Delivery of azithromycin to Chlamydia trachomatis-infected polarized human endometrial epithelial cells by polymorphonuclear leucocytes

Paul, Terry R.; Knight, Stephen; Raulston, Jane E.; Wyrick, Priscilla B.

doi:10.1093/jac/39.5.623

Cited by 22 publications

(21 citation statements)

References 19 publications

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“…In addition to this, it has been suggested by Horner (7) that heterotypic resistance could develop, and this phenomenon happens with chlamydiae at high infectious loads (20,21). Furthermore, the lack of an inflammatory response would remove the possibility of polymorphonuclear leukocytes (PMNs) delivering the Az directly to the site of infection (14). Another possibility is that treatment failures could be a consequence of the single-dose therapy for Az.…”

Section: Discussionmentioning

confidence: 99%

Differential Susceptibilities to Azithromycin Treatment of Chlamydial Infection in the Gastrointestinal Tract and Cervix

Yeruva

Melnyk

Spencer

et al. 2013

Antimicrob Agents Chemother

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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. Chlamydia trachomatis remains the most commonly reported infectious disease in the United States. More than 1.4 million cases of chlamydial infection were reported to the CDC in 2011, the largest number of cases ever reported to the CDC for any infection. The reported numbers of cases are highest for adolescent girls (15 to 19 years of age) and young women (20 to 24 years of age). A major problem with chlamydial infections is that in the majority of cases, the infections remain subclinical and "persist" for long periods of time if not treated. Of course, it is difficult to determine if the "persistent" infections are the original infection or the result of treatment failure or the individual has become reinfected from a partner.Alternatively, it is possible that women become autoinfected from the gastrointestinal (GI) tract. It should be noted that in most animals, including birds, sheep, cattle, pigs, mice, and guinea pigs, the natural site of chlamydial infection is the GI tract, and the organisms are transmitted by the fecal-oral route. We and others have reported that mice remain infected in the GI tract with Chlamydia muridarum indefinitely in the absence of pathology (1-3) even though genital infections resolve within 3 to 4 weeks with an intense inflammatory response. Because chlamydiae persist in the GI tract of other mammalian and avian species, it is plausible that chlamydiae may also establish long-term colonization of the human GI tract. In fact, there is ample evidence that women become infected orally and that chlamydiae can be isolated from rectal swabs in the absence of anal intercourse (4). Jones and colleagues showed that women may be positive in the rectum but negative in the cervix (4...

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Section: Discussionmentioning

confidence: 99%

Differential Susceptibilities to Azithromycin Treatment of Chlamydial Infection in the Gastrointestinal Tract and Cervix

Yeruva

Melnyk

Spencer

et al. 2013

Antimicrob Agents Chemother

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“…Finally, another significant biological function difference involves the pharmacokinetics of antibiotic uptake. Polarized HEC-1B cells internalize and concentrate threefold more [ 14 C]azithromycin than nonpolarized HEC-1B cells (39,51), which is reflected in lower 90% minimal bactericidal concentrations for inhibiting serovar E infection (37).…”

Section: Discussionmentioning

confidence: 99%

Differences in Chlamydia trachomatis Serovar E Growth Rate in Polarized Endometrial and Endocervical Epithelial Cells Grown in Three-Dimensional Culture

et al. 2007

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In vitro studies of obligate intracellular chlamydia biology and pathogenesis are highly dependent on the use of experimental models and growth conditions that mimic the mucosal architecture and environment these pathogens encounter during natural infections. In this study, the growth of Chlamydia trachomatis genital serovar E was monitored in mouse fibroblast McCoy cells and compared to more relevant host human epithelial endometrium-derived HEC-1B and cervix-derived HeLa cells, seeded and polarized on collagencoated microcarrier beads, using a three-dimensional culture system. Microscopy analysis of these cell lines prior to infection revealed morphological differences reminiscent of their in vivo architecture. Upon infection, early chlamydial inclusion distribution was uniform in McCoy cells but patchy in both epithelial cell lines. Although no difference in chlamydial attachment to or entry into the two genital epithelial cell lines was noted, active bacterial genome replication and transcription, as well as initial transformation of elementary bodies to reticulate bodies, were detected earlier in HEC-1B than in HeLa cells, suggesting a faster growth, which led to higher progeny counts and titers in HEC-1B cells upon completion of the developmental cycle. Chlamydial development in the less relevant McCoy cells was very similar to that in HeLa cells, although higher progeny counts were obtained. In conclusion, this three-dimensional bead culture system represents an improved model for harvesting large quantities of infectious chlamydia progeny from their more natural polarized epithelial host cells.Chlamydia trachomatis serovars D to K are oculogenital pathogens and the leading cause of bacterial sexually transmitted diseases (41). It is estimated there are 3 to 4 million cases of chlamydial sexually transmitted diseases annually in the United States and some 90 million cases per year worldwide (7). Since the majority of infected individuals are essentially asymptomatic and do not seek medical attention, ascending migration can occur and lead to serious complications, such as prostatitis and epididymitis in men and pelvic inflammatory disease, salpingitis, ectopic pregnancy, and infertility in women (12,14).Chlamydiae are obligate intracellular bacteria and, as such, must be internalized into superficial epithelial cells of the genital mucosa in order to initiate the infectious process. Infection begins with attachment of the infectious elementary bodies (EB) form to the apical surface of columnar epithelial cells, followed by entry via various endocytic mechanisms. The EBcontaining endosomes exit the endocytic pathway to avoid fusion with lysosomes and travel on microtubules to the nuclear hof, where they undergo homotypic fusion with one another, and then the EBs transform into metabolically active reticulate bodies (RB). Since RB divide by binary fission and the number of progeny increases, the expanding endocytic vesicle is termed an inclusion. Eventually, RB mature back into infectious EB, and this devel...

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“…There are actually fewer chlamydiae in the GI tract than in the genital tract (26), so it is unlikely that failure to cure infection in the GI tract is related to the number of organisms. One possible explanation is that azithromycin is delivered to an infection site by PMNs (59). The lack of inflammation in chlamydial infection of the GI tract in contrast to the genital tract might reduce the amount of azithromycin delivered to the infection site.…”

Section: Implications Of Chlamydial Gi Infection For Persistent or Rementioning

confidence: 99%

Hidden in Plain Sight: Chlamydial Gastrointestinal Infection and Its Relevance to Persistence in Human Genital Infection

2014

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Although the concept of persistence in chlamydial infections has been recognized for about 80 years, there is still very little known about the mechanism by which this occurs. In this review, we revisit an old paradigm, long known to chlamydiologists and veterinarians, that in virtually all hosts of chlamydiae, including mammals and birds, chlamydiae reside in the gastrointestinal tract for long periods of time in the absence of clinical disease. Thus, if gastrointestinal infection occurs in most hosts, then it is very likely that gastrointestinal infection occurs in humans as well. We demonstrate that gastrointestinal infection does indeed occur in humans and propose that this anatomical site is the source of persistent infection in humans. The data in ruminants and animal models demonstrate that the immune system is unable to clear chlamydiae from the gut, so they can remain indefinitely, with continual shedding in feces. Clearly, many women become reinfected from an untreated partner; however, we propose that women, cured of genital infection, remain at risk for autoinoculation from the lower gastrointestinal tract. Moreover, there are substantial data demonstrating treatment failure of chlamydial infections, particularly with azithromycin. New data in the mouse model have shown that azithromycin is far less effective against chlamydial gastrointestinal infection than against genital infections. Therefore, it is possible that women cured of genital infection by antibiotics remain infected in the gastrointestinal tract and can become reinfected by autoinoculation from that site.

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Delivery of azithromycin to Chlamydia trachomatis-infected polarized human endometrial epithelial cells by polymorphonuclear leucocytes

Cited by 22 publications

References 19 publications

Differential Susceptibilities to Azithromycin Treatment of Chlamydial Infection in the Gastrointestinal Tract and Cervix

Differential Susceptibilities to Azithromycin Treatment of Chlamydial Infection in the Gastrointestinal Tract and Cervix

Differences in Chlamydia trachomatis Serovar E Growth Rate in Polarized Endometrial and Endocervical Epithelial Cells Grown in Three-Dimensional Culture

Hidden in Plain Sight: Chlamydial Gastrointestinal Infection and Its Relevance to Persistence in Human Genital Infection

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