In vitro activity of the novel des-F(6) quinolone BMS-284756 against genetically characterized clinical streptococcal isolates, including isolates with reduced quinolone susceptibility

F.-J. Schmitza,b,*, D. Milatovicb, M. Boosa, S. Mayera and A. C. Fluitb

a Institute for Medical Microbiology and Virology, Heinrich-Heine-Universität Düsseldorf, Universitätsstraße 1, Geb. 22.21, D-40225 Düsseldorf, Germany; b Eijkman-Winkler-Institute for Medical Microbiology, Utrecht, The Netherlands

Sir,

The present study was undertaken to determine the in vitro activity of four fluoroquinolones (ciprofloxacin, levofloxacin, gatifloxacin and moxifloxacin) and BMS-284756 against 860 clinical isolates from different streptococcal species, including those isolates with reduced quinolone susceptibility. BMS-284756 (T-3811) is a novel quinolone that lacks a fluorine at the C6 position.1 In addition, the study aimed to analyse the effect of reserpine, an inhibitor of multidrug efflux pumps, on the MICs of BMS-284756 in all the streptococcal isolates tested.

Isolates of Streptococcus pneumoniae (n = 593), Streptococcus mitis (n = 54), Streptococcus sanguis (n = 31), Streptococcus salivarius (n = 12), Streptococcus milleri (n = 40) and Streptococcus pyogenes (n = 130) associated with respiratory tract, skin and soft tissue or blood infections and deemed clinically significant by local criteria were referred from university hospitals in Europe and South Africa during international surveillance studies between 1997 and 2000.2–4 The isolates were identified and characterized using conventional phenotypic and genotypic methods.

The 593 pneumococcal isolates comprised six groups of characterized pneumococci: (1) those fully susceptible to penicillin, erythromycin, clindamycin, tetracycline, trimethoprim/sulfamethoxazole (co-trimoxazole) and levofloxacin (n = 100); (2) those resistant to erythromycin and clindamycin [erm(B) genotype, n = 157]; (3) those resistant to erythromycin but susceptible to clindamycin [mef(E) genotype, n = 58]; (4) those resistant to tetracycline [tet(M) genotype, n = 200]; (5) those resistant to co-trimoxazole (alterations in the dihydrofolate reductase (Ile100->Leu) as well as repetitions of one or two amino acids in the region from Arg58 to Tyr63 of the dihydropteroate synthase (n = 50); and (6) those with a reduced susceptibility to ciprofloxacin (MIC >= 4 mg/L, n = 28). The latter 28 isolates demonstrated the well known key alterations within the quinolone-resistance determining region of ParC (20 isolates Ser79->Phe, six isolates Asp83->Asn and two isolates Asp78->Asn) and GyrA (24 isolates Ser81->Phe and four isolates Ser81->Tyr).

Of the remaining streptococcal isolates, 14 of S. mitis and nine of S. sanguis displayed a reduced quinolone susceptibility with ciprofloxacin MIC >= 4 mg/L. They also displayed the key amino acid changes Ser79->Ile or Phe in ParC and Ser81->Phe or Tyr in GyrA.

Antibiotic susceptibilities were determined using a broth microdilution method as defined by the National Committee for Clinical Laboratory Standards.5 MICs of BMS-284756 were determined both in the absence and presence of reserpine (20 mg/L), as described previously.6 All experiments with reserpine were carried out three times. The results of susceptibility testing are presented as ranges and MIC50 and MIC90 values (TableGo).


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Table. MICs (mg/L) of five quinolones
 
BMS-284756 was very active against all the pneumococcal isolates displaying no reduced quinolone susceptibility with MIC50 and MIC90 values of 0.06 and 0.125 mg/L, respectively. With regard to MIC50 and MIC90 values, no significant difference was observed between the different groups of erm(B), mef(E) or tet(M) harbouring S. pneumoniae isolates or between penicillin-susceptible or co-trimoxazole-resistant isolates. Of those 28 isolates with reduced susceptibility to ciprofloxacin demonstrating combinations of alterations in GyrA and in ParC, the MIC range for ciprofloxacin as the least active compound was from 4 to 64 mg/L and for BMS-284756 as the most active compound from 0.125 to 1 mg/L. BMS-284756 was also very active against all the remaining streptococcal isolates, with MIC50 and MIC90 values of 0.06–0.125 and 0.125–0.25 mg/L, respectively. No difference was observed between the different streptococcal species, including 15 of the erythromycin-resistant S. pyogenes isolates. In streptococcal isolates with reduced ciprofloxacin susceptibility, BMS-284756 was also the most active compound, with the highest MICs being 0.125 mg/L in S. sanguis and 0.25 mg/L in S. mitis.

In previous studies,6 efflux pump activity in streptococcal isolates was inhibited by the plant alkaloid reserpine. The presence of reserpine, which by itself does not affect the growth of the isolates, resulted in a decrease in BMS-284756 MICs in none of the isolates. Thus, BMS-284756 seems not to be a substrate for efflux pump activity in streptococci, in contrast to other quinolones (e.g. ciprofloxacin).3

In summary, the rank order of activity demonstrates that the novel des-6(F) quinolone BMS-284756 was the most active agent against all isolates of the different streptococcal species tested, followed by moxifloxacin, gatifloxacin, levofloxacin and ciprofloxacin. The new quinolone also showed significant activity against the genetically characterized S. pneumoniae isolates that were not susceptible to antibiotics commonly used in anti-pneumococcal therapy (i.e. macrolides, tetracyclines and co-trimoxazole). However, despite the fact that some combinations of alterations in ParC and GyrA raised the MICs of all the quinolones, BMS-284756 remains extremely active, with highest MICs of 1.0 mg/L. Thus, the novel des-6(F) quinolone appears to be a promising new antimicrobial agent for the treatment of streptococcal infections.

Notes

* Corresponding author. Tel/Fax: +49-2132-72040; E-mail: schmitfj{at}uni-duesseldorf.de Back

References

1 . Fung-Tomc, J. C., Minassian, B., Kolek, B., Huczko, E., Aleksunes, L., Stickle, T. et al. (2000). Antibacterial spectrum of a novel des-fluoro(6) quinolone, BMS-284756. Antimicrobial Agents and Chemotherapy 44, 3351–6.[Abstract/Free Full Text]

2 . Milatovic, D., Schmitz, F. J., Brisse, S., Verhoef, J. & Fluit, A. C. (2000). In vitro activities of sitafloxacin (DU-6859a) and six other fluoroquinolones against 8796 clinical bacterial isolates. Antimicrobial Agents and Chemotherapy 44, 1102–7.[Abstract/Free Full Text]

3 . Schmitz, F. J., Fischer, A., Boos, M., Mayer, S., Milatovic, D. & Fluit, A. C. (2001). Quinolone-resistance mechanisms and in-vitro susceptibility patterns among European isolates of Streptococcus mitis, Streptococcus sanguis, and Streptococcus pneumoniae . European Journal of Clinical Microbiology and Infectious Diseases 20, 219–22.[ISI][Medline]

4 . Schmitz, F. J., Verhoef, J. & Fluit, A. C. (1999). Comparative activities of six different fluoroquinolones against 9,682 clinical bacterial isolates from 20 European university hospitals participating in the European SENTRY surveillance program. International Journal of Antimicrobial Chemotherapy 12, 311–7.

5 . National Committee for Clinical Laboratory Standards. (2000). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically—Fifth Edition: Approved Standard M7-A5. NCCLS, Villanova, PA.

6 . Boos, M., Mayer, S., Fischer, A., Köhrer, K., Scheuring, S., Heisig, P. et al. (2001). In-vitro development of resistance to six quinolones in Streptococcus pneumoniae, Streptococcus pyogenes, and Staphylococcus aureus. Antimicrobial Agents and Chemotherapy 45, 938–42.[Abstract/Free Full Text]





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