Recommendations and Rationale for the Treatment of Pelvic Inflammatory Disease

Oluwatosin Jaiyeoba; Gweneth Lazenby; David E Soper

Expert Rev Anti Infect Ther. 2011;9(1):61-70.

Five-year View

There are several important areas in which additional investigation could provide important guidance. Despite the revelation of a polymicrobial etiology of acute PID in 1975, we still do not understand the true importance of anaerobic bacteria as etiologic agents of acute PID. Current data suggest that antimicrobial regimens with little to no anaerobic coverage are highly effective in the treatment of mild-to-moderate PID, even in women with concurrent BV. Prospective studies need to be performed that will compare well-tolerated antibiotic regimens with excellent anaerobic coverage with those with little to no such coverage in the treatment of mild-to-moderate PID. In addition, prospective randomized trials are required to study oral cefixime versus other parenteral cephalosporins. We also understand little with respect to the need for duration of treatment and the frequency of dosing. It would be interesting to see if short courses (<1 week) of therapy are as effective as our now recommended longer courses (2 weeks). The reality of prolonged therapy is that compliance is notoriously poor, so shorter therapy may not only turn out to be more cost effective but may have equal efficacy as well. In addition, pulse dosing, for example, 1 g of azithromycin a week apart, appears promising as an alternative dosing schedule and needs further investigation.

Mycoplasma genitalium is an emerging pathogen of importance as an etiologic agent of lower and upper genital tract infection. Evidence suggests that it is associated with persistent endometritis despite doxycycline therapy and its optimal therapy is unknown. M. genitalium could become the next C. trachomatis if widespread testing was undertaken, yet commercially available nucleic acid tests are not available. It will be important to define the epidemiology, sequelae and most effective therapy for this emerging sexually transmitted infection.

It would be preferable to use a single agent that covers all the potential microbial pathogens, can be administered once daily and is inexpensive. Currently, moxifloxacin (not available as a generic in the USA) comes closest to being this agent but quinolone-resistant N. gonorrhoeae and its cost (US$225.60 for 14 tablets) prevent it from being embraced in this regard. Continued antibiotic development could provide us with this agent in the future.

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Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
writing assistance was utilized in the production of this manuscript.

Cite this: Recommendations and Rationale for the Treatment of Pelvic Inflammatory Disease - Medscape - Jan 01, 2011.

Table 1. Cost of frequently used antibiotics in the treatment of pelvic inflammatory disease.
Drug	Regimen dose	Regimen cost
Azithromycin	500 mg p.o. × one dose followed by 250 mg q.d. × 7 days	Tablets: 250 mg (eight tablets) US$26.40^†
Amoxicillin/clavulanate	875 mg p.o. q 12 h for 12 days	Tablets: 875–125 mg (24 tablets) US$38.40^†
Ampicillin/sulbactam	3 g iv. q 6 h for 48 h	iv. vial: (2 g:1 g) for 48 h US$80^‡
Ceftriaxone	1 g iv. q 12 h for 48 h	iv. vial: (250 mg) US$3; iv. vial: (2 g) for 48 h US$18.28^‡
Cefixime	400 mg p.o. × one dose	Tablets: 400 mg (one tablet) US$11^‡
Cefoxitin	2 g im. × one dose (mild-to- moderate PID) 2 g iv. q 6 h for 48 h in severe PID	iv. vial: (1 g/50 ml) US$11.23^‡US$22.46 for 2 g dose US$179.68 for 48 h
Cefotetan	2 g iv. q 12 h for 48 h	iv. vial: (2 g) US$28.45^‡US$113.8 for 48 h
Clindamycin	900 mg iv. q 8 h	iv. vial: (900 mg) US$13.28^‡US$79.68 for 48 h
Doxycycline	100 mg p.o. q 12 h for 14 days 100 mg iv. q 12 h in severe PID	Capsule: 100 mg (28 capsules) US$12.13^†
Gentamicin	Loading dose 2 mg/kg iv. followed by maintenance dose (1.5 mg/kg) q 8 h single q.d. Dosing may be substituted by 4.5 mg/kg iv. q.d.	Solution: 10 mg/ml (25 vials, 2 ml) US$125^†
Metronidazole	500 mg p.o. q 12 h for 14 days	Tablets: 500 mg (28 tablets) US$12.12^†
Probenecid	1 g p.o. administered concurrently with cefoxitin	Tablets: 500 mg (two tablets) US$1.17^‡
Trimethoprim/sulfamethoxazole	160/800 mg p.o. q 12 h for 12 days	Tablets: 160–800 mg (24 tablets) US$16^†
Ciprofloxacin	500 mg p.o. q 12 h	Tablets: 500 mg (28 tablets) US$11^†
Levofloxacin	500 mg p.o. q.d.	Tablets: 500 mg (14 tablets) US$236.60^†
Moxifloxacin	400 mg p.o. or iv. q.d.	Tablets: 400 mg (14 tablets) US$225.60^†

^†Approximate retail price from [101].
^‡Average wholesale price from [102].
im.: Intramuscularly; iv.: Intravenously; PID: Pelvic inflammatory disease; p.o.: Orally; q: Every; q.d.: Daily.

Box 1. Symptoms in women with clinically suspected pelvic inflammatory disease.
Abdominal pain Abnormal discharge Intermenstrual bleeding Postcoital bleeding Fever Urinary frequency Lower back pain Nausea/vomiting
Data taken from [50,51].

Box 2. Outpatient antibiotic regimen for cervicitis.
Cefixime 400 mg orally in a single dose Plus Azithromycin 1 g orally in a single dose Plus Metronidazole 500 mg orally twice daily for 7 days if bacterial vaginosis or Trichomonas vaginalisis present
Data taken from [10].

Box 3. Criteria for hospitalization in women with pelvic inflammatory disease.
Surgical emergencies (e.g., appendicitis) cannot be excluded Patient is pregnant Patient does not respond clinically to oral antibiotic therapy Patient is unable to follow or tolerate an outpatient oral regimen Patient has severe illness, nausea and vomiting or high fever Patient has a tubo–ovarian abscess
Data from [52].

Box 4. The April 2007 CDC updated recommended oral regimens.
Ceftriaxone 250 mg intramuscularly in a single dose Plus Doxycycline 100 mg orally twice a day for 14 days With or without Metronidazole 500 mg orally twice a day for 14 days Or Cefoxitin 2 g intramuscularly in a single dose and Probenecid 1 g orally administered concurrently in a single dose Plus Doxycycline 100 mg orally twice a day for 14 days With or without Metronidazole 500 mg orally twice a day for 14 days Or Other parenteral third-generation cephalosporins (e.g., ceftizoxime or cefotaxime) Plus Doxycycline 100 mg orally twice a day for 14 days With or without Metronidazole 500 mg orally twice a day for 14 days
Data taken from [18].

Box 5. The April 2007 CDC updated parenteral regimens.
Recommended regimen A Cefotetan 2 g intravenously every 12 h Or Cefoxitin 2 g intravenously every 6 h Plus Doxycycline 100 mg orally or intravenously every 12 h Recommended regimen B Clindamycin 900 mg intravenously every 8 h Plus Gentamicin loading dose intravenously or intramuscularly (2 mg/kg of bodyweight), followed by a maintenance dose (1.5 mg/kg) every 8 h. Single daily dosing may be substituted Alternative regimen Ampicillin/sulbactam 3 g intravenously every 6 h Plus Doxycycline 100 mg orally or intravenously every 12 h
Data taken from [18].

Box 6. Outpatient antibiotic regimen for treatment of mild-to-moderate pelvic inflammatory disease.
Recommended oral regimen Cefixime 400 mg orally in a single dose Plus Azithromycin 500 mg orally followed by 250 mg orally daily for a total of 7 days Or Doxycycline 100 mg orally twice daily for 14 days Alternative regimen Ceftriaxone 250 mg intramuscularly in a single dose Plus Azithromycin 500 mg orally followed by 250 mg orally daily for a total of 7 days Or Doxycycline 100 mg orally twice daily for 14 days Preferred regimen if concurrent bacterial vaginosis infection Cefoxitin 2 g intramuscularly in a single dose and Probenecid 1 g orally administered concurrently in a single dose Plus Azithromycin 500 mg orally followed by 250 mg orally daily for a total of 7 days Or Doxycycline 100 mg orally twice daily for 14 days

Box 7. Inpatient parenteral antibiotic regimens for treatment of severe pelvic inflammatory disease and tubo–ovarian abscess^†.
Recommended regimen^‡ Ceftriaxone 1 g intravenously every 12 h Plus Metronidazole 500 mg intravenously every 6 h Or Clindamycin 900 mg intravenously every 8 h Alternative regimens^‡ Ertapenem 1 g intravenously daily Or Piperacillin/tazobactam 3.375 g intravenously every 6 h Or Ticarcillin/clavulanate 300 mg/kg/day intravenously in divided doses every 4 h Or Ampicillin/sulbactam 3 g intravenously every 6 h Alternative regimen for penicillin-allergic patients^§ Levofloxacin 500 mg orally once daily for 14 days Or Ciprofloxacin 400 mg intravenously every 12 h Plus Metronidazole 500 mg intravenously every 6 h
^†Intravenous antibiotics can be switched to oral antibiotics after 48–72 h of therapy or based on clinical judgment. ^‡If Chlamydiapositive, add either azithromycin or doxycycline. ^§Culture for quinolone-resistant Neisseria gonorrhoeaeis required if the quinolones are used.

Box 8. European guidelines for the management of pelvic inflammatory disease.
Outpatient regimens Ceftriaxone 250 mg intramuscularly in a single dose Or Cefoxitin 2 g intramuscularly in a single dose and Probenecid 1 g orally administered concurrently in a single dose Plus Doxycycline 100 mg orally twice daily for 14 days Plus Metronidazole 400 mg orally twice daily for 14 days Alternative regimen Moxifloxacin 400 mg orally once daily for 14 days Or Ofloxacin 400 mg orally twice daily for 14 days Plus Metronidazole 500 mg orally twice daily for 14 days Inpatient regimens Cefoxitin 2 g intravenously four times daily Or Cefotetan 2 g intravenously twice daily Or Ceftriaxone 1 g intravenously or intramuscularly once daily Plus Doxycycline 100 mg intravenously twice daily (oral doxycycline may be used if tolerated) Followed by Doxycycline 100 mg orally twice daily for a total of 14 days Plus Metronidazole 400 mg orally twice daily for a total of 14 days Or Clindamycin 900 mg intravenously every 8 h Plus Gentamicin intravenously (2 mg/kg loading dose followed by 1.5 mg/kg three times daily^†) Followed by either Clindamycin 450 mg orally four times daily to complete 14 days; or Doxycycline 100 mg orally twice daily for 14 days Plus Metronidazole 400 mg orally twice daily to complete 14 days Alternative regimen Ofloxacin 400 mg intravenously twice daily for 14 days Plus Metronidazole 500 mg intravenously three times daily for 14 days Or Ciprofloxacin 200 mg intravenously twice daily Plus Doxycycline 100 mg intravenously or orally twice daily for 14 days Plus Metronidazole 500 mg intravenously three times daily Antibiotic therapy should be given for 14 days
^†A single dose may be substituted. Adapted from [49].

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Recommendations and Rationale for the Treatment of Pelvic Inflammatory Disease

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