Author: Dr. Ashley Penington

Article: “A randomized controlled trial of ceftriaxone and doxycycline, with or without metronidazole, for the treatment of acute pelvic inflammatory disease” Wiesenfeld and colleagues (2019)


As with most things in the realm of infectious diseases, the treatment guidelines and recommendations for pelvic inflammatory disease (PID) have been constantly evolving through the years. We all have had those patients who we have this on our radar when it comes to the diagnosis-someone presenting with pelvic pain who you know you will have to set up a MacGyver pelvic exam with the flipped over urinal and lighted speculum since we don’t have the privilege of always having beds with stirrups like our OB/Gyn colleagues. But the diagnosis of PID is rather vague; in fact, the diagnosis is based on clinical symptoms rather than a true diagnostic test (see the table below from EM-RAP’s Corependium Chapter on Gynecologic Infections for a nice overview on the diagnosis criteria)

Pathophysiologically, PID arises from the ascent of microorganisms from the vagina or endocervix to the endometrium and fallopian tubes, commonly associated with Chlamydia Trachomatis and Neisseria Gonorrhea as well as other facultative and anaerobic microorganisms. Consequently, inadequate treatment of PID is associated with significant adverse outcomes, including infertility and chronic pelvic pain. With the high prevalence of PID (for example, PID was the most common gynecologic complaint with an annual prevalence of 350,000 visits per year according to ACEP in 2010) in addition to the significant long-term complications that arise from inadequately treated PID, it is important for emergency medicine physicians to be up to date with the current treatment recommendations.

While the CDC recommends a single intramuscular dose of 250 mg Ceftriaxone with 100 mg Doxycycline for 14 days, there is concern for limited anaerobic coverage with these two agents. This led Wiesenfeld and colleagues (2019) to investigate the role of additional Metronidazole (Flagyl) in combination with the dual therapy of Doxycycline and Ceftriaxone for the treatment of PID by assessing tolerability of a 3-drug regimen, clinical improvement of symptoms, as well as reduction in anaerobic organisms within the endometrium at their follow up visit.

Study Question:

Does the addition of Metronidazole to the recommended Ceftriaxone + Doxycycline regimen for PID lead to improved treatment outcomes and reduction of anaerobic organisms?

Design (the quick and dirty version):

  • Randomized, double-blind, placebo controlled
  • Conducted from 2010-2015 with 233 patients enrolled including women between the ages of 15-40 who met criteria for diagnosis of PID
  • All women received dual antibiotic treatment with 250 mg IM Ceftriaxone and 100 mg BID Doxycycline and were then randomized in a 1:1 fashion to also receive 500 mg BID Metronidazole or matching placebo for 14 days
  • Participants were then asked to return at 3-days to assess clinical improvement and again at 30-days for repeat cervical swabs

Results (again, we will keep it simple, or if you are a tables kind of person the results are included below!):

  • 208/233 women returned for the primary outcome visit to assess for clinical improvement 3-days after enrollment
    • 91.3% of participants who returned for evaluation had clinical improvement
    • This was similar for both the women receiving metronidazole and those randomized to the placebo group
  • 184 women (79%) continued study medication and returned for the final assessment at a median 31 days from enrollment
  • The real impact of this study was with the secondary outcomes from evaluating the microbiologic organisms at 30-days after treatment
    • Those randomized to the metronidazole group had reduced cervical infections and detection of M. genitalium one month after treatment compared to the placebo containing group (4% vs 14%, P < .05)
    • Bacterial vaginosis (20% vs 54%, P < .001) and T. vaginalis (5% vs 12%, P = .10) were also less prevalent in those randomized to receive metronidazole

Take Away Points:

  • Patients appeared to have similar clinical improvement in both groups and there was no significant difference in reported symptom improvement in those who received Flagyl compared to placebo
    • However, women treated with metronidazole did have less reported pelvic tenderness at one month compared to placebo
  • Microbiologic outcomes showed significantly fewer anaerobic organisms within the endometrium after treatment with metronidazole
  • One of the concerns we have as providers is whether or not our patients can tolerate the antibiotics we prescribe, as many of these medications do have associated side effects
    • The researchers found that 79% of women continued the medication and returned for final assessment


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