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Treatment of chlamydial infectionsChlamydiae and antibiotic resistance.Tetracycline and erythromycin have been used for decades to treat chlamydial infections, but these drugs are still in wide use, indicating that clinical resistance to them is not yet a major problem [McOrist, 2000]. The efficacy of macrolides such as erythromycin or azalides such as azithromycin probably relates to their ability to achieve high intracellular concentrations, particularly in macrophages [Labro, 1996; Tulkens, 1991]. Macrolides distribute evenly in the cell cytosol and phagosomes / lysosomes, whereas azalides tend to concentrate in phagosomes. Tetracycline also enters cells, but its intracellular location is poorly defined [McOrist, 2000]. Beta-lactam antibiotics (penicillins and cephalosporins) or amino-glycosides (gentamicin) only enter cells slowly and are only moderately or poorly active against chlamydiae. There are substantial technical difficulties in measuring chlamydial antibiotic resistance; Suchland et al., 2003 reported that the minimal inhibitory concentrations (MIC) of various antibiotics against different chlamydial species was dependent on the laboratory cell line used, the time between infection and the addition of antibiotic, the concentration of the inoculum and the passage strategy chosen. In general, in vitro resistance did not correlate well with the patient's apparent clinical outcome. In general obligate intracellular bacteria such as Chlamydia, Rickettsia or Lawsonia all have similar patterns of antibiotic sensitivity [with the possible exception of Simkania]. Antibiotic resistance has been reported for C. trachomatis, [Jones et al., 1990] but this has been disputed [Ridgway, 1997]. Subsequently a strain of C. trachomatis resistant to 64 micrograms per ml of tetracycline was described from France [Lefevre & Lepargneur, 1998]. Somani et al., 2000 in the USA described three isolates of C. trachomatis which showed multidrug resistance to doxycycline, azithromycin and ofloxacin at concentrations exceeding 4 µg per ml. In Israel 44% of clinical isolates were found to be relatively resistant to doxycycline or tetracycline with 4 to 8% of strains resitant to these antibiotics at 4 µg per ml [Samra et al., 2001]. Nevertheless, acquired antibiotic resistance has not so far been a common clinical problem for chlamydiae, although it is a major problem for non intracellular bacteria. Why might this be? Firstly, it has been suggested that bacteria residing almost permanently inside other cells may be incapable of easily acquiring antibiotic resistance genes. The intracellular pathogens Coxiella burnettii (Q fever) and C. trachomatis both carry plasmids which might theoretically be capable of carrying antibiotic resistance genes (see: chlamydial plasmid). However, their function is unknown. The various antibiotic resistance genes carried on plasmids generally might be unavailable to chlamydiae. However chlamydiae do appear to have successfully gained ADP/ATP translocases from plants [see: evolution - ADP/ATP], suggesting that the horizontal transfer of foreign genes to chlamydiae is feasible, at least over evolutionary time scales [Koonin et al., 2001]. Secondly, intracellular bacteria carrying antibiotic resistance genes might have reduced viability [Jones et al., 1990], as indicated in an unconfirmed report of tetracycline resistance in C. trachomatis. Thirdly, the development of tetracycline or macrolide resistance in extracellular bacteria by active efflux out of the bacteria requires significant metabolic energy. This energy might not be so readily available for obligate intracellular bacteria [McOrist, 2000] . The stepwise acquisition of antibiotic resistance by minor mutations in, for example, RNA polymerase (affects rifampicin) or DNA gyrase (affects quinolones) can readily be achieved by step-wise passage in cell culture. In this manner, the resistance of C. trachomatis L2 to various fluoroquinolones was increased up to 1000 fold by 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; see quinolones]. However it was not possible to increase the resistance of C. pneumoniae to fluoroquinolones by serial passage [Morrissey et al., 2002]. The efficacy of antibiotics for eradicating chronic chlamydial infections, e.g. with C. pneumoniae, is uncertain and probably depends on the degree of metabolic activity in the target bacteria. At the present time resistance to the main therapeutic antibiotics used for treating acute human chlamydial infections is not generally thought to be a significant problem. Clinicians, while rejoicing in this situation, nevertheless need to be vigilant as shown by the recent large scale emergence of tetracycline resistant C. suis in pigs in Nebraska [Lennart et al., 2001]. [MEW] January 2003 NEXT: Geoff Ridgway presentation on antibiotic resistance in chlamydiae. 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.
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Jones, R. B., Vanderpol, B., Martin, D. H. et
al., (1990). Partial characterization of C. trachomatis isolates resistant to multiple
antibiotics. Journal of Infectious Diseases 162, 1309 - 1315.
[Describes 5 relatively tetracycline resistant strains
with diminished viability].
Koonin, E. V., Makarova, K. S. & Aravind, L. (2001). Horizontal
gene transfer in prokaryotes: quantification and classification. Annual
Reviews of Microbiology
55, 709 -
742. [Scholarly
Review].
Labro, M. T. (1996). Intracellular bioactivity of macrolides. Clinical Microbiology and Infection 1, Supplement 1, S24 - S30. Lefevre, J. C. & Lepargneur, J. P. (1998). Comparative in vitro
susceptibility of a tetracycline-resistant Chlamydia trachomatis strain
isolated in Toulouse (France). Sexually
Transmitted
Diseases
25, 350
-
352.
[Describes an isolate
resistant to 64 micrograms per ml of tetracycline].
Lenart, J., Andersen, A. A. & Rockey, D. D. (2001). Growth
and development of tetracycline-resistant Chlamydia suis. Antimicrobial
Agents and Chemotherapy
45, 2198
- 2203. Full
article McOrist, S. (2000). Obligate intracellular bacteria and antibiotic resistance. Trends in Microbiology 8, 483 - 486. [Interesting review] 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 Samra, Z., Rosenberg, S., Soffer, Y. & Dan, M. (2001). In vitro susceptibility of recent clinical isolates of Chlamydia trachomatis to macrolides and tetracyclines. Diagnostic Microbiology and Infectious Disease 39, 177 - 179. [4 to 8% of isolates in Israel relatively resistant to tetracyclines]Somani, J., Bhullar, V. B,, Workowski, K. A,, Farshy, C. E. & Black, C. M. (2000). Multiple drug-resistant Chlamydia trachomatis associated with clinical treatment failure. Journal of Infectious Disease 181, 1421 - 1427. Suchland, R. J., Geisler, W. M. & Stamm, W. E. (2003).
Methodologies and Cell Lines Used for Antimicrobial Susceptibility Testing of
Chlamydia spp. Antimicrobial Agents and Chemotherapy
47, 636 - 442.
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