Abstract
Background:
Mycoplasma genitalium (MG) is an emerging sexually transmitted infection. Treatment of MG is complicated by increasing resistance to primary treatment regimens, including macrolides and fluoroquinolones. Understanding the various clinical presentations and relative effectiveness of treatments for MG is crucial to optimizing care.
Methods:
Patients with a positive MG Nucleic Acid Amplification Test (NAAT) between July 1, 2019 and June 30, 2021 at a large health system in New York City were included in a retrospective cohort. Demographics, clinical presentations, coinfections, treatment, and follow-up microbiologic tests were obtained from the electronic medical record. Associations with microbiologic cure were evaluated in bivariate and multivariable logistic regression models.
Results:
Five-hundred and two unique patients had a positive MG NAAT during the study period. Males presented predominantly with urethritis (117/187, 63%) and females with vaginal symptoms (142/315, 45%). Among patients with follow-up testing who received a single antibiotic at the time of treatment, 43% (90/210) had persistent infection and 57% (120/210) had microbiologic cure. Eighty-two percent of patients treated with moxifloxacin had microbiologic cure compared to 41% of patients receiving azithromycin regimens (p<0.001). In multivariable analysis, treatment with moxifloxacin was associated with four times the odds of microbiologic cure relative to low-dose azithromycin (aOR 4.18, 95% CI 1.73–10.13, p <0.01).
Conclusions:
Clinical presentations of MG vary, with urethritis or vaginal symptoms in most cases. Among patients who received a single antibiotic, only treatment with moxifloxacin was significantly associated with microbiologic cure relative to low-dose azithromycin.
Keywords: Mycoplasma genitalium, moxifloxacin, azithromycin, sexually transmitted diseases, persistence
Summary:
In a retrospective cohort of Mycoplasma genitalium infections, treatment with moxifloxacin alone was associated with four times the odds of microbiologic cure relative to a single dose of azithromycin.
Introduction
Mycoplasma genitalium (MG) is an increasingly recognized cause of urethritis, vaginitis, and cervicitis, and is associated with pelvic inflammatory disease (PID) (1–3). Population prevalence of MG in the United States (US) has been estimated to be 1.7% (4). However, prevalence is higher among individuals seeking care in sexually transmitted infection (STI) clinics with a surveillance study of sexual health clinics in the US demonstrating 16.6% prevalence (3, 5–8). Similar to other STIs, many MG infections are asymptomatic (9, 10). While the implications of asymptomatic infections are currently unknown, they likely have a role in continued transmission (11, 12).
Due to lack of a peptidoglycan cell wall and growing resistance to macrolides and fluoroquinolones, treatment of MG infections is challenging, and high-quality data are needed to inform treatment practices (13). The prevalence of macrolide resistance mutations is >50% in a meta-analysis of 59 studies from 21 countries (13). In response to increasing macrolide resistance, the 2021 STI guidelines from the US Centers for Disease Control and Prevention (CDC) and Australian STI Management Guidelines recommend sequential treatment with doxycycline (7 days) followed by either moxifloxacin (7 days) or azithromycin (4 days) depending on macrolide resistance testing (1, 14). This staged approach is based on limited data and differs from single agent regimens used for other STIs (15, 16). European guidelines recommend azithromycin (5 days) as primary treatment and moxifloxacin (7 days) in cases of known or presumed macrolide resistance (17). As guidelines shift towards fluoroquinolones, reports of MG fluoroquinolone resistance are increasing (13, 18).
To enhance understanding of the epidemiology and treatment outcomes of MG infections in a clinical setting, this study describes clinical presentations of individuals with MG at a large health center in Bronx, New York, and evaluates the association of treatment with doxycycline, azithromycin, or moxifloxacin with microbiologic cure.
Materials and Methods
Study population and data collection:
The retrospective, electronic health record (EHR) based study included unique patients with positive MG Nucleic Acid Amplification Test (NAAT) results from urine or anogenital (vaginal, cervical, urethral, or anorectal) samples using the Aptima® MG assay (Hologic, San Diego, California) from clinical encounters at Montefiore Medical Center (MMC) in Bronx, New York between July 1, 2019 and June 30, 2021. A patient’s first positive MG NAAT within the study period was considered initial infection. Follow-up testing data were obtained through August 10, 2022. Importantly, the study period was prior to publication of the 2021 CDC STI guidelines. All MG testing was performed at the discretion of the treating clinicians during clinical encounters and included both asymptomatic and symptomatic patients. Demographics (sex, age, race/ethnicity), specimen source, and microbiologic data for other infections (HIV, Trichomonas vaginalis, bacterial vaginosis, syphilis, Chlamydia trachomatis, and Neisseria gonorrhoeae) were extracted retrospectively from the EHR using structured query language to pull data from Epic’s Clarity database.
Through manual chart review, physicians (C.E.M and E.A.M.) extracted clinical presentation, initial treatments, gender identity of sexual partners, hospital testing location, coinfections at time of initial MG infection, and continued symptoms at follow-up. Pre-established clinical presentation categories included asymptomatic, vaginal symptoms (vaginal discharge or pain), urethritis (dysuria, hematuria, and/or urethral discharge), and PID (documented cervical motion tenderness or associated billing diagnosis code). Additional clinical presentation categories were added after completing chart review. Since not all females received a speculum exam and physical exam documentation varied, prevalence of cervicitis was not reported. A second study team member (K.A.M.) independently extracted clinical presentation in 50 patients for validation, with discrepancies noted in three cases. Initial treatment was validated against extracted EHR prescription data. Due to the presence of bacterial coinfections and the use of empiric and directed therapy, some patients received multiple initial treatments. When evaluating potential associations between treatment and cure, patients receiving multiple treatments were excluded. Due to inconsistent access to moxifloxacin, possibly as a result of insurance restrictions and/or cost, all moxifloxacin prescriptions were manually reviewed to evaluate whether patients received moxifloxacin or required an alternative regimen. Bacterial vaginosis (BV) was defined as the presence of vaginal symptoms with a Nugent score ≥ 7 calculated by a lab pathologist. Aptima® Chlamydia trachomatis (CT), Neisseria gonorrhoeae (NG) and Trichomonas vaginalis (TV) NAAT assays were utilized. Syphilis was defined as a previously unknown infection with a newly detected Treponema pallidum antibody or a fourfold increase in rapid plasma reagin titer. Manual review of persistent infection after moxifloxacin treatment was performed by two team members (C.E.M and K.A.M.) with discrepancies adjudicated by a third member of the study team (E.A.M.).
Among individuals with available follow-up MG NAAT testing, outcomes of microbiologic cure or persistent infection were defined, respectively, based on the first negative or positive test result at least 21 days after initial MG diagnosis. A 21-day period was selected to limit potential capture of residual bacterial nucleic acid shedding (since culture was not available to confirm active infection) based on Australian guidelines for timing of test of cure (14, 19). To account for the likelihood that those without follow-up testing might be more likely to have a clinical cure, sensitivity analyses were performed classifying patients with no follow-up testing and those with subsequent negative tests (microbiologic cure) as having presumed cure.
The study was reviewed and approved by the Albert Einstein College of Medicine Institutional Review Board (Protocol 2021–13668). Informed consent was not required given the retrospective observational study design and minimal risk to patients.
Statistical analysis:
Categorical data were summarized as frequencies and percentages. Continuous variables were summarized as mean with standard deviation or median and interquartile range (IQR). Bivariate associations between cure outcomes and variables of interest were evaluated utilizing chi-squared tests, Fisher exact tests, Wilcoxon rank-sum test, student t-test with equal variance as appropriate. Complete case analyses were performed among patients receiving a single treatment regimen. Multivariable logistic regression was performed to evaluate the association between microbiologic cure and treatment regimen. Treatment regimens were evaluated as mutually exclusive categorical variables among patients who received a single treatment. Initial models for microbiologic cure and presumed cure included age, race and ethnicity, sex, and hospital testing location a priori and variables with statistical significance level less than 0.20 in univariate analysis. The final model was constructed with backward elimination utilizing a likelihood ratio test with significance level of 0.05. The model adjusts for confounders of treatment regimen and coefficients for the other variables in the model cannot be similarly interpreted. Statistical assumptions of the model were evaluated. Associations with obtaining follow-up testing were evaluated separately to evaluate for potential biases. Two-sided p-values less than 0.05 were considered statistically significant. All statistical analyses were performed on STATA (version 17.0, StataCorp, College Station, TX).
Results
Characteristics of individuals with MG infection
Five-hundred and two individuals had a positive MG NAAT and 96% (483/502) received treatment (see Table 1). The mean age of the patients was 27 years (range 14–58). Forty-seven percent (225/480) were non-Hispanic Black and 41% (199/480) Hispanic. Among females, 14% (40/287) had CT, 12% (29/251) had TV, and 54% (45/84) with vaginal symptoms had BV at the time of MG diagnosis. Co-occurring NG infections were higher among males (18/173, 10%) than females (13/287, 4.5%).
Table 1.
Characteristics of individuals with Mycoplasma genitalium (MG) infections by sex
| Total (n=502) n (%) |
Female (n=315) n (%) |
Male (n=187) n (%) |
|
|---|---|---|---|
| Age at diagnosis | |||
| < 20 years | 75 (14.9) | 63 (20.0) | 12 (6.4) |
| 20–29 years | 273 (54.4) | 170 (54.0) | 103 (55.1) |
| 30–39 years | 115 (22.9) | 63 (20.0) | 52 (27.8) |
| ≥ 40 years | 39 (7.8) | 19 (6.0) | 20 (10.7) |
| Race/Ethnicitya | |||
| Non-Hispanic Black | 225 (46.9) | 133 (43.8) | 92 (52.3) |
| Hispanic | 199 (41.5) | 139 (45.7) | 60 (34.1) |
| Other | 56 (11.7) | 32 (10.5) | 24 (13.6) |
| Sexual partnersa | |||
| Females | 124 (26.8) | 2 (0.7) | 122 (71.3) |
| Males | 322 (69.6) | 281 (96.2) | 41 (24.0) |
| Females and males | 17 (3.7) | 9 (3.1) | 8 (4.7) |
| Source of specimen | |||
| Urine | 334 (66.5) | 152 (48.2) | 182 (97.3) |
| Anogenital swab | 168 (33.5) | 163 (51.8) | 5 (2.7) |
| Living with HIVa | |||
| Yes | 39 (9.4) | 14 (5.6) | 25 (15.5) |
| Isolated MG infectionb | |||
| Yes | 216 (67.5) | 135 (66.1) | 81 (69.8) |
| Coinfection at time of MG diagnosisa | |||
| Chlamydia trachomatis | 57 (12.4) | 40 (13.9) | 17 (9.8) |
| Neisseria gonorrhoeae | 31 (6.7) | 13 (4.5) | 18 (10.4) |
| Trichomonas vaginalis | 32 (8.5) | 29 (11.6) | 3 (2.4) |
| Syphilis | 6 (1.5) | 0 (0) | 6 (3.8) |
| Bacterial vaginosis | 45 (53.6) | 45 (53.6) | - |
| Hospital testing location | |||
| Primary Care | 82 (16.3) | 60 (19.0) | 22 (11.8) |
| Obstetrics/Gynecology | 84 (16.7) | 84 (26.7) | - |
| Infectious Diseases | 150 (29.9) | 39 (12.4) | 111 (59.4) |
| Urgent Care/Emergency Department | 165 (32.9) | 116 (36.8) | 49 (26.2) |
| Other | 21 (4.2) | 16 (5.1) | 5 (2.7) |
| Clinical presentation | |||
| Asymptomatic | 181 (36.1) | 113 (35.9) | 68 (36.4) |
| Urethritis | 148 (29.5) | 31 (9.8) | 117 (62.6) |
| Vaginal symptoms | 142 (28.3) | 142 (45.1) | - |
| Pelvic inflammatory disease | 23 (4.6) | 23 (7.3) | - |
| Isolated lower abdominal pain | 9 (1.8) | 9 (2.9) | - |
| Abnormal vaginal bleeding | 9 (1.8) | 9 (2.9) | |
| Testicular pain | 3 (0.6) | - | 3 (1.6) |
| Initial treatmentc | |||
| Low-dose azithromycin | 156 (32.3) | 88 (29.2) | 68 (37.4) |
| High-dose azithromycin | 114 (23.6) | 93 (30.9) | 21 (11.5) |
| Moxifloxacin | 187 (38.7) | 85 (28.2) | 102 (56.0) |
| Doxycycline | 84 (17.4) | 49 (16.3) | 35 (19.2) |
| Other treatment | 30 (6.2) | 22 (7.3) | 8 (4.4) |
| Not treated | 19 (3.8) | 14 (4.4) | 5 (2.7) |
| Clinical outcome | |||
| Microbiologic cure | 156 (31.1) | 78 (24.8) | 78 (41.7) |
| Persistent infection | 113 (22.5) | 85 (27.0) | 28 (15.0) |
| No follow-up testing | 233 (46.4) | 152 (48.2) | 81 (43.3) |
Abbreviations: HIV, human immunodeficiency virus; MG, Mycoplasma genitalium; low-dose azithromycin, azithromycin 1 gram (g) for 1 dose; high-dose azithromycin, azithromycin 1g on day 1 followed by 500 milligrams (mg) daily on days 2–4; moxifloxacin, moxifloxacin 400 mg daily for at least 7 days; doxycycline, any duration of doxycycline 100 mg 2 times daily.
Missing data. Data presented in this table includes race/ethnicity data on 480 patients, sexual partners on 463, living with HIV on 413, isolated MG infection on 302, Chlamydia trachomatis and Neisseria gonorrhoeae testing on 460, Trichomonas vaginalis on 376, syphilis on 397, bacterial vaginosis on 84.
An isolated MG infection required negative testing for gonorrhea, chlamydia, trichomonas, and syphilis at the time of initial M. genitalium diagnosis.
Includes patients who received multiple treatment regimens.
Most males (117/187, 63%) presented with urethritis, and most females (142/315, 45%) presented with vaginal symptoms. When excluding those with NG, CT, TV or BV at the time of MG infection, 60% (95/157) of males presented with urethritis and 58% females (73/198) presented with vaginal symptoms. Of the 23 females presenting with PID, 14 had simultaneous testing for CT, NG, and TV and 9 were positive only for MG. Of patients who were asymptomatic at the time of MG diagnosis, 8% (14/181) had documented exposure to MG and 92% (167/181) received testing as routine STI screening.
Of 483 who received treatment, 39% (187/483) received moxifloxacin as part of initial MG treatment. Of these, 72% (134/187) received only moxifloxacin. Eighty-six percent (270/315) of those not receiving moxifloxacin were treated with azithromycin either at low (1g once) or high dose (1g on day one followed by 500 mg daily on days two through four). Thirty-nine patients received both azithromycin and moxifloxacin, and 17 patients received both doxycycline and moxifloxacin.
Available MG follow-up testing
Follow-up testing at least 21 days after initial positive test was available for 269 patients (54%). Six patients (three positive and three negative) were excluded for follow-up testing before 21 days. Characteristics associated with follow-up testing are shown in Supplemental Table 1. Among those with follow-up testing 84% (85/101) reported symptoms at follow-up. Follow-up testing was associated with hospital location (p<0.01), with the highest percentage in those diagnosed in an infectious diseases (ID) clinic (65%), and the lowest in those diagnosed in the emergency department (ED) or urgent care (47%). Those who received moxifloxacin were more likely to have follow-up testing relative to other regimens (61% vs 39%, p=0.03), a finding attributable to a higher percentage of ID providers prescribing moxifloxacin. Eighty-seven of 144 (60%) patients tested in an ID clinic received moxifloxacin compared to 67/155 (43%) from the ED or urgent care, 20/83 (24%) from obstetrics/gynecology, and 10/80 (12%) from non-ID primary care providers (p<0.001).
Characteristics associated with microbiologic cure of MG
After exclusion of five untreated patients and 54 who received more than one treatment, associations with microbiologic cure of MG were evaluated in 210 patients (Tables 2 and 3). Forty-three percent (90/210) had persistent infection and 57% (120/210) had microbiologic cure. Males had higher percentages of microbiologic cure compared to females (75% vs 48%, p <0.001). Microbiologic cure was significantly associated with hospital testing location with the highest percentage cure among those diagnosed by an ID provider (p<0.01). Patients with urethritis at diagnosis had two times the odds of microbiologic cure versus those without urethritis (OR 2.15, 95% CI 1.12–4.11, p-value 0.02). Among individuals treated with moxifloxacin, the rate of microbiologic cure was 82% (67/82) compared to 43% (25/58) who received low-dose azithromycin, 31% (15/48) who received high-dose azithromycin and 60% (13/22) who received doxycycline (p-value <0.001). Twelve patients who received both moxifloxacin and doxycycline as initial treatment had available follow-up testing, all showing microbiologic cure.
Table 2.
Bivariate associations with microbiologic cure of Mycoplasma genitalium infection among those receiving a single treatment regimen (n=210)
| Persistent Infection (n=90) n (%) |
Microbiologic Cure (n=120) n (%) |
p-value | |
|---|---|---|---|
| Sex | <0.001 | ||
| Male | 18 (25.4) | 53 (74.6) | |
| Female | 72 (51.8) | 67 (48.2) | |
| Age at diagnosis | <0.01 | ||
| Years, mean ± SD | 25.3 ± 7.2 | 28.3 ± 7.2 | |
| Race/Ethnicitya | 0.56 | ||
| Non-Hispanic Black | 46 (44.7) | 57 (55.3) | |
| Hispanic | 33 (41.2) | 47 (58.8) | |
| Other | 6 (31.6) | 13 (68.4) | |
| Time to follow-up test | 0.48 | ||
| Days, median (IQR) | 84 (50–182) | 82 (36–185) | |
| Source of specimen | 0.74 | ||
| Urine | 58 (42.0) | 80 (58.0) | |
| Anogenital swab | 32 (44.4) | 40 (55.6) | |
| Living with HIVa | |||
| Yes | 10 (52.6) | 9 (47.4) | 0.30 |
| Coinfection at time of MG diagnosisa | |||
| Chlamydia trachomatis | 10 (66.7) | 5 (33.3) | <0.05 |
| Neisseria gonorrhoeaeb | 4 (66.7) | 2 (33.3) | 0.24 |
| Trichomonas vaginalisb | 6 (60.0) | 4 (40.0) | 0.32 |
| Syphilisb | 1 (33.3) | 2 (66.7) | 0.76 |
| Bacterial vaginosisc | 6 (25.0) | 18 (75.0) | 0.04 |
| Hospital testing location | <0.01 | ||
| Primary Care | 28 (70.0) | 12 (30.0) | |
| Obstetrics/Gynecology | 20 (47.6) | 22 (52.4) | |
| Infectious Diseases | 20 (29.4) | 48 (70.6) | |
| Urgent Care/Emergency Department | 20 (35.7) | 36 (64.3) | |
| Other | 2 (50.0) | 2 (50.0) | |
| Clinical presentation | |||
| Asymptomatic | 35 (46.0) | 41 (54.0) | 0.48 |
| Urethritis | 17 (29.8) | 40 (70.2) | 0.02 |
| Vaginal symptoms | 34 (47.9) | 37 (52.1) | 0.29 |
| Pelvic inflammatory diseaseb | 3 (50.0) | 3 (50.0) | 0.99 |
| Symptoms at follow-upa | |||
| Yes | 25 (37.9) | 41 (62.1) | 0.29 |
| Initial treatmenta | <0.001 | ||
| Low-dose azithromycin | 33 (56.9) | 25 (43.1) | |
| High-dose azithromycin | 33 (68.8) | 15 (31.2) | |
| Moxifloxacin | 15 (18.3) | 67 (81.7) | |
| Doxycycline | 9 (40.9) | 13 (59.1) |
Abbreviations: HIV, human immunodeficiency virus; MG, Mycoplasma genitalium: low-dose azithromycin, azithromycin 1 g for 1 dose; high-dose azithromycin, azithromycin 1g on day1 followed by 500 mg daily on days 2–4; moxifloxacin, moxifloxacin 400 mg daily for at least 7 days; doxycycline, any duration of doxycycline 100 mg 2 times daily.
Missing Data. Race/ethnicity available on 202 individuals, living with HIV on 188, Chlamydia trachomatis and Neisseria gonorrhoeae on 192, Trichomonas vaginalis on 163, syphilis on 183, bacterial vaginosis on 46, symptoms at follow-up on 170.
Fisher’s exact test performed.
Bacterial vaginosis testing only performed on females.
Table 3:
Associations with microbiologic cure of Mycoplasma genitalium infection among those receiving treatment
| Bivariate Analysis | Multivariate Analysis | |||
|---|---|---|---|---|
| OR (n=210) |
p-value | aOR (n=202) |
p-value | |
| Sex | <0.001 | 0.13 | ||
| Female | 1.0 (ref) | 1.0 (ref) | ||
| Male | 3.16 (1.68–5.94) | 2.00 (0.82–4.88) | ||
| Age at diagnosis | ||||
| Per Year | 1.06 (1.02–1.11) | <0.01 | 1.04 (0.99–1.09) | 0.10 |
| Race/Ethnicitya | ||||
| Non-Hispanic Black | 1.0 (ref) | 1.0 (ref) | ||
| Hispanic | 1.15 (0.64–2.08) | 0.64 | 1.24 (0.62–2.46) | 0.54 |
| Other | 1.75 (0.62–4.96) | 0.29 | 1.65 (0.48–5.62) | 0.42 |
| Hospital testing location | ||||
| Primary Care | 1.0 (ref) | 1.0 (ref) | ||
| Obstetrics/ Gynecology | 2.57 (1.04–6.36) | 0.04 | 2.47 (0.88–6.90) | 0.08 |
| Infectious Diseases | 5.60 (2.38–13.16) | <0.001 | 1.72 (0.58–5.04) | 0.33 |
| Urgent Care/ Emergency Department | 4.20 (1.76–10.02) | <0.01 | 3.35 (1.18–9.54) | 0.02 |
| Other | 2.33 (0.29–18.6) | 0.43 | 1.52 (0.16–14.22) | 0.71 |
| Living with HIVa | ||||
| Yes | 0.61 (0.23–1.57) | 0.30 | ||
| Coinfection at time of MG diagnosisa | ||||
| Chlamydia trachomatis | 0.33 (0.11–1.02) | 0.05 | ||
| Neisseria gonorrhoeae | 0.35 (0.06–1.98) | 0.24 | ||
| Trichomonas vaginalis | 0.47 (0.13–1.72) | 0.25 | ||
| Syphilis | 1.46 (0.13–16.41) | 0.76 | ||
| Bacterial vaginosis | 3.60 (1.03–12.54) | 0.04 | ||
| Clinical presentation | ||||
| Asymptomatic | 0.82 (0.46–1.44) | 0.48 | ||
| Urethritis | 2.15 (1.12–4.11) | 0.02 | ||
| Vaginal symptoms | 0.73 (0.41–1.31) | 0.29 | ||
| Pelvic inflammatory disease | 0.74 (0.15–3.77) | 0.72 | ||
| Initial treatmenta | ||||
| Low-dose azithromycin | 1.0 (ref) | 1.0 (ref) | ||
| High-dose azithromycin | 0.60 (0.27–1.34) | 0.21 | 0.47 (0.19–1.15) | 0.10 |
| Moxifloxacin | 5.90 (2.75–12.67) | <0.001 | 4.18 (1.73–10.13) | <0.01 |
| Doxycycline | 1.91 (0.70–5.16) | 0.20 | 1.39 (0.47–4.15) | 0.55 |
Abbreviations: HIV, human immunodeficiency virus; MG, Mycoplasma genitalium; low-dose azithromycin, azithromycin 1 g for 1 dose; high-dose azithromycin, azithromycin 1g on day 1 followed by 500 mg daily on days 2–4; moxifloxacin, moxifloxacin 400 mg daily for at least 7 days; doxycycline, any duration of doxycycline 100 mg 2 times daily.
Missing data in bivariate analysis. Data presented include Race/ethnicity on 202, living with HIV on 188, Chlamydia trachomatis and Neisseria gonorrhoeae on 192, Trichomonas vaginalis on 203, syphilis on 232 and bacterial vaginosis on 46, initial treatment regimen on 210 patients receiving a single regimen.
Among 163 females with available follow-up testing, 51 with vaginal symptoms were tested for BV, and 26 (51%) had BV. Of all females with follow-up testing including those receiving multiple MG treatment regimens, females with BV had a higher percentage of microbiologic cure relative to both those testing negative for BV (77% vs 40%, p-value <0.01) and all other females (those testing negative and those not tested for BV) (77% vs 43%, p-value <0.01) (See Supplemental Table 2). More females with BV received treatment including moxifloxacin (14/26 or 54%) relative to patients without BV (7/25 or 28%, p-value 0.06) or all other females (31/134 or 23%, p-value <0.01). Of the 26 patients with BV, 21 received BV-directed treatment (2 with boric acid and 19 with oral or intravaginal metronidazole). Among those who received metronidazole, 74% (14/19) had microbiologic cure of MG. Receiving a metronidazole regimen (oral or intravaginal) for BV treatment was not significantly associated with microbiologic cure (p=0.62).
In multivariable analysis including all individuals who received a single agent for treatment, odds of microbiologic cure in patients treated with moxifloxacin was almost nine times (aOR 8.95, 95% CI 3.48–23.02, p <0.001) higher than those receiving high-dose azithromycin, four times (aOR 4.18, 95% CI 1.73–10.13, p <0.01) higher than those receiving low-dose azithromycin and three times (aOR 3.00, 95% CI 0.99–9.10, p=0.05) higher than those receiving doxycycline. Sensitivity analysis was performed classifying both patients with no follow-up testing or those with microbiologic cure as having presumed cure (Supplemental Table 3). This allowed for the most conservative assessment of the impact of moxifloxacin on cure, since those without follow-up testing were less likely to have received moxifloxacin (73/233 (31%) vs. 114/269 (42%), p=0.03). In this multivariable model, odds of presumed cure with moxifloxacin remained significant, aOR 2.83 (95% CI 1.33–6.01, p<0.01).
Moxifloxacin treatment failures
Twenty patients initially treated with a regimen including moxifloxacin had persistent infection. Of these, 15 received moxifloxacin alone, while three received low-dose azithromycin and two received high-dose azithromycin in addition to moxifloxacin. Sixteen eventually achieved microbiologic cure (including 11 treated with moxifloxacin alone) (Table 4). Four individuals remain persistently positive on all available follow-up testing with a median of two positive tests (range 2–4). Thirteen of 16 (81%) with subsequent microbiologic cure had two positive M. genitalium NAATs (initial test and follow-up test), with a negative third sequential test. Eight of 16 (50%) achieved microbiologic cure with a single additional course of moxifloxacin alone. Two of 16 (12.5%) had documentation of incomplete initial treatment. Only one patient had documented partner treatment and 3/16 (19%) had at least one new STI at the time of follow-up testing, suggesting potential for reinfection. One individual with eight documented positive tests was ultimately cured with minocycline, suggesting possible baseline moxifloxacin resistance.
Table 4:
Individuals with persistent infection after moxifloxacin treatment regimen and subsequent microbiologic cure (n=16)
| Days to first negative test – median (range) | 285 (47–957) |
| Total number of positive tests – median (range) | 2 (2–8) |
| Symptoms at follow-up | 7 (43.8) |
| Non-adherence to initial moxifloxacin regimena – n(%) | 2 (12.5) |
| Confirmed partner(s) treatment – n (%) | 1 (6.2) |
| New STI diagnosed at time of repeat testingb – n (%) | 3 (18.8) |
| Treatment prior to microbiologic cure | |
| Moxifloxacin – n (%) | 8 (50.0) |
| Doxycycline alone – n (%) | 4 (25.0) |
| Minocycline – n (%) | 1 (6.2) |
| High-dose azithromycin + doxycycline – n (%) | 1 (6.2) |
| Ciprofloxacin – n (%) | 1 (6.2) |
| No further treatment documented – n (%) | 1 (6.2) |
Abbreviations: STI- sexually transmitted infection; high-dose azithromycin, azithromycin 1 gram (g) on day 1 followed by 500 milligrams (mg) daily on days 2–4; moxifloxacin, moxifloxacin 400 mg daily for at least 7 days; doxycycline, any duration of doxycycline 100 mg 2 times daily; minocycline 100 mg 2 times daily for 4 weeks; ciprofloxacin 500 mg 2 times daily for 7 days.
Non-adherence to initial moxifloxacin regimen was defined by subsequent provider documentation that patient did not complete initial M. genitalium treatment regimen.
Two Chlamydia trachomatis infections and one syphilis infection.
Discussion
This study furthers our understanding of the clinical presentations, epidemiology, and treatment outcomes of MG infections. Most individuals in this US cohort presented with urethritis or vaginal symptoms. Among those with follow-up testing, microbiologic cure was observed in 57% of patients receiving a single treatment regimen. Moxifloxacin achieved the highest percentage of microbiologic cure (82%) relative to 43% with low-dose azithromycin, 31% with high-dose azithromycin, and 60% with doxycycline. Treatment with moxifloxacin alone was associated with four times the odds of microbiologic cure relative to treatment with low-dose azithromycin.
To address concerns that single drug regimens may contribute to resistance, a two-stage regimen of doxycycline followed by either azithromycin or moxifloxacin (based on susceptibility testing) is recommended in CDC and Australian STI guidelines (1, 14). In a prospective evaluation of a resistance guided treatment pathway, sequential treatment with doxycycline-azithromycin and doxycycline-moxifloxacin cured 95% and 92% of macrolide susceptible and macrolide resistant infections, respectively (15). In this study, development of de novo macrolide resistance was observed in all five cases failing doxycycline-azithromycin. However, emergent fluoroquinolone resistance was not observed among those treated with doxycycline-moxifloxacin (18). New resistance mutations were identified in 1.2% (2/167) of those treated with sequential doxycycline-sitafloxacin, both cases in males with rectal infections.
We report an 82% microbiologic cure with moxifloxacin treatment in this study versus a 96% pooled rate in a meta-analysis (20). Only one US-based study was included in this meta-analysis and reported 14/16 (88%) individuals achieved cure with moxifloxacin (21). Although our data are limited by lack of available resistance testing, we suspect low rates of clinical fluoroquinolone resistance in our cohort based on evaluation of those with persistent infections, with non-adherence or reinfection most likely in persistent cases after moxifloxacin treatment. Evidence supporting this assertion includes that few had documented partner treatment, some had additional new STIs at the time of diagnosis of persistent infection, and 50% had a microbiologic cure with a subsequent course of moxifloxacin alone. The lower rates of microbiologic cure with azithromycin treatment (43% with low-dose azithromycin, 31% with high-dose azithromycin) likely reflect higher rates of macrolide resistance in this study population which has been demonstrated in other studies (13).
While our data are retrospective, we present evidence for efficacy of moxifloxacin as initial therapy for MG especially in the absence of empiric doxycycline use. Moxifloxacin-associated side effects should be considered when making clinical decisions about the use of this agent for people with MG infections (15). In this study, all 12 individuals who received both doxycycline and moxifloxacin with follow-up testing achieved a microbiologic cure. While staged treatment is effective (15), our data suggest it may be unnecessary. Additionally, the complex regimen may present adherence barriers in clinical practice.
While screening practices in this study were based on clinical judgement, the many asymptomatic infections identified are similar to prior reports (5, 22, 23). Current European, US CDC, and Australian guidelines do not recommend routine screening of asymptomatic individuals due to concern of rising antibiotic resistance and lack of understanding of natural history of infection (1, 14, 17). However, published guidelines are often not followed by clinicians and screening for MG that occurred in the context of routine STI testing in this study suggests the need for frontline provider education on MG testing recommendations (24). A systematic review and meta-analysis found that 39–50% of heterosexual partners tested positive for MG, suggesting asymptomatic infections likely sustain continued transmission (11, 12). Modeling work suggests potential benefits of identifying and treating asymptomatic cases, including decreasing the population burden of PID (12). In this study, 14 females presenting with PID had simultaneous testing for CT, NG, and TV and nine were positive for only MG. Given the clinical implications and high prevalence of asymptomatic infections, additional studies are needed to understand the natural history of asymptomatic MG infections and to determine whether there are benefits to identifying and treating them.
An association of BV with acquisition of MG has been previously described (25–28). Interestingly, in our study females with BV had higher rates of microbiologic cure. This is likely partially explained by more females with BV receiving moxifloxacin; however, the small sample size limited full analysis. In a randomized controlled trial comparing ceftriaxone, doxycycline, with or without metronidazole for PID, patients treated with metronidazole had decreased cervical MG recovered relative to those not receiving metronidazole (29). While only a small subset received metronidazole treatment for BV in this study, metronidazole was not associated with microbiologic cure of MG. The potential association of BV with microbiologic cure of MG needs further study.
This study is limited by the retrospective design and utilization of EHR-based data which relies on documentation by providers and includes missing data (30). Clinical presentations were extracted with manual chart review and limited to available documentation. Importantly, an independent review of clinical presentations demonstrated very few discrepancies. However, it was not possible to reliably differentiate between women with cervicitis and vaginal symptoms or to determine the role of MG as a colonizer or pathogen among the 34% with coinfection. There were also absence of adherence data and lack of follow-up testing for all patients in this study cohort. To mitigate potential bias of lack of universal follow-up testing, a sensitivity analysis was performed, presuming that those without additional testing were cured, showing continued significance of moxifloxacin with microbiologic cure. Given the retrospective study design, we were unable to differentiate between reinfection, recrudescence, or persistent infection on positive follow-up tests. Prospective studies are needed to define the effectiveness of available treatments for MG infections.
Supplementary Material
Funding:
This work was supported by the National Institutes of Health [UL1 TR002556, 5T32AI070117-16]
Footnotes
Conflict of interest: The authors declare they have no conflict of interest.
References:
- 1.Workowski KA, Bachmann LH. Centers for Disease Control and Prevention’s Sexually Transmitted Diseases Infection Guidelines. Clin Infect Dis. 2022;74(74 Suppl 2):S89–S94. [DOI] [PubMed] [Google Scholar]
- 2.Haggerty CL, Taylor BD. Mycoplasma genitalium: an emerging cause of pelvic inflammatory disease. Infect Dis Obstet Gynecol. 2011;2011:959816. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Manhart LE, Gaydos CA, Taylor SN, et al. Characteristics of Mycoplasma genitalium Urogenital Infections in a Diverse Patient Sample from the United States: Results from the Aptima Mycoplasma genitalium Evaluation Study (AMES). J Clin Microbiol. 2020;58(7). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Torrone EA, Kruszon-Moran D, Philips C, et al. Prevalence of Urogenital Mycoplasma genitalium Infection, United States, 2017 to 2018. Sex Transm Dis. 2021;48(11):e160–e2. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Getman D, Jiang A, O’Donnell M, Cohen S. Mycoplasma genitalium Prevalence, Coinfection, and Macrolide Antibiotic Resistance Frequency in a Multicenter Clinical Study Cohort in the United States. J Clin Microbiol. 2016;54(9):2278–83. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Bachmann LH, Kirkcaldy RD, Geisler WM, et al. Prevalence of Mycoplasma genitalium Infection, Antimicrobial Resistance Mutations, and Symptom Resolution Following Treatment of Urethritis. Clin Infect Dis. 2020;71(10):e624–e32. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Sena AC, Lensing S, Rompalo A, et al. Chlamydia trachomatis, Mycoplasma genitalium, and Trichomonas vaginalis infections in men with nongonococcal urethritis: predictors and persistence after therapy. J Infect Dis. 2012;206(3):357–65. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Manhart LE, Leipertz G, Soge OO, et al. Mycoplasma genitalium in the US (MyGeniUS): Surveillance Data from Sexual Health Clinics in Four US Regions. Clin Infect Dis. 2023. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Anagrius C, Lore B, Jensen JS. Mycoplasma genitalium: prevalence, clinical significance, and transmission. Sex Transm Infect. 2005;81(6):458–62. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Sonnenberg P, Ison CA, Clifton S, et al. Epidemiology of Mycoplasma genitalium in British men and women aged 16–44 years: evidence from the third National Survey of Sexual Attitudes and Lifestyles (Natsal-3). Int J Epidemiol. 2015;44(6):1982–94. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Cina M, Baumann L, Egli-Gany D, et al. Mycoplasma genitalium incidence, persistence, concordance between partners and progression: systematic review and meta-analysis. Sex Transm Infect. 2019;95(5):328–35. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Birger R, Saunders J, Estcourt C, et al. Should we screen for the sexually-transmitted infection Mycoplasma genitalium? Evidence synthesis using a transmission-dynamic model. Sci Rep. 2017;7(1):16162. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Machalek DA, Tao Y, Shilling H, et al. Prevalence of mutations associated with resistance to macrolides and fluoroquinolones in Mycoplasma genitalium: a systematic review and meta-analysis. Lancet Infect Dis. 2020;20(11):1302–14. [DOI] [PubMed] [Google Scholar]
- 14.Ong JJ, Bourne C, Dean JA, et al. Australian sexually transmitted infection (STI) management guidelines for use in primary care 2022 update. Sex Health. 2023;20(1):1–8. [DOI] [PubMed] [Google Scholar]
- 15.Durukan D, Read TRH, Murray G, et al. Resistance-Guided Antimicrobial Therapy Using Doxycycline-Moxifloxacin and Doxycycline-2.5 g Azithromycin for the Treatment of Mycoplasma genitalium Infection: Efficacy and Tolerability. Clin Infect Dis. 2020;71(6):1461–8. [DOI] [PubMed] [Google Scholar]
- 16.Read TRH, Fairley CK, Murray GL, et al. Outcomes of Resistance-guided Sequential Treatment of Mycoplasma genitalium Infections: A Prospective Evaluation. Clin Infect Dis. 2019;68(4):554–60. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Jensen JS, Cusini M, Gomberg M, et al. 2021 European guideline on the management of Mycoplasma genitalium infections. J Eur Acad Dermatol Venereol. 2022;36(5):641–50. [DOI] [PubMed] [Google Scholar]
- 18.Murray GL, Bodiyabadu K, Danielewski J, et al. Moxifloxacin and Sitafloxacin Treatment Failure in Mycoplasma genitalium Infection: Association with parC Mutation G248T (S83I) and Concurrent gyrA Mutations. J Infect Dis. 2020;221(6):1017–24. [DOI] [PubMed] [Google Scholar]
- 19.Falk L, Enger M, Jensen JS. Time to eradication of Mycoplasma genitalium after antibiotic treatment in men and women. J Antimicrob Chemother. 2015;70(11):3134–40. [DOI] [PubMed] [Google Scholar]
- 20.Li Y, Le WJ, Li S, et al. Meta-analysis of the efficacy of moxifloxacin in treating Mycoplasma genitalium infection. Int J STD AIDS. 2017;28(11):1106–14. [DOI] [PubMed] [Google Scholar]
- 21.Manhart LE, Khosropour CM, Gillespie CW, et al. O02.3 Treatment Outcomes For Persistent Mycoplasma Genitalium-Associated NGU: Evidence of Moxifloxacin Treatment Failures. Sexually Transmitted Infections. 2013;89(Suppl 1):A29.1–A. [Google Scholar]
- 22.Baumann L, Cina M, Egli-Gany D, et al. Prevalence of Mycoplasma genitalium in different population groups: systematic review andmeta-analysis. Sex Transm Infect. 2018;94(4):255–62. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Manhart LE, Holmes KK, Hughes JP, et al. Mycoplasma genitalium among young adults in the United States: an emerging sexually transmitted infection. Am J Public Health. 2007;97(6):1118–25. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Landovitz RJ, Gildner JL, Leibowitz AA. Sexually Transmitted Infection Testing of HIV-Positive Medicare and Medicaid Enrollees Falls Short of Guidelines. Sex Transm Dis. 2018;45(1):8–13. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Oakeshott P, Aghaizu A, Hay P, et al. Is Mycoplasma genitalium in women the “New Chlamydia?” A community-based prospective cohort study. Clin Infect Dis. 2010;51(10):1160–6. [DOI] [PubMed] [Google Scholar]
- 26.Lokken EM, Balkus JE, Kiarie J, et al. Association of Recent Bacterial Vaginosis With Acquisition of Mycoplasma genitalium. Am J Epidemiol. 2017;186(2):194–201. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Shipitsyna E, Khusnutdinova T, Budilovskaya O, et al. Bacterial vaginosis-associated vaginal microbiota is an age-independent risk factor for Chlamydia trachomatis, Mycoplasma genitalium and Trichomonas vaginalis infections in low-risk women, St. Petersburg, Russia. Eur J Clin Microbiol Infect Dis. 2020;39(7):1221–30. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Nye MB, Harris AB, Pherson AJ, Cartwright CP. Prevalence of Mycoplasma genitalium infection in women with bacterial vaginosis. BMC Womens Health. 2020;20(1):62. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Wiesenfeld HC, Meyn LA, Darville T, et al. A Randomized Controlled Trial of Ceftriaxone and Doxycycline, With or Without Metronidazole, for the Treatment of Acute Pelvic Inflammatory Disease. Clin Infect Dis. 2021;72(7):1181–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Gianfrancesco MA, Goldstein ND. A narrative review on the validity of electronic health record-based research in epidemiology. BMC Med Res Methodol. 2021;21(1):234. [DOI] [PMC free article] [PubMed] [Google Scholar]
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