Emergence of Rifampin-resistance in Chlamydia trachomatis

Infections caused by the obligate intracellular bacteriumChlamydia trachomatis are among the most prevalent causes of ocular and urogenital diseases worldwide. Clinical manifestations of acute infections related to C. trachomatis serovars A to C or serovars D to K are trachoma or cervicitis and urethritis, respectively. These infections can progress to persistent infections, which may initiate a pathogenic process that leads to chronic diseases including blindness or pelvic inflammatory disease, ectopic pregnancy, tubal factor infertility, and chlamydia-induced arthritis, including Reiter's syndrome.Standard therapy for acute urogenital tract infections is a 7-day course of doxycycline or a single dose of azithomycin. Both regimens have been shown to result in satisfactory cure rates in clinical trials (20,21,32,34,40,43,49).Relapsing chlamydial infections are, however, a common problem, even though patients are often treated appropriately (6, 24, 56). Usually, recurrent infections are supposed to be a consequence of reinfection. Most of the clinical trials that have addressed relapsing chlamydial infections did not distinguish between reinfection and relapse and thus did not define the role of persistence. There are, however, recent reports of recurrent infections after appropriate antibiotic treatment which appeared to be a result of the persistence of chlamydia (15,25,38).This observation presents an apparent contradiction to results of determination of the MIC and the minimum bactericidal concentration (MBC), which clearly indicated successful suppression of chlamydial growth by clinically used antibiotics. The experimental setting involved with this kind of in vitro testing is, however, not truly reflective of the situation in vivo for chlamydial infection. In natural infections, chlamydia are usually exposed to antimicrobials long after an infection has been well established. In contrast, the conventional in vitro systems used for susceptibility testing represent a quite different condition, in that antibiotics are added usually 48 h after the infectious agent is added or are sometimes added simultaneously with the infectious agent. Recently, we could demonstrate that ciprofloxacin and ofloxacin not only failed to eradicate chlamydia from host cells but induced a persistent infection, although both antibiotics are efficient in susceptibility testing (16). Using this in vitro model, we investigated the efficacies of azithromycin, rifampin, and the combination of azithromycin and rifampin for the elimination of chlamydia from epithelial cells. MATERIALS AND METHODSCells. Cells of the HEp-2 cells line, a human laryngeal epidermoid cell line, were maintained at 37°C with 5% CO 2 in RPMI 1640 medium supplemented with 10% fetal calf serum (Seromed, Berlin, Germany), 1% L-glutamine, and 100 g of gentamicin (Seromed) per ml.Growth, purification, and titration of chlamydia. C. trachomatis serovar K/UW-31/Cx (obtained from the Washington Research Foundation, Seattle) was cultured in HEp-2 cells, as described recentl...

Section: Vol 45 2001 Effects Of Azithromycin and Rifampin On C Trasupporting

confidence: 83%

Effects of Azithromycin and Rifampin onChlamydia trachomatisInfection In Vitro

Dreses-Werringloer

Padubrin

Zeidler

et al. 2001

“…Relative resistance of C. trachomatis to erythromycin in vitro has been noted (10), and erythromycin stearate given in 250-mg doses four times daily for 7 days resulted in frequent failure to eradicate C. trachomatis from men with nongonococcal urethritis (W. R. Bowie, unpublished data). Resistance to rifampin is easily produced in vitro (8), and there is concern about resistance arising in vivo.…”

mentioning

confidence: 99%

Lack of in vitro activity of cefoxitin, cefamandole, cefuroxime, and piperacillin against Chlamydia trachomatis

Bowie¹

1982

“…Rifampin and other rifamycins have been known for over 30 years to be very active in vitro against C. trachomatis and C. pneumoniae, with MICs ranging from 0.0075 to 0.03 g/ml (7,8,10,11). However, as early as 1973, Keshishyan et al (8) demonstrated rapid single-step emergence of resistance to rifampin in C. trachomatis in eggs.…”

mentioning

confidence: 99%

“…However, as early as 1973, Keshishyan et al (8) demonstrated rapid single-step emergence of resistance to rifampin in C. trachomatis in eggs. Similar results were also obtained in tissue culture (11).…”

mentioning

confidence: 99%

“…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 g/ml for C. trachomatis and 0.00125 to 0.0025 g/ml for C. pneumoniae. ABI-1648, ABI-1657, and ABI-1131 were 10-to 1,000-fold more active than azithromycin and levofloxacin.Although rifamycins, including rifampin, have been demonstrated to have excellent activity against Chlamydia pneumoniae and Chlamydia trachomatis in vitro, because of concern about the potential rapid development of resistance, these compounds have not been evaluated for the treatment of human chlamydial infections (3,4,7,8,10,11). ABI-1648 (rifalazil, KRM-1648) is a semisynthetic rifamycin which has demonstrated potent activity against a variety of bacteria, including Mycobacterium tuberculosis, Mycobacterium avium complex, gram-positive bacteria including Staphylococcus aureus, Streptococcus pneumoniae, and Streptococcus pyogenes, and most recently Helicobacter pylori (1, 5).…”

mentioning

confidence: 99%

See 1 more Smart Citation

In Vitro Activities of Rifamycin Derivatives ABI-1648 (Rifalazil, KRM-1648), ABI-1657, and ABI-1131 against Chlamydia trachomatis and Recent Clinical Isolates of Chlamydia pneumoniae

Roblin

Reznik

Kutlin

et al. 2003

ABI-1648 (rifalazil) is a semisynthetic rifamycin with potent bactericidal activity against intracellular respiratory bacteria, including Mycobacterium tuberculosis, and a long half-life (ϳ60 h) and thus can be administered once weekly. We therefore tested the in vitro activities of ABI-1648, its derivatives ABI-1657 and ABI-1131, azithromycin, and levofloxacin against 10 strains of Chlamydia trachomatis and 10 recent clinical isolates of Chlamydia 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 g/ml for C. trachomatis and 0.00125 to 0.0025 g/ml for C. pneumoniae. ABI-1648, ABI-1657, and ABI-1131 were 10-to 1,000-fold more active than azithromycin and levofloxacin.Although rifamycins, including rifampin, have been demonstrated to have excellent activity against Chlamydia pneumoniae and Chlamydia trachomatis in vitro, because of concern about the potential rapid development of resistance, these compounds have not been evaluated for the treatment of human chlamydial infections (3,4,7,8,10,11). ABI-1648 (rifalazil, KRM-1648) is a semisynthetic rifamycin which has demonstrated potent activity against a variety of bacteria, including Mycobacterium tuberculosis, Mycobacterium avium complex, gram-positive bacteria including Staphylococcus aureus, Streptococcus pneumoniae, and Streptococcus pyogenes, and most recently Helicobacter pylori (1, 5). ABI-1648 is also distinguished by having a long half-life, approximately 60 h, which has allowed once-weekly dosing in patients with pulmonary tuberculosis (2). Acquired drug resistance did not occur in any patient in this trial (2). We therefore tested the in vitro activities of ABI-1648, its derivatives ABI-1657 and ABI-1131, azithromycin, and levofloxacin against C. trachomatis and recent clinical isolates of C. pneumoniae.Strains of C. trachomatis tested included E-BOUR (ATCC VR-384B), F-IC-CAL3 (ATCC VR-346), H-UW-43 (ATCC VR-879), J-UW-36 (ATCC VR-886), L 2 434 (ATCC VR-902B), and five clinical cervical isolates. Isolates of C. pneumoniae tested included reference isolates TW183 and AR-39 (Washington Research Foundation, Seattle; ATCC VR-2282 and ATCC 53592), six recent clinical isolates (109, 453, 493, 912, 08002, and 08016) from adults enrolled in a multicenter community-acquired pneumonia treatment study conducted in the United States, and W6805 and J21, clinical isolates from Wisconsin and Japan, respectively. ABI-1648, ABI-1657, and ABI-1131 (ActivBiotics, Cambridge, Mass.), azithromycin (Pfizer, New York, N.Y.), and levofloxacin (Ortho Pharmaceuticals, Raritan, N.J.) were supplied as powders and solubilized according to the manufacturers' instructions. Susceptibility testing of C. trachomatis and C. pneumoniae was performed in cell culture with HEp-2 cells grown in 96-well microtiter plates as previously described (6). Each experiment was set up in duplicate plates. Each well was inoculated with 0.1 ml of the test orga...