Sexually Transmitted Diseases (STDs)

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 (382). Sexually transmitted organisms, especially N. gonorrhoeae and C. trachomatis, are implicated in many cases; however, microorganisms that comprise the vaginal flora (e.g., anaerobes, G. vaginalis, Haemophilus influenzae, enteric Gram-negative rods, and Streptococcus agalactiae) also have been associated with PID (383). In addition, cytomegalovirus (CMV), M. hominis, U. urealyticum, and M. genitalium might be associated with some cases of PID (263,384–386). All women who have acute PID should be tested for N. gonorrhoeae and C. trachomatis and should be screened for HIV infection.

Diagnostic Considerations

Acute PID is difficult to diagnose because of the wide variation in the symptoms and signs. Many women with PID have subtle or mild symptoms. 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 easy to justify 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 clinical findings.

The clinical diagnosis of acute PID is imprecise (387,388). Data indicate that a clinical diagnosis of symptomatic PID has a positive predictive value (PPV) for salpingitis of 65%–90% compared with laparoscopy. 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), patients attending STD clinics, and those who live in other settings where the rates of gonorrhea or chlamydia are high. Regardlesss of PPV, however, in all settings, 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 but also 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). Because of the difficulty of diagnosis and the potential for damage to the reproductive health of women (even by apparently mild or subclinical PID), health-care providers should maintain a low threshold for the diagnosis of PID (382).

The optimal treatment regimen and long-term outcome of early treatment of women with asymptomatic or subclinical PID are unknown. The following recommendations for diagnosing PID are intended to help health-care providers recognize when PID should be suspected and when they need to obtain additional information to increase diagnostic certainty. Diagnosis and management of other common causes of lower abdominal pain (e.g., ectopic pregnancy, acute appendicitis, and functional pain) are unlikely to be impaired by initiating empiric antimicrobial therapy for PID.

Empiric 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 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. 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. Upon deciding whether to initiate empiric treatment, clinicians should also consider the risk profile of the patient for STDs.

More elaborate diagnostic evaluation frequently is needed because incorrect diagnosis and management of PID might cause unnecessary morbidity. One or more of the following additional criteria can be used to enhance the specificity of the minimum criteria and support a diagnosis of PID:

• oral temperature >101° F (>38.3° C);
• abnormal cervical or vaginal mucopurulent discharge;
• 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 offers the ability to 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 abnormalities 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 antimicrobial regimens have been effective in achieving clinical and microbiologic cure in randomized clinical trials with short-term follow-up. 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 (389–391).

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 also is present in many women who have PID (383,391). Until treatment regimens that do not adequately cover these 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, patient acceptance, and antimicrobial susceptibility (392).

In women with PID of mild or moderate clinical severity, outpatient therapy yields short- and long-term clinical outcomes similar to inpatient therapy. The decision of whether hospitalization is necessary should be based on the judgment of the provider and whether the patient meets any of the following suggested criteria:

• surgical emergencies (e.g., appendicitis) cannot be excluded;
• the patient is pregnant;
• the patient does not respond clinically to oral antimicrobial therapy;
• the patient is unable to follow or tolerate an outpatient oral regimen;
• the patient has severe illness, nausea and vomiting, or high fever; or
• the patient has a tubo-ovarian abscess.

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

Parenteral Treatment

For women with PID of mild or moderate severity, parenteral and oral therapies appear to have similar clinical efficacy. Many randomized trials have demonstrated the efficacy of both parenteral and oral regimens (390,391,393). 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 direct 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.

Parenteral therapy can be discontinued 24 hours after clinical improvement, but oral therapy with doxycycline (100 mg twice a day) should continue to complete 14 days of therapy. When tubo-ovarian abscess is present, clindamycin or metronidazole with doxycycline can be used for continued therapy rather than doxycycline alone because this regimen provides more effective anaerobic coverage.

Limited data are available to support the use of other second- or third-generation cephalosporins (e.g., ceftizoxime, cefotaxime, and ceftriaxone), which also might be effective therapy for PID and could potentially replace cefotetan or cefoxitin. However, these cephalosporins are less active than cefotetan or cefoxitin against anaerobic bacteria.

Although use of a single daily dose of gentamicin has not been evaluated for the treatment of PID, it is efficacious in analogous situations. Parenteral therapy can be discontinued 24 hours after clinical improvement; ongoing oral therapy should consist of doxycycline 100 mg orally twice a day, or clindamycin 450 mg orally four times a day to complete a total of 14 days of therapy. When tubo-ovarian abscess is present, clindamycin should be continued rather than doxycycline, because clindamycin provides more effective anaerobic coverage.

Alternative Parenteral Regimens

Limited data are available to support the use of other parenteral regimens. The following regimen has been investigated in at least one clinical trial and has broad-spectrum coverage (394).

Ampicillin/sulbactam plus doxycycline is effective against C. trachomatis, N. gonorrhoeae, and anaerobes in women with tubo-ovarian abscess. One trial demonstrated high short-term clinical cure rates with azithromycin, either as monotherapy for 1 week (500 mg IV for 1 or 2 doses followed by 250 mg orally for 5–6 days) or combined with a 12-day course of metronidazole (395).

Oral Treatment

Outpatient, oral therapy can be considered for women with mild-to-moderately severe acute PID, because the clinical outcomes among women treated with oral therapy are similar to those treated with parenteral therapy (390). The following regimens provide coverage against the frequent etiologic agents of PID. Patients who do not respond to oral therapy within 72 hours should be reevaluated to confirm the diagnosis and should be administered parenteral therapy on either an outpatient or inpatient basis.

The optimal choice of a cephalosporin is unclear; although cefoxitin has better anaerobic coverage, ceftriaxone has better coverage against N. gonorrhoeae. A single dose of cefoxitin is effective in obtaining short-term clinical response in women who have PID. However, the theoretical limitations in coverage of anaerobes by recommended cephalosporin antimicrobials might require the addition of metronidazole to the treatment regimen (393). Adding metronidazole also will effectively treat BV, which is frequently associated with PID. No data have been published regarding the use of oral cephalosporins for the treatment of PID.

Alternative Oral Regimens

Although information regarding other outpatient regimens is limited, other regimens have undergone at least one clinical trial and have demonstrated broad spectrum coverage. In a single clinical trial, amoxicillin/clavulanic acid and doxycycline were effective together in obtaining short-term clinical response (394); however, gastrointestinal symptoms might limit compliance with this regimen. Azithromycin has demonstrated short-term effectiveness in one randomized trial (395), and in another study, it was effective when used combination with ceftriaxone 250 mg IM single dose and azithromycin 1 g orally once a week for 2 weeks (396). When considering alternative regimens, the addition of metronidazole should be considered because anaerobic organisms are suspected in the etiology of PID and metronidazole will also treat BV.

As a result of the emergence of quinolone-resistant Neisseria gonorrhoeae, regimens that include a quinolone agent are no longer recommended for the treatment of PID. If parenteral cephalosporin therapy is not feasible, use of fluoroquinolones (levofloxacin 500 mg orally once daily or ofloxacin 400 mg twice daily for 14 days) with or without metronidazole (500 mg orally twice daily for 14 days) can be considered if the community prevalence and individual risk for gonorrhea are low. Diagnostic tests for gonorrhea must be performed before instituting therapy and the patient managed as follows if the test is positive.

• If the culture for gonorrhea is positive, treatment should be based on results of antimicrobial susceptibility.
• 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), parenteral cephalosporin is recommended. However, if cephalosporin therapy is not feasible, the addition of azithromycin 2 g orally as a single dose to a quinolone-based PID regimen is recommended.

Follow-Up

Patients should demonstrate substantial 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. Patients who do not improve within this period usually require hospitalization, additional diagnostic tests, and surgical intervention.

If no clinical improvement has occurred within 72 hours after outpatient oral or parenteral therapy, further assessment
should be performed. Subsequent hospitalization and an assessment of the antimicrobial regimen and diagnostics (including the consideration of diagnostic laparoscopy for alternative diagnoses) are recommended in women without clinical improvement. Women with documented chlamydial or gonococcal infections have a high rate of reinfection within 6 months of treatment. Repeat testing of all women who have been diagnosed with chlamydia or gonorrhea is recommended 3–6 months after treatment, regardless of whether their sex partners were treated (267). All women diagnosed with acute PID should be offered HIV testing.

Management of Sex Partners

Male sex partners of women with PID should be examined and treated if they had sexual contact with the patient during the 60 days preceding the patient’s onset of symptoms. If a patient’s last sexual intercourse was >60 days before onset of symptoms or diagnosis, the patient’s most recent sex partner should be treated. Patients should be instructed to abstain from sexual intercourse until therapy is completed and until they and their sex partners no longer have symptoms. Evaluation and treatment are imperative because of the risk for reinfection of the patient and the strong likelihood of urethral gonococcal or chlamydial infection in the sex partner. Male partners of women who have PID caused by C. trachomatis and/or N. gonorrhoeae frequently are asymptomatic.

Sex partners should be treated empirically with regimens effective against both of these infections, regardless of the etiology of PID or pathogens isolated from the infected woman. Even in clinical settings in which only women are treated, arrangements should be made to provide care or appropriate referral for male sex partners of women who have PID (see Partner Management). Expedited partner treatment and enhanced patient referral (see Partner Management) are alternative approaches to treating male partners of women who have chlamydia or gonococcal infections (68,69).

Prevention

Screening and treating sexually active women for chlamydia reduces their risk for PID (272). Although BV is associated with PID, whether the incidence of PID can be reduced by identifying and treating women with BV is unclear (383,391).

Special Considerations

Pregnancy

Because of the high risk for maternal morbidity and preterm delivery, pregnant women who have suspected PID should be hospitalized and treated with parenteral antibiotics.

HIV Infection

Differences in the clinical manifestations of PID between HIV-infected women and HIV-negative women have not been well delineated. In previous observational studies, HIV-infected women with PID were more likely to require surgical intervention; more comprehensive observational and controlled studies now have demonstrated that HIV-infected women with PID have similar symptoms when compared with uninfected controls (397–399), except they were more likely to have a tubo-ovarian abscess; both groups of women responded equally well to standard parenteral and oral antibiotic regimens. The microbiologic findings for HIV-positive and HIV-negative women were similar, except HIV-infected women had higher rates of concomitant M. hominis, candida, streptococcal, and HPV infections and HPV-related cytologic abnormalities. Regardlesss of these data, whether the management of immunodeficient HIV-infected women with PID requires more aggressive interventions (e.g., hospitalization or parenteral antimicrobial regimens) has not been determined.

Intrauterine Contraceptive Devices

IUDs are popular contraceptive choices for women. Both levonorgestrel and copper-containing devices are marketed in the United States. The risk for PID associated with IUD use is primarily confined to the first 3 weeks after insertion and is uncommon thereafter (400,401). Given the popularity of IUDs, practitioners might encounter PID in IUD users. Evidence is insufficient to recommend that the removal of IUDs in women diagnosed with acute PID. However, caution should be exercised if the IUD remains in place, and close clinical follow-up is mandatory. The rate of treatment failure and recurrent PID in women continuing to use an IUD is unknown, and no data have been collected regarding treatment outcomes by type of IUD (e.g., copper or levonorgestrel).