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Title: Differential susceptibilities to azithromycin treatment of chlamydial infection in the gastrointestinal tract and cervix

Author
item YERUVA, LAXMI - Arkansas Children'S Nutrition Research Center (ACNC)
item MELNYK, STEPAN - University Arkansas For Medical Sciences (UAMS)
item SPENCER, NICHOLE - Arkansas Children'S Nutrition Research Center (ACNC)
item BOWLIN, ANNE - University Arkansas For Medical Sciences (UAMS)
item RANK, ROGER - University Arkansas For Medical Sciences (UAMS)

Submitted to: Antimicrobial Agents and Chemotherapy
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/30/2013
Publication Date: 6/5/2014
Citation: Yeruva, L., Melnyk, S., Spencer, N., Bowlin, A., Rank, R.G. 2014. Differential susceptibilities to azithromycin treatment of chlamydial infection in the gastrointestinal tract and cervix. Antimicrobial Agents and Chemotherapy. 57(12):6290-6294.

Interpretive Summary: Chlamydia trachomatis is the major bacterial cause of sexually transmitted infection in the world with 1.4 million cases annually in the U.S. (CDC, 2011). The greatest portion of cases occurs in adolescents with an incidence of 6.8% in sexually active females aged 14-19. While the majority of infections do not result in clinical signs and symptoms, the organisms may move up the genital tract to the Fallopian tubes where they can cause inflammation, leading to pelvic inflammatory disease, obstruction of the Fallopian tubes and infertility. Rationale: Firstly, we have also shown that the gastro intestinal (GI) infection in mice does not resolve and that there is no inflammatory response to the infection in the GI tract although there is very significant inflammation in the genital tract to genital tract infection. It has also been shown that the standard antibiotic treatment for chlamydial infections, azithromycin, is not effective in some cases of genital and more often in rectal infections. Also, in some cases, although the genital infection has been cured by azithromycin treatment, the individual becomes reinfected, even if they have not been with an infected partner. This suggested to us that azithromycin may not be as effective in curing the infection in the GI tract. We infected mice in both the genital tract and the GI tract and treated them with the standard dose of azithromycin. In every case, the genital infection was cured but a high percentage of mice were not cured of the GI infection even though levels of antibiotic in the genital and GI tracts were the same. This indicated that there is something unique about the infection in the GI tract that either prevents or makes the azithromycin less effective. The importance for humans is that if a woman becomes infected in the GI tract, then she could maintain the infection indefinitely. Considering the variety of sexual practices, it is highly likely that individuals become infected orally with Chlamydia. Thus, even if a woman is treated and cured of a genital infection with antibiotics, she may remain infected in the GI tract. Since long-term immunity to chlamydial infections does not result from an infection, as a result, after the antibiotic is no longer available in the system, she may become reinfected by contamination from the lower GI tract. In addition, when a vaccine becomes available that is able to prevent or reduce the severity of genital infection, the inability of the immune response to cure GI infections suggests that the individual may continue to have infectious organisms in the lower GI tract.

Technical Abstract: Evidence from animal studies suggests that chlamydiae may persist in the gastrointestinal tract (GI) and be a reservoir for reinfection of the genital tract. We hypothesize that there may be a differential susceptibility of organisms in the GI and genital tracts. To determine the effect of azithromycin on persistent chlamydial gut infection, C57BL/6 and BALB/c mice were infected orally and genitally and treated with azithromycin (Az) orally (20, 40, or 80 mg/kg of body weight), and the numbers of chlamydiae were determined from cervix and cecal tissues. The Az concentration in the cecum and cervix was measured by high-performance liquid chromatography with electrochemical detection (HPLC-ECD). Az treatment cleared genital infection in both C57BL/6 and BALB/c mice; however, GI infection was not cleared with the same doses. HPLC data showed the presence of Az at both sites of infection, and significant amounts of Az were measured in treatment groups. However, no significant difference in Az levels between the cecum and the cervix was observed, indicating similar levels of Az reaching both sites of infection. These data indicate that antibiotic levels that are sufficient to cure genital infection are ineffectual against GI infection. The results suggest a reevaluation of antibiotic therapy for chlamydial infection.