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Clearance of Mycoplasma genitalium and Trichomonas vaginalis Among Adolescents and Young Adults With Pelvic Inflammatory Disease: Results From the Tech-N Study

Trent, Maria MD, MPH; Yusuf, Hasiya E. MBBS, MPH; Perin, Jamie PhD; Anders, Jennifer MD; Chung, Shang-en ScM; Tabacco-Saeed, Lisa MPH, MBA; Rowell, Julia BA; Huettner, Steven BS; Rothman, Richard MD, PhD; Butz, Arlene ScD, RN; Gaydos, Charlotte A. MS, DrPH

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doi: 10.1097/OLQ.0000000000001221
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Pelvic inflammatory disease (PID) is a spectrum of upper genital tract infections that include endometritis, salpingitis, pelvic peritonitis, and tubo-ovarian abscess.1Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) are commonly associated with PID. However, PID is a polymicrobial infection,2,3 and more than 70% of PID is caused by organisms other than CT and NG.4 In our recent randomized clinical trial of 286 women aged 13 to 25 years diagnosed with mild to moderate PID, we compared the efficacy of a technology-enhanced health nursing (TECH-N) intervention with the standard of care on the 90-day longitudinal prevalence of CT and NG infections. Findings from the study showed a statistically significant decline in CT and NG infections after the 90-day follow-up period (odds ratio [OR], 0.54; 95% confidence interval, 0.43–0.67; P < 0.001)5 and corroborate the previously demonstrated effectiveness of current PID treatment guidelines against CT and NG.6

Mycoplasma. genitalium (MG) is an emerging organism now implicated in many cases of nongonococcal, nonchlamydial PID.7Trichomonas vaginalis (V) is not discussed in the context of PID in the Centers for Disease Control and Prevention' (CDC's) sexually transmitted disease treatment guidelines, but this infection is disproportionately common in many communities impacted by sexually transmitted infections (STIs) and PID. The persistence and/or reinfection of MG/TV may increase the risk for recurrent STIs and HIV acquisition.8,9

The efficacy of treatment using the current PID treatment guidelines against MG and TV remains unclear.10 Doxycycline, a key component of the national treatment regimen for PID, has limited effectiveness against MG,11 leading to persistence of MG after CT/NG clearance. Likewise, the optional recommendation for use of metronidazole for PID as stipulated in the guidelines often results in nonadherence and predisposes to continued infection.10 Given the increased risk for sequelae after recurrent STIs and PID, efforts to optimize vaginal health after PID may be protective. The objective of this study was to evaluate longitudinal MG and TV outcomes compared with CT/NG outcomes over the 90-day follow-up treatment of PID using data from the TECH-N study.5

METHODS

The TECH-N study is a 2-arm single-blinded randomized clinical trial that includes 286 adolescent and young adult women aged 13 to 25 years with clinically diagnosed mild-moderate PID.12 Participants were recruited at the time of PID diagnosis from the outpatient clinics and Pediatric and Adult Emergency Departments of an urban hospital in Baltimore, MD. Patients were eligible for the study if they were between the ages of 13 and 25 years, were female, and had received a diagnosis of mild-moderate PID not requiring inpatient treatment. Exclusion criteria were pregnancy; hindrances to communication due to language, mental, or cognitive difficulties; or a concurrent diagnosis of sexual assault. All eligible patients completed an audio-computerized self-interview (ACASI) and provided self-collected vaginal specimens for TV and MG testing. Patients enrolled in the TECH-N intervention group received a full course (14 days) of medications at the recruitment visit per national treatment guidelines, a welcome SMS message, daily medication reminders and a triweekly message after the 14-day treatment period up until 30 days, and home visits by a TECH-N representative at 3 to 5, 14, and 30 days after PID diagnosis. The control group only received the 14-day course of treatment. Vaginal specimens were collected at the 30- and 90-day follow-up visits and tested for NG, CT, TV, and MG infections. All participants with positive STI test results were notified of and referred for treatment at no cost to the participant. When the TECH-N protocol was initiated, MG was not considered an STI in national guidelines and TV remains an STI for which symptomatic testing and treatment are the only public health control strategy, except in HIV-positive women where screening is recommended. Human subjects' approval was received from the research center's institutional review board, and written informed consent was obtained from all participants at enrollment.

Generalized estimating equations were used to measure the primary outcome of interest: changes in the prevalence of MG and TV compared with CT/NG infection at 0-, 30-, and 90-day follow-ups in accordance with the timeline for disease clearance and reinfection. Prevalences of MG and CT/NG were modeled jointly conditional on the time of follow-up and allowing for coinfections by specifying individual as the cluster for analysis. Similar models were constructed for the prevalence of TV. Statistical analysis was performed using Stata version 15.0 (StataCorp. 2017; StataCorp LLC, College Station, TX).

RESULTS

Of the 286 enrolled participants, 149 patients (52%) randomized to the intervention group and 137 patients (48%) to the control group were included in this analysis. Selected demographics and baseline STI outcomes for study participants by intervention group and demography are presented in Table 1. The 2 intervention and control groups were similar in distribution for most baseline characteristics.

TABLE 1 - Selected Demographics and STI Results
Baseline Characteristics Total Population (N = 286) Intervention Group (n = 149) Control Group (n = 137) P
Age, mean (SD), y 286 149 18.7 (2.5) 137 18.9 (2.5) 0.639
Race/ethnicity, n % 286 149 137 0.640
 African American 140 (94) 128 (93)
 Hispanic 2 (1) 4 (3)
 White 4 (3) 3 (2)
 Other 3 (2) 2 (1)
Insurance, n (%) 286 149 137 0.382
 Medicaid 131 (88) 116 (85)
 Private 11 (7) 9 (7)
 Self-pay 7 (5) 12 (9)
Ever diagnosed with STI, n (%) 282 148 80 (54) 134 82 (61) 0.227
STI at baseline, n (%)
 CT 271 139 45 (32) 132 25 (19) 0.017
 NG 271 139 11 (8) 132 16 (32) 0.341
 CT or NG 273 140 48 (34) 133 34 (26) 0.116
 MG 276 142 34 (24) 134 29 (22) 0.650
 TV 276 142 25 (18) 134 26 (19) 0.702
 CT, NG, MG, or TV 285 148 77 (52) 137 72 (53) 0.929
CT indicates Chlamydia trachomatis; MG, Mycoplasma genitalium; NG, Neisseria gonorrhoeae; STI, sexually transmitted infection; TV, Trichomonas vaginalis.

Most patients in the study (268; 94%), were African American, with a mean (SD) age of 18.8 (2.5) years, and most (247; 86%) were publicly insured. For most women in the study, sexual debut occurred around the age of 15 years (median, 15 years; interquartile range, 14–19 years), and 186 (57%) had been diagnosed with an STI in the past.

There were 269 (94%) women at the end of the 30-day follow-up period. Of these, 45 (17%) were positive for MG, 25 (9%) were positive for TV, 25 (9%) had either CT or NG, and 17 (6%) and 9 (3%) had CT and NG infections, respectively. At the end of the 90-day study period, vaginal specimens were collected from 260 women. A greater number of women were positive for MG (49; 19%) and TV (34; 13%). The prevalences of CT and NG were lower at 9 (3%) and 11 (4%), respectively. Infection with either of CT or NG was also low, present in only 19 (7%) of women.

Unlike the previously reported declines in NG/CT infection, no significant difference was observed for MG (OR, 0.95; 0.86–1.04; P = 0.265). This OR is interpretable as the change in likelihood of infection with MG with an increase in 1 month of follow-up time. Likewise, TV infections were stable over time (OR, 0.89; 0.75–1.04; P = 0.146) for both treatment groups, even after adjusting for 108 patients prescribed metronidazole (OR, 0.89; 0.75–1.04; P = 0.148). However, the prevalence of any combination of STIs due to CT, NG, or TV showed a statistically significant decline over time (OR, 0.69; 0.61–0.80; P < 0.001). CT, NG, or MG prevalences also declined over the study period (OR, 0.71; 0.64–0.80; P < 0.001). These declines may have been driven by both CT and NG.

Overall, the prevalence of infection was lower in the intervention group (% infected) than in the control group (% infected) at the end of the 90-day follow-up. Consistent with these findings, Figure 1 shows the changes in CT/NG, MG, and TV infections over the entire study duration. Although CT or NG infections progressively declined in both the intervention and control groups,5 infection with MG and TV remained relatively unchanged. The figure also shows the improvement in prevalence of all STIs over time, and this change is not as precipitous as observed with CT or NG infections.

F1
Figure 1:
Prevalence of C. trachomatis or N. gonorrhoeae, M. genitalium, T. vaginalis, and all four infections at 0-, 30-, and 90-day follow-up.

DISCUSSION

This study investigated the clearance of MG and TV infections in women diagnosed with CT and NG STIs over a 90-day follow-up period. The results show a clearance of CT and NG but persistence and/or reinfection with MG and TV despite treatment with the standard recommended STI treatment regimen.

Although MG and TV are not the focus of recommended PID treatment within the CDC sexually transmitted disease treatment guidelines, our work suggests that in communities with high STI prevalence, patients may not have clearance of all STIs at the end of a 14-day treatment course for PID. The persistently high MG infection rates seen at different intervals in our study are consistent with the findings of similar studies where more than 50% of MG infected women treated with macrolides were resistant to treatment13 and 16% of treated patients had persistent infection with MG.14 The proportion of PID attributed to MG in the study (16%) was equally comparable to the 17% to 19% observed here. Similar findings of multiple studies also corroborate the significant role played by MG in the etiology of PID.15

Persistent infection with TV despite treatment of PID can easily be ascribed to the nonprescription of an antibiotic to which TV is susceptible. There is a paucity of studies comparing TV infections among persons treated with and without metronidazole. It is arguable that TV persistence may have resulted from a failure to prescribe metronidazole, as this is optional,10 and other “nonoptional” medications in the treatment guideline are ineffective against TV infections. However, the point prevalence of TV remained unchanged after adjusting for metronidazole prescription. Adherence to metronidazole was not ascertained in this study, and it is likely that adherence was suboptimal given the long course of treatment (14 days). Metronidazole and other nitroimidazole class antibiotics remain the best treatment option for TV.16

Our results must be considered in light of several general limitations. This study has limited generalizability because participants were recruited from a single hospital system and city within the United States, and findings may not be representative for patient populations outside of these institutions and geographic regions. Although all patients were informed of their interim STI results and offered treatment, only 50% of patients consistently pursued treatment of MG/TV, contributing to persistent infections.17 This, however, further highlights the need for close follow-up of patients with PID until point-of-care testing for these organisms are optimized and universally implemented.

In summary, data from this study indicate that persistence or possibly reinfection with MG and TV occurred more frequently than with CT or NG when using the current national treatment guidelines for PID. Although a decline in CT and NG infections was noted, overall clearance of infectious organisms for this polymicrobial disease was less when MG and TV were considered. These findings suggest a need for the revision of the current CDC treatment guidelines to incorporate MG and TV testing and treatment to prevent reinfection and persistence and to avert complications after PID.

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