Pelvic Inflammatory Disease (PID)

Pelvic inflammatory disease (PID) comprises a spectrum of inflammatory disorders of the upper female genital tract, including any combination of endometritis, salpingitis, tubo-ovarian abscess, and pelvic peritonitis (728). Sexually transmitted organisms, especially N. gonorrhoeae and C. trachomatis, are implicated in many cases. Recent studies suggest that the proportion of PID cases attributable to N. gonorrhoeae or C. trachomatis is declining; of women who received a diagnosis of acute PID, <50% test positive for either of these organisms (270,729,730). Microorganisms that comprise the vaginal flora (e.g., anaerobes, G. vaginalis, Haemophilus influenzae, enteric Gram-negative rods, and Streptococcus agalactiae) have been associated with PID (731). In addition, cytomegalovirus (CMV), M. hominis, U. urealyticum, and M. genitalium might be associated with some PID cases (264,265,267,732). Newer data suggest that M. genitalium might play a role in the pathogenesis of PID (270,487) and might be associated with milder symptoms (267), although one study failed to demonstrate a significant increase in PID following detection of M. genitalium in the lower genital tract (733). All women who receive a diagnosis of acute PID should be tested for HIV, as well as gonorrhea and chlamydia, using NAAT. The value of testing women with PID for M. genitalium is unknown, and there is no commercially available diagnostic test that has been cleared by FDA for use in the United States (see Mycoplasma genitalium).

Screening and treating sexually active women for chlamydia reduces their risk for PID (456,682). Although BV is associated with PID, whether the incidence of PID can be reduced by identifying and treating women with BV is unclear (731,734).

Diagnostic Considerations

Acute PID is difficult to diagnose because of the wide variation in symptoms and signs associated with this condition. Many women with PID have subtle or nonspecific symptoms or are asymptomatic. Delay in diagnosis and treatment probably contributes to inflammatory sequelae in the upper reproductive tract. Laparoscopy can be used to obtain a more accurate diagnosis of salpingitis and a more complete bacteriologic diagnosis. However, this diagnostic tool frequently is not readily available, and its use is not easily justifiable when symptoms are mild or vague. Moreover, laparoscopy will not detect endometritis and might not detect subtle inflammation of the fallopian tubes. Consequently, a diagnosis of PID usually is based on imprecise clinical findings (735,736).

Data indicate that a clinical diagnosis of symptomatic PID has a PPV for salpingitis of 65%–90% compared with laparoscopy (737-739). The PPV of a clinical diagnosis of acute PID depends on the epidemiologic characteristics of the population, with higher PPVs among sexually active young women (particularly adolescents), women attending STD clinics, and those who live in communities with high rates of gonorrhea or chlamydia. Regardless of PPV, no single historical, physical, or laboratory finding is both sensitive and specific for the diagnosis of acute PID. Combinations of diagnostic findings that improve either sensitivity (i.e., detect more women who have PID) or specificity (i.e., exclude more women who do not have PID) do so only at the expense of the other. For example, requiring two or more findings excludes more women who do not have PID and reduces the number of women with PID who are identified.

Many episodes of PID go unrecognized. Although some cases are asymptomatic, others are not diagnosed because the patient or the health-care provider fails to recognize the implications of mild or nonspecific symptoms or signs (e.g., abnormal bleeding, dyspareunia, and vaginal discharge). Even women with mild or asymptomatic PID might be at risk for infertility (740). Because of the difficulty of diagnosis and the potential for damage to the reproductive health of women, health-care providers should maintain a low threshold for the diagnosis of PID (729). The following recommendations for diagnosing PID are intended to help health-care providers recognize when PID should be suspected and when additional information should be obtained to increase diagnostic certainty. Diagnosis and management of other common causes of lower abdominal pain (e.g., ectopic pregnancy, acute appendicitis, ovarian cyst, and functional pain) are unlikely to be impaired by initiating antimicrobial therapy for PID.

Presumptive treatment for PID should be initiated in sexually active young women and other women at risk for STDs if they are experiencing pelvic or lower abdominal pain, if no cause for the illness other than PID can be identified, and if one or more of the following minimum clinical criteria are present on pelvic examination:

• cervical motion tenderness
  or
• uterine tenderness
  or
• adnexal tenderness.

The requirement that all three minimum criteria be present before the initiation of empiric treatment could result in insufficient sensitivity for the diagnosis of PID. After deciding whether to initiate empiric treatment, clinicians should also consider the risk profile for STDs.

More elaborate diagnostic evaluation frequently is needed because incorrect diagnosis and management of PID might cause unnecessary morbidity. For example, the presence of signs of lower-genital–tract inflammation (predominance of leukocytes in vaginal secretions, cervical exudates, or cervical friability), in addition to one of the three minimum criteria, increases the specificity of the diagnosis. One or more of the following additional criteria can be used to enhance the specificity of the minimum clinical criteria and support a diagnosis of PID:

• oral temperature >101^°F (>38.3^°C);
• abnormal cervical mucopurulent discharge or cervical friability;
• presence of abundant numbers of WBC on saline microscopy of vaginal fluid;
• elevated erythrocyte sedimentation rate;
• elevated C-reactive protein; and
• laboratory documentation of cervical infection with N. gonorrhoeae or C. trachomatis.

Most women with PID have either mucopurulent cervical discharge or evidence of WBCs on a microscopic evaluation of a saline preparation of vaginal fluid (i.e., wet prep). If the cervical discharge appears normal and no WBCs are observed on the wet prep of vaginal fluid, the diagnosis of PID is unlikely, and alternative causes of pain should be considered. A wet prep of vaginal fluid also can detect the presence of concomitant infections (e.g., BV and trichomoniasis).

The most specific criteria for diagnosing PID include:

• endometrial biopsy with histopathologic evidence of endometritis;
• transvaginal sonography or magnetic resonance imaging techniques showing thickened, fluid-filled tubes with or without free pelvic fluid or tubo-ovarian complex, or Doppler studies suggesting pelvic infection (e.g., tubal hyperemia); or
• laparoscopic findings consistent with PID.

A diagnostic evaluation that includes some of these more extensive procedures might be warranted in some cases. Endometrial biopsy is warranted in women undergoing laparoscopy who do not have visual evidence of salpingitis, because endometritis is the only sign of PID for some women.

Treatment

PID treatment regimens must provide empiric, broad spectrum coverage of likely pathogens. Several parenteral and oral antimicrobial regimens have been effective in achieving clinical and microbiologic cure in randomized clinical trials with short-term follow-up (741,742). However, only a limited number of investigations have assessed and compared these regimens with regard to elimination of infection in the endometrium and fallopian tubes or determined the incidence of long-term complications (e.g., tubal infertility and ectopic pregnancy) after antimicrobial regimens (730,735,743). The optimal treatment regimen and long-term outcome of early treatment of women with subclinical PID are unknown. All regimens used to treat PID should also be effective against N. gonorrhoeae and C. trachomatis because negative endocervical screening for these organisms does not rule out upper-reproductive–tract infection. The need to eradicate anaerobes from women who have PID has not been determined definitively. Anaerobic bacteria have been isolated from the upper-reproductive tract of women who have PID, and data from in vitro studies have revealed that some anaerobes (e.g., Bacteroides fragilis) can cause tubal and epithelial destruction. BV is present in many women who have PID (731,734). Until treatment regimens that do not cover anaerobic microbes have been demonstrated to prevent long-term sequelae (e.g., infertility and ectopic pregnancy) as successfully as the regimens that are effective against these microbes, the use of regimens with anaerobic activity should be considered. Treatment should be initiated as soon as the presumptive diagnosis has been made, because prevention of long-term sequelae is dependent on early administration of appropriate antibiotics. When selecting a treatment regimen, health-care providers should consider availability, cost, and patient acceptance (742). In women with PID of mild or moderate clinical severity, parenteral and oral regimens appear to have similar efficacy. The decision of whether hospitalization is necessary should be based on provider judgment and whether the woman meets any of the following suggested criteria:

• surgical emergencies (e.g., appendicitis) cannot be excluded;
• tubo-ovarian abscess;
• pregnancy;
• severe illness, nausea and vomiting, or high fever;
• unable to follow or tolerate an outpatient oral regimen; or
• no clinical response to oral antimicrobial therapy.

No evidence is available to suggest that adolescents have improved outcomes from hospitalization for treatment of PID, and the clinical response to outpatient treatment is similar among younger and older women. The decision to hospitalize adolescents with acute PID should be based on the same criteria used for older women.

Parenteral Treatment

Several randomized trials have demonstrated the efficacy of parenteral regimens (734,741,742). Clinical experience should guide decisions regarding transition to oral therapy, which usually can be initiated within 24–48 hours of clinical improvement. In women with tubo-ovarian abscesses, at least 24 hours of inpatient observation is recommended.

Because of the pain associated with intravenous infusion, doxycycline should be administered orally when possible. Oral and IV administration of doxycycline provide similar bioavailability. Although use of a single daily dose of gentamicin has not been evaluated for the treatment of PID, it is efficacious in analogous situations.

When using the parenteral cefotetan or cefoxitin regimens, oral therapy with doxycycline 100 mg twice daily can be used 24–48 hours after clinical improvement to complete the 14 days of therapy.  For the clindamycin/gentamicin regimen,  oral therapy with clindamycin (450 mg orally four times daily) or doxycycline (100 mg twice daily) can be used to complete the 14 days of therapy. However, when tubo-ovarian abscess is present, clindamycin (450 mg orally four times daily) or metronidazole (500 mg twice daily) should be used to complete at least 14 days of therapy with doxycycline to provide more effective anaerobic coverage than doxycycline alone.

Limited data are available to support use of other parenteral second- or third-generation cephalosporins (e.g., ceftizoxime, cefotaxime, and ceftriaxone). In addition, these cephalosporins are less active than cefotetan or cefoxitin against anaerobic bacteria.

Alternative Parenteral Regimens

Ampicillin/sulbactam plus doxycycline has been investigated in at least one clinical trial and has broad-spectrum coverage (744). Ampicillin/sulbactam plus doxycycline is effective against C. trachomatis, N. gonorrhoeae, and anaerobes in women with tubo-ovarian abscess. Another trial demonstrated high short-term clinical cure rates with azithromycin, either as monotherapy for 1 week (500 mg IV daily for 1 or 2 doses followed by 250 mg orally for 5–6 days) or combined with a 12-day course of metronidazole (745). Limited data are available to support the use of other parenteral regimens.

Intramuscular/Oral Treatment

Intramuscular/oral therapy can be considered for women with mild-to-moderately severe acute PID, because the clinical outcomes among women treated with these regimens are similar to those treated with intravenous therapy (729). Women who do not respond to IM/oral therapy within 72 hours should be reevaluated to confirm the diagnosis and should be administered intravenous therapy.

*The recommended third-generation cephalsporins 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 (Source: Walker CK, Wiesenfeld HC. Antibiotic therapy for acute pelvic inflammatory disease: the 2006 CDC Sexually Transmitted Diseases Treatment Guidelines. Clin Infect Dis 2007;28[Supp 1]:S29–36).

These regimens provide coverage against frequent etiologic agents of PID, but the optimal choice of a cephalosporin is unclear. Cefoxitin, a second-generation cephalosporin, has better anaerobic coverage than ceftriaxone, and in combination with probenecid and doxycycline has been effective in short-term clinical response in women with PID. Ceftriaxone has better coverage against N. gonorrhoeae. The addition of metronidazole will also effectively treat BV, which is frequently associated with PID.

Alternative IM/Oral Regimens

Although information regarding other IM and oral regimens is limited, a few have undergone at least one clinical trial and have demonstrated broad-spectrum coverage. Azithromycin has demonstrated short-term clinical effectiveness in one randomized trial when used as monotherapy (500 mg IV daily for 1–2 doses, followed by 250 mg orally daily for 12–14 days) or in combination with metronidazole (745), and in another study, it was effective when used 1 g orally once a week for 2 weeks in combination with ceftriaxone 250 mg IM single dose (746). When considering these alternative regimens, the addition of metronidazole should be considered to provide anaerobic coverage. No data have been published regarding the use of oral cephalosporins for the treatment of PID. As a result of the emergence of quinolone-resistant N. gonorrhoeae, regimens that include a quinolone agent are no longer routinely recommended for the treatment of PID. If allergy precludes the use of cephalosporin therapy, if the community prevalence and individual risk for gonorrhea are low, and if follow-up is likely, use of fluoroquinolones for 14 days (levofloxacin 500 mg orally once daily, ofloxacin 400 mg twice daily, or moxifloxacin 400 mg orally once daily) with metronidazole for 14 days (500 mg orally twice daily) can be considered (747–749). Diagnostic tests for gonorrhea must be obtained before instituting therapy, and persons should be managed as follows.

• If the culture for gonorrhea is positive, treatment should be based on results of antimicrobial susceptibility testing.
• If the isolate is determined to be quinolone-resistant N. gonorrhoeae (QRNG) or if antimicrobial susceptibility cannot be assessed (e.g., if only NAAT testing is available), consultation with an infectious-disease specialist is recommended.

Other Management Considerations

To minimize disease transmission, women should be instructed to abstain from sexual intercourse until therapy is completed, symptoms have resolved, and sex partners have been adequately treated (See chlamydia and gonorrhea sections). All women who received a diagnosis of acute PID should be tested for HIV, as well as GC and chlamydia, using NAAT.

Follow-Up

Women should demonstrate clinical improvement (e.g., defervescence; reduction in direct or rebound abdominal tenderness; and reduction in uterine, adnexal, and cervical motion tenderness) within 3 days after initiation of therapy. If no clinical improvement has occurred within 72 hours after outpatient IM/oral therapy, hospitalization, assessment of the antimicrobial regimen, and additional diagnostics (including consideration of diagnostic laparoscopy for alternative diagnoses) are recommended. All women who have received a diagnosis of chlamydial or gonococcal PID should be retested 3 months after treatment, regardless of whether their sex partners were treated (480). If retesting at 3 months is not possible, these women should be retested whenever they next present for medical care in the 12 months following treatment.

Management of Sex Partners

Men who have had sexual contact with a woman with PID during the 60 days preceding her onset of symptoms should be evaluated, tested, and presumptively treated for chlamydia and gonorrhea, regardless of the etiology of PID or pathogens isolated from the woman. If a woman’s last sexual intercourse was >60 days before onset of symptoms or diagnosis, the most recent sex partner should be treated. Male partners of women who have PID caused by C. trachomatis and/or N. gonorrhoeae frequently are asymptomatic. Arrangements should be made to link male partners to care. If linkage is delayed or unlikely, EPT and enhanced referral are alternative approaches to treating male partners of women who have chlamydia or gonococcal infections (see Partner Services) (93,94). Partners should be instructed to abstain from sexual intercourse until they and their sex partners have been adequately treated (i.e., until therapy is completed and symptoms have resolved, if originally present).

Special Considerations

Allergy, Intolerance, and Adverse Reactions

The cross reactivity between penicillins and cephalosporins is <2.5% in persons with a history of penicillin allergy (428-431,464). The risk for penicillin cross-reactivity is highest with first-generation cephalosporins, but is negligible between most second-generation (cefoxitin) and all third-generation (ceftriaxone) cephalosporins (428-431) (see Management of Persons who Have a History of Penicillin Allergy).

Pregnancy

Pregnant women suspected to have PID are at high risk for maternal morbidity and preterm delivery. These women should be hospitalized and treated with intravenous antibiotics.

HIV Infection

Differences in the clinical manifestations of PID between women with HIV infection and women without HIV infection have not been well delineated. In early observational studies, women with HIV infection and PID were more likely to require surgical intervention. More comprehensive observational and controlled studies have demonstrated that women with HIV infection and PID have similar symptoms when compared with HIV-negative women with PID (266,750,751), except they are more likely to have a tubo-ovarian abscess; women with HIV infection responded equally well to recommended parenteral and IM/oral antibiotic regimens as women without HIV infection. The microbiologic findings for women with HIV infection and women without HIV infection were similar, except women with HIV infection had higher rates of concomitant M. hominis and streptococcal infections. These data are insufficient for determining whether women with HIV infection and PID require more aggressive management (e.g., hospitalization or intravenous antimicrobial regimens).

Intrauterine Contraceptive Devices

IUDs are one of the most effective contraceptive methods. Copper-containing and levonorgestrel-releasing IUDs are available in the United States. The risk for PID associated with IUD use is primarily confined to the first 3 weeks after insertion (752,753). If an IUD user receives a diagnosis of PID, the IUD does not need to be removed (63). However, the woman should receive treatment according to these recommendations and should have close clinical follow-up. If no clinical improvement occurs within 48–72 hours of initiating treatment, providers should consider removing the IUD. A systematic review of evidence found that treatment outcomes did not generally differ between women with PID who retained the IUD and those who had the IUD removed (754). These studies primarily included women using copper or other nonhormonal IUDs. No studies are available regarding treatment outcomes in women using levonorgestrel-releasing IUDs.

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