**5. Treatment and control: how far have we come?**

Well we have come far in understanding Chlamydia. Once surprised humans by its lack of peptidoglycan in its structure yet being sensitive to penicillin [37]. Years later research revealed that unlike other bacterial species, members of the Chlamydiacae do not synthesize Peptidoglycan (PG) in their cell wall or "sacculus" but their PG is maintained in a narrow band that corresponds to the plane of septal division [38]. This PG "ring" has an active role in cell division of Chlamydia [39]. It is therefore included in the group of 'peptidoglycan-intermediate' organisms. Other such organisms are the Wolbachia, *Orientia tsutsugamushi* and *Anaplasma marginale* [40]. Peptidoglycan is a potent stimulator of the immune system and Chlamydia has perfectly cloaked it once to be a mystery for quite some time.

Treatment was targeted using the initial available antibiotics such as penicillin, amoxicillin in 1970s. Penicillin did not eradicate *C. trachomatis* but did inhibt its inclusion formation in in vitro studies when added within 1 h [41]. Amoxicillin 10 day course did eradicate it (unpublished observations of W. R. Bowie, E. R. Alexander, and K. K. Holmes). Gentamicin, Streptomycin, metronidazole and nalidixic acid were inactive against *C. trachomatis*. Tetracycline and erythromycin exhibited poor effects clinically, with good in vitro activity. In vitro under all tested conditions, doxycycline, minocycline and rifampin were more efficacious than tetracycline. The emerging most effective antimicrobial agent was turning out to be doxycycline [42].

In 1990s a new azalide antibiotic azithromycin was found effective both in vitro and in vivo; with ability to block formation of elementary bodies [43]. Azithromycin and doxycycline were then extensively investigated various studies and experiments. Studies reported Single dose azithromycin superior to 3 days course of doxycycline for various species of chlamydia [44]. Mass drug administration (MDA) of single dose of Azithromycin began to be employed widely for trachoma as part of its elimination strategy. Later studies emerged which reported that single round of MDA brought down the overall active trachoma prevalence but had no influence on ocular *C. trachomatis* infection [45]. MDA of azithromycin has shown to be inadequate when encountered with heavy infection load, and this leads to persistence of infection post MDA. There is concern that MDA can lead to development of resistance in other organisms, notably *Streptococcus pneumoniae.* This is not after single round of MDA, but multiple rounds [46]. The first report of persistent or relapsing infection due to multidrug-resistant *C. trachomatis* came forward in year 2000. All 3 isolates in the report demonstrated resistance to azithromycin, ofloxacin and doxycycline at concentrations >4.0 μg/mL [47].

Azithromycin rapidly rose as the choice of treatment because of its less frequent dosing and high efficacy, was incorporated in trachoma elimination strategy. In 1998 Centers for Disease Control recommended Azithromycin as the first-line therapeutic regimen to treat genital infections in women and men. But then came growing emergence of resistance to it in urogenital and rectal isolates. Its detailed pharmacokinetics study unearthed the reasons for its new challenges. The action of azithromycin being pH dependant, unionized at high pH and only unionized form can go intracellular. It needs polymorphonuclear cells to be transported to the site of inflammation. More bacterial load is reported in rectoanal samples than endocervical. Higher MIC values have been found for Azithromycin in these samples, almost 2 fold higher.

A double blind RCT (2021) in 177 participants reported a "1-week course of doxycycline was significantly more effective than a single dose of azithromycin for the treatment of rectal CT in MSM" [48]. It is a conundrum that a significant proportion of women, with no history of anal intercourse, have asymptomatic rectal chlamydia infection. In what way this will influence the treatment in women is still unfolding. There is a theory that this rectal infection might be a "reservoir for reinfection of the vagina and sexual transmission" [49]. Hence antibiotic that tackles the rectal *Chlamydia trachomatis* is the need of the hour [50]. For the same STI, same antimicrobial or same regimen of dosing might not be the answer for different sites of infection in the body.

More research and trials, and the limitations with azithromycin are taking us back to Doxycycline when it comes to *C. trachomatis*. Doxycycline is promising even when used as a prophylaxis to prevent bacterial STIs as seen in short term RCTs and clinical studies, but robust evidence is still in need for this [51]. The target population for this need of prophylaxis is MSM, which would also help in less transmission of HIV by maintaining the mucosal integrity that gets broken which allows easy transmission of HIV and vice versa.

But the challenges are increasing each day when it comes to fight with CT. In a study from India that investigated isolates from females with recurrent chlamydial infection, decreased susceptibility to the present first line antibiotics (doxycycline and azithromycin) was noticed [52].

There is indeed a compelling need to research more about the antimicrobial resistance mechanism. There are two types of resistance that have been seen in Chlamydia specieshomotypic and heterotypic. In homotypic resistance the organisms mostly survive above MIC (Minimal Inhibitory Concentration) of the antibiotic, whereas in heterotypic less than 1% of the organisms can survive above MIC [53]. "Azithromycin resistance of *C. trachomatis* is often a result of the mutations in the peptidyl transferase region of 23S rRNA genes, tetracycline resistance is usually linked to the presence of foreign genomic islands

#### *Chlamydia: The Secret Enemy from the Past to Present, and Future DOI: http://dx.doi.org/10.5772/intechopen.110902*

integrated in chlamydial chromosome, a predominant mechanism of fluoroquinolone resistance is a point mutation in the gyrA quinolone-resistance-determining region. A nucleotide substitution in rpoB gene is responsible for rifampin resistance" [54].

As we have no effective new antimicrobials for STI on the horizon, there is a dire need to optimize the use of available antibiotics with respect to their dose, regimen of dosing and their simultaneous use with other antibiotics.

Humans have been devising new control strategies continuously. SAFE has been able to decrease the load of trachoma very well. But when it comes to urogenital and rectal Chlamydia, the screening approaches have their pros and cons. It's still a debate whether universal screening or targeted screening is the solution. Universal screening is indeed obviously more effective, but the question is- is it cost effective?

Who to screen and how is still being subjected to multiple studies and reviews in order to frame the best pronged guidelines. Among 18–31 years old women, Mehta et al. observed that a greater number of PID cases were prevented by screening (universal and selective) using Ligase Chain Reaction (LCR) in urine for chlamydia and gonorrhea as compared to the usual practice of treating only self-reported or symptomatic cases [55]. Combining both standard procedure and screening turned out to be more cost effective in women, as the sequelae affect them for their future lives. Whereas in men the standard method of treating detected cases was better with respect to the cost involved, when compared to enhanced screening [55].

Mass Drug Administration has proven quite useful in control of trachoma, but the frequency of it depends on the prevalence and transmission rates in the area targeted. In high prevalence areas with trachoma annual MDA is not enough, quarterly MDA has been thought as a better control strategy. When it comes to urogenital and rectal Chlamydia control, the acceptability of MDA is not established. Pre-exposure prophylaxis in population at risk e.g. MSM has reduced transmission in pilot studies [56]. Also the impending threat of antibiotic resistance always prevails.

While talking of control practices one thing that should never be missed is safe sexual practices and stress over sex education from early adolescent life can be the best cost effective strategy.
