By Rebecca H. Allen, MD, MPH

Associate Professor, Department of Obstetrics and Gynecology, Warren Alpert Medical School of Brown University, Women and Infants Hospital, Providence, RI

Dr. Allen reports she receives grant/research support from Bayer, and is a consultant for Bayer, Mylan, and Merck.

SYNOPSIS: In this randomized, double-blind, controlled trial, routine treatment with metronidazole compared to placebo in addition to doxycycline and ceftriaxone reduced the presence of endometrial anaerobes, Mycoplasma genitalium, and pelvic tenderness at 30 days post-treatment. However, clinical improvement at three days post-treatment was no different between the two groups.

SOURCE: 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 2020;Feb. 13. [Online ahead of print].

This randomized, double-blind, placebo-controlled trial compared ceftriaxone (250 mg intramuscular once) and doxycycline (100 mg orally twice per day for 14 days) with and without metronidazole (500 mg orally twice per day for 14 days) for the treatment of pelvic inflammatory disease (PID). Women were eligible for participation if they had pelvic or lower abdominal pain and the presence of cervical motion tenderness (CMT), uterine tenderness, or adnexal tenderness on pelvic exam. Exclusion criteria included pregnancy, requirement for inpatient treatment of PID, use of antibiotics in the preceding seven days, allergy to study medications, uterine procedure or miscarriage in the past six weeks, hysterectomy, and menopause.

On enrollment, subjects rated their current pain on a 100 mm visual analog scale, and a clinical tenderness score was determined (CMT, uterine tenderness, and left and right adnexal tenderness graded from 0 [no tenderness] to 3 [tenderness causing marked distress], with a maximal tenderness score of 12). Investigators obtained vaginal fluid samples and an endometrial biopsy. Women returned at three days for a repeat pelvic examination. At 30 days, a repeat pelvic examination was performed, and vaginal fluid and endometrial biopsy samples were taken again. The primary outcome was clinical improvement at the three-day follow-up visit, as measured on the clinical tenderness score.

Two hundred thirty-three women were enrolled between November 2010 and January 2015 at Magee-Women’s Hospital in Pittsburgh. The median age of the study population was 23 years, with a high proportion reporting a history of chlamydia (60%), gonorrhea (27%), and PID (29%). At enrollment, chlamydia was found in 35 (15%) women, gonorrhea in 17 (7%), Mycoplasma genitalium in 41 (18%), bacterial vaginosis in 127 (55%), and trichomonas in 20 (9%). The proportions were similar between the two groups. The follow-up rate for the day 3 visit was 89.3% (208 subjects). Overall, there was no significant difference between the two groups in terms of clinical improvement (92.3% metronidazole vs. 90.4% placebo, P = 0.81). Thirteen women (eight in the metronidazole and five placebo) failed to respond to treatment and were either hospitalized for intravenous antibiotics or elected alternative antibiotics.

The follow-up rate at day 30 was 79% (184 subjects). Clinical improvement in terms of tenderness score was greater in the metronidazole arm (91%) compared to the placebo arm (80%), P < 0.05. Women randomized to metronidazole were less likely to have anaerobes present in the endometrial aspirate (8% vs. 21%, P < 0.05).

Adherence, defined as using 75% of tablets, was similar between the two treatment groups (84% metronidazole vs. 82% placebo). Gastrointestinal symptoms were similar between the two groups, but more vaginal candidiasis was reported in the group receiving metronidazole (15.5% vs. 6.0%, P = 0.02).

COMMENTARY

PID refers to infection of the uterus, fallopian tubes, and ovaries most often caused by sexually transmitted and/or bacterial vaginosis-associated pathogens. The disease can be acute or subclinical, and presentations vary. The Centers for Disease Control and Prevention (CDC) recommends presumptive treatment of PID in women who experience pelvic or lower abdominal pain and when no cause other than PID can be identified, and if they have CMT, uterine tenderness, or adnexal tenderness.¹ Other aides in diagnosis include fever, abnormal cervical mucopurulent discharge or cervical friability, leukorrhea on wet prep of vaginal fluid, and positive testing for Neisseria gonorrhoeae or Chlamydia trachomatis. A wet prep also can identify concomitant bacterial vaginosis and trichomoniasis. The sequelae of PID can include infertility, ectopic pregnancy, hydrosalpinx, and chronic pelvic pain. Therefore, the identification and treatment of this entity is important.

The current CDC recommendations for outpatient treatment of PID are:¹

• Ceftriaxone 250 mg intramuscular in a single dose

PLUS

• Doxycycline 100 mg orally twice per day for 14 days

WITH or WITHOUT

• Metronidazole 500 mg orally twice per day for 14 days.

The caveat to this regimen, according to the CDC, is that “the recommended third-generation cephalosporins are limited in the coverage of anaerobes. Therefore, until it is known that extended anaerobic coverage is not important for treatment of acute PID, the addition of metronidazole to treatment regimens with third-generation cephalosporins should be considered.” There have been questions about whether routine metronidazole is necessary, especially regarding the tolerability of a three-drug regimen. Therefore, Wiesenfeld et al performed this randomized, controlled trial.

The authors concluded the study had a positive result, with fewer women in the metronidazole group with endometrial anaerobic organisms and cervical M. genitalium one month after treatment. Additionally, fewer women in the metronidazole group had pelvic tenderness at one month, and the regimen was well tolerated. The researchers thought the reduction of anaerobic organisms would be beneficial for future reproductive outcomes (e.g., recurrent PID, infertility, and ectopic pregnancy), although the study was not designed to evaluate these longer-term sequelae. Although, traditionally, the focus in terms of PID etiology has been N. gonorrhoeae or C. trachomatis, we see many cases of PID where these organisms are not present. Really, PID is a mixed polymicrobial infection where anaerobes also are causative.

In my practice, we always have added metronidazole to the regimen when bacterial vaginosis, trichomonas, or tubo-ovarian abscesses were present. This study is compelling evidence that metronidazole should be given routinely, and I suspect the next iteration of the CDC’s Sexually Transmitted Diseases Treatment Guidelines will reflect this.

REFERENCE

1. Workowski KA, Bolan GA, Centers for Disease Control and Prevention. Sexually Transmitted Diseases Treatment Guidelines, 2015. MMWR Recomm Rep 2015;64:1-137.