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Antimicrobial Agents and Chemotherapy, November 2003, p. 3542-3547, Vol. 47, No. 11
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.11.3542-3547.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

In Vitro Activities of Garenoxacin (BMS-284756) against Streptococcus pneumoniae, Viridans Group Streptococci, and Enterococcus faecalis Compared to Those of Six Other Quinolones

Patrick Grohs,¹ Serge Houssaye,¹ Agnès Aubert,¹ Laurent Gutmann,^2,3 and Emmanuelle Varon^2,3*

Service de Microbiologie, Hôpital Européen Georges Pompidou,¹ C.N.R. des Pneumocoques, Hôpital Européen Georges Pompidou, 75908 Paris Cedex 15,² L.R.M.A., INSERM E0004 Université Paris VI, 75270 Paris Cedex 06, France³

Received 17 March 2003/ Returned for modification 8 May 2003/ Accepted 21 July 2003

Top Abstract Introduction Materials and Methods Results and Discussion References

 
The activity of garenoxacin, a new quinolone, was determined in comparison with other quinolones against different strains of S. pneumoniae, viridans group streptococci (VGS), and Enterococcus faecalis. Strains were quinolone-susceptible clinical isolates and quinolone-resistant strains with defined mechanisms of resistance obtained from either clinical isolates or derivatives of S. pneumoniae R6. Clinical quinolone-susceptible strains of S. pneumoniae, VGS and E. faecalis showed garenoxacin MICs within a range of 0.03 µg/ml to 0.25 µg/ml. Garenoxacin MICs increased two- to eightfold when one mutation was present in the ParC quinolone resistance-determining region (QRDR), fourfold when one mutation was present in the GyrA QRDR (S. pneumoniae), 8- to 64-fold when two or three mutations were associated in ParC and GyrA QRDR, and 2,048-fold when two mutations were present in both the GyrA and ParC QRDRs (Streptococcus pneumoniae). Increased active efflux had a moderate effect on garenoxacin MICs for S. pneumoniae and VGS. Against S. pneumoniae, garenoxacin behaved like moxifloxacin and sparfloxacin, being more affected by a single gyrA mutation than by a single parC mutation. Although garenoxacin was generally two- to fourfold more active than moxifloxacin against the different wild-type or mutant strains of S. pneumoniae, VGS, and E. faecalis, it was two- to fourfold less active than gemifloxacin. At four times the respective MIC for each strain, the bactericidal effect of garenoxacin, observed at 6 h for S. pneumoniae and at 24 h for S. oralis and E. faecalis, was not influenced by the presence of mutation either in the ParC or in both the ParC and GyrA QRDRs.

Top Abstract Introduction Materials and Methods Results and Discussion References

 
Resistance to beta-lactams and unrelated antimicrobial agents has been reported worldwide against clinical isolates of Streptococcus pneumoniae and viridans group streptococci (VGS) (1, 7, 8, 15, 18, 28). Even if the prevalence of quinolone-resistant pneumococci remains currently low in most countries, recent reports show that the use of these antibiotics for the treatment of a variety of community-acquired infections is associated with an increasing rate of quinolone-resistant strains (4-6, 14, 24). This explains why the development of more active compounds is needed. Garenoxacin, a des-F(6)-quinolone with a difluoromethoxy substituent at C-8, lacks the classical C-6 fluorine previously believed to be essential for the enhanced potency of recent generations of fluoroquinolones. Garenoxacin has a broad spectrum of activity (10, 25), in particular against gram-positive bacteria, including enterococci and some atypical bacteria.

The purpose of this study was to evaluate the in vitro activity of garenoxacin compared with other quinolones, including levofloxacin, moxifloxacin, and gemifloxacin, against a collection of S. pneumoniae, VGS, and E. faecalis strains with defined mechanisms of resistance.

Top Abstract Introduction Materials and Methods Results and Discussion References

 
Antimicrobial agents. The antimicrobial agents were obtained from their manufacturers: penicillin G, Panpharma, France; pefloxacin, levofloxacin, and sparfloxacin, Aventis, Vitry-sur-Seine, France; ciprofloxacin and moxifloxacin, Bayer Pharma, Puteaux, France; garenoxacin, Bristol Myers Squibb Laboratories, Wallingford, Conn.; and gemifloxacin, Smith Kline Beecham Laboratories, Harlow, United Kingdom.

Bacterial strains. Clinical strains of S. pneumoniae, VGS, and E. faecalis were isolated from French hospitals between 1998 and 2002. A collection of strains with defined mechanisms of resistance to quinolones either derived from S. pneumoniae R6, a susceptible derivative of the nonencapsulated Rockefeller University strain R36A, or issued from clinical samples (12, 16, 27, 30, this study) were also studied. Strains were grown either in Mueller-Hinton or in Todd-Hewitt broth supplemented with 0.5% yeast extract (Difco).

MIC determinations. MICs were determined in triplicate by the agar dilution method according to the recommendations of the Société Française de Microbiologie. 10⁴ CFU were spotted on Mueller-Hinton agar plates supplemented or not with 4% horse blood and containing various concentrations of each antibiotic tested. MICs were read after 18 h of incubation at 37°C. In order to detect an active increased efflux, MICs were also determined in the presence of 10 µg of reserpine per ml (Sigma Chemicals, St. Louis, Mo.) (11).

Time-kill curves. The bactericidal activities of garenoxacin and ciprofloxacin were tested at concentrations corresponding to fourfold their respective MICs against a panel of representative strains. For E. faecalis, VGS, and S. pneumoniae, antibiotics were added to a BHI broth culture grown at a cell density of about 10⁶ CFU/ml. Culture samples collected at 0, 6, and 24 h were diluted in distilled water. Bacterial counts were determined by plating 50-µl aliquots on BHI agar with or without 3% horse blood with a spiral dispenser (Spiral Plater, Intersciences, Saint Nom, France). Charcoal (4 mg/ml) was added to BHI (OSI Laboratory, France) to minimize the antibiotic carryover. After incubation at 37°C for 48 h, colony counts were determined with a scanner colony counter (CASBA 4 System, Intersciences, Saint Nom, France).

PCR experiments and DNA sequencing. Since the mechanisms of quinolone resistance had been previously determined for the S. pneumoniae and VGS strains used in this study (12, 16, 27, 30), we only searched for the presence of mutations in the topoisomerase II quinolone resistance-determining region (QRDR) from the quinolone-resistant strains of E. faecalis. For this purpose, amplification was carried out with the following oligonucleotide primers: 5'-TCGAGATGGGCTAAAACCAG-3' and 5'-GAGCTTCTGTATAACGCATCG-3' for parC, 5'-CTGTTCATCGCCGAATCTTA-3' and 5'-TCGTAGCATTTCTAAAGCAATTT-3' for gyrA, 5'-GGAAAATTAACACCGGCTCA-3' and 5'-AAAGTGGTGGTAAGGCAATG-3' for parE, and 5'-AGCTGGCTGATTGCTCAAGT-3' and 5'-TTTTCCCTTGTTTCACACCA-3' for gyrB. The conditions used for amplification were previously described (19).

Top Abstract Introduction Materials and Methods Results and Discussion References

 
For clinical strains of S. pneumoniae and VGS, whether penicillin susceptible or with a sensibility diminished to penicillin, garenoxacin MICs ranged from 0.032 µg/ml for S. pneumoniae to 0.064 and 0.125 µg/ml for VGS and to 0.25 µg/ml for E. faecalis strains (Table 1). Against all these isolates, garenoxacin MICs were two- to fourfold lower than those of moxifloxacin but generally twofold higher than those of gemifloxacin.

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TABLE 1. MICs of seven fluoroquinolones and penicillin G against susceptible clinical strains of S. pneumoniae, VGS, and E. faecalis

Quinolone-resistant S. pneumoniae strains. The quinolone MICs for the S. pneumoniae strains with defined mechanisms of resistance are listed in Table 2. Most of these were R6-derived strains, either obtained after transformation with topoisomerase genes harboring various known mutations or selected after one or two steps on different quinolones (16, 27). When one or two mutations were present in the ParC QRDR, garenoxacin MICs generally increased twofold, while in the presence of one or two mutations in GyrA, garenoxacin MICs generally increased fourfold. Similar to moxifloxacin and sparfloxacin and in contrast to ciprofloxacin and levofloxacin, the increase in garenoxacin MICs was more marked when GyrA mutations were present. This was not the case for gemifloxacin, for which MICs increased similarly (fourfold) when a mutation(s) was present in one of the two topoisomerase II genes.

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TABLE 2. MICs of seven fluoroquinolones and penicillin G against S. pneumoniae strains with defined mechanisms of resistancea

Although we used transformants already harboring QRDR mutations and did not select for garenoxacin first-step mutants, the fact that its MICs were higher for the GyrA than for the ParC mutants suggested that the preferential target of garenoxacin could be GyrA (16, 19, 22). This was in agreement with a previous report, which showed that first-step mutants of S. pneumoniae selected on garenoxacin were GyrA mutants (13). In the same report it was shown that the transformation of R6 with PCR fragment of GyrA or ParC harboring two mutations in the QRDR led to 32-to 64-fold increased MICs of garenoxacin. Although these two mutations within each of the subunits were not exactly the same as those presented in Table 1 (see R6Tr4 and R6Tr8), the increase in MICs was surprisingly higher than those found in this work. The association of the N435D substitution in ParE with a GyrA mutation led to a 16-fold increase in the garenoxacin MICs (see R6Mx9Mx5). When one or two mutations were present in GyrA and ParC, garenoxacin MICs increased 16- to 64-fold and more than 1024-fold when two mutations were present in both GyrA and ParC. Even though the increase in garenoxacin MICs for the different S. pneumoniae mutants was within the same range as that of the other quinolones tested, its MICs remained the lowest, with the exception of gemifloxacin.

The presence of an increased active efflux, which was reported to be frequently encountered in clinical isolates (3), had only a moderate effect on garenoxacin MICs (fourfold increase). Curiously, and in contrast to what was observed for ciprofloxacin, garenoxacin MICs did not decrease in the presence of reserpine.

Quinolone-resistant VGS strains. VGS clinical isolates with defined mechanisms of quinolone resistance (Table 3) were Streptococcus mitis, Streptococcus oralis, and Streptococcus sanguis (12). Similar to S. pneumoniae, when a single mutation was present in ParC QRDR, a two- to fourfold increase in the MICs of garenoxacin was observed. Interestingly, the presence of the R79S substitution in the QRDR of ParC in S. oralis was not accompanied by an increase in MIC of any of the quinolones tested. When one mutation was present in both GyrA and ParC, garenoxacin MICs increased 8- to 16-fold (see SOB11 to SOB13 in Table 3).

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TABLE 3. MICs of seven fluoroquinolones and penicillin G against clinical isolates of VGS with defined mechanism(s) of resistance

The presence of an increased active efflux in VGS was considered if a fourfold decrease in the ciprofloxacin MICs was obtained in the presence of reserpine. As previously reported, an apparent efflux was present among many of the strains tested (12). In particular, three strains, one each of S. mitis, SMB9; S. oralis, SOB5; and S. sanguis, SSB2, presented an active efflux in the absence of any other detectable mechanism of resistance. When compared to their nonisogenic wild-type counterpart, the garenoxacin MICs for these strains were at most two- to fourfold increased, and in contrast to what was observed for ciprofloxacin, were not decreased in the presence of reserpine. Thus, it appears that garenoxacin is a poor substrate for efflux pumps, as previously shown in S. pneumoniae and Staphylococcus aureus (2, 17).

Quinolone-resistant E. faecalis strains. Since garenoxacin, which is not active against E. faecium (10), showed good activity on E. faecalis, it was interesting to test its activity against E. faecalis strains with defined mechanisms of quinolone resistance (Table 4). All were nonrelated clinical isolates as judged from pulsed-field electrophoresis and randomly amplified polymorphic DNA analysis (data not shown). The presence of a single substitution, S85I (numbering according to reference 21) in the ParC QRDR was associated with a two- to eightfold increase in the quinolone MICs. Such a single mutation in the ParC QRDR, but different from those described in this paper (S85R), was reported once in E. faecalis (20).

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TABLE 4. MICs of seven fluoroquinolones and penicillin G against clinical isolates of E. faecalis (EF) with defined mechanisms of resistance

When two mutations were present, one each in the QRDRs of GyrA and ParC, a 4- to 32-fold increase in garenoxacin MICs was observed, depending upon the association of mutations. Among the coupled substitutions, S84Y, S84K, and E88K in GyrA (numbering according to reference 21) with S85I in ParC were not reported previously in E. faecalis (20, 21, 26), yet the association of the S83Y/R/I in GyrA (equivalent to position 84 in E. faecalis) with S80I in ParC (equivalent to position 85 in E. faecalis) was reported in different clinical isolates of Enterococcus faecium (9). The presence of an additional P453S substitution in ParE did not significantly change the MICs of garenoxacin.

Bactericidal activity of garenoxacin. Killing rates were determined to evaluate the bactericidal activity of garenoxacin against representative strains of each species studied in this work and harboring QRDR mutations. At four times their respective MICs, whether or not the strains harbored any mutation in the ParC or GyrA QRDR, a moderate bactericidal effect was observed with a decrease in initial CFU count of 1.8 log₁₀ at 6 h for S. pneumoniae and 2.4 log₁₀ and 2.1 log₁₀ at 24 h for S. oralis and E. faecalis, respectively (Table 5). These results are in the range of those reported by Pankuch for S. pneumoniae (23). Examination of the bactericidal activity at 24 h was not considered for S. pneumoniae because after 6 to 8 h a pronounced autolysis was observed in the absence of antibiotics.

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TABLE 5. Bactericidal activity of garenoxacin and ciprofloxacin against different strains of S. pneumoniae, S. oralis, and E. faecalis with defined mechanisms of resistancea

Overall, the bactericidal effect of garenoxacin against the different species tested was in the range of that of ciprofloxacin. In contrast to garenoxacin, and as expected, none of the concentrations of ciprofloxacin used in this assay would be achievable in serum. Since the same effect was observed for a given multiple of the MIC with and without a QRDR mutation(s), this suggested that the alterations of the target(s) as such were not responsible for a decrease in the bactericidal activity of garenoxacin, although higher quantities of quinolone were necessary to obtain the same efficacy.

In conclusion, the MICs of garenoxacin are well within the achievable levels obtained in serum or in inflammatory exudates (29, D. Grasela, D. Gajjar, A. Bello, Z. Ge, and L. Christopher, Abstr. 40th Intersci. Conf. Antimicrob. Agents Chemother., abstr. 2260, 2000) for S. pneumoniae, VGS, and susceptible E. faecalis strains, as well as for most of the less susceptible strains which harbor mutations in either GyrA or ParC or both. This does not preclude that resistant mutants will not be selected during treatment; although to reach a sufficient level of resistance they will have to either present a new mechanism of resistance or accumulate a sufficient number of mutations in the QRDR of the different topoisomerase II subunits (13, 27; this work).

 
This study was supported by a grant from Bristol Myers Squibb laboratories.

 
* Corresponding author. Mailing address: Centre National de Référence des Pneumocoques, Hôpital Européen Georges Pompidou, 20-40, rue Leblanc, 75908 Paris cedex 15, France. Phone: 33-1-56 09 39 51. Fax: 33-1-56 09 24 46. E-mail: emmanuelle.varon{at}hop.egp.ap-hop-paris.fr.

Top Abstract Introduction Materials and Methods Results and Discussion References

 

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Antimicrobial Agents and Chemotherapy, November 2003, p. 3542-3547, Vol. 47, No. 11
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.11.3542-3547.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

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