William M. Geisler

Duration of Untreated, Uncomplicated Chlamydia trachomatis Genital Infection and Factors Associated with Chlamydia Resolution: A Review of Human Studies

The majority of Chlamydia trachomatis genital infections in humans are asymptomatic and without clinical evidence of complications at the time of diagnosis. The natural history of chlamydial infection in humans, including the duration of infection and factors influencing resolution of infection, is not yet completely understood. This is in part attributable to the inherent challenges and ethical considerations in studying untreated chlamydia in humans. An improved understanding of the natural history of chlamydia in humans has implications for chlamydia screening and treatment recommendations. In April 2008, the Centers for Disease Control and Prevention convened an advisory group for the Chlamydia Immunology and Control Expert Advisory Meeting, in which studies related to chlamydia natural history, pathogenesis, and immunobiology were reviewed and gaps in our knowledge that would have implications for prevention and control of C. trachomatis infection were identified. This article summarizes the key questions posed and the evidence reviewed on the duration of untreated, uncomplicated genital chlamydial infection in humans and the factors associated with chlamydia resolution.

Methodologies and Cell Lines Used for Antimicrobial Susceptibility Testing of Chlamydia spp.

ABSTRACT In vitro susceptibility testing was performed on strains of Chlamydia trachomatis, Chlamydia pneumoniae, and Chlamydia psittaci under various conditions, including the cell line utilized, the time between infection and the addition of an antimicrobial, the concentration of inoculum, and the effect of multiple passage on the minimal chlamydicidal concentrations for the antibiotics doxycycline, azithromycin, erythromycin, ofloxacin, and tetracycline. With macrolides, the MIC varied depending upon the cell line utilized. With all antimicrobials, the MIC was related to the time at which the antimicrobial was added after infection. By an optimized cell culture passage method, all strains of chlamydia tested demonstrated survival after exposure to high levels (>100 times the MIC) of antimicrobials. Furthermore, upon retest, these surviving organisms did not demonstrate increased MICs. Thus, this phenomenon does not reflect selection of antimicrobial-resistant mutants but rather survival of some organisms in high antimicrobial concentrations (heterotypic survival). An additional 44 clinical isolates of C. trachomatis from patients with single-incident infections were tested against those from patients with recurrent or persistent infections, and heterotypic survival was seen in all isolates tested; hence, in vitro resistance did not correlate with the patients apparent clinical outcome.

The natural history of untreated Chlamydia trachomatis infection in the interval between screening and returning for treatment.

Background: Studies of the natural history of genital chlamydial infections in humans are sparse and have had study design limitations. An improved understanding of chlamydial natural history may influence recommendations for elements of control efforts such as chlamydia screening frequency or time parameters for partner notification. Methods: Addressing limitations of prior studies in part, we are prospectively studying chlamydial natural history in sexually transmitted diseases clinic patients in the interval between screening and returning for treatment of positive chlamydial tests. Results of repeat chlamydial testing and clinical outcomes and their associated predictors are being evaluated. Results: In the initial 129 subjects, 89% were female, 88% were black, median age was 21 years, and the median interval between screening and treatment was 13 days. Based on nucleic acid amplification testing at treatment, spontaneous resolution of chlamydia occurred in 18%. Resolution was somewhat more common in subjects with longer intervals between screening and treatment. Persisting infections more often progressed to develop clinical signs at the time of treatment (e.g., urethritis or cervicitis). Two women and one man developed chlamydial complications between screening and treatment. Conclusions: Our findings demonstrate that although spontaneous resolution of chlamydia is common, many persons with persisting chlamydia progress to develop signs of infection and some develop complications.

Spontaneous Resolution of Genital Chlamydia trachomatis Infection in Women and Protection from Reinfection

The natural history of chlamydia is variable and may include persisting asymptomatic infection, complications, or spontaneous resolution before treatment. Reinfection is common. We evaluated whether spontaneous resolution was associated with decreased reinfection in women returning for treatment of a positive chlamydia screening test. At enrollment, participants were tested for chlamydia, treated with azithromycin, and scheduled for a 6-month follow-up visit for repeat testing. Two hundred participants returned 1 to 12 months after treatment. Spontaneous resolution at enrollment was demonstrated in 44 (22.0%). Reinfection at follow-up occurred in 33 (16.5%), being more frequent in those with persisting infection at enrollment versus spontaneous resolution (31 of 156 [19.9%] vs 2 of 44 [4.5%]; P = .016). Adjusting for age, the odds of reinfection was 4 times higher for participants with persisting infection at enrollment (odds ratio 4.0, 95% confidence interval, 1.1-25.6; P = .034). Chlamydia treatment may attenuate protective immunity in some patients.

The relationship of serovar to clinical manifestations of urogenital Chlamydia trachomatis infection.

Background and Goal Studies assessing the relationship of Chlamydia trachomatis serovars or genotypes to clinical manifestations of urogenital disease have produced contradictory results. Possible reasons for this include small sample sizes insufficient to reliably detect associations and failure to address potential confounding factors. Utilizing a large dataset and multivariate analysis to address confounding factors, we undertook this study of the relationship of chlamydial serovars to specific clinical manifestations of urogenital disease. Study Design This was a cross-sectional study of 480 women and 700 heterosexual men with urogenital chlamydial infection attending a sexually transmitted diseases clinic from 1995 to 1999 and a literature review. Results Women (89%) and men (86%) were infected predominately with serovars D, E, F, Ia, and J. After controlling for age and race, we found that women who reported abdominal pain and/or dyspareunia were more often infected with serovar F (P = 0.048). An association of specific clinical manifestations with serovars was not detected in men. Conclusion We conclude that clinical manifestations of C trachomatis urogenital infection are not strongly influenced by the infecting serovar.

Epidemiology of anorectal chlamydial and gonococcal infections among men having sex with men in Seattle: Utilizing Serovar and Auxotype strain typing

Background Bacterial sexually transmitted diseases (STDs) among men who have sex with men (MSM) have recently increased in Seattle. Goals Serovar and auxotype typing of strains was used to assess the epidemiology of anorectal chlamydial and gonococcal infections among MSM attending an STD clinic. Study Design The prevalences of anorectal chlamydial infection and gonorrhea among MSM attending an STD clinic during the period of 1994 to 1996 were compared with prevalences during 1997 to 1999. A retrospective case–control study of MSM attending an STD clinic between 1997 and 1999 was performed. Anorectal chlamydial isolates were characterized by serovar and gonococcal isolates were characterized by serovar and auxotype. Infected MSM were mapped by residence and strain type. Results Prevalences of anorectal chlamydial and gonococcal infections increased from 4.0% and 6.3%, respectively, during 1994–1996 to 7.6% and 8.7%, respectively, during 1997–1999 (P = 0.004 and P = 0.013 for chlamydial infection and gonorrhea, respectively). Most chlamydial infections were caused by serovars G (47.9%) and D (29.6%), and most gonococcal infections were caused by auxotype/serovar classes Proto/IB-1 (43.3%), Proto/IB-3 (16.5%), and Proto/IB-2 (10.3%). MSM with anorectal chlamydial infection more often had chlamydial urethritis (P = 0.005) and were not white (P = 0.046), in comparison with controls. MSM with anorectal gonorrhea more often had pharyngeal gonorrhea (P < 0.001), had a history of gonorrhea (P = 0.003), and were younger than age 30 years (P = 0.039), in comparison with controls. Residences of MSM with anorectal gonorrhea were clustered in urban areas, whereas those of MSM with anorectal chlamydial infection were more dispersed. Conclusion Prevalences of anorectal chlamydial infection and gonorrhea among MSM in Seattle have increased dramatically over the past 3 years. Serovar and auxotype analyses indicate these increases are not clonal but are due to the spread of unique distributions of strains that differ from those causing urogenital infections in the same community.

Epidemiology and Clinical Manifestations of Unique Chlamydia trachomatis Isolates That Occupy Nonfusogenic Inclusions

Unique Chlamydia trachomatis strains characterized by multiple nonfusing inclusions were recently described. These strains lack evidence of the protein IncA in the inclusion membrane and have mutations in the incA gene. This study evaluated the epidemiology and clinical manifestations of patients infected with nonfusing mutant strains (case patients) and compared them with patients infected with wild-type fusing strains (control subjects). Both male and female case patients had fewer signs of infection than did control subjects (P=.016 and P=.019, respectively). Female case patients also had fewer symptoms of infection (P=.02). Median inclusion-forming unit (ifu) counts were lower in male and female case patients (P=.045 and P=.135, respectively). Thus, nonfusing strains of C. trachomatis more often produce subclinical infections than do normal fusing strains and have lower median ifu counts. From a prevention perspective, the data underscore the importance of screening programs to detect and treat inapparent C. trachomatis infection.

Human Leukocyte Antigen and Cytokine Gene Variants as Predictors of Recurrent Chlamydia trachomatis Infection in High-Risk Adolescents

Antigen presentation and immune activation are essential to the effective control of infectious diseases. In 485 North American adolescents at high risk for genital Chlamydia trachomatis infection, we found 2 human leukocyte antigen variants (DRB1*03-DQB1*04 and DQB1*06) to be associated with recurrent Chlamydia infection (adjusted relative odds [RO], >2.0; P<.01, for both variants). A G-C-C haplotype corresponding to variants at IL10 (encoding interleukin-10 [IL-10]) promoter positions -1082, -819, and -592 was underrepresented in individuals with recurrent infection (RO, 0.59; P=.046). These genetic associations were independent of nongenetic factors, including number of sex partners, race, sex, duration of follow-up, and human immunodeficiency virus type 1 seropositivity. Consistent with the observed IL10 association, cervical secretions in female adolescents without the IL10 G-C-C haplotype had elevated IL-10 concentrations after Chlamydia infection, which may reflect involvement of a Chlamydia-specific mechanism for genetically mediated, differential IL-10 expression in the genital tract.

Azithromycin versus Doxycycline for Urogenital Chlamydia trachomatis Infection

BACKGROUND Urogenital Chlamydia trachomatis infection remains prevalent and causes substantial reproductive morbidity. Recent studies have raised concern about the efficacy of azithromycin for the treatment of chlamydia infection. METHODS We conducted a randomized trial comparing oral azithromycin with doxycycline for the treatment of urogenital chlamydia infection among adolescents in youth correctional facilities, to evaluate the noninferiority of azithromycin (1 g in one dose) to doxycycline (100 mg twice daily for 7 days). The treatment was directly observed. The primary end point was treatment failure at 28 days after treatment initiation, with treatment failure determined on the basis of nucleic acid amplification testing, sexual history, and outer membrane protein A (OmpA) genotyping of C. trachomatis strains. RESULTS Among the 567 participants enrolled, 284 were randomly assigned to receive azithromycin, and 283 were randomly assigned to receive doxycycline. A total of 155 participants in each treatment group (65% male) made up the per-protocol population. There were no treatment failures in the doxycycline group. In the azithromycin group, treatment failure occurred in 5 participants (3.2%; 95% confidence interval, 0.4 to 7.4%). The observed difference in failure rates between the treatment groups was 3.2 percentage points, with an upper boundary of the 90% confidence interval of 5.9 percentage points, which exceeded the prespecified absolute 5-percentage-point cutoff for establishing the noninferiority of azithromycin. CONCLUSIONS In the context of a closed population receiving directly observed treatment for urogenital chlamydia infection, the efficacy of azithromycin was 97%, and the efficacy of doxycycline was 100%. The noninferiority of azithromycin was not established in this setting. (Funded by the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT00980148.).

Quantitative Culture of Chlamydia trachomatis: Relationship of Inclusion-Forming Units Produced in Culture to Clinical Manifestations and Acute Inflammation in Urogenital Disease

The relationship of Chlamydia trachomatis inclusion-forming units in quantitative culture to clinical manifestations and inflammation in urogenital disease was assessed in 1179 patients attending a sexually transmitted diseases clinic. In women, greater inclusion-forming unit counts were associated with cervical mucopus (3000 vs. 450 ifu), amount and character of cervical discharge, > or =30 polymorphonuclear cells (PMNL) per high-power field (hpf) on Gram stain (2050 vs. 320 ifu), and diagnoses of mucopurulent cervicitis (MPC; 2550 vs. 300 ifu) and pelvic inflammatory disease (PID; 3000 vs. 578 ifu). In men, greater inclusion-forming unit counts were associated with urethral discharge (85 vs. 44 ifu), amount and character of discharge, and > or =10 PMNL/hpf (95 vs. 50 ifu). These associations persisted on multivariate analysis. Thus, chlamydial replication is associated with MPC and PID in women, urethritis in men, and inflammation in both. Since infections with high inclusion counts may be the most transmissible, identification and treatment of patients with these chlamydia-associated syndromes is important in control programs.