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.

Mild-to-moderate PID

Most cases of PID (diagnosed in women with evidence of lower genital tract inflammation and pelvic organ tenderness but no mass) have mild-to-moderate disease. These patients can safely be treated as outpatients. Treatment of PID should provide high rates of clinical and microbiologic cure for N. gonorrhoeae and C. trachomatis, even in the presence of negative endocervical screening for these organisms. It should also provide coverage for the polymicrobial flora found associated with BV.^[8,11–14]

The Pelvic Inflammatory Disease Evaluation and Clinical Health Randomized Trial (PEACH) provides the best guidance regarding the antibiotic therapy of women with mild-to-moderate PID. In this large, multicentered, prospective randomized trial, a single dose of intramuscular cefoxitin administered with probenecid, followed with 14 days of oral doxycycline, resulted in a similar short-term cure rate (both >98%) in outpatients when compared with multiple parenteral doses of cefoxitin and oral doxycycline in inpatients. There was no difference in the long-term outcomes of fertility and ectopic pregnancies between the two groups. Although two-thirds of the PEACH participants had BV, concurrent metronidazole was not administered. This suggests that a single dose of cefoxitin, which has good activity against Gram-negative anaerobes, and multiple doses of doxycycline, despite suboptimal activity against anaerobic bacteria, are sufficient for clinical cure and apparently do not adversely affect long-term outcome comparatively.^[15] The CDC-recommended regimens allow substitution of cefoxitin with other extended-spectrum cephalosporins such as ceftriaxone, ceftizoxime and cefotaxime. The CDC-recommended regimens also allow the clinician discretion to extend the anaerobic coverage by prescribing oral metronidazole in addition to the aforementioned doxycycline (Box 4).

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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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