The quinolone antibiotics act by interfering with the folding of bacterial nucleic acid (DNA) by DNA gyrase and topoisomerase IV. DNA gyrase, encoded by gyrA and gyrB, is the enzyme responsible for inducing negative supercoils in DNA, whereas topoisomerase IV, encoded by parC and parE, is involved in DNA relaxation and separation. In general, inhibition of both enzymes is necessary for bactericidal activity and the in vitro activity of a fluoroquinolone is dictated by the relative affinity for both target enzymes [Jones, 2002].

In general, the older quinolone antibiotics, e.g. ciprofloxacin or perfloxacin, have not proved clinically useful against chlamydiae despite their reasonable in vitro performance [Ridgway, 1997].  However ofloxacin, which is only twice as effective as ciprofloxacin in vitro, is very effective in eradicating C trachomatis in cases of urethritis or cervicitis [Blomer et al., 1988; Hooton et al., 1992; Kitchen et al., 1990] The CDC in 1993 recommended 300 mg of ofloxacin twice a day for seven days for uncomplicated chlamydial genital tract infections [CDC, 1993]. However, in some countries, including the United Kingdom, ofloxacin is not marketed in a 300 mg formulation. In the UK, ofloxacin can be used either at a single dose of 400 mg daily, or two doses of 200 mg daily, for seven days [Ridgway, 1997; 2000]. Further studies are required to establish the ideal treatment regime, particularly with respect to the efficacy of single daily dosage and the length of the course, with prolonged follow-up emphasising clinical cure (disappearance of symptoms) rather than organism eradication [Ridgway, 1998]. However Kitchen et al., 1990 found that clinical cure rates using 400 mg of ofloxacin once daily for 7 days for uncomplicated male or female C. trachomatis genital tract infection were similar to those for conventional doxycycline, for which they considered it to be a safe and effective alternative.

Levofloxacin, the L- optical isomer (structurally a mirror image) of ofloxacin, has similar activity to ofloxacin in the laboratory and had similar efficacy to the macrolides against respiratory infection with C. pneumoniae [Hammerschlag & Roblin, 2000].

The spectrum of activity of quinolones suggests that they might be useful for the treatment of pelvic inflammatory disease [infection of the female upper genital tract] as, although C. trachomatis is the main causative agent in many areas of the world, there are a number of other bacteria which may also be involved. These include  Neisseria gonorrhoeae (the cause of gonorrhoea), Mycoplasma hominis [a cause of non specific lower genital tract infection] and coliform bacteria and non-sporing anaerobic bacteria probably originating from the bowel flora. Often antibiotic treatment has to be given empirically in the absence of clear identification of the causative bacterium in a particular case. The antibiotic chosen should cover the potential agents, as the newer quinolones such as ofloxacin generally do. 

Ofloxacin 400 mg twice a day for 14 days or Levofloxacin 500 mg orally once daily for 14 days, with or without metronidazole 500 mg orally twice a day for 14 days were recommended by the CDC in 2002 as one alternative for the oral therapy of pelvic inflammatory disease. Some of the newer quinolones have greater activity in the laboratory against anaerobic bacteria and might be expected to give better clinical results.

Chlamydial resistance to quinolones

There are disturbing reports of C. trachomatis, under laboratory conditions, developing resistance to both sparfloxacin and ofloxacin [Hammerschlag & Roblin, 2000]. Multiple quinolone resistance has been observed involving sparfloxacin, ofloxacin, perfloxacin, ciprofloxacin and norfloxacin; the result of a mutation in the gyrA gene encoding the DNA gyrase. High level resistance to ciprofloxacin and ofloxacin has also been reported [Ridgway, 2000]. Serial passage increased the resistance of C. trachomatis L2 to various fluoroquinolones up to 1000 fold. In two different studies the basis of quinolone resistance was a mutation in gyrA leading to an isoleucine for serine substitution at position 83 in DNA gyrase [Desus-Babus et al., 1998; Morrissey et al., 2002]. Interestingly it was not similarly possible to increase the resistance of C. pneumoniae to fluoroquinolones by serial passage [Morrissey et al., 2002; see:  chlamydial antibiotic resistance].

Garenoxacin

Gieffers et al., 2001 compared the susceptibility of C. pneumoniae growing in endothelial or smooth muscle cell culture to various quinolones (ofloxacin, levofloxacin, trovafloxacin, moxifloxacin). They found that moxifloxacin and trovafloxacin were as effective as the macrolides.  

The activity of the new generation fluoroquinolones against C. pneumoniae has recently been reviewed by Jones, 2002. In one study, garenoxacin was the most active fluoroquinolone tested against four isolates of C. pneumoniae, with the highest MIC of only 0.008 µg/ml, compared with 0.5 µg/ml for levofloxacin and ciprofloxacin. In two other studies, the MIC₉₀ for levofloxacin was 0.5 and 1 µg/ml against 45 isolates of C. pneumoniae [Jones, 2002].  Roblin et al., 2003 reported an MIC90 and an MBC90 of 0.03 mg per litre (range 0.015 - 0.03 mg per litre) for 30 recent clinical isolates of C. pneumoniae.

Donati et al., 2002 compared the in vitro susceptibilities of 33 isolates of C. trachomatis, C.  pneumoniae and C.  psittaci to garenoxacin (the former BMS-284756) and to levofloxacin, ciprofloxacin, doxycycline, erythromycin and roxithromycin. Again, garenoxacin was the most active of the quinolone drugs tested, with minimal inhibitory concentration of antibiotic identical to the minimal chlamydicidal concentration and in the range 0.007 to 0.03 µg/ml. Comparable figures for the other two quinolones tested, levofloxacin and ciprofloxacin, were 0.25 to 2 µg/ml.

Ameyama et al., 2003 cloned the gyrA and gyrB DNA gyrase genes of C. pneumoniae TW-183 and tested the activity of various quinolones against the expressed DNA gyrase protein. The 50% inhibitory concentrations of garenoxacin, sparfloxacin, moxifloxacin, gatifloxacin, and levofloxacin were 10.1, 47.5, 39.6, 64.2, and 156.9 micrograms per millilitre. The MICs against C. pneumoniae TW-183 were 0.008, 0.016, 0.063, 0.125, and 0.25 micrograms per millilitre respectively again indicating that garenoxacin is a particularly active quinolone against this organism.

NEXT: penicillins and cephalosporins

[MEW] August 2003

References

Ameyama, S., Shinmura, Y. & Takahata, M. (2003). Inhibitory activities of quinolones against DNA gyrase of Chlamydia pneumoniae. Antimicrobial Agents and Chemotherapy 47, 2327 - 2329.

Blomer, A., Bruch, K. & Klose, U. (1988). Ofloxacin in the treatment of gonococcal and chlamydial urethritis. Clinical Therapy 10, 263 - 265.

Centers for Disease Control and Prevention (1993). Recommendations for the prevention and management of Chlamydia trachomatis infections. Morbidity and Mortality Weekly Reports 42, (RR-12): 1 - 102.

Centers for Disease Control and Prevention (1998). Guidelines for Treatment of Sexually Transmitted Diseases. Morbidity and Mortality Weekly Reports 47, (RR-1); 1 - 118.

CDC Guidelines on screening tests to detect C. trachomatis and N. gonorrhoeae. October 2002

Dessus-Babus, S., Bebear, C. M., Charron, A., Bebear, C. & de Barbeyrac, B. (1998). Sequencing of gyrase and topoisomerase IV quinolone-resistance-determining regions of Chlamydia trachomatis and characterization of quinolone-resistant mutants obtained in vitro. Antimicrobial Agents and Chemotherapy 42, 2474 - 2481.  Full article

Donati, M., Pollini, G. M., Sparacino, M., Fortugno, M. T., Laghi, E. & Cevenini, R. (2002). Comparative in vitro activity of garenoxacin against Chlamydia spp. Journal of Antimicrobial Chemotherapy 50, 407 - 410.

Gieffers, J., Solbach, W., Maass, M. (2001). In vitro susceptibility and eradication of Chlamydia pneumoniae cardiovascular strains from coronary artery endothelium and smooth muscle cells. Cardiovascular Drugs and Therapy 15, 259 - 262.

Hammerschlag, M. H. & Roblin, P. M., (2000). Microbiologic efficacy of levofloxacin for the treatment of community-acquired pneumonia (CAP) due to C. pneumoniae. Page 396. Abstract in: Proceedings of the Fourth Meeting of the European Society for Chlamydial Research (Saikku, P. ed)., pub Editrice Esculapio, Bologna, Italy. ISBN 88-86524-41-2.

Hooton, T. M., Batteiger, S. E., Judson, F. N., Spruance, S. L. & Stamm, W. E. (1992). Ofloxacin versus doxycycline for treatment of cervical infection with Chlamydia trachomatis. Antimicrobial Agents and Chemotherapy 36, 1144 - 1146.

Jones, R. N. (2002). Microbiology of newer fluoroquinolones: focus on respiratory pathogens. Diagnostic Microbiology and Infectious Disease 44, 213 - 220.

Kitchen, V. S., Donegan, C., Ward, H., Thomas, B., Harris, J. R. & Taylor-Robinson, D. (1990). Comparison of ofloxacin with doxycycline in the treatment of non-gonococcal urethritis and cervical chlamydial infection. Journal of Antimicrobial Chemotherapy 26 Suppl D, 99 - 105.

Morrissey, I., Salman, H., Bakker, S., Farrell, D., Bebear, C. M. & Ridgway, G. (2002). Serial passage of Chlamydia spp. in sub-inhibitory fluoroquinolone concentrations. Journal of Antimicrobial Chemotherapy 49, 757 - 761.

Ridgway, G. L. (1997). Treatment of chlamydial genital infection. Journal of Antimicrobial Chemotherapy 40, 311 - 314. Full article    [Good review].

Ridgway, G. L. (1998). Treatment of Chlamydia trachomatis infections. 4^th Bandolier Conference on Evidence Based Medicine.

Ridgway, G. (2000). Treatment of Chlamydia trachomatis infections. Pages 387-390. In: Proceedings of the Fourth Meeting of the European Society for Chlamydial Research (Saikku, P. ed)., pub Editrice Esculapio, Bologna, Italy. ISBN 88-86524-41-2.

Roblin, P. M., Reznik, T. & Hammerschlag, M. R. (2003). In vitro activity of garenoxacin against recent clinical isolates of Chlamydia pneumoniae. International Journal of Antimicrobial Agents 21, 578 - 580.

NEXT: penicillins and cephalosporins