Toward Control of Sexually Transmitted Chlamydial Infections

In 1985, the Centers for Disease Control and Prevention (CDC) published the first edition of guidelines for the prevention and control of Chlamydia trachomatis infections [1]. These guidelines outlined the high prevalence and enormous morbidity associated with chlamydial infection, delineated the specific syndromes in which chlamydia was a major etiologic agent, and recommended empiric treatment of these syndromes. Recently, the CDC published an updated set of guidelines for the prevention and control of Chlamydia trachomatis infections [2]. These 1993 guidelines advocate new approaches to prevention and control of chlamydial infection made possible by scientific advances of the last decade. Among these advances is a clearer understanding of the high frequency of asymptomatic unrecognized infection, especially in adolescents and young adults [3]. Although the occurrence of asymptomatic chlamydial infections had long been known, the prevalence and epidemiologic significance of such infections was not fully appreciated because research studies initially placed emphasis on the symptomatic syndromes caused by chlamydia, including nongonococcal urethritis, epididymitis, mucopurulent cervicitis, the dysuria-pyuria syndrome, and pelvic inflammatory disease [4]. In actuality, most cervical infections in women can be regarded as asymptomatic, and, more importantly, upper genital tract infection in women may also be asymptomatic in many instances. Approximately 50% of women with infertility attributable to chlamydia-induced distal tubal scarring have no history of overt pelvic inflammatory disease [5]. In addition, asymptomatic chlamydial urethritis in young men appears to be an important and previously underemphasized reservoir of infections that may be transmitted to young women [6]. Taken together, these considerations suggest a twofold approach to the control of chlamydial infections. First, symptomatic infections must be diagnosed and treated; simultaneously, the sexual partners of the index patients, who often have unrecognized infections, should also be tested and treated. Second, we must implement programs to screen at-risk populations to identify and treat patients with asymptomatic infection. Because women experience the most serious acute illness (pelvic inflammatory disease) and residual morbidity (infertility and ectopic pregnancy) attributable to chlamydial infections, as well as incur the bulk of chlamydia-related health care costs, prevention programs should be targeted to women. Women attending facilities generally associated with a high prevalence of chlamydial infection should undergo routine testing [2]. Such facilities include sexually transmitted disease clinics, abortion clinics, juvenile detention centers, family planning clinics, and teen health clinics. Similarly, at-risk pregnant women should be screened in the third trimester for chlamydial infection. In addition to population-based screening, practitioners can use well-delineated risk factors to identify individual patients who should be screened regardless of the health care setting. Such risk factors include young age (especially adolescents), a history of recent multiple or new sexual partners, presence of another sexually transmitted disease, and the use of nonbarrier contraceptive methods [2]. Routine testing of all sexually active young women under 20 years old whenever a pelvic examination is done and annual testing of sexually active women between 20 and 25 years old for chlamydial infection have been recommended [2]. For years, the only diagnostic test for chlamydial infectionisolation in cell culturewas not widely available. Now, new noncultural diagnostic tests, primarily based on antigen detection or nucleic acid hybridization methods, offer reasonably sensitive, specific, less expensive, and easy-to-perform means of confirming chlamydial infection [7, 8]. Commercial development of nucleic acid amplification methods for the diagnosis of chlamydial infection using polymerase chain reaction or ligase chain reaction may soon provide even more sensitive assays. Three types of tests are currently marketed: fluorescent monoclonal antibody tests for the direct visualization of chlamydial elementary bodies on smears, enzyme immunoassays to detect chlamydial antigens, and a nucleic acid hybridization test. Because these tests do not require the strict transport and handling conditions that culture does and because they are easier to perform and less expensive than culture, increasing numbers of laboratories are offering tests for chlamydia. Although none of these tests is as sensitive or specific as high-quality cultures for chlamydia, all have reasonable sensitivity (70% to 90%) and specificity (96% to 99%) in groups where the prevalence of chlamydial infection exceeds 8% to 10% [8]. In groups where the prevalence of chlamydial infection is 5% or less, however, the predictive value of a positive test may fall to 50% or less, and, for this reason, positive test results in such settings should be considered presumptive until confirmed. Confirmatory testing is especially important in circumstances where a positive nonculture test could lead to adverse medical or social consequences for the patient, such as an unexpected positive test in a monogamous woman. As discussed in the new guidelines, confirmation of presumptive positive tests can be accomplished in several ways. Some commercially available tests have marketed confirmatory assays that use blocking antibodies or competitive probes to distinguish true-positive from false-positive results. Alternatively, a different nonculture test can be performed on the same specimen to confirm the initial result. For example, the transport buffer for an enzyme immunoassay can be centrifuged, pelleted, placed on a slide, and stained with fluorescein-conjugated monoclonal antibody to confirm the immunoassay result. It should be emphasized that reported experience with the nonculture tests has principally involved studies of high-prevalence populations. In this setting, the tests appear to work especially well in cervical infections, where the number of chlamydial organisms is frequently much higher than in male urethral infections. Thus, the sensitivity of these tests is often lower when used to detect urethral infections in men. Recent studies indicate that testing first-void urine for chlamydial antigen or nucleic acid may prove to be a more acceptable and effective means of testing men for chlamydial urethritis than urethral swabs [9]. Further studies of this approach in low-prevalence settings will be of great interest. The number of available nonculture tests has expanded rapidly, and large-scale comparative studies are needed to ascertain which tests will provide the highest-quality performance in screening programs [10]. The CDC should assume a leadership role in facilitating such standardized evaluation of diagnostic testing for chlamydial infection, perhaps in collaboration with the Food and Drug Administration and regional participating laboratories, and should also foster the development of quality-assurance programs. Until these programs are in place, the new guidelines provide tables intended to help practitioners select diagnostic tests and determine the necessity for confirmatory assays in specific circumstances [2]. Given the wider availability of chlamydia testing, clinicians should now use specific diagnostic testing in patients suspected of having chlamydia-associated syndromes. A presumptive diagnosis of mucopurulent cervicitis or pelvic inflammatory disease, for example, is markedly strengthened by the presence of a positive test for chlamydia. Knowledge of a positive test also facilitates patient compliance with prescribed medication and the likelihood of a patient referring sexual partners for evaluation and treatment. Thus, despite the fact that empiric therapy will be given before the results of the test for chlamydia have been obtained in such symptomatic patients, testing in these circumstances still offers substantial benefits. Unlike gonococci, which may rapidly acquire antimicrobial resistance via several mechanisms, chlamydia have not yet shown clinically significant antimicrobial resistance. However, other problems have limited the effectiveness of antichlamydial therapy. Because many patients are initially asymptomatic, antibiotic treatment is all too often discontinued if symptoms or side effects arise while receiving a 7-day course of doxycycline or erythromycin therapy, resulting in treatment failure. For this reason, the most exciting advance in antichlamydial therapy has been the approval of azithromycin, given as a single 1-g dose for treatment of uncomplicated chlamydial infections [11]. The ability to provide effective antichlamydial therapy in a single-dose regimen, ensuring compliance, represents a major step forward in the treatment of chlamydial infection. In studies published to date, azithromycin appeared to be as effective as doxycycline in the treatment of uncomplicated chlamydial infections and was equivalent to doxycycline in terms of frequency of side effects [11]. Azithromycin has not yet been evaluated in pregnant women. Further studies are also needed to assess the effectiveness of azithromycin in the empiric treatment of syndromes such as mucopurulent cervicitis and nongonococcal urethritis, which may or may not be caused by chlamydia. As one might expect, the major impediment to the use of this new compound is its cost, currently about $32.00 for a 1-g treatment regimen as compared with approximately $5.00 for a 7-day course of doxycycline. Regrettably, the high cost will probably prevent the use of the compound in settings where it would be most valuable, namely, public clinics. Negotiations are under way to address this problem, perhaps by developing a specific formulation for treatment of chlamydial infection. Although many of the fluoroquino