What evidence supports the addition of metronidazole to the standard regimen of ceftriaxone and doxycycline for the treatment of pelvic inflammatory disease?

Introduction
Pelvic inflammatory disease (PID) is an infection of the upper female genital tract involving the uterus, fallopian tubes, and/or ovaries.^1,2 Risk factors for PID include young age, multiple or new sexual partners, unprotected sexual intercourse, early sexual debut (ie, <15 years of age), and a history of sexually transmitted infections (STIs).² According to self-reported data collected from 2013 to 2014, the lifetime prevalence of PID in the United States is estimated to be 4.4% among sexually experienced women 18 to 44 years of age.³ Women with PID may present with lower abdominal, pelvic, or back pain and abnormal vaginal discharge, though some patients may be asymptomatic.^4,5 Gynecologic evaluation usually reveals cervical motion tenderness, uterine tenderness, or adnexal tenderness. Pelvic inflammatory disease may lead to endometritis, salpingitis, peritonitis, perihepatitis, and/or tubo-ovarian abscess; and may potentially result in infertility and increased risk of ectopic pregnancy.² Infections such as bacterial vaginosis tend to co-occur with PID and may also be used to support a PID diagnosis.^2,5

All patients with an acute PID diagnosis – whether asymptomatic, mild-to-moderately severe, or severe – are treated with empiric, broad-spectrum therapy.⁴ Choice of empiric regimen is guided by severity of presentation. Pelvic inflammatory disease of a mild to moderate severity is generally treated with an outpatient combination regimen of intramuscular (IM) and oral agents, whereas severe illness may warrant inpatient parenteral therapy. Timely diagnosis and treatment of this infection are necessary to prevent long-term reproductive complications such as infertility.

Anaerobic coverage in pelvic inflammatory disease
Pelvic inflammatory disease is most often caused by sexually transmitted microorganisms Neisseria gonorrhea and Chlamydia trachomatis, though many patients may not be infected with either.^4-6 Anaerobic microorganisms that are commonly associated with bacterial vaginosis have also been implicated in the pathogenesis of PID and may cause tubal damage or recurrent PID;¹ in one study, the majority of endometrial samples from affected patients revealed anaerobic organisms such as Gardnerella vaginalis, Atopobium vaginae, and Prevotella species.⁷ While anaerobic coverage by way of metronidazole or clindamycin is the recommended treatment regimen for bacterial vaginosis, the merits of including anaerobic coverage as part of a PID treatment regimen have been contested due to limited evidence demonstrating the superiority of a regimen that includes anaerobic coverage over one that does not.⁴

Guideline recommendations
The 2015 US treatment recommendations from the Centers for Disease Control and Prevention (CDC) suggest a standard outpatient regimen of ceftriaxone (single 250-mg IM dose) and doxycycline (100 mg orally twice daily for a 14-day course) in patients with mild-to-moderately severe acute PID to provide coverage for both N. gonorrhea and C. trachomatis.⁴ While the 2015 CDC guideline for PID does not definitively support anaerobic coverage, the addition of metronidazole to the outpatient ceftriaxone/doxycycline regimen is provided as an option. This stands in contrast to the European STI guideline developed in 2017, which recommends metronidazole therapy in combination with a ceftriaxone/doxycycline regimen.⁵ Notably, the European guideline recognizes that anaerobic coverage may be more beneficial in severe PID than in less severe forms of PID for which positive outcomes have been observed without the use of metronidazole. Based on conflicting guideline recommendations and the controversial role of anaerobic coverage in therapy, the purpose of this review is to summarize a recent randomized controlled trial that evaluated addition of metronidazole to ceftriaxone and doxycycline. Prompted by recent data, a 2021 update of the 2015 CDC guideline is expected to include add-on metronidazole as a definitive recommendation as opposed to an optional one.⁸

Systematic review
Limitations to the existing evidence assessing metronidazole for PID were highlighted by a systematic review and meta-analysis published in 2020 that did not suggest any clinical advantage of regimens that include metronidazole.⁹ The authors evaluated studies in which metronidazole was added to various treatment regimens in patients with mild to moderate PID (6 studies; 2660 women) or severe PID (11 studies; 1383 women). The primary outcome of clinical cure was defined by the treating physician, such as resolution or improvement in signs or symptoms of PID. The analysis revealed a minimal difference in clinical cure rates between those who received metronidazole and those who did not for both mild to moderate and severe PID, suggesting that inclusion of anaerobic coverage has no effect on treatment outcomes. Further, the meta-analysis found little or no difference in adverse events related to metronidazole that led to treatment discontinuation. Of 17 included studies, 10 did not report adverse events related to metronidazole. Among 6 studies that reported serious adverse events leading to discontinuation, the rate was 2% with metronidazole (95% CI, 1.5 to 2.7%) and 1.9% (95% CI, 1.4 to 2.6%) without metronidazole. Notably, however, only 1 of the studies included in the analysis evaluated the addition of metronidazole to the CDC-recommended regimen of ceftriaxone plus doxycycline, limiting the applicability of the results. This study was the previously published abstract of the Wiesenfeld et al study described below.^9,10 In addition, efficacy outcomes other than clinical cure were not assessed for metronidazole.

Treatment outcomes with and without metronidazole
Though data supporting the value of add-on metronidazole therapy have been lacking, the results of a recently published randomized, double-blind, placebo-controlled trial suggest benefit.¹¹ Women 15 to 40 years of age with signs or symptoms of acute PID were recruited from multiple centers in Pittsburgh, Pennsylvania; those with severe PID requiring hospitalization and inpatient treatment were excluded from participation. Of the 233 enrolled women with mild to moderate acute PID, 117 were randomized to the CDC-recommended regimen of ceftriaxone (single 250-mg IM dose) and doxycycline (100 mg orally twice daily for a 14-day course), and 116 were randomized to ceftriaxone and doxycycline plus metronidazole (500 mg orally twice daily for 14 days). At baseline, median age was 23 years old, 59% of women were black, 15% of enrolled women were positive for C. trachomatis, 7% were positive for N. gonorrhea, and 55% of women had bacterial vaginosis.

The primary study outcome was clinical improvement at day 3 post-enrollment; clinical improvement was defined as a reduction in clinical tenderness, graded on a scale of 0 to 12 (with 12 representing maximal tenderness).¹¹ Clinical improvement at day 3 did not differ significantly between groups, with 80.3% (94/117) of patients in the placebo group and 82.8% (96/116) of patients in the metronidazole group reporting improvement in clinical tenderness (p=0.74). Secondary outcomes such as pelvic pain at days 3 and 30 and clinical cure at day 30 were also similar between treatment groups. Results are provided in the Table. For the outcome of pelvic tenderness at day 30, however, women treated with add-on metronidazole were significantly less likely to report tenderness than women who received only ceftriaxone and doxycycline; only 8.9% of women in the metronidazole group reported pelvic tenderness, compared with 20.2% of women in the placebo group (p<0.05).

Women treated with metronidazole were significantly less likely than the non-metronidazole cohort to have G. vaginalis, A. vaginae, and other anaerobic organisms isolated from the endometrium at day 30 post-treatment (Table).¹¹ Bacterial vaginosis was also significantly less prevalent at day 30 in the metronidazole group (20.5%) than in the non-metronidazole group (54.4%).

While a frequently-dosed add-on agent may raise concerns from a medication adherence perspective, adherence (defined as having taken ≥75% of all tablets) was similar between the placebo and metronidazole treatment groups (82% and 84%, respectively; p=0.85).¹¹ Additionally, while the overall proportion of patients who experienced at least 1 adverse event was numerically higher in the metronidazole group than in the placebo group (89.7% vs. 80.3% respectively, p=0.07), the frequencies for most events were not significantly different between the 2 populations – with the exception of vulvovaginal candidiasis and genital irritation, which were significantly more common in patients treated with metronidazole. Despite concerns, add-on metronidazole therapy does not negatively impact regimen adherence in patients being treated for mild-to-moderately severe acute PID.

Despite significantly improving pelvic tenderness and decreasing recovery of anaerobic organisms within the endometrium at day 30, the benefits of add-on metronidazole therapy for long-term PID-associated sequelae such as infertility and ectopic pregnancy were not studied and are therefore not known.

Conclusions
The publication of recent clinical data has demonstrated benefit of twice-daily add-on metronidazole to ceftriaxone and doxycycline for short-term clinical outcomes such as pelvic tenderness in women with mild-to-moderate PID. In addition, there was a low risk of adverse events associated with metronidazole and the addition of metronidazole did not significantly affect adherence. These data have contributed to a practice change that is expected to be released by the CDC in a 2021 update to the 2015 guidance. Metronidazole will now be included as recommended (instead of optional) for women with mild-to-moderate PID receiving ceftriaxone and doxycycline. Further data are needed, however, to demonstrate benefit of add-on metronidazole for long-term outcomes such as preservation of fertility.

References

1. Haggerty CL, Totten PA, Gong T, et al. Identification of novel microbes associated with pelvic inflammatory disease and infertility. Sex Transm Infect. 2016;92(6):441-446. doi:10.1136/sextrans-2015-052285
2. Curry A, Williams T, Penny ML. Pelvic inflammatory disease: diagnosis, management, and prevention. Am Fam Physician. 2019;100(6):357-364.
3. Kreisel K, Torrone E, Bernstein K, Hong J, Gorwitz R. Prevalence of pelvic inflammatory disease in sexually experienced women of reproductive age – United States, 2013-2014. MMWR Morb Mortal Wkly Rep. 2017;66(3):80-83. doi:10.15585/mmwr.mm6603a3
4. Workowski KA, Bolan GA; Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines, 2015. MMWR Recomm Rep. 2015;64(RR-03):1-137.
5. Ross J, Guaschino S, Cusini M, Jensen J. 2017 European guideline for the management of pelvic inflammatory disease. Int J STD AIDS. 2018;29(2):108-114. doi:10.1177/0956462417744099
6. Ness RB, Soper DE, Holley RL, et al. Effectiveness of inpatient and outpatient treatment strategies for women with pelvic inflammatory disease: results from the Pelvic Inflammatory Disease Evaluation and Clinical Health (PEACH) randomized trial. Am J Obstet Gynecol. 2002;186(5):929-937. doi:10.1067/mob.2002.121625
7. Petrina MAB, Cosentino LA, Wiesenfeld HC, Darville T, Hiller SL. Susceptibility of endometrial isolates recovered from women with clinical pelvic inflammatory disease or histological endometritis to antimicrobial agents. Anaerobe. 2019; 56:61-65. doi:10.1016/j.anaerobe.2019.02.005
8. STI Treatment Guidelines Webinar Questions and Answers. Centers for Disease Control and Prevention (CDC). January 27, 2021. Accessed June 15, 2021. https://www.cdc.gov/std/treatment-guidelines/qa.htm
9. Savaris RF, Fuhrich DG, Maissiat J, Duarte RV, Ross J. Antibiotic therapy for pelvic inflammatory disease. Cochrane Database Syst Rev. 2020;8(8):CD010285. doi:10.1002/14651858.CD010285.pub3
10. Wiesenfeld H, Hillier S, Meyn L, et al. Impact of metronidazole on clearance of anaerobes in women with acute pelvic inflammatory disease: the ACE trial. Am J Obstet Gynecol. 2017;217(6):714. doi.org/10.1016/J.AJOG.2017.08.081
11. Wiesenfeld HC, Meyn LA, Darville T, Macio IS, Hillier SL. 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):1181-1189. doi:10.1093/cid/ciaa101

Prepared by:
Rosa Macrito, PharmD Candidate Class of 2023
University of Illinois at Chicago College of Pharmacy

Reviewed by:
Patricia Hartke, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy

July 2021

The information presented is current as May 27, 2021. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.