INTRODUCTION — Chlamydia trachomatis, a small gram-negative bacterium, is the most common cause of bacterial sexually transmitted infection (STI) in both males and females [1]. In the United States, it is the most commonly reported nationally notifiable disease following SARS-CoV-2 infection (COVID-19). A significant proportion of patients are asymptomatic, thereby providing an ongoing reservoir for infection. The most frequent clinical manifestation of chlamydial infection in males is urethritis, while the most common finding in females is cervicitis.
The treatment of urethritis, cervicitis, proctitis, and epididymitis secondary to C. trachomatis infection as well as the treatment of asymptomatic infection will be reviewed here. The epidemiology, clinical manifestations, and diagnosis of these diseases, as well as other types of C. trachomatis-related diseases, such as pelvic inflammatory disease (PID), reactive arthritis, lymphogranuloma venereum, and endemic trachoma (an ocular infection seen commonly in the developing world), are discussed separately. (See "Clinical manifestations and diagnosis of Chlamydia trachomatis infections" and "Epidemiology of Chlamydia trachomatis infections" and "Screening for sexually transmitted infections", section on 'Chlamydia and gonorrhea' and "Approach to infectious causes of dysuria in the adult man" and "Pelvic inflammatory disease: Clinical manifestations and diagnosis" and "Reactive arthritis" and "Lymphogranuloma venereum" and "Trachoma".)
GENERAL PRINCIPLES
Goals of treatment — The goals of management are to:
●Prevent complicated infections related to chlamydia and their sequelae (eg, pelvic inflammatory disease [PID], infertility, chronic pelvic pain, ectopic pregnancy, epididymitis). Several trials have suggested that screening and treating young females for C. trachomatis infection reduces the rate of subsequent PID [2-4]; in turn, early therapy of PID, particularly when C. trachomatis is detected, is associated with a reduced risk of ectopic pregnancy and infertility compared with delayed therapy [5].
●Decrease the risk of transmission to others; this includes sex partners and infants at delivery, of whom the latter are at risk of acquiring ocular or pulmonary chlamydial infection from an infected mother. (See "Chlamydia trachomatis infections in the newborn".)
●Resolve symptoms; between 83 and 86 percent of symptomatic patients with cervicitis or urethritis improve clinically within two weeks of starting treatment with doxycycline or azithromycin [6].
●Prevent reinfection; persons with prior chlamydia infection are at high risk for reacquisition. (See 'Follow-up testing' below.)
Indications for empiric therapy — Empiric therapy for chlamydial infection should be offered to persons who present with symptoms of cervicitis, PID, urethritis, epididymitis, or acute proctitis. Empiric therapy of these syndromes is discussed in detail elsewhere. (See "Pelvic inflammatory disease: Treatment in adults and adolescents", section on 'Antibiotic selection' and "Urethritis in adult males", section on 'Initial therapy' and "Acute scrotal pain in adults", section on 'Acute epididymitis or epididymo-orchitis' and 'Proctitis and rectal infection' below and "Acute cervicitis", section on 'Empiric therapy'.)
Patients with a recent known or possible sexual exposure to chlamydia should also be offered empiric therapy. (See 'Management of sex partners' below and "Clinical manifestations and diagnosis of Chlamydia trachomatis infections", section on 'Patients with recent exposure'.)
In addition, empiric therapy for chlamydia should be given to patients with documented gonococcal infection, unless nucleic acid amplification testing (NAAT) is negative. (See "Disseminated gonococcal infection", section on 'Treatment of Chlamydia coinfection' and "Treatment of uncomplicated Neisseria gonorrhoeae infections", section on 'Initial treatment of urogenital and anorectal infection'.)
Antimicrobial susceptibility — C. trachomatis is uniformly susceptible to tetracyclines and macrolides, and to some but not all fluoroquinolones [7]. Penicillins are associated with in vitro persistence of C. trachomatis [8], although amoxicillin has been effective. Sulfonamides and cephalosporins have limited activity, and the aminoglycosides are inactive. However, for those agents with activity against C. trachomatis, development of antibiotic resistance is exceedingly rare.
The unique life cycle of C. trachomatis limits the breadth of active agents [1]. The infectious form of the organism, the extracellular elementary body, is metabolically inert and resistant to killing. Thus, antibiotics must target the sequestered intracellular and intravacuolar phases of the life cycle of this pathogen. For this reason, antibiotics with good intracellular penetration must be used.
In addition, antibiotic concentrations must be present throughout the entire 36- to 48-hour life cycle of the organism. Thus, either a prolonged course of therapy or selection of an antibiotic with a long half-life is required to ensure adequate levels of the antibiotic agent.
The rarity of emergent antibiotic resistance may be due in part to the intracellular nature of the pathogen, which eliminates the opportunity for rapid evolution of cell surface components that could contribute to drug resistance. Furthermore, the elementary body is relatively inert, which limits opportunities for replication and the generation of antibiotic-resistant mutations. (See 'Management of repeat infection' below and "Clinical manifestations and diagnosis of Chlamydia trachomatis infections".)
Defining antibiotic efficacy — For an antimicrobial regimen to be recommended for treatment of a sexually transmitted infection (STI), the United States Centers for Disease Control and Prevention (CDC) has specifically incorporated the microbiologic eradication as one of four principal outcomes (in addition to symptom resolution, prevention of sequelae, and prevention of transmission) [9]. Microbial cure is a more reliable parameter for drug efficacy than clinical cure for two reasons: (1) a significant proportion of patients may have other coinfections that will not respond to the administered drug; and (2) most patients have no clinical manifestations at baseline.
However, the accuracy of microbiologic tests used to assess eradication varies. Cell culture is less sensitive than NAAT, and older studies that relied on culture to detect microbiologic treatment failure tended to overestimate cure rates. (See 'Doxycycline as preferred agent' below.)
COMPREHENSIVE TREATMENT APPROACH — Complete care of the patients with C. trachomatis infection includes antibiotic treatment of the infection as well as evaluation and treatment of other sexually transmitted infections (STIs; including gonorrhea and HIV), counseling on adherence and sexual activity, follow-up testing, and management of sex partners. Most infections in females and many in males are asymptomatic and are only found on screening; nevertheless, these should also be treated promptly as outlined below. (See "Screening for sexually transmitted infections", section on 'Chlamydia and gonorrhea'.)
Our treatment approach is consistent with recommendations from the United States Centers for Disease Control and Prevention (CDC) [9].
Antibiotic treatment of chlamydia
Doxycycline as preferred agent — We agree with CDC recommendations to use doxycycline as the preferred agent to treat C. trachomatis infection in nonpregnant individuals [9]. Doxycycline is given as 100 mg twice daily for seven days; patients should be counseled on the need for adherence for optimal outcome. Delayed-release doxycycline (200 mg daily for seven days) appears as effective as and better tolerated than twice-daily doxycycline but is more costly and may not be available to many patients [10]. Dispensing the drug on site and observing administration of the first dose (directly observed therapy) improve compliance and are recommended when possible [9].
Single-dose azithromycin had previously been another preferred option, but based on mounting evidence that the microbial efficacy of doxycycline is superior, especially for rectal infection and possibly pharyngeal infection [11-17], azithromycin is now considered an alternative option. We reserve use of azithromycin for individuals who are unlikely to be able to complete the seven-day doxycycline course (eg, those for whom adherence may be a concern) and administer it as a single, directly observed 1 g dose. Azithromycin is also the preferred option for pregnant individuals. (See 'Alternative antibiotics' below and 'Pregnant women' below.)
Preference for doxycycline over azithromycin is based on the following observations:
●Slightly superior microbiologic outcomes overall – Trials indicate superior microbiologic outcomes, particularly among males; among symptomatic individuals, clinical cure rates are comparable [15]. In a meta-analysis of 23 randomized trials with over 2000 patients that compared the efficacy of doxycycline with that of azithromycin for the treatment of uncomplicated genital C. trachomatis infections in males and females, microbial cure rates were slightly but significantly higher with doxycycline than azithromycin (97.4 versus 96.2 percent, respectively) [13]. A subsequent meta-analysis also reported a higher likelihood of microbiologic cure with doxycycline than with azithromycin, although the difference was only statistically significant among males (relative risk of failure with azithromycin 2.45 [95% CI 1.36-4.41] in males and 1.71 [95% CI 0.48-6.16] in females) [15]. However, earlier studies included in those meta-analyses determined microbiologic cure with culture or enzyme immunoassay testing rather than the more sensitive nucleic acid amplification test (NAAT), so they may not have captured all failures adequately. In one of the trials included in the meta-analyses that randomly assigned males with nongonococcal urethritis to different antibiotic regimens and used NAAT to assess microbiologic cure, a doxycycline-based regimen resulted in a higher clearance rate among 115 males with C. trachomatis infection compared with an azithromycin-based regimen (94.8 versus 77.4 percent, respectively) [11].
●Substantially superior microbiologic outcomes with rectal infection – Randomized trials of patients with rectal C. trachomatis infection indicate much higher microbiologic cure rates with doxycycline than with azithromycin (see 'Proctitis and rectal infection' below). Microbial eradication at the rectal site is important for females with urogenital chlamydia, since the majority (approximately 68 percent) of those with C. trachomatis detected on vaginal specimens have concomitant rectal infection [18]; inadequately treated rectal C. trachomatis infection among such individuals may place them at risk for repeat urogenital C. trachomatis infection through autoinoculation from the anorectal site and increase the risk for transmission [19].
●Comparable adverse effect profile – Adverse effects are largely similar with the two agents. In comparative studies of doxycycline and azithromycin, adverse events occurred in approximately one-quarter of the patients in both treatment arms [16,20]. The most frequently reported adverse events were gastrointestinal in nature and included diarrhea, abdominal pain, nausea and vomiting, and dyspepsia; no serious adverse events were reported.
The main advantage of azithromycin is that it can be provided as a single dose on site at the time of diagnosis, thus ensuring adherence and immediate treatment, which are important to reduce the risk of complications, such as pelvic inflammatory disease (PID), with untreated infection. This is particularly important when asymptomatic C. trachomatis infection is detected as part of routine screening, since it is unclear how long the patient may have been infected. In one study of 4158 females with positive screening tests for C. trachomatis, only 24 percent were treated presumptively on the day of their visit [21]. Treatment was ultimately administered in 96 percent of the remaining patients but at a median interval of 21 days. Completion of the multiday doxycycline schedule is not guaranteed since directly observed therapy for the full course of doxycycline is rarely possible [22]. However, whether seven full days of twice-daily dosing are required for clinical cure is unclear, since microbiologic cures have been attained in patients with suboptimal adherence to a seven-day regimen [23].
Other antibiotic alternatives are discussed below.
Alternative antibiotics — The main alternative agents for treatment of C. trachomatis are azithromycin and the fluoroquinolones levofloxacin and ofloxacin.
●Azithromycin (1 g orally as a single dose, ideally administered with directly observed therapy) – As discussed above, azithromycin is highly effective against C. trachomatis and offers the potential for directly observed therapy at the time of diagnosis. However, it is considered an alternative because of evidence indicating a lower microbiologic cure rate with azithromycin compared with doxycycline. For nonpregnant individuals, we reserve it for patients who are unlikely to be able to complete the full doxycycline course. (See 'Doxycycline as preferred agent' above.)
●Levofloxacin (500 mg orally once daily for seven days) – Levofloxacin is highly effective against C. trachomatis, as is ofloxacin (300 mg twice daily for seven days), an alternative fluoroquinolone that may be of limited availability. However, neither offers an advantage over doxycycline, and they are generally more costly. Fluoroquinolones are also associated with potentially severe adverse effects, so for uncomplicated infections, they are generally reserved for cases when other agents are not appropriate. We rarely use fluoroquinolones to treat C. trachomatis. However, if there are other pathogens that should be covered and are expected to be susceptible to quinolones (eg, with epididymitis in males who practice insertive anal sex), it is reasonable to use levofloxacin (or ofloxacin) as an antichlamydial agent. (See 'Epididymitis' below.)
These fluoroquinolones previously had a greater role in therapy when they were used to provide coverage for both gonococcal and chlamydial infections, which can coexist. However, because of the emergence of fluoroquinolone drug resistance, they are no longer adequate coverage for Neisseria gonorrhoeae. (See 'Evaluate for and treat gonococcal coinfection' below.)
Fluoroquinolones are not as well studied for targeted therapy for C. trachomatis as doxycycline or azithromycin. Several small trials have failed to demonstrate a difference in microbiologic cure rates with various fluoroquinolones (eg, ofloxacin) versus doxycycline [15,24-26]. However, not all fluoroquinolones are appropriate; specifically, ciprofloxacin results in poor microbiologic outcomes [27]. In contrast, moxifloxacin has not been studied as targeted therapy for C. trachomatis but has demonstrated good efficacy in treating PID and is recommended as an alternative treatment regimen in select females with PID. (See "Pelvic inflammatory disease: Treatment in adults and adolescents", section on 'For outpatients who cannot receive cephalosporins'.)
Penicillins and erythromycin are notably inferior in their ability to result in microbial cure, with cure rates in the range of 85 to 89 percent [9,28]. Penicillins (ie, amoxicillin) are mainly an alternative for pregnant individuals who cannot take other agents. If these options are used for treatment of C. trachomatis, a test of cure is indicated. (See 'Test of cure for select patients' below.)
Sulfonamides and cephalosporins have limited activity and should not be used.
Evaluate for and treat gonococcal coinfection — Chlamydial and gonococcal infections may coexist in a significant percentage of community patients. All patients with chlamydia should also be tested for gonorrhea. All individuals with a positive NAAT for N. gonorrhoeae warrant treatment for gonorrhea in addition to chlamydia, even if they are asymptomatic. Those who have a negative NAAT for N. gonorrhoeae do not need additional treatment for gonorrhea. Antimicrobial regimens for treatment of gonorrhea are discussed elsewhere. (See "Treatment of uncomplicated Neisseria gonorrhoeae infections".)
In patients with chlamydia who are not tested for gonorrhea, presumptive treatment for gonorrhea is warranted in the following situations:
●In males with intracellular gram-negative diplococci on a Gram stain of urethral discharge, which has a high degree of sensitivity and specificity for gonococci. (See "Urethritis in adult males", section on 'Gonococcal urethritis'.)
●The risk of gonococcal infection is high, either because of high individual risk (eg, partner with new diagnosis of gonorrhea) or because of high local prevalence rates of gonorrhea (eg, greater than 5 percent) [9]. This type of information is obtained by calling the local public health department or checking surveillance information on the CDC website.
Presumptive treatment of gonorrhea coinfection in all patients with chlamydia is not routinely warranted because the prevalence of gonorrhea in patients with chlamydia is highly variable and often low. In certain high-risk populations, such as adolescents entering juvenile detention centers, coinfection rates as high as 50 percent have been documented [29,30]. However, in a study of more than 14,000 young adults aged 18 to 26 years in the general community, the overall prevalence of chlamydia was 4.1 percent, and the rate of concomitant gonococcal infection among those with chlamydia was 7.3 percent [31].
Screen for HIV and other STIs — As infection with one sexually transmitted infection (STI) increases the risk of infection with others, individuals diagnosed with C. trachomatis infection should be tested for other STIs, including HIV, gonorrhea, and syphilis [9]. Screening for STIs is discussed in detail elsewhere. (See "Screening for sexually transmitted infections" and "Screening and diagnostic testing for HIV infection".)
Among individuals who do not have HIV, diagnosis of a bacterial STI, such as C. trachomatis, should trigger evaluation for pre-exposure prophylaxis candidacy. (See "Patient evaluation and selection for HIV pre-exposure prophylaxis", section on 'Candidates for PrEP'.)
Pregnancy testing — Individuals of child-bearing potential with chlamydial infection should undergo pregnancy testing. This is particularly important if treatment with doxycycline is planned, as doxycycline is generally avoided during pregnancy.
Counseling
Medication adherence — It is important to educate the patient regarding treatment adherence, particularly if doxycycline is prescribed. A test of cure is indicated if nonadherence is suspected. (See 'Test of cure for select patients' below.)
One study of males and females with uncomplicated genital chlamydial infection evaluated medication adherence to doxycycline treatment by administering medications through an electronic medication system in which all pill box openings were electronically recorded [32]. Eighty percent of 223 patients returned their pill bottles for assessment. Patients were considered strictly adherent if they had opened their bottles for at least 12 of 14 doses; only 25 percent of the patients demonstrated this level of adherence.
The importance of medication adherence was illustrated by a study in which imperfect adherence to a week-long course of oral doxycycline, defined as missing one or more doses, conferred a ninefold risk of microbiologic failure among males with urethritis due to C. trachomatis [33].
Sexual activity — To avoid reinfection, patients should be instructed to abstain from sexual intercourse until they and their sex partners have been adequately treated (ie, after completion of a seven-day regimen or for seven days after a single-dose regimen) and any symptoms have resolved.
Follow-up testing — There are two different strategies for testing for chlamydia after treatment, retesting and test of cure.
Retesting for all patients — We agree with CDC recommendations to retest all patients with documented chlamydial infection for C. trachomatis three months after treatment (or at first opportunity prior to standard annual screening). The primary purpose of retesting is to detect reinfection with C. trachomatis. Retesting should be performed regardless of whether sex partners were treated and even if a test of cure four weeks after treatment completion was negative.
Epidemiologic studies have documented that persons with chlamydial infection often have a history of recently treated infection in the preceding months [34,35]. A systematic review of 38 studies of females with C. trachomatis reported a median reinfection rate of 14 percent (range 0 to 32 percent); higher rates were associated with younger age [36]. Similarly, in a study of over 144,000 positive chlamydia tests performed at a single large laboratory in the United States, the rates of repeat positive tests were 16, 14, and 15 percent among males and nonpregnant and pregnant females, respectively [37]. Repeat infections confer an increased risk of developing complicated genital infections, such as PID. Retesting is particularly important in the pregnant woman since recurrent infection could put the infant at risk of C. trachomatis ocular infection at birth [9].
Most recurrent chlamydial infections result from resumption of unprotected sex with an untreated sex partner; a history that all partners were treated is often unreliable. Some recurrent infections are acquired from new partners.
Test of cure for select patients — "Test of cure" means diagnostic testing to assess whether the administered antibiotic regimen eradicated the pathogen. Test of cure is not routinely warranted. We suggest test of cure in the following situations, when there is a risk of suboptimal microbiologic cure rates:
●Pregnancy, regardless of treatment administered
●Persistent symptoms
●Concern for nonadherence to the regimen
●Use of a regimen with inferior cure rates, such as erythromycin or amoxicillin
●Azithromycin treatment of patients with or at high risk for rectal infection
In these situations, test of cure should be performed no sooner than four weeks after treatment is completed. This is especially important when NAATs are used because C. trachomatis nucleic acid may still be detectable several weeks after treatment despite an absence of viable organisms [38,39].
Management of sex partners — Infected sex partners are often asymptomatic and, unless treated, can reinfect the index patient or transmit infection to other partners. In fact, rates of reinfection among index cases of females with C. trachomatis range from 15 to 30 percent and are typically associated with resumption of sex with previously established partners [40].
Partner assessment and treatment — Ideally, sex partners of individuals with C. trachomatis infection should be examined, tested for C. trachomatis and N. gonorrhoeae, presumptively treated, and counseled on prevention. This should occur for all individuals who had sexual contact with the patient within the 60 days prior to infection or the most recent sex partner if the last contact was more than 60 days prior.
Using public health field workers to notify exposed sex partners to have them present to medical attention or be evaluated and treated in the field is costly and not available in most areas. With few exceptions, patients and their health care providers must assume responsibility for partner management. In such cases, expedited partner therapy (EPT) is a potential recourse, as discussed below.
Expedited partner therapy — A strategy termed "expedited partner therapy" (EPT) is a way to increase the proportion of sex partners receiving treatment and to decrease rates of reinfection in the index patient. EPT refers to facilitating treatment (without examination) by giving an antibiotic or a prescription to the index patient so they can provide it to their partners or by calling in a prescription directly for the partner [41]. We suggest EPT when it is uncertain whether sex partners of individuals with C. trachomatis infection will attend a clinical facility for evaluation and treatment. However, for men who have sex with men (MSM), the decision to use EPT should be weighed against the potential missed opportunities to evaluate and counsel partners around other potential coinfections, including HIV [9]. In the United States, EPT is not prohibited in any state [42].
Regimen selection for EPT is the same as for treatment of chlamydia in general, which is discussed elsewhere (see 'Antibiotic treatment of chlamydia' above). EPT regimens for partners who warrant therapy for gonorrhea as well (eg, because of documented or presumptive infection in the index individual) are also discussed elsewhere (see "Treatment of uncomplicated Neisseria gonorrhoeae infections", section on 'Management of sexual partners'). Partners should also be provided with information on the importance of treatment, symptoms of complications to watch for, and potential adverse effects of therapy.
Several trials have supported the role of EPT; however, these were conducted among heterosexual individuals. Data on EPT among MSM are limited. In a meta-analysis of five trials evaluating patient-delivered partner therapy, the risk of persistent or recurrent C. trachomatis or N. gonorrhoeae infection was lower compared with simple patient referral for partner management (summary risk ratio 0.73, 95% CI 0.57-0.93) [43]. One of the included trials had randomly assigned 2751 patients (23 percent male) with diagnosed C. trachomatis infection, N. gonorrhoeae infection, or both to either an "expedited treatment group" or a standard referral group [44]. Patients in the expedited treatment group were given packets of cefixime and/or azithromycin to distribute to their partners, without requiring a formal medical evaluation of the partners. In the standard referral arm, patients simply notified their sex partners of the need for evaluation and treatment. Patients assigned to expedited treatment of sex partners were significantly more likely to report that all of their partners had been treated compared with those assigned to the standard referral arm (61 versus 49 percent). The trial also demonstrated a reduction in recurrent infections among those assigned to expedited treatment (relative risk of reinfection 0.75, 95% CI 0.56 to 0.97) [45].
The limitations of EPT include lost opportunities for screening and counseling [46] and a risk of adverse events related to antibiotic administration. Implementation research has also indicated that prescription EPT (in which patients are given prescriptions to provide to their partners) has more barriers to partner treatment than patient-delivered antibiotic [47]. Individual health care institutions also may have policies or regulations that preclude treatment of persons not enrolled in the institution. In the United States, however, the CDC consensus is that EPT offers a valuable means to control STIs and is an option for partner management, although ongoing evaluation of this approach is needed [45].
CONSIDERATIONS FOR EXTRAGENITAL INFECTIONS
Proctitis and rectal infection
●Proctitis – Empiric therapy for both chlamydia and gonorrhea is indicated for the treatment of patients with sexually acquired proctitis. An empiric regimen of doxycycline (100 mg twice daily) plus a single intramuscular dose of ceftriaxone (500 mg [or 1 g for individuals ≥150 kg]) is active against both [9,48]. The duration of doxycycline therapy depends on the severity of symptoms. Patients with severe proctitis may have lymphogranuloma venereum infection (LGV), which requires a full three-week course of doxycycline [49]. For patients with mild proctitis, seven days of therapy are likely adequate; however, some clinicians reasonably opt to treat these patients with the three-week course recommended for presumed LGV, particularly if nucleic acid amplification testing (NAAT) for C. trachomatis is positive. The clinical features of chlamydial proctitis and suspected LGV are discussed elsewhere (see "Lymphogranuloma venereum" and "Clinical manifestations and diagnosis of Chlamydia trachomatis infections", section on 'Proctitis and rectal infection'). Consideration of other potential pathogens in proctitis among men who have sex with men (MSM) is also discussed elsewhere. (See "Evaluation of anorectal symptoms in men who have sex with men", section on 'Proctitis'.)
●Asymptomatic rectal infection – Individuals who have isolated C. trachomatis infection of the rectum detected on screening (ie, positive C. trachomatis NAAT with negative N. gonorrhoeae NAAT) can be treated with doxycycline (100 mg twice daily) alone for one week.
We strongly favor doxycycline over azithromycin as the anti-chlamydial agent for acute proctitis and rectal infection because evidence indicates it eradicates infection considerably more effectively, although data on clinical cure for symptomatic infection are sparse.
Among males, two randomized, placebo-controlled trials of MSM who had a positive C. trachomatis NAAT on rectal screening demonstrated higher microbiologic cure rates at four weeks with one week of doxycycline than with single-dose azithromycin (in one trial of 177 participants: 91 versus 71 percent, difference 20 percent, 95% CI 9-31; and in another trial of 587 participants: 97 versus 76 percent, adjusted difference 20 percent, 95% CI 16-25) [50,51]. Almost all participants in both trials reported adherence to the seven-day course of doxycycline or placebo.
Among females, a randomized open-label trial of 357 participants with concurrent vaginal and anorectal C. trachomatis infection also demonstrated higher microbiologic cure rates at six weeks with one week of doxycycline than with single-dose azithromycin (94 versus 85 percent, adjusted difference 9 percent, 95% CI 6-13) [52].
Observational studies in males and females have similarly suggested that doxycycline is associated with higher microbiologic cure rates [53,54]. Pharmacokinetic and animal studies also suggest that azithromycin may not be optimal for rectal infection [55,56].
Epididymitis — N. gonorrhoeae and C. trachomatis are the most frequent laboratory-identified pathogens causing epididymitis among sexually active males <35 years of age. Empiric treatment of acute epididymitis covers these organisms [57]. Management of patients with acute epididymitis is discussed elsewhere. (See "Acute scrotal pain in adults", section on 'Management'.)
We recommend the combination of ceftriaxone (500 mg [or 1 g for individuals ≥150 kg]) as a single dose plus doxycycline (100 mg orally twice daily) for 10 days for the treatment of sexually transmitted acute epididymitis [9,48]. There are no data on the use of azithromycin for chlamydia in patients with epididymitis. Azithromycin can be an alternative for patients with a history of intolerance/allergy to doxycycline, but follow-up to evaluate for symptom resolution should be conducted.
Ofloxacin (300 mg orally twice daily for 10 days) or levofloxacin (500 mg daily for 10 days) is given instead of doxycycline (with ceftriaxone) to patients with epididymitis who practice insertive anal sex (because of the possible involvement with enteric organisms) and can also be used for patients who are allergic to tetracyclines; these fluoroquinolones are also active against chlamydia.
Pelvic inflammatory disease — When cervical infection is untreated, C. trachomatis ascends to the upper genital tract at least 20 percent of the time, which may manifest as either silent infection ("subclinical" pelvic inflammatory disease [PID] or silent endometritis) or overt PID [58,59]. Therefore, females with cervicitis should undergo a physical examination to exclude signs of upper tract disease (eg, cervical motion, uterine, or adnexal tenderness). Apart from direct involvement of the pelvic organs, PID can also include peritonitis and inflammation of the liver capsule (Fitzhugh-Curtis syndrome). Treatment for PID should provide broad coverage for the wide array of implicated pathogens, including antibiotics active against C. trachomatis, most commonly doxycycline. The management of PID is discussed in detail elsewhere. (See "Pelvic inflammatory disease: Treatment in adults and adolescents".)
Oropharyngeal infection — The clinical significance of oropharyngeal chlamydia is uncertain. Some studies have suggested the feasibility of transmission from oropharyngeal to genital sites [60,61]. However, a subsequent study suggested that the incidence and duration of pharyngeal chlamydia were lower than those of other extragenital STIs [62]. The implications of these findings for population-level transmission are unclear.
Although the optimal treatment regimen for oropharyngeal chlamydia has not been well studied, doxycycline is the preferred option if C. trachomatis is detected from an oropharyngeal sample [9]. (See 'Doxycycline as preferred agent' above.)
SPECIAL POPULATIONS
Pregnant women
Antibiotic selection — In addition to reducing the risk of complications of chlamydia in the mother, treatment of C. trachomatis during pregnancy prevents transmission to infants during passage through the birth canal, which can result in neonatal conjunctivitis or pneumonia. The recommended regimen for treatment of pregnant individuals is azithromycin (1 g orally given as a single dose) [9]. Amoxicillin (500 mg orally three times daily for seven days) is an alternative for those who cannot use azithromycin.
Macrolides (eg, azithromycin) are commonly used during pregnancy. Although first-trimester use of macrolides (primarily erythromycin administered for several days) was associated with an increased risk of congenital malformations compared with penicillins in one large study, the risk associated with a single dose of azithromycin remains unknown [63]. We feel that the benefits of azithromycin in this situation outweigh the possible risk. The efficacy of azithromycin is discussed elsewhere. (See 'Antibiotic treatment of chlamydia' above.)
Amoxicillin is an alternative because in vitro studies raised concern that penicillins could induce a persistent state that allowed re-emergence of viable pathogen after discontinuation [8]. Doxycycline, levofloxacin, ofloxacin, and erythromycin estolate are contraindicated in pregnancy and lactation.
Females who present in labor with an untreated prior positive C. trachomatis screening test should be treated immediately. However, this may not substantially decrease the risk of transmission of chlamydia to the newborn. (See "Chlamydia trachomatis infections in the newborn", section on 'Risk of transmission' and "Chlamydia trachomatis infections in the newborn", section on 'Prevention'.)
Follow-up — Follow-up of pregnant women treated for documented C. trachomatis infection includes both test of cure and repeat testing for reinfection.
Cure rates of C. trachomatis in pregnant females are generally lower than in nonpregnant females [64], particularly with the alternative agent amoxicillin. For this reason, a test of cure is recommended for all pregnant women and should be performed no earlier than three weeks after treatment is completed. (See 'Test of cure for select patients' above.)
As with all patients with documented C. trachomatis infection, pregnant individuals should undergo repeat testing to evaluate for reinfection three months following treatment. (See 'Retesting for all patients' above.)
Patients with HIV — The treatment of patients with HIV and C. trachomatis infections is the same as in patients without HIV.
PERSISTENT OR RECURRENT SYMPTOMS
Evaluation — It is important that patients treated for chlamydia be counseled to monitor for symptom resolution and return for evaluation of persistent or recurrent symptoms. Such symptoms could reflect incomplete adherence to the therapeutic regimen, reinfection, or infection with another pathogen not optimally treated with the initial antibiotic regimen.
For patients with persistent or recurrent symptoms, clinicians should evaluate for possible reinfection, including inquiring about whether sex partners were treated, and for other sexually transmitted infections (STIs). Other etiologic agents to consider include Mycoplasma genitalium, Trichomonas vaginalis, and genital herpes.
Evaluation and empiric management of recurrent urethritis, cervicitis, and other syndromes associated with C. trachomatis are discussed in detail elsewhere.
●(See "Urethritis in adult males", section on 'Recurrent or persistent symptoms'.)
●(See "Acute cervicitis", section on 'Recurrent or persistent disease'.)
●(See "Pelvic inflammatory disease: Treatment in adults and adolescents", section on 'Follow-up'.)
●(See "Acute scrotal pain in adults", section on 'Acute epididymitis or epididymo-orchitis'.)
Persistent symptoms after appropriate therapy with good adherence are usually not due to primary treatment failure, as suggested by studies that evaluated the likelihood of the organism persisting after appropriate antibiotic therapy:
●In a detailed prospective evaluation of 20 females with culture-proven and polymerase chain reaction (PCR)-proven C. trachomatis urogenital infections treated with doxycycline, no evidence of persistent infection was detected after five months of serial sampling with PCR, culture, and serial measurements of local and systemic antibody to C. trachomatis [65].
●One longitudinal prospective study of adolescent females with chlamydia used DNA genotyping and behavioral histories to assess whether repeated chlamydial infections may be related to reinfection versus treatment failure with azithromycin [66]. Of 183 repeat infections, only 25 (14 percent) were classified as probable or possible treatment failures.
Management of repeat infection — If C. trachomatis is again detected on repeat testing for persistent or recurrent symptoms or on routine repeat testing, we treat with the same regimen recommended for initial therapy. (See 'Doxycycline as preferred agent' above.)
Persistence or recurrence of symptoms should not be attributed to C. trachomatis drug resistance [67]; drug resistance to doxycycline (or azithromycin) has not been demonstrated to date.
Although the swine pathogen, Chlamydia suis, is commonly tetracycline resistant, there are no examples of stable tetracycline resistance in clinical strains of C. trachomatis. One in vitro study was able to demonstrate that a clinical strain of C. trachomatis was able to acquire a resistance element from a C. suis strain within coculture experiments [68].
SCREENING FOR CHLAMYDIA — Screening for C. trachomatis is a critically important tool in the control of this infection and is discussed in a separate topic review. (See "Screening for sexually transmitted infections", section on 'Chlamydia and gonorrhea'.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Sexually transmitted infections".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topic (see "Patient education: Chlamydia and gonorrhea (The Basics)")
●Beyond the Basics topic (see "Patient education: Chlamydia (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Goals of treatment – These are to prevent complicated infections related to chlamydia (eg, pelvic inflammatory disease [PID], infertility, ectopic pregnancy), decrease the risk of transmission to others, resolve symptoms in those who have them, and prevent reinfection. (See 'General principles' above.)
●Antimicrobial susceptibility – Agents with excellent activity against Chlamydia trachomatis include doxycycline (a tetracycline) and azithromycin (a macrolide). Certain fluoroquinolones (levofloxacin and ofloxacin) also have good activity but are infrequently used. Penicillins are associated with persistence of C. trachomatis in vitro, and cephalosporins and sulfonamides have limited activity. (See 'Antimicrobial susceptibility' above.)
●Doxycycline as preferred therapy – For nonpregnant individuals with C. trachomatis infection, we suggest doxycycline rather than azithromycin (Grade 2C). Although clinical cure rates are comparable, microbial cure rates with azithromycin are lower than those with doxycycline, particularly for genital infection in males and rectal infection; this has potential important public health consequences and, in females, might increase the risk of repeat genital infection from an inadequately treated rectal infection.
•Doxycycline is dosed at 100 mg twice daily for seven days, and patients should be counseled on treatment adherence. Individuals of child-bearing age should also have pregnancy testing prior to taking doxycycline. (See 'Doxycycline as preferred agent' above.)
•Azithromycin (1 g as a single dose, ideally directly observed) is an appropriate alternative for those who cannot take doxycycline or who may not be able to complete the full course. It is also the preferred option for pregnant individuals. (See 'Alternative antibiotics' above.)
•Fluoroquinolones (levofloxacin 500 mg once daily or ofloxacin 300 mg twice daily, each for seven days) are reserved for situations in which other fluoroquinolone-susceptible pathogens need to be covered (eg, epididymitis in individuals who practice insertive anal sex). (See 'Alternative antibiotics' above.)
●Testing for and treating other STIs – Patients with C. trachomatis infection should be tested and treated for Neisseria gonorrhoeae as well as other sexually transmitted infections (STIs), including HIV. (See 'Evaluate for and treat gonococcal coinfection' above.)
●Sexual activity – Individuals should refrain from sexual intercourse until they have completed the seven-day treatment regimen (or seven days have elapsed after single-dose treatment), any symptoms have resolved, and sex partners have been treated.
●Management of sex partners – If sex partners of persons with C. trachomatis infection are unlikely to present for evaluation and treatment, we suggest expedited partner therapy (EPT) (Grade 2C). This entails providing the index patient with a prescription so they can pass it to their partner or calling it in directly to the partner. For men who have sex with men (MSM), the decision to use EPT should be weighed against the potential missed opportunities to evaluate and counsel partners around other potential coinfections, including HIV. (See 'Management of sex partners' above.)
●Follow-up testing – All individuals treated for C. trachomatis infection should undergo retesting after three months to identify reinfection. Test of cure at four weeks after treatment is warranted for pregnant individuals, persistent symptoms, and concern for nonadherence to the treatment regimen. (See 'Follow-up testing' above.)
●Recurrent infection – This is most likely due to reinfection and is treated with the same approach as for initial infection. Drug resistance to doxycycline, azithromycin, or fluoroquinolones has not been described. (See 'Management of repeat infection' above.)
