938-942, Vol. 45, No. 3
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.3.938-942.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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