< > Home : FAQ : Professional : Chlamydiales : Immunobiology : Infections : Diagnosis & Treatment : Links : Contact Us

Treatment of chlamydial infections

It has long been known that rifampin [Vesely et al., 1998], an antibiotic produced by Streptomyces mediterranei is one of the most highly active drugs against chlamydiae but resistance to it is easily produced by passage in vitro in increasing concentrations of the drug.  Resistance arises by single or multi-step mutations in the rpoB gene encoding bacterial RNA polymerase subunit B. The drug blocks the initiation but not elongation of RNA transcripts from prokaryotic but not eukaryotic DNA. Resistance is associated with limited amino acid changes in a few mutational hot spots on rpoB [Dreses-Werringloer et al., 2003]. In this respect chlamydiae are similar to other bacteria. The drug penetrates cells well, making it potentially useful for treating infections with intracellular bacterial pathogens. However because of resistance, rifampin is usually used in combination therapy [Dreses-Werringloer et al., 2003; Vesely et al., 1998].  Dreses-Werringloer et al., 2001 compared the effect of long term azithromycin, rifampin or azithromycin plus rifampin therapy on C. trachomatis infection in cell culture. Prolonged treatment with azithromycin failed to eliminate the chlamydial infection leading to a state of persistent infection characterised by culture-negative, but viable, metabolically active chlamydiae, as demonstrated by the presence of short-lived rRNA transcripts, with aberrant inclusions and an altered steady-state level of chlamydial antigens with a predominance of chsp60 protein compared to the major outer membrane protein. Eventually treatment with azithromycin resulted in suppression of rRNA synthesis. Rifampin in contrast was highly active by in vitro susceptibility testing, but prolonged exposure lead to the emergence of resistance. In combination with azithromycin, no rifampin resistance emerged and the combined regime was more effective than azithromycin alone in that suppression of rRNA synthesis occurred earlier. Wolf & Malinverni 1999 also found that azithromycin plus rifampin was more effective than azithromycin alone at eradicating experimental C. pneumoniae infection of the mouse lung.

Side effects of rifampin therapy include neutropaenia, eye and muscle irritation and orange discolouration of the skin and urine. This, together with the usefulness of rifampin in combination therapy for treating tuberculosis and concerns over resistance has lead to the drug being largely restricted to the treatment of mycobacterial infections or the pre-emptive treatment of susceptible persons in close contact with cases of meningococcal meningitis. However, new semi-synthetic derivatives designed to replace rifampicin and the related rifabutin are emerging with valuable pharmacological properties.

Rifalazil^®, benzoxazinorifamycin, is one of a new generation of semi synthetic rifamycins, the ansamycins, with a unique four ring structure [Rothstein et al., 2003] and which has a half life of some 60 hours making it, like azithromycin, particularly suitable for single dose therapy of  patients with genitourinary chlamydial infection where compliance with therapy is often a problem. Roblin et al., 2003 compared the in vitro activities of rifalazil and its derivatives ABI-1657 and ABI-1131, azithromycin, and levofloxacin against 10 strains of C. trachomatis and 10 recent clinical isolates of C. pneumoniae. The MICs at which 90% of the isolates were inhibited and the minimal bactericidal concentration at which 90% of the isolates were killed for ABI-1648, ABI-1657, and ABI-1131 were 0.0025 micro g/ml for C. trachomatis and 0.00125 to 0.0025 micro g/ml for C. pneumoniae. Thus these semi-synthetic rifamycins were 10- to 1,000-fold more active than azithromycin and levofloxacin. Rifalazil is at the early stages of clinical trial, but early results [Dietze et al., 2001] indicate that the drug is reasonably well tolerated despite transient reductions in neutrophil counts in 10 to 20% of patients undergoing treatment for tuberculosis.

Conclusion

The rifamycins are potentially valuable drugs against chlamydiae when used in combination therapy, because of their high activity and good intracellular penetration but there is insufficient clinical evidence. Rifalazil awaits adequate clinical trial in a chlamydial setting, but in vitro results suggest that, used with azithromycin, it may be more effective than azithromycin alone for eradicating chronic C. trachomatis and C. pneumoniae infection. Combination therapy with these two drugs is likely to be expensive. Careful clinical trials are indicated in order to determine whether the potential benefits of combined therapy using a rifamycin outweighs possible adverse reactions which include neutropaenia. Thus this combination is currently indicated for approved clinical experimental studies only.

[MEW] August 2003

NEXT:  

References