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Diseases Characterized by Vaginal DischargeManagement of Patients Who Have Vaginal InfectionsVaginal infection is usually characterized by a vaginal discharge or vulvar itching and irritation; a vaginal odor may be present. The three diseases most frequently associated with vaginal discharge are trichomoniasis (caused by T. vaginalis), bacterial vaginosis (caused by a replacement of the normal vaginal flora by an overgrowth of anaerobic microorganisms, mycoplasmas, and Gardnerella vaginalis), and candidiasis (usually caused by Candida albicans). MPC caused by C. trachomatis or N. gonorrhoeae can sometimes cause vaginal discharge. Although vulvovaginal candidiasis and bacterial vaginosis are not usually transmitted sexually, they are included in this section because these infections are often diagnosed in women being evaluated for STDs. The cause of vaginal infection can be diagnosed by pH and microscopic examination of the discharge. The pH of the vaginal secretions can be determined by narrow-range pH paper for the elevated pH (>4.5) typical of BV or trichomoniasis. Discharge can be examined by diluting one sample in one to two drops of 0.9% normal saline solution on one slide and a second sample in 10% potassium hydroxide (KOH) solution. An amine odor detected before or immediately after applying KOH suggests BV. A cover slip is placed on the slides, and they are examined under a microscope at low- and high-dry power. The motile T. vaginalis or the clue cells of BV usually are identified easily in the saline specimen. The yeast or pseudohyphae of Candida species are more easily identified in the KOH specimen. However, their absence does not preclude candidal or trichomonal infection, because several studies have demonstrated the presence of these pathogens by using polymerase chain reaction (PCR) after a negative microscopic exam. The presence of objective signs of external vulvar inflammation in the absence of vaginal pathogens, along with a minimal amount of discharge, suggests the possibility of mechanical, chemical, allergic, or other noninfectious irritation of the vulva. Culture for T. vaginalis is more sensitive than microscopic examination. Laboratory testing fails to identify the cause of vaginitis among a minority of women. Bacterial VaginosisBV is a clinical syndrome resulting from replacement of the normal H2O2-producing Lactobacillus sp. in the vagina with high concentrations of anaerobic bacteria (e.g., Prevotella sp. and Mobiluncus sp.), G. vaginalis, and Mycoplasma hominis. BV is the most prevalent cause of vaginal discharge or malodor; however, up to 50% of women with BV may not report symptoms of BV. The cause of the microbial alteration is not fully understood. BV is associated with having multiple sex partners, douching, and lack of vaginal lactobacilli; it is unclear whether BV results from acquisition of a sexually transmitted pathogen. Women who have never been sexually active are rarely affected. Treatment of the male sex partner has not been beneficial in preventing the recurrence of BV. Diagnostic Considerations BV can be diagnosed by the use of clinical or Gram-stain criteria. Clinical criteria require three of the following symptoms or signs:
When a Gram stain is used, determining the relative concentration of the bacterial morphotypes characteristic of the altered flora of BV is an acceptable laboratory method for diagnosing BV. Culture of G. vaginalis is not recommended as a diagnostic tool because it is not specific. However, a DNA probe based test for high concentrations of G. vaginalis (Affirm™ VP III, manufactured by Becton Dickinson, Sparks, Maryland) may have clinical utility. Cervical Pap tests have limited clinical utility for the diagnosis of BV because of low sensitivity. Other commercially available tests that may be useful for the diagnosis of BV include a card test for the detection of elevated pH and trimethylamine (FemExam® test card, manufactured by Cooper Surgical, Shelton, Connecticut) and prolineaminopeptidase (Pip Activity TestCard™, manufactured by Litmus Concepts, Inc., Santa Clara, California). Treatment The established benefits of therapy for BV in non-pregnant women are to a) relieve vaginal symptoms and signs of infection and b) reduce the risk for infectious complications after abortion or hysterectomy. Other potential benefits include the reduction of other infectious complications (e.g., HIV and other STDs). All women who have symptomatic disease require treatment. BV during pregnancy is associated with adverse pregnancy outcomes, including premature rupture of the membranes, preterm labor, preterm birth, and postpartum endometritis. The established benefit of therapy for BV in pregnant women is to relieve vaginal symptoms and signs of infection. Additional potential benefits of therapy include a) reducing the risk for infectious complications associated with BV during pregnancy and b) reducing the risk for other infections (e.g., other STDs or HIV). The results of several investigations indicate that treatment of pregnant women who have BV and who are at high risk for preterm delivery (i.e., those who previously delivered a premature infant) may reduce the risk for prematurity (52--54). Therefore, high-risk pregnant women who have asymptomatic BV may be evaluated for treatment. The bacterial flora that characterizes BV have been recovered from the endometria and salpinges of women who have PID. BV has been associated with endometritis, PID, and vaginal cuff cellulitis after invasive procedures, including endometrial biopsy, hysterectomy, hysterosalpingography, placement of an IUD, cesarean section, and uterine curettage. The results of two randomized controlled trials indicated that treatment of BV with metronidazole substantially reduced postabortion PID (55,56). Three trials that evaluated the use of anaerobic antimicrobial coverage (metronidazole) for routine operative prophylaxis before abortion and seven trials that evaluated this additional coverage for women undergoing hysterectomy found a substantial reduction (range: 10%--75%) in post-operative infectious complications (57--66). Because of the increased risk for postoperative infectious complications associated with BV, some specialists recommend that before performing surgical abortion or hysterectomy, providers screen and treat women with BV in addition to providing routine prophylaxis. However, more information is needed before recommending treatment of asymptomatic BV before other invasive procedures.
NOTE: Patients should be advised to avoid consuming alcohol during treatment with metronidazole and for 24 hours thereafter. Clindamycin cream and ovules are oil-based and might weaken latex condoms and diaphragms. Refer to condom product labeling for additional information. The recommended metronidazole regimens are equally efficacious. The vaginal clindamycin cream appears less efficacious than the metronidazole regimens. The alternative regimens have lower efficacy for BV.
One randomized trial evaluating the clinical equivalency of intravaginal metronidazole gel 0.75% once daily versus twice daily found similar cure rates 1 month after therapy (67). One randomized trial that evaluated the equivalency of clindamycin cream and clindamycin ovules found that cure rates did not differ significantly (68). Metronidazole 2 g single-dose therapy is an alternative regimen because of its lower efficacy for treatment of BV. Although FDA has approved metronidazole 750-mg extended release tablets once daily for 7 days, no data have been published on the clinical equivalency of this regimen with other regimens. Studies are currently underway to evaluate the efficacy of vaginal lactobacilli suppositories in addition to oral metronidazole for the treatment of BV. No data support the use of non-vaginal lactobacilli or douching for the treatment of BV. Follow-Up Follow-up visits are unnecessary if symptoms resolve. Because recurrence of BV is not unusual, women should be advised to return for additional therapy if symptoms recur. Another recommended treatment regimen may be used to treat recurrent disease. No long-term maintenance regimen with any therapeutic agent is recommended. Management of Sex Partners The results of clinical trials indicate that a woman's response to therapy and the likelihood of relapse or recurrence are not affected by treatment of her sex partner(s) (69--71). Therefore, routine treatment of sex partners is not recommended. Special Considerations Allergy or Intolerance to the Recommended Therapy Clindamycin cream or oral clindamycin is preferred in case of allergy or intolerance to metronidazole. Metronidazole gel can be considered for patients who do not tolerate systemic metronidazole, but patients allergic to oral metronidazole should not be administered metronidazole vaginally. Pregnancy All symptomatic pregnant women should be tested and treated. BV has been associated with adverse pregnancy outcomes (e.g., premature rupture of the membranes, chorioamnionitis, preterm labor, preterm birth, postpartum endometritis, and post-cesarean wound infection). Some specialists prefer using systemic therapy to treat possible subclinical upper genital tract infections among women at low risk for preterm delivery (i.e., those who have no history of delivering an infant before term). Existing data do not support the use of topical agents during pregnancy. Evidence from three trials suggests an increase in adverse events (e.g., prematurity and neonatal infections), particularly in newborns, after use of clindamycin cream (72--74). Multiple studies and meta-analyses have not demonstrated a consistent association between metronidazole use during pregnancy and teratogenic or mutagenic effects in newborns (75--77).
Because treatment of BV in asymptomatic pregnant women at high risk for preterm delivery (i.e., those who have previously delivered a premature infant) with a recommended regimen has reduced preterm delivery in three of four randomized controlled trials (52--54,78), some specialists recommend the screening and treatment of these women. However, the optimal treatment regimens have not been established. The screening (if conducted) and treatment should be performed at the first prenatal visit. The two trials that examined the use of metronidazole during pregnancy used the 250-mg regimen; the recommended regimen for BV in nonpregnant women is 500 mg twice daily. Some specialists also recommend this higher dose for treatment of pregnant women. In one published study, women with BV were treated at 19 weeks with a regimen of an initial dose of 2 g, followed by a 2-g dose 2 days later; the regimen was repeated 4 weeks later (78). This regimen was not effective in reducing preterm birth in any group of women. Data are conflicting regarding whether treatment of asymptomatic pregnant women who are at low risk for preterm delivery reduces adverse outcomes of pregnancy. Several unpublished trials have evaluated screening and treatment for BV among asymptomatic low-risk pregnant women in the first or early second trimester. One trial, using oral clindamycin, demonstrated a reduction in spontaneous preterm birth; another indicated a reduction in postpartum infectious complications (79). Follow-Up of Pregnant Women Treatment of BV in asymptomatic pregnant women who are at high risk for preterm delivery might prevent adverse pregnancy outcomes. Therefore, a follow-up evaluation 1 month after completion of treatment should be considered to evaluate whether therapy was effective. HIV Infection Patients who have BV and also are infected with HIV should receive the same treatment regimen as those who are HIV-negative. TrichomoniasisTrichomoniasis is caused by the protozoan T. vaginalis. Most men who are infected with T. vaginalis do not have symptoms; others have NGU. Many infected women have symptoms characterized by a diffuse, malodorous, yellow-green discharge with vulvar irritation. However, some women have minimal or no symptoms. Diagnosis of vaginal trichomoniasis is usually performed by microscopy of vaginal secretions, but this method has a sensitivity of only about 60%--70%. Culture is the most sensitive commercially available method of diagnosis. No FDA-approved PCR test for T. vaginalis is available in the United States, but such testing may be available from commercial laboratories that have developed their own PCR tests.
The nitroimidazoles comprise the only class of drugs useful for the oral or parenteral therapy of trichomoniasis. Of these, only metronidazole is readily available in the United States and approved by the FDA for the treatment of trichomoniasis. In randomized clinical trials, the recommended metronidazole regimens have resulted in cure rates of approximately 90%--95%; ensuring treatment of sex partners might increase this rate. Treatment of patients and sex partners results in relief of symptoms, microbiologic cure, and reduction of transmission. Metronidazole gel has been approved for treatment of BV. However, like other topically applied antimicrobials that are unlikely to achieve therapeutic levels in the urethra or perivaginal glands, it is considerably less efficacious for treatment of trichomoniasis (<50%) than oral preparations of metronidazole. Therefore, metronidazole gel is not recommended for use. Several other topically applied antimicrobials have occasionally been used for treatment of trichomoniasis, but it is unlikely that these preparations have greater efficacy than metronidazole gel. Follow-Up Follow-up is unnecessary for men and women who become asymptomatic after treatment or who are initially asymptomatic. Certain strains of T. vaginalis can have diminished susceptibility to metronidazole; however, infections caused by most of these organisms respond to higher doses of metronidazole. If treatment failure occurs with either regimen, the patient should be re-treated with metronidazole 500 mg twice a day for 7 days. If treatment failure occurs again, the patient should be treated with a single, 2-g dose of metronidazole once a day for 3--5 days. Patients with laboratory-documented infection who do not respond to the 3--5 day treatment regimen and who have not been reinfected should be managed in consultation with a specialist; evaluation of such cases should ideally include determination of the susceptibility of T. vaginalis to metronidazole. Consultation is available from CDC (tel: 770-488-4115; website: http://www.cdc.gov/std/). Management of Sex Partners Sex partners of patients with T. vaginalis should be treated. Patients should be instructed to avoid sex until they and their sex partners are cured (i.e., when therapy has been completed and patient and partner(s) are asymptomatic [in the absence of a microbiologic test of cure]). Special Considerations Allergy, Intolerance, and Adverse Reactions Patients with an immediate-type allergy to metronidazole can be managed by desensitization (80). Topical therapy with drugs other than nitroimidazoles can be attempted, but cure rates are low (<50%). Pregnancy Vaginal trichomoniasis has been associated with adverse pregnancy outcomes, particularly premature rupture of the membranes, preterm delivery, and low birthweight. Data have not indicated that treating asymptomatic trichomoniasis during pregnancy lessens that association (81). Women who are symptomatic with trichomoniasis should be treated to ameliorate symptoms. Women may be treated with 2 g of metronidazole in a single dose. Multiple studies and meta-analyses have not demonstrated a consistent association between metronidazole use during pregnancy and teratogenic or mutagenic effects in infants (75--77). HIV Infection Patients who have trichomoniasis and also are infected with HIV should receive the same treatment regimen as those who are HIV-negative. Vulvovaginal CandidiasisVulvovaginal candidiasis (VVC) usually is caused by C. albicans but occasionally is caused by other Candida sp. or yeasts. Typical symptoms of VVC include pruritus and vaginal discharge. Other symptoms include vaginal soreness, vulvar burning, dyspareunia, and external dysuria. None of these symptoms is specific for VVC. An estimated 75% of women will have at least one episode of VVC, and 40%--45% will have two or more episodes. On the basis of clinical presentation, microbiology, host factors, and response to therapy, VVC can be classified as either uncomplicated or complicated (Box 2). Approximately 10%--20% of women will have complicated VVC, suggesting diagnostic and therapeutic considerations. Box 2. Classification of vulvovaginal candidiasis (VVC)
Uncomplicated VVC Diagnostic Considerations in Uncomplicated VVC A diagnosis of Candida vaginitis is suggested clinically by pruritus and erythema in the vulvovaginal area; a white discharge may be present. The diagnosis can be made in a woman who has signs and symptoms of vaginitis when either a) a wet preparation (saline, 10% KOH) or Gram stain of vaginal discharge demonstrates yeasts or pseudohyphae or b) a culture or other test yields a positive result for a yeast species. Candida vaginitis is associated with a normal vaginal pH (<4.5). Use of 10% KOH in wet preparations improves the visualization of yeast and mycelia by disrupting cellular material that might obscure the yeast or pseudohyphae. Identifying Candida by culture in the absence of symptoms is not an indication for treatment, because approximately 10%--20% of women harbor Candida sp. and other yeasts in the vagina. VVC can occur concomitantly with STDs, and treatment of all pathogens present is warranted. Most healthy women with uncomplicated VVC have no precipitating factors. However, in a minority of women who have asymptomatic Candida colonization, antibiotic use precipitates VVC. Treatment Short-course topical formulations (i.e., single dose and regimens of 1--3 days) effectively treat uncomplicated VVC. The topically applied azole drugs are more effective than nystatin. Treatment with azoles results in relief of symptoms and negative cultures in 80%--90% of patients who complete therapy.
*** Over-the-counter (OTC) preparations. NOTE: The creams and suppositories in this regimen are oil-based and may weaken latex condoms and diaphragms. Refer to condom product labeling for further information. Preparations for intravaginal administration of butaconazole, clotrimazole, miconazole, and tioconazole are available over-the-counter (OTC). Self-medication with OTC preparations should be advised only for women who have been diagnosed previously with VVC and who have a recurrence of the same symptoms. Any woman whose symptoms persist after using an OTC preparation or who has a recurrence of symptoms within 2 months should seek medical care. Unnecessary or inappropriate use of OTC preparations is common and can lead to delay of treatment of other etiologies of vulvovaginitis that could result in adverse clinical outcomes. Follow-Up Patients should be instructed to return for follow-up visits only if symptoms persist or recur within 2 months of onset of initial symptoms. Management of Sex Partners VVC is not usually acquired through sexual intercourse; treatment of sex partners is not recommended but may be considered in women who have recurrent infection. A minority of male sex partners may have balanitis, which is characterized by erythematous areas on the glans of the penis in conjunction with pruritus or irritation. These men benefit from treatment with topical antifungal agents to relieve symptoms. Special Considerations Allergy to or Intolerance of the Recommended Therapy. Topical agents usually cause no systemic side effects, although local burning or irritation may occur. Oral agents occasionally cause nausea, abdominal pain, and headache. Therapy with the oral azoles has been associated rarely with abnormal elevations of liver enzymes. Clinically important interactions might occur when these oral agents are administered with other drugs, including astemizole, calcium channel antagonists, cisapride, coumadin, cyclosporin A, oral hypoglycemic agents, phenytoin, protease inhibitors, tacrolimus, terfenadine, theophylline, trimetrexate, and rifampin. Complicated VVC Recurrent Vulvovaginal Candidiasis Recurrent VVC (RVVC), usually defined as four or more episodes of symptomatic VVC each year, affects a small percentage of women (<5%). The pathogenesis of RVVC is poorly understood, and most women who have RVVC have no apparent predisposing or underlying conditions. Vaginal cultures should be obtained from patients with RVVC to confirm the clinical diagnosis and to identify unusual species, including non-albicans species, particularly Candida glabrata (C. glabrata does not form pseudohyphae or hyphae and is not easily recognized on microscopy). C. glabrata and other non-albicans Candidia species are found in 10%--20% of patients with RVVC. Conventional antimycotic therapies are not as effective against these species as against C. albicans. Treatment Each individual episode of RVVC caused by C. albicans responds well to short duration oral or topical azole therapy. However, to maintain clinical and mycologic control, specialists recommend a longer duration of initial therapy (e.g., 7--14 days of topical therapy or a 150-mg, oral dose of fluconazole repeated 3 days later) to achieve mycologic remission before initiating a maintenance antifungal regimen. Maintenance Regimens Maintenance antifungals are selected on the basis of pharmacologic characteristics of individual agents and route of administration. Recommended regimens include clotrimazole (500-mg dose vaginal suppositories once weekly), ketoconazole (100-mg dose once daily), fluconazole (100--150-mg dose once weekly), and itraconazole (400-mg dose once monthly or 100-mg dose once daily). Although all maintenance regimens should be continued for 6 months, an estimated one in 10,000--15,000 persons exposed to ketoconazole may develop hepatotoxicity. Patients receiving long-term ketoconazole should be monitored for toxicity. Suppressive maintenance antifungal therapies are effective in reducing RVVC. However, 30%--40% of women will have recurrent disease once maintenance therapy is discontinued. Routine treatment of sex partners is controversial. Although C. albicans azole resistance is rare in vaginal isolates, surveillance of recurrent isolates for development of resistance is prudent. Severe VVC Severe vulvovaginitis (i.e., extensive vulvar erythema, edema, excoriation, and fissure formation) has lower clinical response rates in patients treated with short courses of topical or oral therapy. Either 7--14 days of topical azole or 150 mg of fluconazole in two sequential doses (second dose 72 hours after initial dose) is recommended. Non-albicans VVC The optimal treatment of non-albicans VVC remains unknown. Longer duration of therapy (7--14 days) with a non-fluconazole azole drug is recommended as first-line therapy. If recurrence occurs, 600 mg of boric acid in a gelatin capsule is recommended, administered vaginally once daily for 2 weeks. This regimen has clinical and mycologic eradication rates of approximately 70%. Additional options include topical 4% flucytosine; however, referral to a specialist is advised. Safety data regarding the long-term use of these regimens are lacking. If non-albicans VVC continues to recur, a maintenance regimen of 100,000 units of nystatin delivered daily via vaginal suppositories has been successful. Compromised Host Women with underlying debilitating medical conditions (e.g., those with uncontrolled diabetes or those receiving corticosteroid treatment) do not respond as well to short-term therapies. Efforts to correct modifiable conditions should be made, and more prolonged (i.e., 7--14 days) conventional antimycotic treatment is necessary. Pregnancy VVC often occurs during pregnancy. Only topical azole therapies, applied for 7 days, are recommended for use among pregnant women. HIV Infection The attack rate of VVC in HIV-infected women is unknown. Vaginal Candida colonization rates in HIV-infected women are higher than among seronegative women with similar demographic characteristics and high-risk behaviors, and the colonization rates correlate with increasing severity of immunosuppression. Symptomatic VVC is more frequent in seropositive women and similarly correlates with severity of immunodeficiency. In addition, among HIV-infected women, systemic azole exposure is associated with the isolation of non-albicans Candida species from the vagina. Based on available data, therapy for VVC in HIV-infected women should not differ from that for seronegative women. Although long-term prophylactic therapy with fluconazole at a dose of 200 mg weekly has been effective in reducing C. albicans colonization and symptomatic VVC, it is not recommended for routine primary prophylaxis in HIV-infected women in the absence of recurrent VVC. Given the frequency with which RVVC occurs in the immmunocompetent healthy population, RVVC should not be considered a sentinel sign to justify HIV testing. Pelvic Inflammatory DiseasePID comprises a spectrum of inflammatory disorders of the upper female genital tract, including any combination of endometritis, salpingitis, tubo-ovarian abscess, and pelvic peritonitis. 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. In addition, cytomegalovirus (CMV), M. hominis, and U. urealyticum may be the etiologic agents in some cases of PID. Diagnostic ConsiderationsAcute 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 effective 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 often 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 may 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. Data indicate that a clinical diagnosis of symptomatic PID has a PPV for salpingitis of 65%--90% compared with laparoscopy. The PPV of a clinical diagnosis of acute PID differs depending on epidemiologic characteristics and the clinical setting, with higher PPV among sexually active young women (particularly adolescents) and among patients attending STD clinics or from settings in which rates of gonorrhea or chlamydia are high. In all settings, however, no single historical, physical, or laboratory finding is both sensitive and specific for the diagnosis of acute PID (i.e., can be used both to detect all cases of PID and to exclude all women without 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 undiagnosed 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 atypical PID, health-care providers should maintain a low threshold for the diagnosis of PID. The optimal treatment regimen and long-term outcome of early treatment of women with asymptomatic or atypical 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 of PID should be initiated in sexually active young women and other women at risk for STDs if the following minimum criteria are present and no other cause(s) for the illness can be identified:
Requiring all minimum criteria may result in low sensitivity in patients at high risk for infection. In patients with both pelvic tenderness and signs of lower genital tract inflammation, the diagnosis of PID should be considered. Treatment may be indicated based on a patient's risk profile. More elaborate diagnostic evaluation often is needed, because incorrect diagnosis and management might cause unnecessary morbidity. These additional criteria may be used to enhance the specificity of the minimum criteria. Additional criteria that support a diagnosis of PID include the following:
Most women with PID have either mucopurulent cervical discharge or evidence of WBCs on a microscopic evaluation of a saline preparation of vaginal fluid. If the cervical discharge appears normal and no white blood cells are found on the wet prep, the diagnosis of PID is unlikely, and alternative causes of pain should be investigated. The most specific criteria for diagnosing PID include the following:
A diagnostic evaluation that includes some of these more extensive studies may be warranted in certain cases. TreatmentPID treatment regimens must provide empiric, broad-spectrum coverage of likely pathogens. Antimicrobial coverage should include N. gonorrhoeae, C. trachomatis, anaerobes, Gram-negative facultative bacteria, and streptococci. Several antimicrobial regimens have been effective in achieving clinical and microbiologic cure in randomized clinical trials with short-term follow- up. However, few 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) of antimicrobial regimens. All regimens should be effective against N. gonorrhoeae and C. trachomatis, because negative endocervical screening does not preclude 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 certain anaerobes (e.g., Bacteroides fragilis) can cause tubal and epithelial destruction. In addition, BV also is present in many women who have PID. Until treatment regimens that do not adequately cover these microbes have been demonstrated to prevent sequelae as successfully as the regimens that are effective against these microbes, the recommended regimens should provide anaerobic coverage. Treatment should be initiated as soon as the presumptive diagnosis has been made, because prevention of long-term sequelae has been linked directly with immediate administration of appropriate antibiotics. When selecting a treatment regimen, health-care providers should consider availability, cost, patient acceptance, and antimicrobial susceptibility. In the past, many specialists recommended that all patients who had PID be hospitalized so that bed rest and supervised treatment with parenteral antibiotics could be initiated. However, hospitalization is no longer synonymous with parenteral therapy. No currently available data compare the efficacy of parenteral with oral therapy or inpatient with outpatient treatment settings. The decision of whether hospitalization is necessary should be based on the discretion of the health-care provider. The following criteria for hospitalization are based on observational data and theoretical concerns:
No data are available that suggest that adolescent women benefit from hospitalization for treatment of PID. Whether women in their later reproductive years benefit from hospitalization for treatment of PID is also unclear, although women aged >35 years who are hospitalized with PID are more likely than are younger women to have a complicated clinical course. Parenteral Treatment No efficacy data compare parenteral with oral regimens. Many randomized trials have demonstrated the efficacy of both parenteral and oral regimens (82). Although most trials have used parenteral treatment for at least 48 hours after the patient demonstrates substantial clinical improvement, this time designation is arbitrary. Clinical experience should guide decisions regarding transition to oral therapy, which usually can be initiated within 24 hours of clinical improvement. Most clinicians recommend at least 24 hours of direct inpatient observation for patients who have tubo-ovarian abscesses, after which time home antimicrobial therapy is adequate.
NOTE: Because of pain associated with infusion, doxycycline should be administered orally when possible, even when the patient is hospitalized. Both oral and IV administration of doxycycline provide similar bioavailability. Parenteral therapy may be discontinued 24 hours after a patient improves clinically, and oral therapy with doxycycline (100 mg twice a day) should continue to complete 14 days of therapy. When tubo-ovarian abscess is present, many health-care providers use clindamycin or metronidazole with doxycycline for continued therapy rather than doxycycline alone, because it provides more effective anaerobic coverage. Clinical data are limited regarding the use of other second- or third-generation cephalosporins (e.g., ceftizoxime, cefotaxime, and ceftriaxone), which also may be effective therapy for PID and may 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 other analogous situations. Parenteral therapy can be discontinued 24 hours after a patient improves clinically; continuing 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, many health-care providers use clindamycin for continued therapy rather than doxycycline, because clindamycin provides more effective anaerobic coverage.
Limited data support the use of other parenteral regimens, but the following three regimens have been investigated in at least one clinical trial, and they have broad spectrum coverage.
IV ofloxacin has been investigated as a single agent; however because of concerns regarding its spectum, metronidazole may be included in the regimen. Preliminary data suggest that levofloxacin is as effective as ofloxacin and may be substituted; its single daily dosing makes it advantageous from a compliance perspective (83). Ampicillin/sulbactam plus doxycycline has good coverage against C. trachomatis, N. gonorrhoeae, and anaerobes and is effective for patients who have tubo-ovarian abscess. Oral Treatment As with parenteral regimens, clinical trials of outpatient regimens have provided minimal information regarding intermediate and long-term outcomes. The following regimens provide coverage against the frequent etiologic agents of PID, but evidence from clinical trials supporting their use is limited. 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.
Oral ofloxacin has been investigated as a single agent in two well-designed clinical trials, and it is effective against both N. gonorrhoeae and C. trachomatis (84,85). Despite the results of these trials, lack of anaerobic coverage with ofloxacin is a concern; the addition of metronidazole to the treatment regimen provides this coverage. Preliminary data suggest that levofloxacin is as effective as ofloxacin and may be substituted (83); its single daily dosing makes it advantageous from a compliance perspective.
The optimal choice of a cephalosporin for Regimen B is unclear; although cefoxitin has better anaerobic coverage, ceftriaxone has better coverage against N. gonorrhoeae. Clinical trials have demonstrated that a single dose of cefoxitin is effective in obtaining short-term clinical response in women who have PID; however, the theoretical limitations in its coverage of anaerobes may require the addition of metronidazole to the treatment regimen (86). The 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. Limited data suggest that the combination of oral metronidazole plus doxycycline after primary parenteral therapy is safe and effective (87,88). Alternative Oral Regimens Although information regarding other outpatient regimens is limited, one other regimen has undergone at least one clinical trial and has broad spectrum coverage. Amoxicillin/clavulanic acid plus doxycycline was effective in obtaining short-term clinical response in a single clinical trial; however, gastrointestinal symptoms might limit compliance with this regimen. Several recent investigations have evaluated the use of azithromycin in the treatment of upper reproductive tract infections; however, the data are insufficient to recommend this agent as a component of any of the oral treatment regimens for PID. Follow-UpPatients 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 the health-care provider prescribes outpatient oral or parenteral therapy, a follow-up examination should be performed within 72 hours using the criteria for clinical improvement described previously. If the patient has not improved, hospitalization for parenteral therapy and further evaluation are recommended. Some specialists also recommend rescreening for C. trachomatis and N. gonorrhoeae 4--6 weeks after therapy is completed in women with documented infection with these pathogens. Management of Sex PartnersMale 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. 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 often 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 for male sex partners of women who have PID. When this is not feasible, health-care providers should ensure that sex partners are referred for appropriate treatment. PreventionPrevention of chlamydial infection by screening and treating high-risk women reduces the incidence of PID. Theoretically, most cases of PID can be prevented by screening all women or those determined to be at high-risk (based on age or other factors) using DNA amplification on cervical specimens (in women receiving pelvic exams) and on urine (in women not undergoing exams). Although BV is associated with PID, whether the incidence of PID can be reduced by identifying and treating women with BV is unclear. Special ConsiderationsPregnancy Because of the high risk for maternal morbidity, fetal wastage, 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 early observational studies, HIV-infected women with PID were more likely to require surgical intervention. In recent, more comprehensive observational and controlled studies, HIV-infected women with PID had similar symptoms when compared with uninfected controls (89--91). They were more likely to have a tubo-ovarian abscess, but responded equally well to standard parenteral and oral antibiotic regimens when compared with HIV-negative women. The microbiologic findings for HIV-positive and HIV-negative women were similar, except for a) higher rates of concomitant M. hominis, candida, streptococcal, and HPV infections and b) HPV-related cytologic abnormalities among those with HIV infection. 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. |
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