Treatment of chlamydial infections
Erythromycin has long been used as an alternative drug to the tetracyclines for the treatment of chlamydial infection. The drug is usually recommended as erythromycin base, 500 mg 6 hourly for 7 days. The minimal inhibitory concentration of the drug for C. trachomatis, like the tetracyclines, is in the range 0.03-0.06 mg per litre. However the drug is far from ideal as systemic absorption of erythromycin into the body is variable and the drug is not well tolerated, frequently giving rise to gastrointestinal side effects. Erythromycin may also be given as the stearate, 500 mg twice daily for 10 days. This may have the merit of better absorption but the incidence of gastrointestinal side effects with both erythromycins and the tetracylines leads to unreliable compliance. Both erythromycin and doxycycline are cheap and act by selectively inhibiting chlamydial protein synthesis. Erythromycin unlike tetracyclines, does not discolour teeth or bind significantly to bone. It is also not active against Mycoplasma hominis. Both drugs are far from ideal, with clinical cure rates of only 80% even though their ability to eradicate C. trachomatis approaches 100% [Ridgway, 1997].
In recent years a number of new macrolide type antibiotics have become available for the treatment of chlamydial infections, of which azithromycin® is probably the most widely used.
Azithromycin and the azalides
Azithromycin (Zithromax ®) has in many ways revolutionized the treatment of chlamydial infections. Its importance derives from its unusual pharmacokinetic properties. Strictly speaking the drug is an azalide and not a macrolide, having a 15 member ring with a methyl substituted nitrogen in the aglycone ring. This confers acid stability, high tissue penetration, low serum levels and a very long half life [Bryskier et al., 1993]. Anti-chlamydial levels of the drug are readily achieved inside cells or tissues, particularly useful for treating intracellular chlamydial infections. Furthermore adequate intracellular levels may be sustained for several days because of the slow efflux of the drug from cells. This is particularly useful when it is uncertain whether a patient will comply with a longer course of antibiotic therapy. A single 1 g oral dose of azithromycin® is of equivalent efficacy to oral doxycycline 100 mg twice a day for seven days. Accordingly azithromycin® is recommended in the US as a first-line treatment for uncomplicated urethral, cervical and rectal chlamydial infection [CDC 1993; 1998]. The drug also gives comparable results to tetracycline eye ointment for the community wide eradication of trachoma but has significant advantages arising from the fact it is much simpler to administer and, as a systemic rather than local treatment, it can eradicate nasopharyngeal carriage with C. trachomatis, as well as genital, respiratory or skin infections with other sensitive bacteria. Typical microbiological cure rates (eradication of C. trachomatis) in uncomplicated genital tract infection are 90% or more. However, what most matters to the infected person is the clinical cure rate, that is, the resolution of symptoms. Typically this of the order of ~80% clinical cure at 2 weeks for uncomplicated chlamydial urethritis or cervicitis after conventional azithromycin® or doxycycline therapy [Ridgway 1997; 1998; 2000].
At first sight, cost is an issue with azithromycin® therapy although this is now much less an issue even though single dose azithromycin therapy is generally more expensive than a seven day course of doxycycline. In the UK, the approximate cost of 1 g azithromycin is £7-£9, ($US 10-13) compared with £ 3-5 ($US 4-7) for a week's course of doxycycline (100 mg twice a day). However, if the cost of follow-up clinic visits is also taken into account, it is calculated that for every 100 patients there was an overall saving of £360 in the azithromycin-treated group compared with the doxycycline-treated group [Carlin & Barton, 1996]. In Canada, the cost of successfully treating a laboratory confirmed case of C. trachomatis female genital tract infection was $Can 184.76 for azithromycin® versus $240.59 for doxycycline. For presumptive treatment based on clinical acumen alone, the comparable figures were $Can 51.48 for azithromycin versus $51.82 for doxycycline [Marra et al., 1997].
The usefulness of azithromycin in more complicated upper genital tract infection in women is less clear. In pelvic inflammatory disease a preliminary study of 500mg iv on day one, followed by 250 mg orally daily for 6 days, without metronidazole, eradicated 100% of C. trachomatis, _and 100% of _Neisseria gonorrhoeae with a clinical cure rate of 96.7% [Ridgway 2000].
Anti chlamydial therapy in pregnancy is a problem, because tetracycline is contra-indicated and erythromycin is often poorly tolerated. Azithromycin is also recommended by the US Center for Disease Control and Prevention for the treatment of chlamydial genital tract infection in pregnant women [CDC 1998], because it is better tolerated in pregnancy than is erythromycin. A recent Cochrane review of published studies of the treatment of _ C. trachomatis infections_ in pregnancy concluded that azithromycin was probably effective in these circumstances, but numbers were small [Brocklehurst & Rooney, 2002].
Azithromycin® or tetracycline are also part of the WHO Prevention of Blindness programme for reducing the blinding sequelae of trachoma. A Cochrane meta-analysis of tetracycline/chlortetracycline eye ointment versus oral azithromycin® in 15 studies which randomised 8678 participants concluded that, although there was some evidence that antibiotics reduce active trachoma, the results were not consistent and cannot be pooled [Mabey & Fraser-Hurt, 2002].
Other macrolides or ketolides
Other new macrolide antibiotics of similar anti-chlamydial efficacy to standard doxycycline therapy include: roxithromycin®, josamycin®, and clarithromycin®, of which roxithromycin® is reported to be the most effective against chlamydiae in laboratory culture [Ridgway, 1998; Gieffers et al., 2001]. Unlike azithromycin®, however, these drugs normally have to be given once or twice daily for 7 or more days.
Recently telithromycin®, the first of a new family of antibacterials, the ketolides, has been evaluated. The drug was originally designed to overcome erythromycin A resistance within Gram-positive cocci by removing the 3-L-cladinose sugar moiety from erythronolide A and oxidising the resulting 3-hydroxyl. To the 3-keto group thereby formed is attributed a lack of induction of macrolide resistance, high stability in acidic environments, and the ability to overcome resistance caused by methylation of 23SrRNA. Furthermore the C11 - C12 carbamate ketolides are able to overcome efflux and hydrolysis mechanisms of resistance and have additional ribosomal mechanisms of action against bacterial protein synthesis compared with erythromycin A. The side-chain substituting the C11 - C12 carbamate residue also enhances its in vitro and in vivo activities compared with clarithromycin, its pharmacodynamic and pharmacokinetic properties, intracellular and tissue penetration, and patient tolerance. Further modifications of the C11 - C12 side-chain are likely to lead to the development of new ketolides [Bryskier, 2000]. Telithromycin® has been advocated for the treatment of community acquired pneumoniae due to C. pneumoniae and other respiratory organisms [Hammerschlag et al., 2001; Miyashita et al., 2001]. The in vitro pharmacokinetics and chlamydiacidal activity of telithromycin and another ketolide against two strains of C. pneumoniae have been reported by Gustafsson et al., 2000. Another study reported that the in vitro activity of telithromycin against twenty strains of C. pneumoniae ranged between 0.031 and 0.25 mg/L [Miyashita et al., 2001]. To put this in perspective, telithromycin was twice as active as roxithromycin, azithromycin or erythromycin A, but less active than clarithromycin [Miyashita et al., 2001] or another experimental ketolide, ABT 773 [Stringl et al., 2000], which had a minimal bactericidal concentration at which 90% of twenty C. pneumoniae isolates were killed of 0.015 mg/L.
INDEX: Antibiotic treatment web home.
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Bryskier A., Agouridas, C. & Chantot, J. F. (1993). Structure and activity. In: _New Macrolides, Azalides and Streptogramins (Neu, H et al., Eds) pp3 - 11, Marcel Dekker, New York [Book]
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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.
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.
Gustafsson, I., Hjelm, E. & Cars, O. (2000). In vitro pharmacodynamics of the new ketolides HMR 3004 and HMR 3647 (Telithromycin) against Chlamydia pneumoniae. Antimicrobial Agents and Chemotherapy *44, 1846 - 1849. Full article
Hammerschlag, M. R., Roblin, P. M. & Bebear, C. M. (2001). Activity of telithromycin, a new ketolide antibacterial, against atypical and intracellular respiratory tract pathogens. Journal of Antimicrobial Chemotherapy *48 Suppl T1, 25 - 31. [Review].
Mabey, Denise & Fraser-Hurt, N. (2002). Antibiotics for trachoma (Cochrane Review). In: The Cochrane Library, Issue 2, 2002. Oxford: Update Software.
Marra, F., Marra, C. A., Patrick, D. M. (1997). Cost effectiveness analysis of azithromycin and doxycycline for Chlamydia trachomatis infection in women. A Canadian perspective. Canadian Journal of Infectious Diseases 8, 202 - 208.
Miyashita, N., Fukano, H., Niki, Y. & Matsushima, T. (2001). In vitro activity of telithromycin, a new ketolide, against Chlamydia pneumoniae. Journal of Antimicrobial Chemotherapy 48, 403 - 405.
Ridgway, G. L. (1997). Treatment of chlamydial genital infection. Journal of Antimicrobial Chemotherapy 40, 311 - 314. Full article [Review].
Ridgway, G. L. (1998). Treatment of Chlamydia trachomatis infections. 4th Bandolier Conference on Evidence Based Medicine.
Ridgway, G. L. (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.
Strigl, S., Roblin, P. M., Reznik, T. & Hammerschlag, M. R. (2000). In vitro_ activity of ABT 773, a new ketolide antibiotic, against Chlamydia pneumoniae. Antimicrobial Agents and Chemotherapy 44, 1112 - 1113. Full article
INDEX: Antibiotic treatment web home.