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JAC Advance Access originally published online on April 24, 2006
Journal of Antimicrobial Chemotherapy 2006 58(1):202-204; doi:10.1093/jac/dkl152
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© The Author 2006. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Comparative in vitro activity of PGE 9262932 and fluoroquinolones against Canadian clinical Streptococcus pneumoniae isolates, including molecularly characterized ciprofloxacin-resistant isolates

Heather J. Adam1,*, Kristen N. Schurek1, Melanie R. DeCorby1, Barbara Weshnoweski2, Ravinder Vashisht2, Kathy Karlowsky1, Daryl J. Hoban1,2 and George G. Zhanel1–,3

1 Department of Medical Microbiology, Faculty of Medicine, University of Manitoba 730 William Avenue, Winnipeg, Manitoba, R3E 0W3, Canada 2 Department of Clinical Microbiology, Health Sciences Centre 820 Sherbrook Street, Winnipeg, Manitoba, R3A 1R9, Canada 3 Department of Medicine, Health Sciences Centre 820 Sherbrook Street, Winnipeg, Manitoba, R3A 1R9, Canada

*Correspondence address. Clinical Microbiology, Health Sciences Centre, MS673-820 Sherbrook Street, Winnipeg, Manitoba, R3A 1R9, Canada. Tel: +1-204-787-4684; Fax: +1-204-787-4699; E-mail: hjadam{at}gmail.com

Received 6 February 2006; returned 13 March 2006; revised 28 March 2006; accepted 30 March 2006


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Objectives: The aim of this study was to assess the in vitro activity of the non-fluorinated quinolone PGE 9262932 against Streptococcus pneumoniae isolates with various resistance phenotypes: ciprofloxacin-resistant, macrolide-resistant, penicillin-resistant and trimethoprim/sulfamethoxazole-resistant.

Methods: The in vitro activity of PGE 9262932 against 2585 recent Canadian S. pneumoniae isolates with various resistance phenotypes was determined and compared with that of gatifloxacin, gemifloxacin, levofloxacin and moxifloxacin. In particular, the activity of PGE 9262932 against ciprofloxacin-resistant isolates with defined parC and gyrA mutations was assessed.

Results: PGE 9262932 MIC90s were ≤0.015 mg/L for all S. pneumoniae and 0.12 mg/L for the ciprofloxacin-resistant isolates. Resistance to penicillin, macrolides or trimethoprim/sulfamethoxazole had little effect on the PGE 9262932 MICs. The quinolone MIC50/90s were only slightly affected by the presence of one parC or gyrA mutation, but increased 2- to 16-fold in the presence of mutations in both parC and gyrA, depending on the specific quinolone. With each quinolone resistance genotype, the order of activity, based on MIC90, against the ciprofloxacin-resistant isolates was PGE 9262932, gemifloxacin, moxifloxacin, gatifloxacin and levofloxacin.

Conclusions: PGE 9262932 was the most active quinolone against all S. pneumoniae isolates, regardless of resistance phenotype.

Keywords: quinolones , resistance , pneumococcus


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Antimicrobial resistance in Streptococcus pneumoniae and other respiratory tract pathogens has emerged as a serious problem worldwide. The increasing prevalence of resistance to ß-lactams, macrolides and trimethoprim/sulfamethoxazole has led to a rise in the use of fluoroquinolones and an urgent need for new agents.

Fluoroquinolone resistance in S. pneumoniae is typically attributed to mutations in the quinolone resistance determining regions (QRDR) of parC and/or gyrA.1,2 Efflux may also contribute to resistance.1,3 To overcome rising fluoroquinolone resistance, non-fluorinated quinolones, which lack fluorine at position 6 on the quinolone nucleus, have recently been developed. PGE 9262932 is an 8-methoxy non-fluorinated quinolone, developed by Procter and Gamble Pharmaceuticals (Cincinnati, OH, USA), that exhibits a broad spectrum of activity and has been shown to have high in vitro activity against fluoroquinolone and multidrug-resistant S. pneumoniae.4,5

Previous studies have indicated that PGE 9262932 and other similar non-fluorinated quinolones possess good activity against Gram-positive pathogens.4,5 The aim of this study was to assess the in vitro activity of the non-fluorinated quinolone PGE 9262932 against S. pneumoniae isolates with different resistance phenotypes, in particular, ciprofloxacin-resistant isolates (MIC ≥ 4 mg/L) with defined parC and gyrA mutations. The activity of PGE 9262932 was compared with the marketed fluoroquinolones gatifloxacin, gemifloxacin, levofloxacin and moxifloxacin.


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S. pneumoniae isolates

Clinical isolates of S. pneumoniae (n = 2585) collected in 2004 and 2005 as part of the Canadian Respiratory Organism Susceptibility Study (CROSS) were included in the study.6 Additionally, all ciprofloxacin-resistant isolates (n = 189) collected between 1997 and 2005 as part of CROSS were tested.

Susceptibility testing

The susceptibilities of organisms to PGE 9262932, ciprofloxacin, clarithromycin, gatifloxacin, gemifloxacin, levofloxacin, moxifloxacin, penicillin and trimethoprim/sulfamethoxazole were tested by broth microdilution as described by the CLSI guidelines (M7-A6 and M100-S15).7,8

QRDR sequencing

The QRDRs of gyrA and parC of the ciprofloxacin-resistant isolates collected between 1997 and 2004 (n = 151) were sequenced using previously described primers and methodologies.9,10


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Table 1 displays the in vitro activities of PGE 9262932, gatifloxacin, gemifloxacin, levofloxacin and moxifloxacin against all tested S. pneumoniae isolates and specifically, the ciprofloxacin-resistant isolates. PGE 9262932 was found to be the most active quinolone. The MIC90s against all 2585 S. pneumoniae isolates were ≤0.015, 0.5, 0.03, 1 and 0.25 mg/L for PGE 9262932, gatifloxacin, gemifloxacin, levofloxacin and moxifloxacin, respectively. When tested against isolates resistant to penicillin, macrolides or trimethoprim/sulfamethoxazole, the MIC50/90s of these quinolones remained basically unchanged. However, the MIC90s against the subset of ciprofloxacin-resistant isolates increased dramatically, by 8- to 16-fold, to 0.12, 8, 0.5, 16 and 4 mg/L for PGE 9262932, gatifloxacin, gemifloxacin, levofloxacin and moxifloxacin, respectively. Nonetheless PGE 9262932 remained the most active quinolone against the ciprofloxacin-resistant S. pneumoniae isolates. These results agree with those previously reported by Jones et al.5 who demonstrated that PGE 9262932 retained good in vitro activity against ciprofloxacin-resistant S. pneumoniae isolates, with maximal MICs of 0.5 mg/L.


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  		Table 1. In vitro activities of PGE 9262932 and comparator fluoroquinolones against 2585 S. pneumoniae isolates

 
The in vitro activities of PGE 9262932 and the comparator fluoroquinolones against the ciprofloxacin-resistant isolates were analysed by QRDR genotype. The QRDR amino acid substitutions observed in the ciprofloxacin-resistant isolates included Ser-81->Phe/Tyr and Glu-85->Gly/Lys in GyrA and Asp-78->Ala, Ser-79->Ala/Phe/Tyr and Asp-83->Ala/Asn/Gly/Tyr in ParC. Mutational analysis was not conducted for gyrB or parE so the impact of mutations in these genes on the activity of PGE 9262932 could not be assessed. Similarly to the results reported by Jones et al.,5 the MIC ranges observed in this study were ≤0.015–0.06 mg/L for isolates with no QRDR mutations (n = 14), 0.06–0.25 mg/L for isolates with a single gyrA mutation (n = 3), ≤0.015–0.12 mg/L for isolates with a single parC mutation (n = 40) and ≤0.015–0.5 mg/L for isolates with mutations in gyrA and parC (n = 94). The MIC50/90s of all the quinolones were only slightly affected by the presence of one mutation, in either gyrA or parC, compared with the isolates without QRDR mutations. However, the MIC50/90s increased for the isolates with two QRDR mutations. The MIC50/90s against the isolates with two QRDR mutations increased 2- to 4-fold for PGE 9262932, 4-fold for gemifloxacin and levofloxacin, 4- to 8-fold for gatifloxacin and 8- to 16-fold for moxifloxacin compared with the isolates with one QRDR mutation. The MIC increases observed for the isolates with two QRDR mutations resulted in resistance rates of 74% for gatifloxacin, 34% for gemifloxacin, 82% for levofloxacin and 25% for moxifloxacin in this subset of isolates. As resistance breakpoints do not currently exist for PGE 9262932, a resistance rate could not be determined. With each QRDR genotype, the order of activity based on MIC90 against the ciprofloxacin-resistant isolates was PGE 9262932, gemifloxacin, moxifloxacin, gatifloxacin and levofloxacin.

In summary, our data showed that PGE 9262932 was the most active quinolone against all S. pneumoniae isolates, regardless of resistance phenotype. Against the ciprofloxacin-resistant isolates, PGE 9262932 was 128-fold more active, by MIC90, than levofloxacin. Therefore, PGE 9262932 appears to be a promising agent against resistant strains of S. pneumoniae. In light of recent fluoroquinolone treatment failures due to S. pneumoniae isolates with undetected parC mutations,11 newer quinolones that remain highly active in vitro and also in vivo (due to excellent pharmacodynamics) against S. pneumoniae isolates with QRDR mutations will be valuable additions to the fluoroquinolone class.


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Heather Adam is supported by the University of Manitoba Canadian Institutes of Health Research-funded International Centre for Infectious Diseases National Training programme. K. N. S. is supported by a Manitoba Research Health Council fellowship. G. G. Z. has received research funding from Bayer, Bristol Myers Squibb, Ortho McNeil and Schering-Plough. D. J. H. has received research funding from Astra/Zeneca, Bayer Canada, Bristol Myers Squibb Canada, Janssen-Ortho Inc., Merck Frosst, Pfzier Canada, Sanofi-Aventis and Wyeth. This research was funded by Procter and Gamble Pharmaceuticals.


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1 Bast DJ, Low DE, Duncan CL, et al. (2000) Fluoroquinolone resistance in clinical isolates of Streptococcus pneumoniae: contributions of type II topoisomerase mutations and efflux to levels of resistance. Antimicrob Agents Chemother 44:3049–54.[Abstract/Free Full Text]

2 Pan XS, Ambler J, Mehtar S, et al. (1996) Involvement of topoisomerase IV and DNA gyrase as ciprofloxacin targets in Streptococcus pneumoniae. Antimicrob Agents Chemother 40:2321–6.[Abstract]

3 Gill MJ, Brenwald NP, Wise R. (1999) Identification of an efflux pump gene, pmrA, associated with fluoroquinolone resistance in Streptococcus pneumoniae. Antimicrob Agents Chemother 43:187–9.[Abstract/Free Full Text]

4 Barry AL, Fuchs PC, Brown SD. (2001) In vitro activities of three nonfluorinated quinolones against representative bacterial isolates. Antimicrob Agents Chemother 45:1923–7.[Abstract/Free Full Text]

5 Jones ME, Critchley IA, Karlowsky JA, et al. (2002) In vitro activities of novel nonfluorinated quinolones PGE 9262932 and PGE 9509924 against clinical isolates of Staphylococcus aureus and Streptococcus pneumoniae with defined mutations in DNA gyrase and topoisomerase IV. Antimicrob Agents Chemother 46:1651–7.[Abstract/Free Full Text]

6 Zhanel GG, Palatnick L, Nichol KA, et al. (2003) Antimicrobial resistance in respiratory tract Streptococcus pneumoniae isolates: results of the Canadian Respiratory Organism Susceptibility Study, 1997 to 2002. Antimicrob Agents Chemother 47:1867–74.[Abstract/Free Full Text]

7 National Committee for Clinical Laboratory Standards. (2003) Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically. Approved Standard M7-A6 (NCCLS, Wayne, PA, USA).

8 Clinical and Laboratory Standards Institute. (2005) Performance Standards for Antimicrobial Susceptibility Testing: Fifteenth Informational Supplement M100-S15 (CLSI, Wayne, PA, USA).

9 Zhanel GG, Walkty A, Nichol KA, et al. (2003) Molecular characterization of fluoroquinolone resistant Streptococcus pneumoniae clinical isolates obtained from across Canada. Diagn Microbiol Infect Dis 45:63–7.[CrossRef][ISI][Medline]

10 Morrissey I and George JT. (2000) Purification of pneumococcal type II topoisomerases and inhibition by gemifloxacin and other quinolones. J Antimicrob Chemother 45:Suppl 1, 101–6.[Abstract/Free Full Text]

11 Davidson R, Cavalcanti R, Brunton JL, et al. (2002) Resistance to levofloxacin and failure of treatment of pneumococcal pneumonia. N Engl J Med 346:747–50.[Free Full Text]


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This Article
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