STDs (Sexually Transmitted Diseases Treatment)

Sexually transmitted diseases (STDs), or sexually transmitted infections (STIs), are infections that are passed from one person to another through sexual contact. The contact is usually vaginal, oral, and anal sex. But sometimes they can spread through other intimate physical contact. This is because some STDs, like herpes and HPV, are spread by skin-to-skin contact.

Effective clinical management of patients with treatable STDs requires treatment of the patients’ recent sex partners to prevent reinfection and curtail further transmission. Patients should be instructed to refer their sex partners for evaluation and treatment. Sex partners of patients with N. gonorrhoeae infection whose last sexual contact with the patient was within 60 days before the onset of symptoms or diagnosis of infection in the patient should be evaluated and treated for N. gonorrhoeae and C. trachomatis infections. If a patient’s last sexual intercourse was >60 days before the 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.

For heterosexual patients with gonorrhea whose, partners’ treatment cannot be ensured or is unlikely, delivery of antibiotic therapy for gonorrhea (as well as for chlamydia) by the patients to their partners can be considered (see Partner Management). Use of this approach (68,71) should always be accompanied by efforts to educate partners about symptoms and to encourage partners to seek clinical evaluation. For male patients informing female partners, educational materials should include information about the importance of seeking medical evaluation for PID (especially if symptomatic). Possible undertreatment of PID in female partners and possible missed opportunities to diagnose other STDs are of concern and have not been evaluated in comparison with patient-delivered therapy and partner referral. This approach should not be considered a routine partner management strategy in MSM because of the high risk for coexisting undiagnosed STDs or HIV infection.

Special Considerations

Allergy, Intolerance, and Adverse Reactions

Reactions to first generation cephalosporins occur in approximately 5%–10% of persons with a history of penicillin allergy and occur less frequently with third-generation cephalosporins (239). In those persons with a history of penicillin allergy, the use of cephalosporins should be contraindicated only in those with a history of a severe reaction to penicillin (e.g., anaphylaxis, Stevens Johnson syndrome, and toxic epidermal necrolysis) (316).

Because data are limited regarding alternative regimens for treating gonorrhea among persons who have severe cephalosporin allergy, providers treating such patients should consult infectious disease specialists. Azithromycin 2 g orally is effective against uncomplicated gonococcal infection, but because of concerns over emerging antimicrobial resistance to macrolides, its use should be limited. Cephalosporin treatment following desensitization is impractical in most clinical settings.

Pregnancy

As with other patients, pregnant women infected with N. gonorrhoeae should be treated with a recommended or alternate cephalosporin. Because spectinomycin is not available in the United States, azithromycin 2 g orally can be considered for women who cannot tolerate a cephalosporin. Either azithromycin or amoxicillin is recommended for treatment of presumptive or diagnosed C. trachomatis infection during pregnancy (see Chlamydial Infections).

HIV Infection

Patients who have gonococcal infection and also are infected with HIV should receive the same treatment regimen as those who are HIV negative.

Suspected Cephalosporin Treatment Failure or Resistance

Suspected treatment failure has been reported among persons receiving oral and injectable cephalosporins (300—304). Therefore, clinicians of patients with suspected treatment failure or persons infected with a strain found to demonstrate in vitro resistance should consult an infectious disease specialist, conduct culture and susceptibility testing of relevant clinical specimens, retreat with at least 250 mg of ceftriaxone IM or IV, ensure partner treatment, and report the situation to CDC through state and local public health authorities.

Gonococcal Conjunctivitis

In the only published study of the treatment of gonococcal conjunctivitis among U.S. adults, all 12 study participants responded to a single 1-g IM injection of ceftriaxone (317).

Recommended Regimen

Ceftriaxone 1 g IM in a single dose

Consider lavage of the infected eye with a saline solution once. Persons treated for gonococcal conjunctivitis should be treated presumptively for concurrent C. trachomatis infection.

Management of Sex Partners

Patients should be instructed to refer their sex partners for evaluation and treatment (see Gonococcal Infections, Management of Sex Partners).

Disseminated Gonococcal Infection (DGI)

DGI frequently results in petechial or pustular acral skin lesions, asymmetrical arthralgia, tenosynovitis, or septic arthritis. The infection is complicated occasionally by perihepatitis and rarely by endocarditis or meningitis. Some strains of N. gonorrhoeae that cause DGI can cause minimal genital inflammation. No recent studies have been published on the treatment of DGI.

Treatment

Hospitalization is recommended for initial therapy, especially for patients who might not comply with treatment, for those in whom diagnosis is uncertain, and for those who have purulent synovial effusions or other complications. Examination for clinical evidence of endocarditis and meningitis should be performed. Persons treated for DGI should be treated presumptively for concurrent C. trachomatis infection.

Recommended Regimen

Ceftriaxone 1 g IM or IV every 24 hours

Alternative Regimens

Cefotaxime 1 g IV every 8 hours OR Ceftizoxime 1 g IV every 8 hours

All of the preceding regimens should be continued for 24–48 hours after improvement begins, at which time therapy can be switched to cefixime 400 mg orally twice daily to complete at least 1 week of antimicrobial therapy. No treatment failures have been reported with the recommended regimens.

Management of Sex Partners

Gonococcal infection frequently is asymptomatic in sex partners of patients who have DGI. As with uncomplicated gonococcal infections, patients should be instructed to refer their sex partners for evaluation and treatment (see Gonococcal Infection, Management of Sex Partners).

Gonococcal Meningitis and Endocarditis

Recommended Regimen

Ceftriaxone 1–2 g IV every 12 hours

Therapy for meningitis should be continued for 10–14 days; therapy for endocarditis should be continued for at least 4 weeks. Treatment of complicated DGI should be undertaken in consultation with an infectious disease specialist.

Management of Sex Partners

Patients should be instructed to refer their sex partners for evaluation and treatment (see Gonococcal Infection, Management of Sex Partners).

Gonococcal Infections Among Infants

Gonococcal infection among infants usually is caused by exposure to infected cervical exudate at birth. It is usually an acute illness that manifests 2–5 days after birth. The prevalence of infection among infants depends on the prevalence of infection among pregnant women, whether pregnant women are screened for gonorrhea, and whether newborns receive ophthalmia prophylaxis. The most severe manifestations of N. gonorrhoeae infection in newborns are ophthalmia neonatorum and sepsis, which can include arthritis and meningitis. Less severe manifestations include rhinitis, vaginitis, urethritis, and reinfection at sites of fetal monitoring.

Ophthalmia Neonatorum Caused by N. gonorrhoeae

Although N. gonorrhoeae causes ophthalmia neonatorum relatively infrequently in the United States, identifying and treating this infection is especially important because ophthalmia neonatorum can result in perforation of the globe of the eye and blindness.

Diagnostic Considerations

Infants at increased risk for gonococcal ophthalmia are those who do not receive ophthalmia prophylaxis and those whose mothers have had no prenatal care or whose mothers have a history of STDs or substance abuse. Gonococcal ophthalmia is strongly suspected when intracellular gram-negative diplococci are identified in conjunctival exudate, justifying presumptive treatment for gonorrhea after appropriate cultures for N. gonorrhoeae are obtained. Appropriate chlamydial testing should be done simultaneously. Presumptive treatment for N. gonorrhoeae might be indicated for newborns who are at increased risk for gonococcal ophthalmia and who have increased WBCs (but not gonococci) in a Gram-stained smear of conjunctival exudate.

In all cases of neonatal conjunctivitis, conjunctival exudates should be cultured for N. gonorrhoeae and tested for antibiotic susceptibility before a definitive diagnosis is made. A definitive diagnosis is vital because of the public health and social consequences of a diagnosis of gonorrhea. Nongonococcal causes of neonatal ophthalmia include Moraxella catarrhalis and other Neisseria species, organisms that are indistinguishable from N. gonorrhoeae on Gram-stained smear but can be differentiated in the microbiology laboratory.

Recommended Regimen

Ceftriaxone 25–50 mg/kg IV or IM in a single dose, not to exceed 125 mg

Topical antibiotic therapy alone is inadequate and is unnecessary if systemic treatment is administered.

Other Management Considerations

Simultaneous infection with C. trachomatis should be considered when a patient does not improve after treatment. Both mother and infant should be tested for chlamydial infection at the same time that gonorrhea testing is conducted (see Ophthalmia Neonatorum Caused by C. trachomatis). Ceftriaxone should be administered cautiously to hyperbilirubinemic infants, especially those born prematurely.

Follow-Up

Infants who have gonococcal ophthalmia should be hospitalized and evaluated for signs of disseminated infection (e.g., sepsis, arthritis, and meningitis). One dose of ceftriaxone is adequate therapy for gonococcal conjunctivitis.

Management of Mothers and Their Sex Partners

The mothers of infants who have gonococcal infection and the mothers’ sex partners should be evaluated and treated according to the recommendations for treating gonococcal infections in adults (see Gonococcal Infections in Adolescents and Adults).

DGI and Gonococcal Scalp Abscesses in Newborns

Sepsis, arthritis, and meningitis (or any combination of these conditions) are rare complications of neonatal gonococcal infection. Localized gonococcal infection of the scalp can result from fetal monitoring through scalp electrodes. Detection of gonococcal infection in neonates who have sepsis, arthritis, meningitis, or scalp abscesses requires cultures of blood, CSF, and joint aspirate on chocolate agar. Specimens obtained from the conjunctiva, vagina, oropharynx, and rectum that are cultured on gonococcal selective medium are useful for identifying the primary site(s) of infection, especially if inflammation is present. Positive Gram-stained smears of exudate, CSF, or joint aspirate provide a presumptive basis for initiating treatment for N. gonorrhoeae. Diagnoses based on Gram-stained smears or presumptive identification of cultures should be confirmed with definitive tests on culture isolates.

Recommended Regimens

Ceftriaxone 25–50 mg/kg/day IV or IM in a single daily dose for 7 days, with a duration of 10–14 days, if meningitis is documented OR Cefotaxime 25 mg/kg IV or IM every 12 hours for 7 days, with a duration of 10–14 days, if meningitis is documented

Prophylactic Treatment for Infants Whose Mothers Have Gonococcal Infection

Infants born to mothers who have untreated gonorrhea are at high risk for infection.

Recommended Regimen in the Absence of Signs of Gonococcal Infection

Ceftriaxone 25–50 mg/kg IV or IM, not to exceed 125 mg, in a single dose

Other Management Considerations

Both mother and infant should be tested for chlamydial infection.

Follow-Up

Follow-up examination is not required.

Management of Mothers and Their Sex Partners

The mothers of infants who have gonococcal infection and the mothers’ sex partners should be evaluated and treated according to the recommendations for treatment of gonococcal infections in adults (see Gonococcal Infections).

Gonococcal Infections Among Children

Sexual abuse is the most frequent cause of gonococcal infection in preadolescent children (see Sexual Assault or Abuse of Children). For preadolescent girls, vaginitis is the most common manifestation of this infection; gonococcal-associated PID after vaginal infection is likely less common in preadolescents than adults. Among sexually abused children, anorectal and pharyngeal infections with N. gonorrhoeae are common and frequently asymptomatic.

Diagnostic Considerations

Because of the legal implications of a diagnosis of N. gonorrhoeae infection in a child, culture remains the preferred method for diagnosis. Gram stains are inadequate for evaluating prepubertal children for gonorrhea and should not be used to diagnose or exlude gonorrhea. NAATs for the detection of N. gonorrhoeae can be used under certain circumstances (see Sexual Assault or Abuse of Children)

Recommended Regimen for Children Who Weigh >45 kg

Treat with one of the regimens recommended for adults (see Gonococcal Infections)

Recommended Regimen for Children Who Weigh ≤45 kg and Who Have Uncomplicated Gonococcal Vulvovaginitis, Cervicitis, Urethritis, Pharyngitis, or Proctitis

Ceftriaxone 125 mg IM in a single dose

Recommended Regimen for Children Who Weigh ≤45 kg and Who Have Bacteremia or Arthritis

Ceftriaxone 50 mg/kg (maximum dose: 1 g) IM or IV in a single dose daily for 7 days

Recommended Regimen for Children Who Weigh >45 kg and Who Have Bacteremia or Arthritis

Ceftriaxone 50 mg/kg IM or IV in a single dose daily for 7 days

Follow-Up

Follow-up cultures are unnecessary if ceftriaxone is used.

Other Management Considerations

Only parenteral cephalosporins (i.e., ceftriaxone) are recommended for use in children; cefotaxime is approved for gonococcal ophthalmia only. No data are available regarding the use of oral cefixime to treat gonococcal infections in children.

All children found to have gonococcal infections should be evaluated for coinfection with syphilis and C. trachomatis. (For a discussion of concerns regarding sexual assault, see Sexual Assault or Abuse of Children.)

Ophthalmia Neonatorum Prophylaxis

To prevent gonococcal ophthalmia neonatorum, a prophylactic agent should be instilled into the eyes of all newborn infants; this procedure is required by law in most states. All of the recommended prophylactic regimens in this section prevent gonococcal ophthalmia. However, the efficacy of these preparations in preventing chlamydial ophthalmia is less clear, and they do not eliminate nasopharyngeal colonization by C. trachomatis. The diagnosis and treatment of gonococcal and chlamydial infections in pregnant women is the best method for preventing neonatal gonococcal and chlamydial disease. Not all women, however, receive prenatal care, and therefore go untreated. Ocular prophylaxis is warranted for neonates, because it can prevent sight-threatening gonococcal ophthalmia and because it is safe, easy to administer, and inexpensive.

Recommended Regimen

Erythromycin (0.5%) ophthalmic ointment in each eye in a single application

This preparation should be instilled into both eyes of every neonate as soon as possible after delivery. Ideally, ointment should be applied using single-use tubes or ampules rather than multiple-use tubes. If prophylaxis is delayed (i.e., not administered in the delivery room), a monitoring system should be established to ensure that all infants receive prophylaxis. All infants should be administered ocular prophylaxis, regardless of whether they are delivered vaginally or by cesarean section.

Erythromycin is the only antibiotic ointment recommended for use in neonates. Silver nitrate and tetracycline ophthalmic ointment are no longer manufactured in the United States, bacitracin is not effective, and povidone iodine has not been studied adequately. If erythromycin ointment is not available, infants at risk for exposure to N. gonorrhoeae (especially those born to a mother with untreated gonococcal infection or who has received no prenatal care) can be administered ceftriaxone 25-50 mg/kg IV or IM, not to exceed 125 mg in a single dose.

Diseases Characterized by Vaginal Discharge

Most women will have a vaginal infection, characterized by discharge, itching, or odor, during their lifetime. With the availability of complementary and alternative therapies and over-the-counter medications for candidiasis, many symptomatic women seek these products before or in addition to an evaluation by a medical provider.

Obtaining a medical history alone has been shown to be insufficient for accurate diagnosis of vaginitis and can lead to the inappropriate administration of medication. Therefore, a careful history, examination, and laboratory testing to determine the etiology of vaginal complaints are warranted. Information on sexual behaviors and practices, gender of sex partners, menses, vaginal hygiene practices (such as douching), and other medications should be elicited. The three diseases most frequently associated with vaginal discharge are BV (caused by the replacement of the vaginal flora by an overgrowth of anaerobic bacteria including Prevotella sp., Mobiluncus sp., G. vaginalis, Ureaplasma, Mycoplasma, and numerous fastidious or uncultivated anaerobes) trichomoniasis (caused by T. vaginalis), and candidiasis (usually caused by Candida albicans). Cervicitis also can sometimes cause a vaginal discharge. Although vulvovaginal candidiasis (VVC) usually is not transmitted sexually, it is included in this section because it is frequently diagnosed in women who have vaginal complaints or who are being evaluated for STDs.

Various diagnostic methods are available to identify the etiology of an abnormal vaginal discharge. Clinical laboratory testing can identify the cause of vaginitis in most women and is discussed in detail in the sections of this report dedicated to each condition. In the clinician’s office, the cause of vaginal symptoms might be determined by pH, a potassium hydroxide (KOH) test, and microscopic examination of fresh samples of the discharge. The pH of the vaginal secretions can be determined by narrow-range pH paper; an elevated pH (i.e., >4.5) is common with BV or trichomoniasis. Because pH testing is not highly specific, discharge should be further examined microscopically by first diluting one sample in one to two drops of 0.9% normal saline solution on one slide and a second sample in 10% KOH solution (samples that emit an amine odor immediately upon application of KOH suggest BV or trichomoniasis infection). Cover slips are then placed on the slides, and they are examined under a microscope at low and high power.

The saline-solution specimen might yield motile T. vaginalis, or clue cells (i.e., epithelial cells with borders obscured by small bacteria), which are characteristic of BV, whereas the presence of WBCs without evidence of trichomonads or yeast in this solution is suggestive of cervicitis (see Cervicitis). The KOH specimen typically is used to identify the yeast or pseudohyphae of Candida species. However, the absence of trichomonads or pseudohyphae in KOH samples does not rule out these infections, because the sensitivity of microscropy is approximately 50% compared with NAAT (trichomoniasis) or culture (yeast).

In settings where pH paper, KOH, and microscopy are not available, alternative commercially available point-of-care tests or clinical laboratory testing can be used to diagnose vaginitis. The presence of objective signs of vulvar inflammation in the absence of vaginal pathogens after laboratory testing, along with a minimal amount of discharge, suggests the possibility of mechanical, chemical, allergic, or other noninfectious irritation of the vulva.

Bacterial Vaginosis

BV is a polymicrobial clinical syndrome resulting from replacement of the normal hydrogen peroxide producing Lactobacillus sp. in the vagina with high concentrations of anaerobic bacteria (e.g., Prevotella sp. and Mobiluncus sp.), G. vaginalis, Ureaplasma, Mycoplasma, and numerous fastidious or uncultivated anaerobes. Some women experience transient vaginal microbial changes, whereas others experience them for a longer intervals of time. Among women presenting for care, BV is the most prevalent cause of vaginal discharge or malodor; however, in a nationally representative survey, most women with BV were asymptomatic (318).

BV is associated with having multiple male or female partners, a new sex partner, douching, lack of condom use, and lack of vaginal lactobacilli; women who have never been sexually active can also be affected. The cause of the microbial alteration that characterizes BV is not fully understood, nor is whether BV results from acquisition of a sexually transmitted pathogen. Nonetheless, women with BV are at increased risk for the acquisition of some STDs (e.g., HIV, N. gonorrhoeae, C. trachomatis, and HSV- 2), complications after gynecologic surgery, complications of pregnancy, and recurrence of BV. Treatment of male sex partners has not been beneficial in preventing the recurrence of BV.

Diagnostic Considerations

BV can be diagnosed by the use of clinical criteria (i.e., Amsel’s Diagnostic Criteria) (319) or Gram stain. A Gram stain (considered the gold standard laboratory method for diagnosing BV) is used to determine the relative concentration of lactobacilli (i.e., long Gram-positive rods), Gram-negative and Gram-variable rods and cocci (i.e., G. vaginalis, Prevotella, Porphyromonas, and peptostreptococci), and curved Gram-negative rods (i.e., Mobiluncus) characteristic of BV. If a Gram stain is not available, clinical criteria can be used and require three of the following symptoms or signs:

• homogeneous, thin, white discharge that smoothly coats the vaginal walls;

• presence of clue cells on microscopic examination;

• pH of vaginal fluid >4.5; or

• a fishy odor of vaginal discharge before or after addition of 10% KOH (i.e., the whiff test).

Detection of three of these criteria has been correlated with results by Gram stain (320). Other tests, including a DNA probe-based test for high concentrations of G. vaginalis (Affirm VP III, Becton Dickinson, Sparks, Maryland), a prolineaminopeptidase test card (Pip Activity TestCard, Quidel, San Diego, California), and the OSOM BVBlue test have acceptable performance characteristics compared with Gram stain. Although a card test is available for the detection of elevated pH and trimethylamine, it has low sensitivity and specificity and therefore is not recommended. PCR also has been used in research settings for the detection of a variety of organisms associated with BV, but evaluation of its clinical utility is uncertain. Detection of one organism or group of organisms might be predictive of BV by Gram stain (321). However, additional evaluations are needed to confirm these associations. Culture of G. vaginalis is not recommended as a diagnostic tool because it is not specific. Cervical Pap tests have no clinical utility for the diagnosis of BV because of their low sensitivity.

Treatment

Treatment is recommended for women with symptoms. The established benefits of therapy in nonpregnant women are to relieve vaginal symptoms and signs of infection. Other potential benefits to treatment include reduction in the risk for acquiring C. trachomatis or N. gonorrhoeae (322), HIV, and other viral STDs.

Recommended Regimens

Metronidazole 500 mg orally twice a day for 7 days* OR Metronidazole gel 0.75%, one full applicator (5 g) intravaginally, once a day for 5 days OR Clindamycin cream 2%, one full applicator (5 g) intravaginally at bedtime for 7 days†

* Consuming alcohol should be avoided during treatment and for 24 hours thereafter. † Clindamycin cream is oil-based and might weaken latex condoms and diaphragms for 5 days after use (refer to clindamycin product labeling for additional information).

Providers should consider patient preference, possible side-effects, drug interactions, and other coinfections when selecting a regimen. Women should be advised to refrain from intercourse or to use condoms consistently and correctly during the treatment regimen. Douching might increase the risk for relapse, and no data support the use of douching for treatment or relief of symptoms.

Alternative Regimens

Tinidazole 2 g orally once daily for 3 days OR Tinidazole 1 g orally once daily for 5 days OR Clindamycin 300 mg orally twice daily for 7 days OR Clindamycin ovules 100 mg intravaginally once at bedtime for 3 days

Alternative regimens include several tinidazole regimens (323) or clindamycin (oral or intravaginal) (324). Additional regimens include metronidazole (750-mg extended release tablets once daily for 7 days), or a single dose of clindamycin intravaginal cream, although data on the performance of these alternative regimens are limited.

Several studies have evaluated the clinical and microbiologic efficacy of using intravaginal lactobacillus formulations to treat BV and restore normal flora (325—327). Further research efforts to determine the role of these regimens in BV treatment and prevention are ongoing.

Follow-Up

Follow-up visits are unnecessary if symptoms resolve. Because recurrence of BV is common, women should be advised to return for evaluation if symptoms recur. Detection of certain BV-associated organisms have been associated with antimicrobial resistance and might determine risk for subsequent treatment failure (328—333). Limited data are available regarding optimal management strategies for women with early treatment failure. Using a different treatment regimen might be an option in patients who have a recurrence; however, re-treatment with the same topical regimen is another acceptable approach for treating recurrent BV during the early stages of infection (334). For women with multiple recurrences after completion of a recommended regimen, metronidazole gel twice weekly for 4-6 months has been shown to reduce recurrences, although this benefit might not persist when suppressive therapy is discontinued (335). Limited data suggest that oral nitroimidazole followed by intravaginal boric acid and suppressive metronidazole gel for those women in remission might be an option in women with recurrent BV (336). Monthly oral metronidazole administered with fluconazole has also been evaluated as suppressive therapy (337).

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). Therefore, routine treatment of sex partners is not recommended.

Special Considerations

Allergy or Intolerance to the Recommended Therapy

Intravaginal clindamycin cream is preferred in case of allergy or intolerance to metronidazole or tinidazole. Intravaginal metronidazole gel can be considered for women who do not tolerate systemic metronidazole. Intravaginal metronidazole should not be administered to women allergic to metronidazole.

Pregnancy

Treatment is recommended for all pregnant women with symptoms. Although BV is associated with adverse pregnancy outcomes, including premature rupture of membranes, preterm labor, preterm birth, intra-amniotic infection, and postpartum endometritis, the only established benefit of therapy for BV in pregnant women is the reduction of symptoms and signs of vaginal infection. Additional potential benefits include reducing the risk for infectious complications associated with BV during pregnancy and reducing the risk for other infections (other STDs or HIV).

Several trials have been undertaken to determine the efficacy of BV treatment among pregnant women. Two trials demonstrated that metronidazole was efficacious during pregnancy using the 250-mg regimen (338,339); however, metronidazole administered at 500 mg twice daily can be used. One trial involving a limited number of participants revealed that treatment with oral metronidazole 500 mg twice daily was equally effective as metronidazole gel, with cure rates of 70% using Amsel criteria to define cure (340), and a recent trial demonstrated a cure rate of 85% using Gram stain criteria after 4 weeks with oral clindamycin (341). Multiple studies and meta-analyses have not demonstrated an association between metronidazole use during pregnancy and teratogenic or mutagenic effects in newborns (342,343). Regardless of the antimicrobial agent used to treat pregnant women, oral therapy is preferred because of the possibility of subclinical upper-genital–tract infection.

Recommended Regimens for Pregnant Women

Metronidazole 500 mg orally twice a day for 7 days OR Metronidazole 250 mg orally three times a day for 7 days OR Clindamycin 300 mg orally twice a day for 7 days

Treatment of asymptomatic BV among pregnant women who are at high risk for preterm delivery (i.e., those with a previous preterm birth) has been evaluated by several studies, which have yielded mixed results. Seven trials have evaluated treatment of pregnant women with asymptomatic BV at high risk for preterm delivery; one showed harm (344), two showed no benefit (345,346), and four demonstrated benefit (338,339,347,348). Therefore, evidence is insufficient to assess the impact of screening for BV in pregnant women at high risk for preterm delivery (85).

Similarly, data are inconsistent regarding whether the treatment of asymptomatic pregnant women with BV who are at low risk for preterm delivery reduces adverse outcomes of pregnancy. Although USPSTF recommends against screening these women (85), one trial demonstrated a 40% reduction in spontaneous preterm birth among women using oral clindamycin during weeks 13–22 of gestation (348). Several additional trials have shown that intravaginal clindamycin given at an average gestation of later than 20 weeks did not reduce preterm birth, and in three of these trials, intravaginal clindamycin cream administered at 16–32 weeks’ gestation was associated with an increase in adverse events (e.g., low birth weight and neonatal infections) in newborns (346,349—351). Providers should be aware that intravaginal clindamycin cream might be associated with adverse outcomes if used in the latter half of pregnancy.

HIV Infection

BV appears to recur with higher frequency in HIV-positive women (352). Patients who have BV and also are infected with HIV should receive the same treatment regimen as those who are HIV negative.

Trichomoniasis

Trichomoniasis is caused by the protozoan T. vaginalis. Some men who are infected with T. vaginalis might not have symptoms; others have NGU. Some women have symptoms characterized by a diffuse, malodorous, yellow-green vaginal discharge with vulvar irritation. However, many women have minimal or no symptoms. Because of the high prevalence of trichomoniasis in clinical and nonclinical settings (64,92,353,354), testing for T. vaginalis should be performed in women seeking care for vaginal discharge. Screening for T. vaginalis in women can be considered in those at high risk for infection (i.e., women who have new or multiple partners, have a history of STDs, exchange sex for payment, and use injection drugs).

Diagnosis of vaginal trichomoniasis is usually performed by microscopy of vaginal secretions, but this method has a sensitivity of only approximately 60%–70% and requires immediate evaluation of wet preparation slide for optimal results. FDA-cleared tests for trichomoniasis in women include OSOM Trichomonas Rapid Test (Genzyme Diagnostics, Cambridge, Massachusetts), an immunochromatographic capillary flow dipstick technology, and the Affirm VP III (Becton Dickenson, San Jose, California), a nucleic acid probe test that evaluates for T. vaginalis, G. vaginalis, and C. albicans. Each of these tests, which are performed on vaginal secretions, have a sensitivity of >83% and a specificity of >97%. Both tests are considered point-of-care diagnostics. The results of the OSOM Trichomonas Rapid Test are available in approximately 10 minutes, whereas results of the Affirm VP III are available within 45 minutes. Although these tests tend to be more sensitive than those requiring vaginal wet preparation, false positives might occur, especially in populations with a low prevalence of disease.

Culture is another sensitive and highly specific commercially available method of diagnosis. Among women in whom trichomoniasis is suspected but not confirmed by microscopy, vaginal secretions should be cultured for T. vaginalis. While the sensitivity of a Pap test for T. vaginalis diagnosis is poor, use of a liquid-based testing has demonstrated enhanced sensitivity; however, false-positive tests can occur, and confirmatory testing might be needed in some circumstances (355). An FDA-cleared PCR assay for detection of gonorrhea and chlamydial infection (Amplicor, manufactured by Roche Diagnostic Corp.) has been modified for T. vaginalis detection in vaginal or endocervical swabs and in urine from women and men; sensitivity ranges from 88%–97% and specificity from 98%–99% (356). APTIMA T. vaginalis Analyte Specific Reagents (ASR; manufactured by Gen-Probe, Inc.) also can detect T. vaginalis RNA by transcription-mediated amplification using the same instrumentation platforms available for the FDA-cleared APTIMA Combo2 assay for diagnosis of gonorrhea and chlamydial infection; published validation studies of T. vaginalis ASR found sensitivity ranging from 74%–98% and specificity of 87%–98% (357—359). Laboratories that use the Gen-Probe APTIMA Combo2 test for detection of N. gonorrhoeae and C. trachomatis can consider adding the T. vaginalis ASR to their testing armentarium, as long as the necessary CLIA verification studies have been conducted.

In men, wet preparation is not a sensitive test, and no approved point-of-care tests are available. Culture testing of urethral swab, urine, or semen is one diagnostic option; however, NAATs (i.e., PCR or transcription-mediated amplification [TMA]) have superior sensitivity for T. vaginalis diagnosis in men (356,359). T. vaginalis has not been found to infect oral sites, and rectal prevalence appears low in MSM (360). Therefore, oral and rectal testing for T. vaginalis is not recommended.

Recommended Regimens

Metronidazole 2 g orally in a single dose OR Tinidazole 2 g orally in a single dose

Alternative Regimen

Metronidazole 500 mg orally twice a day for 7 days*

* Patients should be advised to avoid consuming alcohol during treatment with metronidazole or tinidazole. Abstinence from alcohol use should continue for 24 hours after completion of metronidazole or 72 hours after completion of tinidazole.

The nitroimidazoles comprise the only class of drugs useful for the oral or parenteral therapy of trichomoniasis. Of these drugs, metronidazole and tinidazole are available in the United States and are cleared 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%, and the recommended tinidazole regimen has resulted in cure rates of approximately 86%–100%. The appropriate treatment of sex partners might increase these reported rates. Randomized controlled trials comparing single 2-g doses of metronidazole and tinidazole suggest that tinidazole is equivalent or superior to metronidazole in achieving parasitologic cure and resolution of symptoms (361). Treatment of patients and sex partners results in relief of symptoms, microbiologic cure, and reduction of transmission.

Metronidazole gel is considerably less efficacious for the treatment of trichomoniasis (<50%) than oral preparations of metronidazole. Topically applied antimicrobials (e.g., metronidazole gel) are unlikely to achieve therapeutic levels in the urethra or perivaginal glands; therefore, use of this gel is not recommended. Several other topically applied antimicrobials occasionally have been used for treatment of trichomoniasis; however, these preparations likely are no more effective than metronidazole gel.

Follow-Up

Because of the high rate of reinfection among patients in whom trichomoniasis was diagnosed (17% were reinfected within 3 months in one study), rescreening for T. vaginalis at 3 months following initial infection can be considered for sexually active women with trichomoniasis; the benefit of this approach, however, has not been fully evaluated (64). No data support rescreening in men diagnosed with T. vaginalis. While most recurrent T. vaginalis infections are thought to result from having sex with an untreated partner (i.e., reinfection), some recurrent cases can be attributed to diminished susceptibility to metronidazole. Low-level metronidazole resistance has been identified in 2%–5% of cases of vaginal trichomoniasis (362,363), but high-level resistance only rarely occurs. Fortunately, infections caused by most of these organisms respond to tinidazole or higher doses of metronidazole. Tinidazole has a longer serum half-life and reaches higher levels in genitourinary tissues than metronidazole. In addition, many T. vaginalis isolates have lower minimal lethal concentrations (MLCs) to tinidazole than metronidazole.

If treatment failure occurs with metronidazole 2-g single dose and reinfection is excluded, the patient can be treated with metronidazole 500 mg orally twice daily for 7 days. For patients failing this regimen, treatment with tinidazole or metronidazole at 2 g orally for 5 days should be considered. If these therapies are not effective, further management should be discussed with a specialist. The consultation should ideally include determination of the susceptibility of T. vaginalis to metronidazole and tinidazole. Consultation and T. vaginalis susceptibility testing is available from CDC (telephone: 404-718-4141; 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 abstain from sex until they and their sex partners are cured (i.e., when therapy has been completed and patient and partner[s] are asymptomatic). Existing data suggest that patient-delivered partner therapy might have a role in partner management for trichomoniasis; however, no one partner management intervention has shown superiority over another in reducing reinfection rates (72,73). Although no data are available to guide treatment of the male partners of women with nitroimidazole treatment failure, on the basis of expert opinion, male partners should be evaluated and treated with either tinidazole in a single dose of 2 g orally or metronidazole twice a day at 500 mg orally for 7 days.

Special Considerations

Allergy, Intolerance, and Adverse Reactions

Metronidazole and tinidazole are both nitroimidazoles. Patients with an immediate-type allergy to a nitroimidazole can be managed by metronidazole desensitization in consultation with a specialist (364—366). 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 membranes, preterm delivery, and low birth weight. However, metronidazole treatment has not been shown to reduce perinatal morbidity. Although some trials suggest the possibility of increased prematurity or low birth weight after metronidazole treatment, limitations of the studies prevent definitive conclusions regarding risks for treatment (367,368). Treatment of T. vaginalis might relieve symptoms of vaginal discharge in pregnant women and might prevent respiratory or genital infection of the newborn and further sexual transmission. Clinicians should counsel patients regarding the potential risks and benefits of treatment and communicate the option of therapy deferral in asymptomatic pregnant women until after 37 weeks’ gestation. All symptomatic pregnant women should not only be considered for treatment regardless of pregnancy stage, but be provided careful counseling regarding condom use and the continued risk of sexual transmission.

Women can be treated with 2 g metronidazole in a single dose at any stage of pregnancy. Multiple studies and meta-analyses have not demonstrated an association between metronidazole use during pregnancy and teratogenic or mutagenic effects in infants (342,343,369). The safety of tinidazole in pregnant women, however, has not been well evaluated.

In lactating women who are administered metronidazole, withholding breastfeeding during treatment and for 12–24 hours after the last dose will reduce the exposure of the infant to metronidazole. For women treated with tinidazole, interruption of breastfeeding is recommended during treatment and for 3 days after the last dose.

HIV Infection

There is increasing evidence for epidemiologic and biologic interaction between HIV and T. vaginalis (370—375). T. vaginalis infection in HIV-infected women might enhance HIV transmission by increasing genital shedding of the virus (376,377), and treatment for T. vaginalis has been shown to reduce HIV shedding (376,377). For sexually active women who are HIV-positive, screening for trichomoniasis at entry into care with subsequent screening performed at least annually is recommended based on the reported prevalence of T. vaginalis, the effect of treatment at reducing vaginal HIV shedding, and the potential complications of upper-genital-tract infections among women who are left untreated (130,370—375). Rescreening 3 months after completion of therapy should be considered among HIV-positive women with trichomoniasis, a recommendation based on the high proportion of recurrent or persistent infection and the association between HIV and T. vaginalis infection (64,374,378).

A recent randomized clinical trial involving women coinfected with trichomoniasis and HIV demonstrated that a single dose of metronidazole 2 gm orally was not as effective as 500 mg twice daily for 7 days (379). Therefore, a multi-dose treatment regimen for T. vaginalis can be considered in HIV-infected women.

Vulvovaginal Candidiasis

VVC usually is caused by C. albicans, but occasionally is caused by other Candida sp. or yeasts. Typical symptoms of VVC include pruritus, vaginal soreness, dyspareunia, external dysuria, and abnormal vaginal discharge. 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 within their lifetime. On the basis of clinical presentation, microbiology, host factors, and response to therapy, VVC can be classified as either uncomplicated or complicated (Box 3). Approximately 10%–20% of women will have complicated VVC that necessitates diagnostic and therapeutic considerations.

Uncomplicated VVC

Diagnostic Considerations

A diagnosis of Candida vaginitis is suggested clinically by the presence of external dysuria and vulvar pruritus, pain, swelling, and redness. Signs include vulvar edema, fissures, excoriations, or thick, curdy vaginal discharge. The diagnosis can be made in a woman who has signs and symptoms of vaginitis when either 1) a wet preparation (saline, 10% KOH) or Gram stain of vaginal discharge demonstrates yeasts, hyphae, or pseudohyphae or 2) a culture or other test yields a yeast species. Candida vaginitis is associated with a normal vaginal pH (<4.5), and therefore, pH testing is not a useful diagnostic tool. 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. Examination of a wet mount with KOH preparation should be performed for all women with symptoms or signs of VVC, and women with a positive result should receive treatment. For women with negative wet mounts who are symptomatic, vaginal cultures for Candida should be considered. If the wet mount is negative and Candida cultures cannot be done, empiric treatment can be considered for symptomatic women with any sign of VVC on examination. Identifying Candida by culture in the absence of symptoms or signs 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. Most healthy women with uncomplicated VVC have no identifiable precipitating factors.

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.

Recommended Regimens

Over-the-Counter Intravaginal Agents:

Butoconazole 2% cream 5 g intravaginally for 3 days OR Clotrimazole 1% cream 5 g intravaginally for 7–14 days OR Clotrimazole 2% cream 5 g intravaginally for 3 days OR Miconazole 2% cream 5 g intravaginally for 7 days OR Miconazole 4% cream 5 g intravaginally for 3 days OR Miconazole 100 mg vaginal suppository, one suppository for 7 days OR Miconazole 200 mg vaginal suppository, one suppository for 3 days OR Miconazole 1,200 mg vaginal suppository, one suppository for 1 day OR Tioconazole 6.5% ointment 5 g intravaginally in a single application

Prescription Intravaginal Agents:

Butoconazole 2% cream (single dose bioadhesive product), 5 g intravaginally for 1 day OR Nystatin 100,000-unit vaginal tablet, one tablet for 14 days OR Terconazole 0.4% cream 5 g intravaginally for 7 days OR Terconazole 0.8% cream 5 g intravaginally for 3 days OR Terconazole 80 mg vaginal suppository, one suppository for 3 days

Oral Agent:

Fluconazole 150 mg oral tablet, one tablet in single dose

The creams and suppositories in this regimen are oil-based and might weaken latex condoms and diaphragms. Patients and providers should refer to condom product labeling for further information.

Intravaginal preparations of butaconazole, clotrimazole, miconazole, and tioconazole are available over-the-counter (OTC). Women whose condition has previously been diagnosed with VVC are not necessarily more capable of diagnosing themselves; therefore, any woman whose symptoms persist after using an OTC preparation or who has a recurrence of symptoms within 2 months should be evaluated with office-based testing. Unnecessary or inappropriate use of OTC preparations is common and can lead to a delay in the treatment of other vulvovaginitis etiologies, which can 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 the initial symptoms.

Management of Sex Partners

VVC is not usually acquired through sexual intercourse; no data support the treatment of sex partners. A minority of male sex partners might 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, Intolerance, and Adverse Reactions

Topical agents usually cause no systemic side effects, although local burning or irritation might 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 can occur when these oral agents are administered with other drugs, including astemizole, calcium channel antagonists, cisapride, cyclosporin A, oral hypoglycemic agents, phenytoin, protease inhibitors, tacrolimus, terfenadine, theophylline, trimetrexate, rifampin, and warfarin.

Complicated VVC

Recurrent Vulvovaginal Candidiasis (RVVC)

RVVC, usually defined as four or more episodes of symptomatic VVC in 1 year, affects a small percentage of women (<5%). The pathogenesis of RVVC is poorly understood, and most women with 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 nonalbicans species), particularly Candida glabrata. Although C. glabrata and other nonalbicans Candidia species are observed in 10%–20% of patients with RVVC, C. glabrata does not form pseudohyphae or hyphae and is not easily recognized on microscopy. Conventional antimycotic therapies are not as effective against these species as they are 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, some specialists recommend a longer duration of initial therapy (e.g., 7–14 days of topical therapy or a 100-mg, 150-mg, or 200-mg oral dose of fluconazole every third day for a total of 3 doses [day 1, 4, and 7]) to attempt mycologic remission before initiating a maintenance antifungal regimen.

Maintenance Regimens

Oral fluconazole (i.e., 100-mg, 150-mg, or 200-mg dose) weekly for 6 months is the first line of treatment. If this regimen is not feasible, topical treatments used intermittently as a maintenance regimen can be considered.

Suppressive maintenance antifungal therapies are effective in reducing RVVC. However, 30%–50% of women will have recurrent disease after maintenance therapy is discontinued. Routine treatment of sex partners is controversial. C. albicans azole resistance is rare in vaginal isolates, and susceptibility testing is usually not warranted for individual treatment guidance.

Severe VVC

Severe vulvovaginitis (i.e., extensive vulvar erythema, edema, excoriation, and fissure formation) is associated with 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.

Nonalbicans VVC

The optimal treatment of nonalbicans VVC remains unknown. Options include longer duration of therapy (7–14 days) with a nonfluconazole azole drug (oral or topical) 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% (380). If symptoms recur, referral to a specialist is advised.

Special Considerations

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 frequently occurs during pregnancy. Only topical azole therapies, applied for 7 days, are recommended for use among pregnant women.

HIV Infection

The incidence of VVC in HIV-infected women is unknown. Vaginal Candida colonization rates among HIV-infected women are higher than among those for 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 nonalbicans Candida species from the vagina.

On the basis of 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 (381), this regimen is not recommended for routine primary prophylaxis in HIV-infected women in the absence of recurrent VVC (129). Given the frequency at which RVVC occurs in the immmunocompetent healthy population, the occurrence of RVVC should not be considered an indication for HIV testing among women previously testing HIV negative. Although VVC is associated with increased HIV seroconversion in HIV-negative women and increased HIV cervicovaginal levels in HIV-positive women, the effect of treatment for VVC on HIV acquisition and transmission remains unknown.

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.

Recommended Parenteral Regimen A

Cefotetan 2 g IV every 12 hours OR Cefoxitin 2 g IV every 6 hours PLUS Doxycycline 100 mg orally or IV every 12 hours

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.

Recommended Parenteral Regimen B

Clindamycin 900 mg IV every 8 hours PLUS Gentamicin loading dose IV or IM (2 mg/kg of body weight), followed by a maintenance dose (1.5 mg/kg) every 8 hours. Single daily dosing (3–5 mg/kg) can be substituted.

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).

Alternative Parenteral Regimens

Ampicillin/Sulbactam 3 g IV every 6 hours PLUS Doxycycline 100 mg orally or IV every 12 hours

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.

Recommended Regimen

Ceftriaxone 250 mg IM 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 IM 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 cephalosporin (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

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).

Epididymitis

Acute epididymitis is a clinical syndrome consisting of pain, swelling, and inflammation of the epididymis that lasts <6 weeks (402). Chronic epididymitis is characterized by a ≥6 week history of symptoms of discomfort and/or pain in the scrotum, testicle, or epididymis. In most cases of acute epididymitis, the testis is also involved in the process — a condition referred to as epididymo-orchitis. Chronic epididymitis has been subcategorized into inflammatory chronic epididymitis, obstructive chronic epididymitis, and chronic epididymalgia (403).

Among sexually active men aged <35 years, acute epididymitis is most frequently caused by C. trachomatis or N. gonorrhoeae. Acute epididymitis caused by sexually transmitted enteric organisms (e.g., Escherichia coli and Pseudomonas spp.) also occurs among men who are the insertive partner during anal intercourse. Sexually transmitted acute epididymitis usually is accompanied by urethritis, which frequently is asymptomatic. In men aged >35 years, sexually transmitted epididymitis is uncommon, whereas bacteriuria secondary to obstructive urinary disease (e.g., benign prostatic hyperplasia) is more common. In this older population, nonsexually transmitted epididymitis is associated with urinary tract instrumentation or surgery, systemic disease, and immunosuppression.

Chronic infectious epididymitis is most frequently seen in conditions associated with granulomatous reaction; Mycobacterium tuberculosis (TB) is the most common granulomatous disease affecting the epididymis. Up to 25% of patients can have bilateral disease, with ultrasound demonstrating an enlarged hyperemic epididymis with multiple cysts and calcifications. Tuberculous epididymitis should be suspected in all patients with a known history of or recent exposure to TB or in patients whose clinical status worsens despite appropriate antibiotic treatment.

Diagnostic Considerations

Men who have acute epididymitis typically have unilateral testicular pain and tenderness; hydrocele and palpable swelling of the epididymis usually are present. Although the inflammation and swelling usually begin in the tail of the epididymis, they can spread to involve the rest of the epididymis and testicle. The spermatic cord is usually tender and swollen. Testicular torsion, a surgical emergency, should be considered in all cases, but it occurs more frequently among adolescents and in men without evidence of inflammation or infection. Emergency testing for torsion might be indicated when the onset of pain is sudden, pain is severe, or the test results available during the initial examination do not support a diagnosis of urethritis or urinary-tract infection. If the diagnosis is questionable, a urologist should be consulted immediately because testicular viability might be compromised. Radionuclide scanning of the scrotum is the most accurate radiologic method of diagnosis, but it is not routinely available. Although ultrasound is primarily used for ruling out torsion of the spermatic cord in cases of acute scrotum swelling, it will often demonstrate epididymal hyperemia and swelling in men with epididymitis. However, differentiation between testicular torsion and epididymitis must be made on the basis of clinical evaluation, because partial spermatic cord torsion can mimic epididymitis on scrotal ultrasound. Ultrasound provides minimal utility for men with a clinical presentation consistent with epididymitis; a negative ultrasound does not alter physician management of clinical epididymitis. Ultrasound, therefore, should be reserved for patients with scrotal pain who cannot be diagnosed accurately by physical examination, history, and objective laboratory findings.

The evaluation of men for epididymitis should include one of the following:

• Gram stain of urethral secretions demonstrating ≥5 WBC per oil immersion field. Gram stain is the preferred rapid diagnostic test for evaluating urethritis because it is highly sensitive and specific for documenting both urethritis and the presence or absence of gonococcal infection. Gonococcal infection is established by documenting the presence of WBC containing intracellular Gram-negative diplococci on urethral Gram stain.

• Positive leukocyte esterase test on first-void urine or microscopic examination of first-void urine sediment demonstrating ≥10 WBC per high power field.

Culture, nucleic acid hybridization tests, and NAATs are available for the detection of both N. gonorrhoeae and C. trachomatis. Culture and nucleic acid hybridization tests require urethral swab specimens, whereas amplification tests can be performed on urine or urethral specimens. Because of their higher sensitivity, amplification tests are preferred for the detection of C. trachomatis. Depending on the risk, patients whose conditions are associated with acquiring an STD should receive testing for other STDs.

Treatment

Empiric therapy is indicated before laboratory test results are available. The goals of treatment of acute epididymitis caused by C. trachomatis or N. gonorrhoeae are 1) microbiologic cure of infection, 2) improvement of signs and symptoms, 3) prevention of transmission to others, and 4) a decrease in potential complications (e.g., infertility or chronic pain). As an adjunct to therapy, bed rest, scrotal elevation, and analgesics are recommended until fever and local inflammation have subsided. Because empiric therapy is often initiated before laboratory tests are available, all patients should receive ceftriaxone plus doxycycline for the initial therapy of epididymitis. Additional therapy can include a fluoroquinolone if acute epididymitis is not found to be caused by gonorrhea by NAAT or if the infection is most likely caused by enteric organisms. For men who are at risk for both sexually transmitted and enteric organisms (e.g., MSM who report insertive anal intercourse), ceftriaxone with a fluoroquinolone are recommended.

Recommended Regimens

Ceftriaxone 250 mg IM in a single dose PLUS Doxycycline 100 mg orally twice a day for 10 days For acute epididymitis most likely caused by enteric organisms Levofloxacin 500 mg orally once daily for 10 days OR Ofloxacin 300 mg orally twice a day for 10 days

Although most patients can be treated on an out-patient basis, hospitalization should be considered when severe pain suggests other diagnoses (e.g., torsion, testicular infarction, or abscess) or when patients are unable or unlikely to comply with an antimicrobial regimen. Because high fever is uncommon and indicates a complicated infection, these patients should be admitted for further evaluation.

Follow-Up

Patients should be instructed to return to their health-care providers if their symptoms fail to improve within 48 hours of the initiation of treatment. Signs and symptoms of epididymitis that do not subside within 3 days requires re-evaluation of the diagnosis and therapy. Swelling and tenderness that persist after completion of antimicrobial therapy should be evaluated comprehensively. Differential diagnoses include tumor, abscess, infarction, testicular cancer, TB, and fungal epididymitis.

Management of Sex Partners

Patients who have acute epididymitis that is confirmed or suspected to be caused by N. gonorrhoeae or C. trachomatis should be instructed to refer sex partners for evaluation and treatment if their contact with the index patient was within the 60 days preceding onset of their own symptoms.

Patients 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 patient and partners no longer have symptoms).

Special Considerations

HIV Infection

Patients who have uncomplicated acute epididymitis and also are infected with HIV should receive the same treatment regimen as those who are HIV negative. Other etiologic agents have been implicated in acute epididymitis in HIV infection including CMV, salmonella, toxoplasmosis, Ureaplasma urealyticum, Corynebacterium sp., Mycoplasma sp., and Mima polymorpha. Fungi and mycobacteria are also more likely to cause acute epididymitis in immunosuppressed men than in immunocompetent men.

Human Papillomavirus (HPV) Infection

More than 100 types of HPV exist, more than 40 of which can infect the genital area. Most HPV infections are asymptomatic, unrecognized, or subclinical. Oncogenic, or high-risk HPV types (e.g., HPV types 16 and 18), are the cause of cervical cancers. These HPV types are also associated with other anogenital cancers in men and women, including penile, vulvar, vaginal, and anal cancer, as well a subset of oropharyngeal cancers (404). Nononcogenic, or low-risk HPV types (e.g., HPV types 6 and 11), are the cause of genital warts and recurrent respiratory papillomatosis. Asymptomatic genital HPV infection is common and usually self-limited; it is estimated that more than 50% of sexually active persons become infected at least once in their lifetime (405). Persistent oncogenic HPV infection is the strongest risk factor for development of precancers and cancers.

HPV Tests

HPV tests are available for women aged >30 years undergoing cervical cancer screening. These tests should not be used for men, for women <20 years of age, or as a general test for STDs. These HPV tests detect viral nucleic acid (i.e., DNA or RNA) or capsid protein. Four tests have been approved by the FDA for use in the United States: the HC II High-Risk HPV test (Qiagen), HC II Low-Risk HPV test (Qiagen), Cervista HPV 16/18 test, and Cervista HPV High-Risk test (Hologics).

Treatment

Treatment is directed to the macroscopic (i.e., genital warts) or pathologic (i.e, precancerous) lesions caused by infection. Subclinical genital HPV infection typically clears spontaneously, and therefore specific antiviral therapy is not recommended to eradicate HPV infection. In the absence of lesions, treatment is not recommended for subclinical genital HPV infection whether it is diagnosed by colposcopy, acetic acid application, or by laboratory tests for HPV DNA. Treatment also is not recommended for cervical intraepithelial neoplasia 1 (CIN1).

Prevention

Two HPV vaccines are licensed in the United States: a bivalent vaccine (Cervarix) containing HPV types 16 and 18 and a quadrivalent vaccine (Gardasil) vaccine containing HPV types 6, 11, 16, and 18. Both vaccines offer protection against the HPV types that cause 70% of cervical cancers (i.e., types 16 and 18), and the quadrivalent HPV vaccine also protects against the types that cause 90% of genital warts (i.e., types 6 and 11). Either vaccine can be administered to girls aged 11–12 years and can be administered to those as young as 9 years of age (15,16); girls and women ages 13–26 years who have not started or completed the vaccine series also should receive the vaccine. HPV vaccine is indicated for girls in this age group, because benefit is greatest if it is administered before the onset of sexual activity. The quadrivalent (Gardasil) HPV vaccine can also be used in males aged 9–26 years to prevent genital warts (17). Administering the vaccine to boys before the onset of sexual activity is optimal. Both HPV vaccines are administered as a 3-dose series of IM injections over a 6-month period, with the second and third doses given 1–2 and then 6 months after the first dose. Ideally, the same vaccine product should be used for the entire 3-dose series. HPV vaccine is available for eligible children and adolescents aged <19 years through the Vaccines for Children (VFC) program (available by calling CDC INFO [800-232-4636]).

Women who have received HPV vaccine should continue routine cervical cancer screening because 30% of cervical cancers are caused by HPV types other than 16 or 18. In the United States, the vaccines are not licensed or recommended for use in women >26 years of age. No published data are available on the effectiveness, programmatic requirements, or cost-effectiveness of administering the HPV vaccine in STD clinic settings.

Genital Warts

Of genital warts, 90% are caused by HPV 6 or 11. HPV types 6 or 11 are commonly found before, or at the time of, detection of genital warts (406). HPV types 16, 18, 31, 33, and 35 are found occasionally in visible genital warts (usually as coinfections with HPV 6 or 11) and can be associated with foci of high-grade intraepithelial neoplasia, particularly in persons who are infected with HIV infection. In addition to warts on genital areas, HPV types 6 and 11 have been associated with conjunctival, nasal, oral, and laryngeal warts.

Genital warts are usually asymptomatic, but depending on the size and anatomic location, they can be painful or pruritic. Genital warts are usually flat, papular, or pedunculated growths on the genital mucosa. Genital warts occur commonly at certain anatomic sites, including around the introitus in women, under the foreskin of the uncircumcised penis, and on the shaft of the circumcised penis. Genital warts can also occur at multiple sites in the anogenital epithelium or within the anogenital tract (e.g., cervix, vagina, urethra, perineum, perianal skin, and scrotum). Intra-anal warts are observed predominantly in persons who have had receptive anal intercourse, but they can also occur in men and women who do not have a history of anal sexual contact.

Diagnosis of genital warts is usually clinical, made by visual inspection. Genital warts can be confirmed by biopsy, which might be indicated if 1) the diagnosis is uncertain; 2) the lesions do not respond to standard therapy; 3) the disease worsens during therapy; 4) the lesion is atypical; 5) the patient has comprised immunity; or 6) the warts are pigmented, indurated, fixed, bleeding, or ulcerated. Genital warts are usually asymptomatic, but depending on the size and anatomic location, they might be painful or pruritic. The use of HPV DNA testing for genital wart diagnosis is not recommended, because test results would not alter clinical management of the condition.

The application of 3%–5% acetic acid, which causes skin color to turn white, has been used by some providers to detect HPV-infected genital mucosa. However, acetic acid application is not a specific test for HPV infection. Therefore, the routine use of this procedure for screening to detect mucosal changes attributed to HPV infection is not recommended.

Treatment

The primary reason for treating genital warts is the amelioration of symptoms (including relieving cosmetic concerns) and ultimately, removal of the warts. In most patients, treatment can induce wart-free periods. If left untreated, visible genital warts can resolve on their own, remain unchanged, or increase in size or number. Available therapies for genital warts likely reduce, but probably do not eradicate, HPV infectivity. Whether the reduction in HPV viral DNA resulting from treatment reduces future transmission remains unclear. No evidence indicates that the presence of genital warts or their treatment is associated with the development of cervical cancer.

Regimens

Treatment of genital warts should be guided by the preference of the patient, available resources, and the experience of the health-care provider. No definitive evidence suggests that any of the available treatments are superior to any other, and no single treatment is ideal for all patients or all warts. The use of locally developed and monitored treatment algorithms has been associated with improved clinical outcomes and should be encouraged. Because of uncertainty regarding the effect of treatment on future transmission of HPV and the possibility of spontaneous resolution, an acceptable alternative for some persons is to forego treatment and wait for spontaneous resolution.

Factors that influence selection of treatment include wart size, wart number, anatomic site of the wart, wart morphology, patient preference, cost of treatment, convenience, adverse effects, and provider experience. Factors that might affect response to therapy include the presence of immunosuppression and compliance with therapy, which can consist of either a single treatment or complete course of treatment. In general, warts located on moist surfaces or in intertriginous areas respond best to topical treatment. The treatment modality should be changed if a patient has not improved substantially after a complete course of treatment or if side effects are severe. Most genital warts respond within 3 months of therapy. The response to treatment and any side effects should be evaluated throughout the course of therapy.

Complications occur rarely when treatment is administered properly. Patients should be warned that persistent hypopigmentation or hyperpigmentation occurs commonly with ablative modalities and has also been described with immune modulating therapies (imiquimod). Depressed or hypertrophic scars are uncommon but can occur, especially if the patient has had insufficient time to heal between treatments. Rarely, treatment can result in disabling chronic pain syndromes (e.g., vulvodynia and hyperesthesia of the treatment site) or, in the case of anal warts, painful defecation or fistulas. A limited number of case reports of severe systemic effects resulting from treatment with podophyllin resin and interferon have been documented.

Treatment regimens are classified into patient-applied and provider-applied modalities. Patient-applied modalities are preferred by some patients because they can be administered in the privacy of the patient’s home. To ensure that patient-applied modalities are effective, patients must comply with the treatment regimen and must be capable of identifying and reaching all genital warts. Follow-up visits are not required for persons using patient-applied therapy. However, follow-up visits after several weeks of therapy enable providers to answer any questions patients might have about the use of the medication and any side effects they have experienced; follow-up visits also facilitate the assessment of a patient’s response to treatment.

Recommended Regimens for External Genital Warts

Patient-Applied:

Podofilox 0.5% solution or gel OR Imiquimod 5% cream OR Sinecatechins 15% ointment

Provider—Administered:

Cryotherapy with liquid nitrogen or cryoprobe. Repeat applications every 1–2 weeks. OR Podophyllin resin 10%–25% in a compound tincture of benzoin OR Trichloroacetic acid (TCA) or Bichloroacetic acid (BCA) 80%–90% OR Surgical removal either by tangential scissor excision, tangential shave excision, curettage, or electrosurgery.

Podofilox is an antimitotic drug that destroys warts, is relatively inexpensive, easy to use, safe, and self-applied. Podofilox solution should be applied with a cotton swab, or podofilox gel with a finger, to visible genital warts twice a day for 3 days, followed by 4 days of no therapy. This cycle can be repeated, as necessary, for up to four cycles. The total wart area treated should not exceed 10 cm2, and the total volume of podofilox should be limited to 0.5 mL per day. If possible, the health-care provider should apply the initial treatment to demonstrate the proper application technique and identify which warts should be treated. Mild to moderate pain or local irritation might develop after treatment. The safety of podofilox during pregnancy has not been established.

Imiquimod is a topically active immune enhancer that stimulates production of interferon and other cytokines. Imiquimod cream should be applied once daily at bedtime, three times a week for up to 16 weeks (407). The treatment area should be washed with soap and water 6–10 hours after the application. Local inflammatory reactions, including redness, irritation, induration, ulceration/erosions, and vesicles, are common with the use of imiquimod, and hypopigmentation has also been described (408). Imiquimod might weaken condoms and vaginal diaphragms. The safety of imiquimod during pregnancy has not been established.

Sinecatechin ointment, a green-tea extract with an active product (catechins), should be applied three times daily (0.5-cm strand of ointment to each wart) using a finger to ensure coverage with a thin layer of ointment until complete clearance of warts. This product should not be continued for longer than 16 weeks (409—411). The medication should not be washed off after use. Sexual (i.e., genital, anal, or oral) contact should be avoided while the ointment is on the skin. The most common side effects of sinecatechins 15% are erythema, pruritis/burning, pain, ulceration, edema, induration, and vesicular rash. This medication may weaken condoms and diaphragms. No clinical data are available regarding the efficacy or safety of sinecatechins compared with other available anogenital wart treatment modalities. The medication is not recommended for HIV-infected persons, immunocompromised persons, or persons with clinical genital herpes because the safety and efficacy of therapy in these settings has not been established. The safety of sinecatechins during pregnancy also is unknown.

Cryotherapy destroys warts by thermal-induced cytolysis. Health-care providers must be trained on the proper use of this therapy because over- and undertreatment can result in complications or low efficacy. Pain after application of the liquid nitrogen, followed by necrosis and sometimes blistering, is common. Local anesthesia (topical or injected) might facilitate therapy if warts are present in many areas or if the area of warts is large.

Pedophyllin resin 10%–25% should be applied to each wart and allowed to air-dry before the treated area comes into contact with clothing; overapplication or failure to air dry can result in local irritation caused by spread of the compound to adjacent areas. The treatment can be repeated weekly, if necessary. To avoid the possibility of complications associated with systemic absorption and toxicity, two guidelines should be followed: 1) application should be limited to <0.5 mL of podophyllin or an area of <10 cm2 of warts per session and 2) the area to which treatment is administered should not contain any open lesions or wounds. The preparation should be thoroughly washed off 1–4 hours after application to reduce local irritation. The safety of podophyllin during pregnancy has not been established. Podophyllin resin preparations differ in the concentration of active components and contaminants. The shelf life and stability of podophyllin preparations are unknown.

Both TCA and BCA are caustic agents that destroy warts by chemical coagulation of proteins. Although these preparations are widely used, they have not been investigated thoroughly. TCA solutions have a low viscosity comparable with that of water and can spread rapidly if applied excessively; therefore, they can damage adjacent tissues. A small amount should be applied only to the warts and allowed to dry before the patient sits or stands, at which time a white frosting develops. If pain is intense, the acid can be neutralized with soap or sodium bicarbonate. If an excess amount of acid is applied, the treated area should be powdered with talc, sodium bicarbonate (i.e., baking soda), or liquid soap preparations to remove unreacted acid. This treatment can be repeated weekly, if necessary.

Surgical therapy has the advantage of usually eliminating warts at a single visit. However, such therapy requires substantial clinical training, additional equipment, and a longer office visit. After local anesthesia is applied, the visible genital warts can be physically destroyed by electrocautery, in which case no additional hemostasis is required. Care must be taken to control the depth of electrocautery to prevent scarring. Alternatively, the warts can be removed either by tangential excision with a pair of fine scissors or a scalpel, by laser, or by curettage. Because most warts are exophytic, this procedure can be accomplished with a resulting wound that only extends into the upper dermis. Hemostasis can be achieved with an electrocautery unit or a chemical styptic (e.g., an aluminum chloride solution). Suturing is neither required nor indicated in most cases if surgical removal is performed properly. Surgical therapy is most beneficial for patients who have a large number or area of genital warts. Both carbon dioxide laser and surgery might be useful in the management of extensive warts or intraurethral warts, particularly for those persons who have not responded to other treatments.

Because all available treatments have shortcomings, some clinics employ combination therapy (simultaneous use of two or more modalities on the same wart at the same time). Data are limited regarding the efficacy or risk of complications associated with use of such combinations.

Alternative Regimens

Alternative regimens include treatment options that might be associated with more side effects and/or less data on efficacy. Alternative regimens include intralesional interferon, photodynamic therapy, and topical cidofovir.

Recommended Regimen for Cervical Warts

For women who have exophytic cervical warts, a biopsy evaluation to exclude high-grade SIL must be performed before treatment is initiated. Management of exophytic cervical warts should include consultation with a specialist.

Recommended Regimens for Vaginal Warts

Cryotherapy with liquid nitrogen. The use of a cryoprobe in the vagina is not recommended because of the risk for vaginal perforation and fistula formation. OR TCA or BCA 80%–90% applied to warts. A small amount should be applied only to warts and allowed to dry, at which time a white frosting develops. If an excess amount of acid is applied, the treated area should be powdered with talc, sodium bicarbonate, or liquid soap preparations to remove unreacted acid. This treatment can be repeated weekly, if necessary.

Recommended Regimens for Urethral Meatus Warts

Cryotherapy with liquid nitrogen OR Podophyllin 10%–25% in compound tincture of benzoin. The treatment area and adjacent normal skin must be dry before contact with podophyllin. This treatment can be repeated weekly, if necessary. The safety of podophyllin during pregnancy has not been established. Data are limited on the use of podofilox and imiquimod for treatment of distal meatal warts.

Recommended Regimens for Anal Warts

Cryotherapy with liquid nitrogen OR TCA or BCA 80%–90% applied to warts. A small amount should be applied only to warts and allowed to dry, at which time a white frosting develops. If an excess amount of acid is applied, the treated area should be powdered with talc, sodium bicarbonate, or liquid soap preparations to remove unreacted acid. This treatment can be repeated weekly, if necessary. OR Surgical removal

Intra-anal warts should be managed in consultation with a specialist. Many persons with warts on the anal mucosa also have warts on the rectal mucosa, so persons with anal and/or intra-anal warts might benefit from an inspection of the rectal mucosa by digital examination, standard anoscopy, or high-resolution anoscopy.

Counseling

The following key counseling messages should be conveyed to all patients diagnosed with HPV infection:

• Genital HPV infection is very common. Many types of HPV are passed on through genital contact, most often during vaginal and anal sexual contact. HPV can also be spread by oral sexual contact.

• Most sexually active adults will get HPV at some point in their lives, though most will never know it because HPV infection usually has no signs or symptoms.

• In most cases, HPV infection clears spontaneously, without causing any health problems. Nevertheless, some infections do progress to genital warts, precancers, and cancers.

• The types of HPV that cause genital warts are different from the types that can cause anogenital cancers.

• Within an ongoing sexual relationship, both partners are usually infected at the time one person is diagnosed with HPV infection, even though signs of infection might not be apparent.

• A diagnosis of HPV in one sex partner is not indicative of sexual infidelity in the other partner.

• Treatments are available for the conditions caused by HPV (e.g., genital warts), but not for the virus itself.

• HPV does not affect a woman’s fertility or ability to carry a pregnancy to term.

• Correct and consistent male condom use might lower the chances of giving or getting genital HPV, but such use is not fully protective, because HPV can infect areas that are not covered by a condom.

• Sexually active persons can lower their chances of getting HPV by limiting their number of partners. However, HPV is common and often goes unrecognized; persons with only one lifetime sex partner can have the infection. For this reason, the only definitive method to avoid giving and getting HPV infection and genital warts is to abstain from sexual activity.

• Tests for HPV are now available to help providers screen for cervical cancer in certain women. These tests are not useful for screening adolescent females for cervical cancer, nor are they useful for screening for other HPV-related cancers or genital warts in men or women. HPV tests should not be used to screen:
  — men;
  — partners of women with HPV;
  — adolescent females; or
  — for health conditions other than cervical cancer.

• Two HPV vaccines are available, both of which offer protection against the HPV types that cause 70% of cervical cancers (i.e., types 16 and 18); the quadrivalent vaccine (Gardasil) also protects against the types that cause 90% of genital warts (i.e., types 6 and 11). These vaccines are most effective when all doses are administered before sexual contact. Either vaccine is recommended for 11- and 12-year-old girls and for females aged 13–26 years who did not receive or complete the vaccine series when they were younger. The quadrivalent HPV vaccine can be used in males aged 9–26 years to prevent genital warts.

The following are specific counseling messages for those persons diagnosed with genital warts and their partners:

• Genital warts are not life threatening. If left untreated, genital warts might go away, stay the same, or grow in size or number. Except in very rare and unusual cases, genital warts will not turn into cancer.

• It is difficult to determine how or when a person became infected with HPV; genital warts can be transmitted to others even when no visible signs of warts are present, even after warts are treated.

• It is not known how long a person remains contagious after warts are treated. It is also unclear whether informing subsequent sex partners about a past diagnosis of genital warts is beneficial to the health of those partners.

• Genital warts commonly recur after treatment, especially in the first 3 months.

• Women should get regular Pap tests as recommended, regardless of vaccination or genital wart history. Women with genital warts do not need to get Pap tests more often than recommended.

• HPV testing is unnecessary in sexual partners of persons with genital warts.

• If one sex partner has genital warts, both sex partners benefit from getting screened for other STDs.

• Persons with genital warts should inform current sex partner(s) because the warts can be transmitted to other partners. In addition, they should refrain from sexual activity until the warts are gone or removed.

• Correct and consistent male condom use can lower the chances of giving or getting genital warts, but such use is not fully protective because HPV can infect areas that are not covered by a condom.

• The Gardasil vaccine, which has been approved for use in males and females aged 9–26 years, protects against the HPV types that cause 90% of genital warts (i.e., types 6 and 11).

Special Considerations

Pregnancy

Imiquimod, sinecatechins, podophyllin, and podofilox should not be used during pregnancy. Genital warts can proliferate and become friable during pregnancy. Although removal of warts during pregnancy can be considered, resolution might be incomplete or poor until pregnancy is complete. Rarely, HPV types 6 and 11 can cause respiratory papillomatosis in infants and children, although the route of transmission (i.e., transplacental, perinatal, or postnatal) is not completely understood. Whether cesarean section prevents respiratory papillomatosis in infants and children also is unclear (412); therefore, cesarean delivery should not be performed solely to prevent transmission of HPV infection to the newborn. Cesarean delivery is indicated for women with genital warts if the pelvic outlet is obstructed or if vaginal delivery would result in excessive bleeding. Pregnant women with genital warts should be counseled concerning the low risk for warts on the larynx (recurrent respiratory papillomatosis) in their infants or children.

HIV Infection

Persons who are HIV-infected are more likely to develop genital warts then persons who are not HIV-infected (413); moreover, lesions are more recalcitrant to treatment due to depressed cell-mediated immunity. No data suggest that treatment modalities for external genital warts should be different for HIV-infected persons. However, persons who are immunosuppressed because of HIV or other reasons might have larger or more numerous warts, might not respond as well as immunocompetent persons to therapy for genital warts, and might have more frequent recurrences after treatment (414—416). Squamous cell carcinomas arising in or resembling genital warts might occur more frequently among immunosuppressed persons, therefore requiring biopsy for confirmation of diagnosis for suspicious cases. Because of the increased incidence of anal cancer in HIV-infected MSM, screening for anal intraepithelial neoplasia by cytology can be considered (417). However, evidence is limited concerning the natural history of anal intraepithelial neoplasias, the reliability of screening methods, the safety and response to treatments, and the programmatic considerations that would support this screening approach.

Squamous Cell Carcinoma in Situ

Persons in whom squamous cell carcinoma in situ of the genitalia is diagnosed should be referred to a specialist for treatment. Ablative modalities usually are effective, but careful follow-up is essential for patient management.

Cervical Cancer Screening for Women Who Attend STD Clinics or Have a History of STDs

Women attending STD clinics for the treatment of genital infection with high-risk types of Human Papillomavirus (HR-HPV) might be at increased risk for cervical cancer; persistence of HR-HPV can cause cervical cancer and its precancerous lesions. One study demonstrated an HR-HPV prevalence of 27% among women receiving treatment in an STD clinic setting; prevalence was highest among persons aged 14–19 and decreased with increasing age (418). In an evaluation of women attending STD clinics, over half of women were at increased risk for cervical cancer as a result of HPV infection, cervical disease, or history of cervical disease compared with women without these characteristics (419).

Cervical cytology (i.e., a Pap test) is an effective, low-cost screening test for preventing invasive cervical cancer. In a 2004 survey, 49% of all STD clinics in the United States reported providing cervical screening services, and 20% reported use of HPV DNA testing (419).

Current guidelines from USPSTF and ACOG recommend that cervical screening begin at age 21 years (96,97). This recommendation is based on the low incidence of cervical cancer and limited utility of screening in younger women (98). ACS recommends that women start cervical screening with Pap tests after 3 years of initiating sexual activity but by no later than age 21 years (98). Recommended screening intervals (http://www.cdc.gov/cancer/cervical/pdf/guidelines.pdf ) should continue through 65 years according to USPSTF (http://www.ahrq.gov/clinic/uspstf/uspscerv.htm) or 70 years according to ACS (http://cancer.org/docroot/ped/content/ped_2_3x_acs_cancer detection_guidelines_36.asp).

Screening Recommendations

STD clinics that provide routine cervical screening services should follow the available guidelines. However, to ensure the provision of adequate care, follow-up and referral sources must be in place. Cervical screening should be performed using either conventional or liquid-based cytologic tests (i.e., Pap tests) and can include HR-HPV DNA tests in specific circumstances (420). For cythopathologic and HPV/DNA testing, STD clinics should use CLIA certified laboratories (421) and those that report cytopathology findings according to the following Bethesda 2001 terminology (422): atypical squamous cells (ASC), low-grade squamous intraepithelial lesions (LSIL), and high-grade intraepithelial lesions (HSIL). The ASC category is subdivided into atypical squamous cells of undetermined significance (ASC-US) and atypical squamous cells—cannot exclude HSIL (ASC-H).

During appointments in which a pelvic examination for STD screening is performed, the health-care provider should inquire about the result of the patient’s most recent Pap test and discuss the following information with the patient:

• the purpose and importance of a Pap test;

• the need for regularly scheduled Pap tests between 21–65 years of age;

• whether a Pap test will be obtained during this clinic visit; and

• if a Pap test will not be obtained during this examination, the names of local providers or referral clinics that can perform Pap tests and adequately follow up results.

If a woman has not had a Pap test during the previous 12 months (2-year intervals for women aged 21–29 years and 3-year intervals for women aged ≥30 years with a history of three normal Pap tests) and cervical screening is indicated, a Pap test should be obtained as part of the routine pelvic examination. Health-care providers should be aware that many women frequently equate having a pelvic examination with having a Pap test; they erroneously believe that a sample for Pap testing was taken, when in reality, only a pelvic examination was performed. Because self-reports of Pap tests often are not accurate, STD clinics should have a protocol for conducting cervical cancer screening and obtaining a Pap test during the routine clinical evaluation of women who do not have clinical-record documentation of a normal Pap test within the preceding 12 months and do not have another provider for screening services.

HPV Tests

HPV tests are available for clinical use and are recommended for the triage of women aged ≥21 years who have abnormal Pap test results (ASC-US). Additionally, these tests can be used in conjunction with a Pap test (adjunct testing) for cervical cancer screening of women aged ≥30 years. These tests should not be used for women aged <20 years for screening or management of abnormal Pap tests or for STD screening. Current FDA-approved HPV tests detect viral nucleic acid (DNA). Several FDA-approved tests for high-risk HPV testing are available for use in the United States. The Hybrid Capture 2 High-Risk HPV DNA test (Qiagen, Gaithersburg, Maryland) and the Cervista HPV High-Risk test (Hologics, Beford, Massachusetts) detect any of 13–14 high-risk HPV types, whereas the Cervista HPV 16/18 test detects type-specific infection with HPV types 16 and 18. The Digene HC2 HPV DNA test (Qiagen, Gaithersburg, Maryland) detects any of 13 high-risk or five low-risk HPV types, although use of this test is not indicated in the STD clinic setting (i.e., only high-risk HPV DNA testing is necessary) (423).

High-risk HPV DNA tests are recommended for the triage of women aged ≥21 years who have ASC-US cytology results. In addition, these tests are recommended for routine adjunctive testing (along with cervical cytology) used to screen women aged ≥30 years (424).

HPV DNA testing (including HR HPV and HPV 16/18 tests) is not recommended for the following situations (425—427):

• deciding whether to vaccinate for HPV;

• conducting STD screening for HPV;

• triaging LSIL;

• testing adolescents aged <21 years; and

• screening for primary cervical cancer as a stand-alone test (i.e., without a Pap test).

Women might benefit from receiving printed information about the value of and indication for cervical cancer screening (i.e., Pap testing), and they should be provided a clinic visit report that states whether a Pap test was obtained during the clinic visit. When available, a copy of the Pap test result should be provided. Women with abnormal screening or diagnostic tests should be referred to clinic settings that employ providers who are experienced in managing these cases (see Follow-Up). Cervical screening programs should screen women who have received HPV vaccination in the same manner as unvaccinated women.

Follow-Up

Among women aged ≥30 years with normal Pap tests and negative tests for HR-HPV, the screening interval can be increased to 3 years. At that time, routine testing with either a Pap test or a Pap and HR-HPV testing can resume (428).

If the results of the Pap test are abnormal, follow-up care should be provided according to the ASCCP 2006 Consensus Guidelines for Management of Abnormal Cervical Cytology (429) (information regarding management and follow-up care is available at http://www.asccp.org). If resources in STD clinics do not allow for follow-up of women with abnormal results, protocols for referral for follow-up and case management should be in place.

• According to American Society for Colposcopy and Cervical Pathology (ASCCP) guidelines, women with Pap tests results indicating ASC-H, low- or high-grade squamous intraepithelial lesion should be referred to a clinician who can perform a colposcopic examination of the lower genital tract and, if indicated, conduct a colposcopically directed biopsy. For women aged <21 years, referral to colposcopy for ASC-US and LSIL is not recommended, because rates of spontaneous clearance are high in this population; repeat Pap testing at 12 and 24 months is recommended for these women.

• For women aged ≥21 years with a Pap test report of ASC-US, three options are available for follow-up management: 1) prompt colposcopy, 2) repeat Pap tests at 6 and 12 months, and 3) a high-risk HR HPV DNA test. Colposcopy is appropriate if the provider has concerns about adherence with recommended follow-up or concerns about other clinical indications. High-grade histological changes (i.e., CIN 2 or higher) after colposcopic evaluation for ASC-US Pap test reports is typically detected in <12% of cases. If repeat Pap tests are used (instead of prompt colposcopy) to follow ASC-US results, tests should be performed at 6- and 12-month intervals until two consecutive negative results are noted, at which time cervical cancer screening at a normal interval for age can be resumed. If subsequent Pap tests demonstrate ASC or a more serious condition, follow-up should be conducted according to ASCCP 2006 Consensus Guidelines (424). A third strategy for managing patients with ASC-US Pap test results involves testing for high-risk HPV DNA (423,424,430,431). Whereas conducting high-risk HPV testing might not be possible in some STD clinics because of resource limitations, such testing might be appropriate in other public health clinic settings. HPV tests that detect low-risk HPV types are not recommended for use in STD clinics, because they are not beneficial in this setting.

• If indicated, high-risk HPV DNA testing can be performed by 1) collecting a specimen for Pap test and HPV DNA on the same swab, 2) using a supplied swab at the time of the Pap test, if conventional cytology is used, 3) reflex testing (if liquid-based cytology is used and enough residual material is available in the cytology test vial), or 4) scheduling a separate follow-up appointment when the Pap test report results are known. If the high-risk HPV DNA test is negative, a repeat Pap test should be performed at 12 months. If the test is positive, the patient should be referred immediately for colposcopy, and if indicated, directed cervical biopsy.

Because many public health clinics (including most STD clinics) cannot provide clinical follow-up of abnormal Pap tests, women with Pap tests demonstrating low- or high-grade SIL or ASC-US usually need a referral to other local health-care providers or clinics for colposcopy and biopsy. Clinics and health-care providers who offer cervical screening services but cannot provide appropriate colposcopic follow-up of abnormal Pap tests should arrange referral to health-care facilities that will promptly evaluate and treat patients and report evaluation results to the referring clinic or health-care provider. Clinics and health-care providers should develop protocols that identify women who miss follow-up appointments so that these women can be located and scheduled for needed studies and management, and they should reevaluate these protocols routinely. Pap-test results, type and location of follow-up appointments, and results of follow-up appointment should be clearly documented in the clinic record. The establishment of colposcopy and biopsy services in local health departments, especially in circumstances in which referrals are difficult and follow-up is unlikely, should be considered if resources are available.

Other Management Considerations

The following additional considerations are associated with performing Pap tests:

• The Pap test should not be considered a screening test for STDs.

• All women receiving care in an STD-clinic setting should be considered for cervical cancer screening, regardless of sexual orientation (i.e., heterosexual women and those who identify themselves as lesbian or bisexual).

• If a woman is menstruating, a conventional cytology Pap test should be postponed, and the woman should be advised to have a Pap test at the earliest opportunity.

• If specific infections other than HPV are identified, the patient might need to have a repeat Pap test after appropriate treatment for those infections. However, in most instances (even in the presence of some severe infections), Pap tests will be reported as satisfactory for evaluation, and reliable final reports can be produced without the need to repeat the Pap test after treatment is received.

• When it is necessary to repeat the Pap test because the report was interpreted as unsatisfactory, the repeat test must be determined by the laboratory to be satisfactory and negative before screening can be resumed at regularly scheduled intervals.

• The presence of a mucopurulent discharge should not delay the Pap test. The test can be performed after careful removal of the discharge with a saline-soaked cotton swab.

• In the absence of other indications, women who have external genital warts do not need Pap tests more frequently than women who do not have warts.

• The sequence of Pap testing in relation to collection of other cervicovaginal specimens has not been shown to influence Pap test results or their interpretation (432).

• Women who have had a total hysterectomy do not require a routine Pap test unless the hysterectomy was performed because of cervical cancer or its precursor lesions. As recommended by ACOG, for women with hysterectomy resulting from CIN 2 or higher, cervical or vaginal cuff screening can be discontinued once three normal Pap tests have been documented. In these situations, women should be advised to continue follow-up with the physician(s) who provided health care at the time of the hysterectomy, if possible. In women whose cervix remains intact after a hysterectomy, regularly scheduled Pap tests should be performed as indicated (433—435).

• Health-care providers who receive basic retraining on Pap-test collection and clinics that use simple quality assurance measures are more likely to obtain satisfactory test results as determined by the laboratory. The use of cytobrushes and brooms also improves the number of satisfactory Pap tests.

• Although evidence supports the option of HPV testing for the triage of women with ASC-US Pap test results, this option might not be feasible in an STD clinic because of limited resources.

• iquid-based cytology is an acceptable alternative to conventional Pap tests, as it has similar test-performance characteristics.

Special Considerations

Pregnancy

Pregnant women should be screened at the same frequency as nonpregnant women; however, recommendations for management differ in this population (83,84,424). A swab and an Ayre’s spatula can be used for obtaining Pap tests in pregnant women, but cytobrushes are not recommended.

HIV Infection

Several studies have documented an increased prevalence of SIL in HIV-infected women (416,436). The following recommendations for Pap test screening among HIV-infected women are consistent with most of the guidelines published by the U.S. Department of Health and Human Services (HHS) (129) and are based partially on the opinions of professionals knowledgeable about the care and management of cervical cancer and HIV infection in women.

HIV-positive women should be provided cervical cytology screening twice (every 6 months) within the first year after initial HIV diagnosis and, if both tests are normal, annual screening can be resumed thereafter. HIV-positive women with ASC-H, LSIL, or HSIL on cytologic screening should undergo colposcopic evaluation. Recommendations for management of HIV-positive women with ASC-US vary. HHS recommends a more conservative management approach (i.e., immediate colposcopy), whereas ASCCP recommends that these women be managed like HIV-negative women with ASC-US (i.e., tested for HR HPV DNA) (424,429).

Adolescents

Prevalence of HR HPV is high among adolescents aged <21 years (425). Infections in adolescent patients tend to clear rapidly, and lesions caused by these infections also have high rates of regression to normal. Therefore, ASCCP and ACOG recommend that adolescents with ASC-US or low-grade SIL be managed with repeat cytologic testing at 12 months and 24 months. Only those with HSIL at either follow-up visit or persistence of ASC-US or LSIL at 24 months should be referred for colposcopic evaluation.

Counseling Messages for Women Receiving Cervical Cancer Screening and HPV Testing

When a woman receives abnormal cervical cytology test results, she might experience considerable anxiety, distress, fear, and confusion, which can serve as barriers to follow-up care. Furthermore, a positive HPV DNA test result might exacerbate these feelings and might also elicit partner concerns, worry about disclosure, and feelings of guilt, anger, and stigmatization.

Health-care providers are the most trusted source of information about HPV and abnormal cervical cytology test results. Therefore, they have an important role to play in educating women about high-risk HPV and moderating the psychosocial impact of the diagnosis.

STD clinic providers should offer patients counseling and information both verbally and in print when delivering HPV and Pap test results. Print materials are available at several websites (http://www.cdc.gov/std/hpv/common/; http://www.ashastd.org/hpv/hpv_publications.cfm). The manner in which this information is communicated to patients can influence the psychological effect of this diagnosis, as well as a woman’s likelihood of following up with necessary testing or treatment. Providers should frame high-risk HPV in a neutral, nonstigmatizing context and emphasize its common, asymptomatic, and transient nature. Also, the provider should emphasize that HPV is often shared between partners and can lie dormant for many years; having HPV does not imply infidelity, nor should it necessarily raise concerns about a partner’s health.

In counseling women with high-risk HPV infections about partner management, messages should be tailored to the individual woman’s circumstances. While no evidence supports either partner notification (PN) or clinical-evaluation referral for partners of patients with high-risk HPV, some women might benefit from having an informed discussion about their diagnosis with their partners. This type of communication can foster partner support and ensure the sharing of information that can inform decision-making (e.g., decisions regarding condom use).

The following specific key messages should be communicated to patients receiving cervical screening:

• The purpose of regular, lifelong cervical cancer screening is to identify cervical cancer precursors, which can be treated before progression to cervical cancer.

• A positive high-risk HPV DNA test or an abnormal cervical cytology test is not indicative of cervical cancer. Appropriate follow-up is necessary to ensure that cervical abnormalities do not progress.

• Some women might have a normal Pap test and a positive high-risk HPV test. A positive high risk HPV DNA test indicates a HPV infection of the cervix, but does not indicate cervical cancer. A normal cervical cytology test indicates that no cellular abnormalities were detected at the time of testing, but women who have HPV infection of the cervix have a higher likelihood of developing cell changes, which could lead to cervical cancer over time. Follow-up evaluation is essential to monitor cervical cytology.

• A Pap test that reveals ASC-US indicates some abnormal areas on the cervix that may require close follow-up or treatment so that they do not progress. Additional testing might be required to confirm these results. It is essential that patients return for all follow-up appointments and recommended tests.

Discussion concerning disclosure of a positive high-risk HPV test to sex partners might be appropriate and can include the following information:

• HPV is very common. It can infect the genital areas of both men and women. It usually has no signs or symptoms.

• Most sexually active persons get HPV at some time in their lives, though most will never know it. Even persons with only one lifetime sex partner can get HPV if their partner was infected.

• While the immune system clears HPV infection most of the time, in some persons, HPV infection does not resolve.

• No clinically validated test exists for men to determine if they have HPV infection. The most common manifestation of HPV infection in men is genital warts. High-risk HPV types seldom cause genital warts.

• Partners who are in a long-term relationship tend to share HPV. Sexual partners of HPV-infected patients also likely have HPV, even though they might have no signs or symptoms of infection.

• Detection of high-risk HPV infection in a woman does not mean that the woman or her partner is engaging in sexual activity outside of a relationship. HPV infection can be present for many years before it is detected, and no method can accurately confirm when HPV infection was acquired.

Prevention measures for current and subsequent sex partners and risk reduction should be discussed. Providers should counsel women about condom use depending on their current circumstances. Consistent condom use by male partners of sexually active women can reduce the risk for cervical and vulvovaginal HPV infection (25), and condom use by couples in long-term partnerships might decrease the time required to clear HPV in the infected woman. Skin not covered by a condom remains vulnerable to HPV infection. HPV vaccines are available and recommended for girls and young women aged 9–26 years, even those who have been diagnosed with HPV infection. Male partners can be vaccinated with the quadrivalent vaccine (Gardasil) to prevent genital warts.

Vaccine-Preventable STDs

Several STDs can be effectively prevented through pre-exposure vaccination with widely available vaccines, including HAV, HBV, and HPV. Vaccines for other STDs (e.g., HIV and HSV) are under development or are undergoing clinical trials. This guidance focuses largely on integrating the use of available vaccines into STD prevention and treatment activities.

Every person being evaluated or treated for an STD should receive hepatitis B vaccination unless already vaccinated. In addition, some persons (e.g., MSM and IDUs) should receive hepatitis A vaccination.

Hepatitis A

Hepatitis A, caused by infection with HAV, has an incubation period of approximately 28 days (range: 15–50 days). HAV replicates in the liver and is shed in high concentrations in feces from 2 weeks before to 1 week after the onset of clinical illness. HAV infection produces a self-limited disease that does not result in chronic infection or chronic liver disease (CLD). However, 10%–15% of patients experience a relapse of symptoms during the 6 months after acute illness. Acute liver failure from hepatitis A is rare (overall case-fatality rate: 0.5%). The risk for symptomatic infection is directly related to age, with >80% of adults having symptoms compatible with acute viral hepatitis and most children having either asymptomatic or unrecognized infection. Antibody produced in response to HAV infection persists for life and confers protection against reinfection.

HAV infection is primarily transmitted by the fecal-oral route, by either person-to-person contact or through consumption of contaminated food or water. Although viremia occurs early in infection and can persist for several weeks after onset of symptoms, bloodborne transmission of HAV is uncommon. HAV occasionally is detected in saliva in experimentally infected animals, but transmission by saliva has not been demonstrated.

In the United States, almost half of all persons with hepatitis A report having no risk factor for the disease. Among adults with identified risk factors, most cases occur among international travelers, household or sexual contacts, nonhousehold contacts (e.g., those encountered through play and daycare), and IDUs (437). Because transmission of HAV during sexual activity probably results from fecal-oral contact, measures typically used to prevent the transmission of other STDs (e.g., use of condoms) do not prevent HAV transmission. In addition, efforts to promote good personal hygiene have not been successful in interrupting outbreaks of hepatitis A. Vaccination is the most effective means of preventing HAV transmission among persons at risk for infection (e.g., MSM, illegal drug users, and persons with CLD), many of whom might seek services in STD clinics.

Diagnosis

The diagnosis of hepatitis A cannot be made on clinical grounds alone; serologic testing also is required. The presence of IgM antibody to HAV is diagnostic of acute HAV infection. A positive test for total anti-HAV indicates immunity to HAV infection but does not differentiate current from previous HAV infection. Although usually not sensitive enough to detect the low level of protective antibody after vaccination, anti-HAV tests also might be positive after hepatitis A vaccination.

Treatment

Patients with acute hepatitis A usually require only supportive care, with no restrictions in diet or activity. Hospitalization might be necessary for patients who become dehydrated because of nausea and vomiting and is critical for patients with signs or symptoms of acute liver failure. Medications that might cause liver damage or are metabolized by the liver should be used with caution among persons with hepatitis A.

Prevention

Two products are available for the prevention of HAV infection: hepatitis A vaccine (Table 2) and immune globulin (IG) for IM administration. Hepatitis A vaccines are prepared from formalin-inactivated, cell-culture–derived HAV and have been available in the United States since 1995, initially for persons aged ≥2 years. In 2005, the vaccines were approved by FDA for persons aged ≥12 months, and the vaccine is available for eligible children and adolescents aged <19 years through the VFC program (telephone: 800-232-4636).

Administered IM in a 2-dose series at 0 and 6–12 months, these vaccines induce protective antibody levels in virtually all adults. By 1 month after the first dose, 94%–100% of adults have protective antibody levels; 100% of adults develop protective antibody after a second dose. In randomized controlled trials, the equivalent of 1 dose of hepatitis A vaccine administered before exposure has been 94%–100% effective in preventing clinical hepatitis A (2). Kinetic models of antibody decline indicate that protective levels of antibody persist for at least 20 years.

IG is a sterile solution of concentrated immunoglobulins prepared from pooled human plasma processed by cold ethanol fractionation. In the United States, IG is produced only from plasma that has tested negative for hepatitis B surface antigen, antibodies to HIV and HCV, and HCV RNA. In addition, the process used to manufacture IG inactivates viruses (e.g., HBV, HCV, and HIV). When administered IM before or within 2 weeks after exposure to HAV, IG is >85% effective in preventing HAV infections.

A combined hepatitis A and hepatitis B vaccine has been developed and licensed for use as a 3-dose series in adults aged ≥18 years (Table 3). When administered IM on a 0-, 1-, and 6-month schedule, the vaccine has equivalent immunogenicity to that of the monovalent vaccines.

Pre-exposure Vaccination

Persons in the following groups who are likely to be treated in STD clinic settings should be offered hepatitis A vaccine: 1) all MSM; 2) illegal drug users (of both injection and noninjection drugs); and 3) persons with CLD, including persons with chronic HBV and HCV infection who have evidence of CLD.

Prevaccination Serologic Testing for Susceptibility

Approximately one third of the U.S. population has serologic evidence of previous HAV infection, which increases with age and reaches 75% among persons aged >70 years. Screening for HAV infection might be cost-effective in populations where the prevalence of infection is likely to be high (e.g., persons aged >40 years and persons born in areas of high HAV endemicity). The potential cost-savings of testing should be weighed against the cost and the likelihood that testing will interfere with initiating vaccination. Vaccination of a person who is already immune is not harmful.

Postvaccination Serologic Testing

Postvaccination serologic testing is not indicated because most persons respond to the vaccine. In addition, the commercially available serologic test is not sensitive enough to detect the low, but protective, levels of antibody produced by vaccination.

Postexposure Prophylaxis

Persons who recently have been exposed to HAV and who previously have not received hepatitis A vaccine should be administered a single dose of single-antigen vaccine or IG (0.02 mL/kg) as soon as possible. Information about the relative efficacy of vaccine compared with IG postexposure is limited, and no data are available for persons aged >40 years or those with underlying medical conditions. Therefore, decisions to use vaccine or IG should take into account patient characteristics associated with more severe manifestations of hepatitis A, including older age and CLD.

For healthy persons aged 12 months to 40 years, single-antigen hepatitis A vaccine at the age-appropriate dose is preferred over IG because of vaccine advantages, including long-term protection and ease of administration. For persons aged >40 years, IG is preferred because of the absence of information regarding vaccine performance and the more severe manifestations of hepatitis A in this age group; vaccine can be used if IG cannot be obtained. The magnitude of the risk for HAV transmission from the exposure should be considered in decisions to use IG or vaccine. IG should be used for children aged <12 months, immunocompromised persons, persons who have had diagnosed CLD, and persons for whom vaccine is contraindicated.

If IG is administered to persons for whom hepatitis A vaccine also is recommended, a dose of vaccine should be provided simultaneously with IG. The second vaccine dose should be administered according to the licensed schedule to complete the series. The efficacy of IG or vaccine when administered >2 weeks after exposure has not been established (438).

Special Considerations

Limited data indicate that vaccination of persons with CLD and of persons with advanced HIV infection results in lower seroprotection rates and antibody concentrations (4). In HIV-infected persons, antibody response might be directly related to CD4+ levels.

Hepatitis B

Hepatitis B is caused by infection with the hepatitis B virus (HBV). The incubation period from the time of exposure to onset of symptoms is 6 weeks to 6 months. The highest concentrations of HBV are found in blood, with lower concentrations found in other body fluids including wound exudates, semen, vaginal secretions, and saliva (439,440). HBV is more infectious and relatively more stable in the environment than other bloodborne pathogens like HCV and HIV.

HBV infection can be self-limited or chronic. In adults, only approximately half of newly acquired HBV infections are symptomatic, and approximately 1% of reported cases result in acute liver failure and death. Risk for chronic infection is inversely related to age at acquisition; approximately 90% of infected infants and 30% of infected children aged <5 years become chronically infected, compared with 2%–6% of persons who become infected as adults. Among persons with chronic HBV infection, the risk for premature death from cirrhosis or hepatocellular carcinoma (HCC) is 15%–25%.

HBV is efficiently transmitted by percutaneous or mucous membrane exposure to blood or body fluids that contain blood. The primary risk factors associated with infection among adolescents and adults are unprotected sex with an infected partner, unprotected sex with more than one partner, MSM, history of other STDs, and illegal injection-drug use. In addition, several studies have demonstrated the horizontal transmission of HBV, including through premastication, as a less common source of transmission (441,442).

CDC’s national strategy to eliminate transmission of HBV infection includes 1) prevention of perinatal infection through routine screening of all pregnant women for HBsAg and immunoprophylaxis of infants born to HBsAg-positive mothers or mothers whose HBsAg status is unknown, 2) routine infant vaccination, 3) vaccination of previously unvaccinated children and adolescents through age 18 years, and 4) vaccination of previously unvaccinated adults at increased risk for infection (3,4). High vaccination coverage rates, with subsequent declines in acute hepatitis B incidence, have been achieved among infants and adolescents (4,437,443). In contrast, vaccination coverage among most high-risk adult groups (e.g., persons with more than one sex partner in the previous 6 months, MSM, and IDUs) has remained low, and most new infections occur in these high-risk groups (3,108,444—446). STD clinics and other settings that provide services to high-risk adults are ideal sites in which to provide hepatitis B vaccination to adults at risk for HBV infection. All unvaccinated adults seeking services in these settings should be assumed to be at risk for hepatitis B and should be offered hepatitis B vaccination.

Diagnosis

Diagnosis of acute or chronic HBV infection requires serologic testing (Table 4). Because HBsAg is present in both acute and chronic infection, the presence of IgM antibody to hepatitis B core antigen (IgM anti-HBc) is diagnostic of acute or recently acquired HBV infection. Antibody to HBsAg (anti-HBs) is produced after a resolved infection and is the only HBV antibody marker present after vaccination. The presence of HBsAg and total anti-HBc, with a negative test for IgM anti-HBc, indicates chronic HBV infection. The presence of anti-HBc alone might indicate a false-positive result or acute, resolved, or chronic infection.

Treatment

No specific therapy is available for persons with acute hepatitis B; treatment is supportive. Persons with chronic HBV infection should be referred for evaluation to a physician experienced in the management of CLD. Therapeutic agents cleared by FDA for treatment of chronic hepatitis B can achieve sustained suppression of HBV replication and remission of liver disease in some persons. In addition, patients with chronic hepatitis B might benefit from screening to detect HCC at an early stage.

Prevention

Two products have been approved for hepatitis B prevention: hepatitis B immune globulin (HBIG) and hepatitis B vaccine (3,4). HBIG provides temporary (i.e., 3–6 months) protection from HBV infection and is typically used as PEP either as an adjunct to hepatitis B vaccination in previously unvaccinated persons or alone in persons who have not responded to vaccination. HBIG is prepared from plasma known to contain high concentrations of anti-HBs. The recommended dose of HBIG is 0.06 mL/kg.

Hepatitis B vaccine contains HBsAg produced in yeast by recombinant DNA technology and provides protection from HBV infection when used for both pre-exposure vaccination and PEP. The two available monovalent hepatitis B vaccines for use in adolescents and adults are Recombivax HB (Merck and Co., Inc., Whitehouse Station, New Jersey) and Engerix-B (GlaxoSmithKline Biologicals, Pittsburgh, Pennsylvania). A combination vaccine (hepatitis A and hepatitis B) for use in adults, Twinrix (GlaxoSmithKline Biologicals, Pittsburgh, Pennsylvania), also is available. The recommended HBV dose varies by product and age of recipient (Table 3).

When selecting a hepatitis B vaccination schedule, the health-care provider should consider the need to achieve completion of the vaccine series. Approved adolescent and adult schedules for both monovalent hepatitis B vaccine (i.e., Engerix-B and Recombivax HB) include the following: 0, 1, and 6 months; 0, 1, and 4 months; and 0, 2, and 4 months. A 4-dose schedule of Engerix-B at 0, 1, 2, and 12 months is licensed for all age groups. A 2-dose schedule of Recombivax HB adult formulation (10 µg) is licensed for adolescents aged 11–15 years. When scheduled to receive the second dose, adolescents aged >15 years should be switched to a 3-dose series, with doses two and three consisting of the pediatric formulation (5 µg) administered on an appropriate schedule. Twinrix can be administered to persons aged ≥18 years at risk for both HAV and HBV infections at 0, 1, and 6 months.

Hepatitis B vaccine should be administered IM in the deltoid muscle and can be administered simultaneously with other vaccines. For adolescents and adults, the needle length should be 1–2 inches, depending on the recipient’s weight (1 inch for females weighing <70 kg, 1.5 inches for males weighing <120 kg, and 2 inches for males and females weighing >120 kg and >100 kg, respectively). A 22- to 25-gauge needle is recommended. If the vaccine series is interrupted after the first or second dose of vaccine, the missed dose should be administered as soon as possible. The series does not need to be restarted after a missed dose.

In adolescents and healthy adults aged <40 years, approximately 30%–55% acquire a protective antibody response (anti-HBs ≥10 mIU/mL) after the first vaccine dose, 75% after the second, and >90% after the third. Vaccine-induced immune memory has been demonstrated to persist for at least 15–20 years. Periodic testing to determine antibody levels after routine vaccination in immunocompetent persons is not necessary, and booster doses of vaccine are not currently recommended.

Hepatitis B vaccination is generally well-tolerated by most recipients. Pain at the injection site and low-grade fever are reported by a minority of recipients. For children and adolescents, a causal association exists between receipt of hepatitis B vaccination and anaphylaxis: for each 1.1 million doses of vaccine administered, approximately one vaccinee will experience this type of reaction. No deaths have been reported in these patients (3,4,447). Vaccine is contraindicated in persons with a history of anaphylaxis after a previous dose of hepatitis B vaccine and in persons with a known anaphylactic reaction to any vaccine component. No evidence for a causal association has been demonstrated for other adverse events after administration of hepatitis B vaccine.

Pre-exposure Vaccination

Hepatitis B vaccination is recommended for all unvaccinated adolescents, all unvaccinated adults at risk for HBV infection, and all adults seeking protection from HBV infection. For adults, acknowledgement of a specific risk factor is not a requirement for vaccination.

Hepatitis B vaccine should be routinely offered to all unvaccinated persons attending STD clinics and to all unvaccinated persons seeking treatment for STDs in other settings. Other settings where all unvaccinated adults should be assumed to be at risk for hepatitis B and should receive hepatitis B vaccination include correctional facilities, facilities providing drug abuse treatment and prevention services, health-care settings serving MSM, and HIV testing and treatment facilities. All persons who receive clinical services in these settings should be offered hepatitis B vaccine unless they have a reliable vaccination history (i.e., a written, dated record of each dose of a complete series). In all settings, vaccination should be initiated even when completion of the vaccine series cannot be ensured.

Prevaccination Antibody Screening

Prevaccination serologic testing for susceptibility might be considered to reduce the cost of vaccinating adult populations that have an expected high prevalence (20%–30%) of HBV infection (e.g., IDUs and MSM, especially those in older age groups). In addition, prevaccination testing for susceptibility is recommended for unvaccinated household, sexual, and needle-sharing contacts of HBsAg-positive persons (108).

Anti-HBc is the test of choice for prevaccination testing; persons who are anti-HBc–positive should be tested for HBsAg. If persons are determined to be HBsAg negative, no further action is required. If persons are determined to be HBsAg positive, the person should be referred for medical follow-up to include counseling and evaluation for antiviral treatment (see Management of HBsAg-Positive Persons). In addition, all household members, sex partners, and needle-sharing partners of HBsAg-positive persons should be vaccinated.

Serologic testing should not be a barrier to vaccination of susceptible persons, especially in populations that are difficult to access. In most cases, the first vaccine dose should be administered immediately after collection of the blood sample for serologic testing. Vaccination of persons who are immune to HBV infection because of current or previous infection or vaccination does not increase the risk for adverse events.

Postvaccination Testing for Serologic Response

Serologic testing for immunity is not necessary after routine vaccination of adolescents or adults. However, such testing is recommended for persons whose subsequent clinical management depends on knowledge of their immune status (e.g., health-care workers or public safety workers at high risk for continued percutaneous or mucosal exposure to blood or body fluids). In addition, postvaccination testing is recommended for 1) HIV-infected persons and other immunocompromised persons to determine the need for revaccination and the type of follow-up testing and 2) sex and needle-sharing partners of HBsAg-positive persons to determine the need for revaccination and for other methods to protect themselves from HBV infection.

If indicated, testing should be performed 1–2 months after administration of the last dose of the vaccine series by using a method that allows determination of a protective level of anti-HBs (i.e., ≥10 mIU/mL). Persons determined to have anti-HBs levels of <10 mIU/mL after the primary vaccine series should be revaccinated with a 3-dose series and provided with anti-HBs testing 1–2 months after the third dose. Persons who do not respond to revaccination should be tested for HBsAg. If HBsAg positive, the person should receive appropriate management (see Management of HBsAg-Positive Persons); if HBsAg negative, the person should be considered susceptible to HBV infection and counseled concerning precautions to prevent HBV infection and the need for HBIG PEP for any known exposure (see Postexposure Prophylaxis).

Postexposure Prophylaxis

Both passive-active PEP (the administration of HBIG and hepatitis B vaccine at separate sites) and active PEP (the administration of hepatitis B vaccination alone) have been demonstrated to be highly effective in preventing transmission after exposure to HBV (4). HBIG alone also has been demonstrated to be effective in preventing HBV transmission, but with the availability of hepatitis B vaccine, HBIG typically is used as an adjunct to vaccination.

Exposure to HBsAg-Positive Source

Unvaccinated persons or persons known not to have responded to a complete hepatitis B vaccine series should receive both HBIG and hepatitis vaccine as soon as possible (preferably ≤24 hours) after a discrete, identifiable exposure to blood or body fluids that contain blood from an HBsAg-positive source (Table 5). Hepatitis B vaccine should be administered simultaneously with HBIG at a separate injection site, and the vaccine series should be completed by using the age-appropriate vaccine dose and schedule (Table 3). Exposed persons who are in the process of being vaccinated but who have not completed the vaccine series should receive the appropriate dose of HBIG (i.e., 0.06 mL/kg) and should complete the vaccine series. Exposed persons who are known to have responded to vaccination are considered protected; therefore, they need no additional doses of vaccine. Persons who have written documentation of a complete hepatitis B vaccine series who did not receive postvaccination testing should receive a single vaccine booster dose. Alternatively, these persons can be managed according to guidelines for management of persons with occupational exposure to blood or body fluids that contain blood (446).

Exposure to Source with Unknown HBsAg Status

Unvaccinated persons who have a discrete, identifiable exposure to blood or body fluids containing blood from a source with unknown HBsAg status should receive the hepatitis B vaccine series, with the first dose initiated as soon as possible after exposure (preferably within 24 hours) and the series completed by using the age-appropriate dose and schedule. Exposed persons who are not fully vaccinated should complete the vaccine series. Exposed persons with written documentation of a complete hepatitis B vaccine series require no further treatment.

Special Considerations

Pregnancy

All pregnant women receiving STD services should be tested for HBsAg, regardless of whether they have been previously tested or vaccinated. All HBsAg-positive pregnant women should be reported to state and local perinatal hepatitis B prevention programs. HBsAg-negative pregnant women seeking STD treatment who have not been previously vaccinated should receive hepatitis B vaccination. Additional information regarding management of HBsAg-positive pregnant women and their infants is available at http://www.cdc.gov/mmwr/PDF/rr/rr5416.pdf .

HIV Infection

HIV infection can impair the response to hepatitis B vaccination. HIV-infected persons should be tested for anti-HBs 1–2 months after the third vaccine dose (see Postvaccination Testing for Serologic Response). Modified dosing regimens, including a doubling of the standard antigen dose and administration of additional doses, might increase the response rate (130).

Management of HBsAg-Positive Persons

This section provides recommendations for management of all HBsAg-positive persons. Additional recommendations for management of HBsAg-positive persons who are coinfected with HIV are available (130).

• All persons with HBsAg-positive laboratory results should be reported to the state or local health department.

• To verify the presence of chronic HBV infection, HBsAg-positive persons should be retested. The absence of IgM anti-HBc or the persistence of HBsAg for 6 months indicates chronic HBV infection.

• Persons with chronic HBV infection should be referred for evaluation to a physician experienced in the management of CLD. Some patients with chronic hepatitis B will benefit from early intervention with antiviral treatment or screening to detect HCC at an early stage.

• Household, sexual, and needle-sharing contacts of chronically infected persons should be identified. Unvaccinated sex partners and household and needle-sharing contacts should be tested for susceptibility to HBV infection (see Prevaccination Antibody Screening) and should receive the first dose of hepatitis B vaccine immediately after collection of the blood sample for serologic testing. Susceptible persons should complete the vaccine series by using an age-appropriate vaccine dose and schedule.

• Sex partners of HBsAg-positive persons should be counseled to use latex condoms (448) to protect themselves from sexual exposure to infectious body fluids (e.g., semen and vaginal secretions), unless they have been demonstrated to be immune after vaccination (anti-HBs ≥10 mIU/mL) or previously infected (anti-HBc positive).

• To prevent or reduce the risk for transmission to others, HBsAg-positive persons should be advised about the risk for transmission to household, sexual, and needle-sharing contacts and the need for such contacts to receive hepatitis B vaccination. HBsAg-positive persons also should be advised to:
  — use methods (e.g., condoms) to protect nonimmune sex partners from acquiring HBV infection from sexual activity until the partner can be vaccinated and immunity documented;
  — cover cuts and skin lesions to prevent spread by infectious secretions or blood;
  — refrain from donating blood, plasma, body organs, other tissue, or semen; an
  — refrain from sharing household articles (e.g., toothbrushes, razors, or personal injection equipment) that could become contaminated with blood. In addition, HBsAg-positive persons should refrain from premasticating food provided to susceptible persons.

• To protect the liver from further harm, HBsAg-positive persons should be advised to:
  — avoid or limit alcohol consumption because of the effects of alcohol on the liver;
  — refrain from starting any new medicines, including OTC and herbal medicines, without checking with their health-care provider; and
  — obtain vaccination against hepatitis A if liver disease is determined to be present.

When seeking medical or dental care, HBsAg-positive persons should be advised to inform their health-care providers of their HBsAg status so that they can be appropriately evaluated and managed. The following counseling messages should be considered for HBsAg-positive persons:

• HBV is not usually spread by hugging, coughing, food or water, sharing eating utensils or drinking glasses, or casual contact.

• Persons should not be excluded from work, school, play, child care, or other settings because they are infected with HBV.

• Involvement with a support group might help patients cope with chronic HBV infection.

Hepatitis C

Hepatitis C virus (HCV) infection is the most common chronic bloodborne infection in the United States; an estimated 3.2 million persons are chronically infected (449). Although HCV is not efficiently transmitted sexually, persons at risk for infection through injection-drug use might seek care in STD treatment facilities, HIV counseling and testing facilities, correctional facilities, drug treatment facilities, and other public health settings where STD and HIV prevention and control services are available.

Persons newly infected with HCV typically are either asymptomatic or have a mild clinical illness. HCV RNA can be detected in blood within 1–3 weeks after exposure. The average time from exposure to antibody to HCV (anti-HCV) seroconversion is 8–9 weeks, and anti-HCV can be detected in >97% of persons by 6 months after exposure. Chronic HCV infection develops in 70%–85% of HCV-infected persons; 60%–70% of chronically infected persons develop evidence of active liver disease. Most infected persons remain unaware of their infection because they are not clinically ill. However, infected persons serve as a source of transmission to others and are at risk for CLD and other HCV-related chronic diseases for decades after infection.

HCV is transmitted through parenteral exposures to contaminated blood, usually through use of injection drugs (sharing of needles or works) and to a lesser extent through exposures in health-care settings as a consequence of inadequate infection-control practices. Transmission rarely follows receipt of blood, tissues, and organs from HCV-infected donors who were not identified during routine screening activities, which have been mandated in the United States since 1992. Occupational and perinatal exposures, although less efficient, also can result in transmission of HCV.

Sexual transmission of HCV had been considered to occur rarely. However, recent data indicate that sexual transmission of HCV can occur, especially among HIV-infected persons. CDC surveillance data demonstrate that 10% of persons with acute HCV infection report contact with a known HCV-infected sex partner as their only risk for infection (437). Specific studies of HCV transmission between heterosexual or homosexual couples have yielded mixed results, but generally have found low but increased rates of HCV infection in partners of persons with HCV infection compared with those whose partners are not HCV-infected (450—455). Several studies have revealed that risk increases commensurate with increasing numbers of sex partners among heterosexual persons (450,451,456—458) and MSM (459—462), especially if those partners are coinfected with HIV (459—465).

Apparent sexual transmission of HCV has recently been reported among HIV-infected MSM in multiple European cities (464,465) and New York City (466). Common practices associated with these clusters of infection include serosorting (i.e., HIV-infected men having sex with one another), group sex, and the use of cocaine and other nonintravenous drugs during sex.

All persons with HIV infection should undergo serologic testing for HCV at initial evaluation (130,131). HIV-infected MSM can also acquire HCV after initial screening. Liver function tests should be serially monitored for abnormalities that could be caused by acute viral hepatitis or medication toxicity. HIV-infected persons with new and unexplained increases in ALT should be tested for acute HCV infection. To ensure the detection of acute HCV infection among HIV-infected MSM with high-risk sexual behaviors or concomitant ulcerative STDs, routine HCV testing of HIV-infected MSM should be considered. Acute hepatitis C is a reportable condition in 49 states, and matching viral hepatitis and HIV surveillance registries can facilitate early detection of social networks of HCV transmission among HIV-infected MSM. Suspected clusters of acute infection should be reported to the appropriate public health authorities. Unprotected sexual contact between HIV-infected partners can facilitate spread of HCV, as the virus can be recovered from the semen of men coinfected with HIV (467). Specific prevention practices (e.g., barrier precautions that limit contact with body fluids during sexual contact with other MSM) should be discussed with patients.

Diagnosis and Treatment

Anti-HCV testing is recommended for routine screening of asymptomatic persons based on their risk for infection or based on a recognized exposure (see Hepatitis C, Prevention). For such persons, testing for HCV infection should include the use of an FDA-cleared test for antibody to HCV (i.e., immunoassay, EIA, or enhanced chemiluminescence imunoassay and, if recommended, a supplemental antibody test) (468).

Persons counseled and tested for HCV infection and determined to be anti-HCV positive should be evaluated (by referral or consultation, if appropriate) for the presence of active infection, presence or development of CLD, and possible treatment. Nucleic acid testing, including reverse transcriptase polymerase chain reaction (RT-PCR) to detect HCV RNA, is necessary to confirm the diagnosis of current HCV infection, and an elevated ALT level is biochemical evidence of CLD. Combination therapy with pegylated interferon and ribavirin is the treatment of choice for patients with chronic hepatitis C. Providers should consult with specialists knowledgeable about management of hepatitis C infection because these experts remain cognizant of the latest advances in the field of antiviral therapy for acute and chronic hepatitis C.

Prevention

No vaccine for hepatitis C is available, and prophylaxis with immune globulin is not effective in preventing HCV infection after exposure. Reducing the burden of HCV infection and disease in the United States requires implementation of both primary and secondary prevention activities. Primary prevention reduces or eliminates HCV transmission, whereas secondary prevention activities are aimed at reducing CLD and other chronic diseases in HCV-infected persons by first identifying them and then providing medical management and antiviral therapy, if appropriate.

Most scientific evidence demonstrates that although HCV can be transmitted sexually, such transmission happens rarely. Because incident HCV has not been demonstrated to occur in heterosexual partner-pairs followed over time (452—454), condom use might not be necessary in such circumstances. However, heterosexual and homosexual persons, especially those with concurrent HIV infection or with more than one partner, should protect themselves and their partners against transmission of HCV, HBV, HIV, and other pathogens by use of male latex condoms. Condom use is especially important for HIV-infected men, who might spread HCV to other men though unprotected sexual activity (464—466).

Providers in STD clinics and other primary-care settings should identify those persons who should be offered HCV counseling and testing. In STD clinics and other settings that serve large numbers of persons at high risk for bloodborne infections (e.g., correctional settings), the major risk factor necessitating screening for HCV infection is past or current injection of illegal drugs. Because both HCV and HIV are transmitted through injection-drug use, about one fourth of all HIV patients are also coinfected with HCV. For this reason, all persons with HIV infection should be offered HCV counseling and testing. Other risk factors for which routine HCV testing is recommended include:

• having had a blood transfusion or solid organ transplant before July 1992;

• having received clotting factor concentrates produced before 1987;

• having been on long-term dialysis; and

• having signs and symptoms of liver disease (e.g., abnormal ALT).

Persons who test negative for anti-HCV who had an exposure previously should be reassured that they are not infected. Those who test positive for anti-HCV (see Diagnosis and Treatment) should be provided information regarding how to protect their liver from further harm; for instance, HCV-positive persons should be advised to avoid drinking alcohol and taking any new medicines (including OTC and herbals) without checking with their clinician.

To reduce the risk for transmission to others, HCV-positive persons should be advised to 1) not donate blood, body organs, other tissue, or semen; 2) not share any personal items that might have blood on them (e.g., toothbrushes and razors); and 3) cover cuts and sores on the skin to keep the virus from spreading by blood or secretions. HCV-positive persons with one long-term, steady sex partner do not need to change their sexual practices. They should discuss the low but present risk for transmission with their partner and discuss the need for counseling and testing. HCV-positive women do not need to avoid pregnancy or breastfeeding.

HCV-positive persons should be evaluated (by referral or consultation, if appropriate) to detect active HCV infection and the presence of CLD. Evaluation should involve testing for liver function, additional assessment of the severity of liver disease, possible treatment, and the determination for the need of hepatitis A and B vaccination.

Regardless of test results, persons who use or inject illegal drugs should be counseled to stop using and injecting drugs and to enter and complete substance abuse treatment (including relapse prevention). Persons who continue to inject drugs despite counseling should be encouraged to take the following steps to reduce personal and public health risks:

• never reuse or share syringes, water, or drug preparation equipment;

• only use syringes obtained from a reliable source (e.g., pharmacies);

• use a new, sterile syringe to prepare and inject drugs;

• if possible, use sterile water to prepare drugs; otherwise, use clean water from a reliable source (e.g., fresh tap water);

• use a new or disinfected container (i.e., cooker) and a new filter (i.e., cotton) to prepare drugs;

• clean the injection site before injection with a new alcohol swab;

• safely dispose of syringes after one use;

• get vaccinated for hepatitis A and B if nonimmune; and

• get tested for HIV infection.

Postexposure Follow-Up

No PEP has been demonstrated to be effective against HCV. Testing to determine whether HCV infection has developed is recommended for health-care workers after percutaneous or permucosal exposures to HCV-positive blood. Children born to HCV-positive women also should be tested for HCV. Prompt identification of acute infection is important, because outcomes are improved when treatment is initiated earlier in the course of illness.

Special Considerations

Pregnancy

Routine testing for HCV infection is not recommended for all pregnant women. Pregnant women with a known risk factor for HCV infection should be offered counseling and testing. Patients should be advised that approximately six of every 100 infants born to HCV-infected woman become infected; this infection occurs predominantly during or near delivery, and no treatment or delivery method—such as caesarian section—has been demonstrated to decrease this risk. The risk is increased, however, by the presence of maternal HCV viremia at delivery and also is greater (2–3 times) if the woman is coinfected with HIV. HCV has not been shown to be transmitted through breast milk, although HCV-positive mothers should consider abstaining from breastfeeding if their nipples are cracked or bleeding. Infants born to HCV-positive mothers should be tested for HCV infection and, if positive, evaluated for the presence of CLD.

HIV Infection

Because of the high prevalence of HIV/HCV coinfection and because of critical clinical management issues for coinfected persons, all persons with HIV infection should undergo serologic testing for HCV. Providers should be aware of the likelihood that HIV-infected MSM will acquire HCV after initial screening. Liver function tests should be serially monitored, and those persons with new and unexplained increases in ALT should be tested for acute HCV infection. To detect acute HCV infection among HIV-infected MSM with high-risk sexual behaviors or concomitant ulcerative STDs, routine HCV testing of HIV-infected MSM should be considered. Because a small percentage of coinfected persons fail to acquire HCV antibodies, HCV RNA should be tested in HIV-positive persons with unexplained liver disease who are anti-HCV negative. The course of liver disease is more rapid in HIV/HCV coinfected persons, and the risk for cirrhosis is nearly twice that of persons with HCV infection alone. Coinfected persons receiving HIV antiviral regimens are now being treated for HCV after their CD4+ cell counts increase, optimizing their immune response.

Proctitis, Proctocolitis, and Enteritis

Sexually transmitted gastrointestinal syndromes include proctitis, proctocolitis, and enteritis. Evaluation for these syndromes should include appropriate diagnostic procedures (e.g., anoscopy or sigmoidoscopy, stool examination, and culture).

Proctitis is inflammation of the rectum (i.e., the distal 10–12 cm) that can be associated with anorectal pain, tenesmus, or rectal discharge. N. gonorrhoeae, C. trachomatis (including LGV serovars), T. pallidum, and HSV are the most common sexually transmitted pathogens involved. In patients coinfected with HIV, herpes proctitis can be especially severe. Proctitis occurs predominantly among persons who participate in receptive anal intercourse.

Proctocolitis is associated with symptoms of proctitis, diarrhea or abdominal cramps, and inflammation of the colonic mucosa extending to 12 cm above the anus. Fecal leukocytes might be detected on stool examination, depending on the pathogen. Pathogenic organisms include Campylobacter sp., Shigella sp., Entamoeba histolytica, and LGV serovars of C. trachomatis. CMV or other opportunistic agents can be involved in immunosuppressed HIV-infected patients. Proctocolitis can be acquired by the oral route or by oral-anal contact, depending on the pathogen.

Enteritis usually results in diarrhea and abdominal cramping without signs of proctitis or proctocolitis; it occurs among persons whose sexual practices include oral-anal contact. In otherwise healthy persons, Giardia lamblia is most frequently implicated. When outbreaks of gastrointestinal illness occur among social or sexual networks of MSM, clinicians should consider sexual transmission as a mode of spread and provide counseling accordingly. Among HIV-infected patients, gastrointestinal illness can be caused by other infections that usually are not sexually transmitted, including CMV, Mycobacterium avium—intracellulare, Salmonella sp., Campylobacter sp., Shigella sp., Cryptosporidium, Microsporidium, and Isospora. Multiple stool examinations might be necessary to detect Giardia, and special stool preparations are required to diagnose cryptosporidiosis and microsporidiosis. In addition, enteritis can be directly caused by HIV infection.

When laboratory diagnostic capabilities are available, treatment decisions should be based on the specific diagnosis. Diagnostic and treatment recommendations for all enteric infections are beyond the scope of these guidelines.

Treatment for Proctitis

Acute proctitis of recent onset among persons who have recently practiced receptive anal intercourse is usually sexually acquired (469,470). Such patients should be examined by anoscopy and should be evaluated for infection with HSV, N. gonorrhoeae, C. trachomatis, and T. pallidum. If an anorectal exudate is detected on examination or if polymorphonuclear leukocytes are detected on a Gram-stained smear of anorectal secretions, the following therapy should be prescribed while awaiting additional laboratory tests.

Recommended Regimen

Ceftriaxone 250 mg IM PLUS Doxycycline 100 mg orally twice a day for 7 days

Patients with suspected or documented herpes proctitis should be managed in the same manner as those with genital herpes (see Genital HSV Infections). If painful perianal ulcers are present or mucosal ulcers are detected on anoscopy, presumptive therapy should include a regimen for genital herpes and LGV. Appropriate diagnostic testing for LGV should be conducted in accordance with state or federal guidelines, and doxycycline therapy should be administered 100 mg orally twice daily for 3 weeks.

For MSM, treatment for LGV proctitis/proctocolitis with 3 weeks of doxycycline in those with anorectal chlamydia and either 1) proctitis (as detected by proctoscopic examination and the presence of >10 white-blood cells upon high-power field examination of an anorectal smear specimen) or 2) HIV infection can be considered.

Follow-Up

Follow-up should be based on specific etiology and severity of clinical symptoms. Reinfection might be difficult to distinguish from treatment failure.

Management of Sex Partners

Partners of persons with sexually transmitted enteric infections should be evaluated for any diseases diagnosed in the index patient.

Ectoparasitic Infections

Pediculosis Pubis

Persons who have pediculosis pubis (i.e., pubic lice) usually seek medical attention because of pruritus or because they notice lice or nits on their pubic hair. Pediculosis pubis is usually transmitted by sexual contact.

Recommended Regimens

Permethrin 1% cream rinse applied to affected areas and washed off after 10 minutes OR Pyrethrins with piperonyl butoxide applied to the affected area and washed off after 10 minutes

Alternative Regimens

Malathion 0.5% lotion applied for 8–12 hours and washed off OR Ivermectin 250 µg/kg orally, repeated in 2 weeks

Reported resistance to pediculicides has been increasing and is widespread (471—473). Malathion can be used when treatment failure is believed to have resulted from drug resistance. The odor and long duration of application for malathion make it a less attractive alternative than the recommended pediculcides. Ivermectin has been successfully used to treat lice, but it has only been evaluated in studies involving a limited number of participants.

Other Management Considerations

The recommended regimens should not be applied to the eyes. Pediculosis of the eyelashes should be treated by applying occlusive ophthalmic ointment to the eyelid margins twice a day for 10 days. Bedding and clothing should be decontaminated (i.e., either dry cleaned or machine-washed and dried using the heat cycle) or removed from body contact for at least 72 hours. Fumigation of living areas is not necessary.

Patients with pediculosis pubis should be evaluated for other STDs.

Follow-Up

Patients should be evaluated after 1 week if symptoms persist. Retreatment might be necessary if lice are found or if eggs are observed at the hair-skin junction. Patients who do not respond to one of the recommended regimens should be retreated with an alternative regimen.

Management of Sex Partners

Sex partners that have had sexual contact with the patient within the previous month should be treated. Patients should abstain from sexual contact with their sex partner(s) until patients and partners have been treated and reevaluated to rule out persistent disease.

Special Considerations

Pregnancy

Pregnant and lactating women should be treated with either permethrin or pyrethrins with piperonyl butoxide; lindane and ivermectin are contraindicated in pregnancy and lactating women.

HIV Infection

Patients who have pediculosis pubis and also are infected with HIV should receive the same treatment regimen as those who are HIV negative.

Scabies

The predominant symptom of scabies is pruritus, but sensitization to Sarcoptes scabiei occurs before pruritus begins. The first time a person is infested with S. scabiei, sensitization can take several weeks to develop. However, pruritus might occur within 24 hours after a subsequent reinfestation. Scabies in adults frequently is sexually acquired, although scabies in children usually is not.

Recommended Regimens

Permethrin cream (5%) applied to all areas of the body from the neck down and washed off after 8–14 hours OR Ivermectin 200ug/kg orally, repeated in 2 weeks

Alternative Regimen

Lindane (1%) 1 oz. of lotion (or 30 g of cream) applied in a thin layer to all areas of the body from the neck down and thoroughly washed off after 8 hours

Lindane is not recommended as first-line therapy because of toxicity (471). It should only be used as an alternative if the patient cannot tolerate other therapies or if other therapies have failed.

Lindane should not be used immediately after a bath or shower, and it should not be used by persons who have extensive dermatitis, women who are pregnant or lactating, or children aged <2 years. Lindane resistance has been reported in some areas of the world, including parts of the United States (474). Seizures have occurred when lindane was applied after a bath or used by patients who had extensive dermatitis. Aplastic anemia after lindane use also has been reported (471, 474).

Permethrin is effective and safe and less expensive than ivermectin (471, 474). One study demonstrated increased mortality among elderly, debilitated persons who received ivermectin, but this observation has not been confirmed in subsequent studies (475).

Other Management Considerations

Bedding and clothing should be decontaminated (i.e., either dry cleaned or machine-washed and dried using the hot cycle) or removed from body contact for at least 72 hours. Fumigation of living areas is unnecessary.

Crusted Scabies

Crusted scabies (i.e., Norwegian scabies) is an aggressive infestation that usually occurs in immunodeficient, debilitated, or malnourished persons (476). Patients who are receiving systemic or potent topical glucocorticoids, organ transplant recipients, mentally retarded or physically incapacitated persons, HIV-infected or human T-lymphotrophic virus-1-infected persons, and persons with various hematologic malignancies are at risk for developing crusted scabies. Crusted scabies is associated with greater transmissibility than scabies. No controlled therapeutic studies for crusted scabies have been conducted, and the appropriate treatment remains unclear. Substantial risk for treatment failure might exist with a single topical scabicide or with oral ivermectin treatment. Combined treatment with a topical scabicide and repeated treatment with oral ivermectin 200 µg/kg on days 1, 2, 8, 9, and 15 are suggested. Additional treatment on days 22 and 29 might be required for severe cases. Ivermectin should be combined with the application of either 5% topical benzyl benzoate or 5% topical permethrin (full body application to be repeated daily for 7 days then 2 times weekly until release from care or cure). Lindane should be avoided because of the risks for neurotoxicity associated with both heavy applications and denuded skin. Fingernails should be closely trimmed to reduce injury from excessive scratching.

Follow-Up

Patients should be informed that the rash and pruritus of scabies might persist for up to 2 weeks after treatment. Symptoms or signs that persist for >2 weeks can be attributed to several factors. Treatment failure can be caused by resistance to medication, although faulty application of topical scabicides also can contribute to persistence — patients with crusted scabies might have poor penetration into thick scaly skin and harbor mites in these difficult-to-penetrate layers. Particular attention must be given to the fingernails of these patients. Reinfection from family members or fomites can occur in the absence of appropriate contact treatment and washing of bedding and clothing. Even when treatment is successful and reinfection is avoided, symptoms can persist or worsen as a result of allergic dermatitis. Finally, the presence of household mites can cause symptoms to persist as a result of cross reactivity between antigens. Retreatment can be considered after 1–2 weeks for patients who are still symptomatic or if live mites are present. Treatment with an alternative regimen is recommended for persons who do not respond to the recommended treatment.

Management of Sex Partners and Household Contacts

Sexual contacts and those that have had close personal or household contact with the patient within the preceding month should be examined and treated.

Management of Outbreaks in Communities, Nursing Homes, and Other Institutional Settings

Scabies outbreaks frequently occur in nursing homes, hospitals, residential facilities, and other communities. Control of an epidemic can only be achieved by treatment of the entire population at risk. Ivermectin can be considered in this setting, especially if treatment with topical scabicides fails. Epidemics should be managed in consultation with an infectious disease specialist.

Special Considerations

Infants, Young Children, and Pregnant or Lactating Women

Infants, young children, and pregnant or lactating women should not be treated with lindane; however, they can be treated with permethrin. Ivermectin is not recommended for pregnant or lactating patients, and the safety of ivermectin in children who weigh <15 kg has not been determined.

HIV Infection

Patients who have uncomplicated scabies and also are infected with HIV should receive the same treatment regimens as those who are HIV negative. HIV-infected patients and others who are immunosuppressed are at increased risk for crusted scabies, for which ivermectin has been reported to be effective in noncontrolled studies involving only a limited number of participants. HIV-infected patients with crusted scabies should be managed in consultation with an infectious disease specialist.

Sexual Assault and STDs

Adults and Adolescents

The recommendations in this report are limited to the identification, prophylaxis, and treatment of STDs and conditions commonly identified in the management of such infections. The documentation of findings, collection of nonmicrobiologic specimens for forensic purposes, and management of potential pregnancy or physical and psychological trauma are beyond the scope of this report.

Examinations of survivors of sexual assault should be conducted by an experienced clinician in a way that minimizes further trauma to the survivor. The decision to obtain genital or other specimens for STD diagnosis should be made on an individual basis. Care systems for survivors should be designed to ensure continuity (including timely review of test results), support adherence, and monitor for adverse reactions to any therapeutic or prophylactic regimens prescribed at initial examination. Laws in all 50 states strictly limit the evidentiary use of a survivor’s previous sexual history, including evidence of previously acquired STDs, as part of an effort to undermine the credibility of the survivor’s testimony. Evidentiary privilege against revealing any aspect of the examination or treatment also is enforced in most states. Although it rarely occurs, STD diagnoses might later be accessed, and the survivor and clinician might opt to defer testing for this reason. While collection of specimens at initial examination for laboratory STD diagnosis gives the survivor and clinician the option to defer empiric prophylactic antimicrobial treatment, compliance with follow up visits is traditionally poor (477,478). Among sexually active adults, the identification of an STD might represent an infection acquired prior to the assault, and therefore might be more important for the psychological and medical management of the patient than for legal purposes.

Trichomoniasis, BV, gonorrhea, and chlamydial infection are the most frequently diagnosed infections among women who have been sexually assaulted. Such conditions are relatively prevalent, and the presence after an assault does not necessarily imply acquisition during the assault. However, a postassault examination presents an important opportunity to identify or prevent STDs. Chlamydial and gonococcal infections in women are of particular concern because of the possibility of ascending infection. In addition, HBV infection can be prevented by postexposure administration of hepatitis B vaccine. Reproductive-aged female survivors should be evaluated for pregnancy, if appropriate.

Evaluating Adults and Adolescents for Sexually Transmitted Diseases

Initial Examination

An initial examination might include the following procedures:

• NAATs for C. trachomatis and N. gonorrhoeae. These tests are preferred for the diagnostic evaluation of sexual assault victims, regardless of the sites of penetration or attempted penetration (197).

• Wet mount and culture or point-of-care testing of a vaginal-swab specimen for T. vaginalis infection. The wet mount also should be examined for evidence of BV and candidiasis, especially if vaginal discharge, malodor, or itching is evident.

• A serum sample for immediate evaluation for HIV infection, hepatitis B, and syphilis. Decisions to perform these tests should be made on an individual basis.

Follow-Up Examinations

After the initial postassault examination, follow-up examinations provide an opportunity to 1) detect new infections acquired during or after the assault; 2) complete hepatitis B vaccination, if indicated; 3) complete counseling and treatment for other STDs; and 4) monitor side effects and adherence to postexposure prophylactic medication, if prescribed.

Examination for STDs can be repeated within 1–2 weeks of the assault. Because infectious agents acquired through assault might not have produced sufficient concentrations of organisms to result in positive test results at the initial examination, testing can be repeated during the follow-up visit, unless prophylactic treatment was provided. If treatment was provided, testing should be conducted only if the survivor reports having symptoms. If treatment was not provided, follow-up examination should be conducted within 1 week to ensure that results of positive tests can be discussed promptly with the survivor and that treatment is provided. Serologic tests for syphilis and HIV infection can be repeated 6 weeks, 3 months, and 6 months after the assault if initial test results were negative and infection in the assailant could not be ruled out (see Sexual Assault and STDs, Risk for Acquiring HIV Infection).

Prophylaxis

Compliance with follow-up visits is poor among survivors of sexual assault (477,478). As a result, routine preventive therapy after a sexual assault should be encouraged. The following prophylactic regimen is suggested as preventive therapy:

• Postexposure hepatitis B vaccination, without HBIG. This vaccine should be administered to sexual assault survivors at the time of the initial examination if they have not been previously vaccinated. Follow-up doses of vaccine should be administered 1–2 and 4–6 months after the first dose.

• An empiric antimicrobial regimen for chlamydia, gonorrhea, and trichomonas.

• Emergency contraception. (This measure is necessary only when the assault could result in pregnancy in the survivor.)

Recommended Regimens

Ceftriaxone 250 mg IM in a single dose OR Cefixime 400 mg orally in a single dose PLUS Metronidazole 2 g orally in a single dose PLUS Azithromycin 1 g orally in a single dose OR Doxycycline 100 mg orally twice a day for 7 days

For those requiring alternative treatments, refer to the specific sections in this report relevant to the specific agent. The efficacy of these regimens in preventing infections after sexual assault has not been evaluated. Clinicians should counsel patients regarding the possible benefits and toxicities associated with these treatment regimens; gastrointestinal side effects can occur with this combination.

Other Management Considerations

At the initial examination and, if indicated, at follow-up examinations, patients should be counseled regarding 1) symptoms of STDs and the need for immediate examination if symptoms occur and 2) abstinence from sexual intercourse until STD prophylactic treatment is completed.

Risk for Acquiring HIV Infection

HIV seroconversion has occurred in persons whose only known risk factor was sexual assault or sexual abuse, but the frequency of this occurrence is probably low. In consensual sex, the risk for HIV transmission from vaginal intercourse is 0.1%–0.2% and for receptive rectal intercourse, 0.5%–3% (479). The risk for HIV transmission from oral sex is substantially lower. Specific circumstances of an assault (e.g., bleeding, which often accompanies trauma) might increase risk for HIV transmission in cases involving vaginal, anal, or oral penetration. Site of exposure to ejaculate, viral load in ejaculate, and the presence of an STD or genital lesions in the assailant or survivor also might increase the risk for HIV.

Children might be at higher risk for transmission, because the sexual abuse of children is frequently associated with multiple episodes of assault and might result in mucosal trauma (see Sexual Assault or Abuse of Children).

Postexposure therapy with zidovudine was associated with a reduced risk for acquiring HIV in a study of health-care workers who had percutaneous exposures to HIV-infected blood (480). On the basis of these results and the results of animal studies, PEP has been recommended for health-care workers who have occupational exposures to HIV (446). These findings have been extrapolated to other types of HIV exposure, including sexual assault (78). If HIV exposure has occurred, initiation of PEP as soon as possible after the exposure likely increases benefit. Although a definitive statement of benefit cannot be made regarding PEP after sexual assault, the possibility of HIV exposure from the assault should be assessed at the time of the postassault examination. The possible benefit of PEP in preventing HIV infection also should be discussed with the assault survivor if the assault poses a risk for HIV exposure.

Several factors impact the medical recommendation for PEP and affect the assault survivor’s acceptance of that recommendation, including 1) the likelihood of the assailant having HIV, 2) any exposure characteristics that might increase the risk for HIV transmission, 3) the time elapsed after the event, and 4) the potential benefits and risks associated with the PEP (78). Determination of the assailant’s HIV status at the time of the assault examination usually in not possible. Therefore, the health-care provider should assess any available information concerning 1) characteristics and HIV risk behaviors of the assailant(s) (e.g., a man who has sex with other men and persons who use injection drugs or crack cocaine), 2) local epidemiology of HIV/AIDS, and 3) exposure characteristics of the assault. When an assailant’s HIV status is unknown, factors that should be considered in determining whether an increased risk for HIV transmission exists include 1) whether vaginal or anal penetration occurred; 2) whether ejaculation occurred on mucous membranes; 3) whether multiple assailants were involved; 4) whether mucosal lesions are present in the assailant or survivor; and 5) any other characteristics of the assault, survivor, or assailant that might increase risk for HIV transmission.

If PEP is offered, the following information should be discussed with the patient: 1) the unproven benefit and known toxicities of antiretrovirals; 2) the importance of close follow-up; 3) the benefit of adherence to recommended dosing; and 4) the necessity of early initiation of PEP to optimize potential benefits (i.e., as soon as possible after and up to 72 hours after the assault). Providers should emphasize that PEP appears to be well-tolerated in both adults and children and that severe adverse effects are rare (481—483). Clinical management of the survivor should be implemented according to the following guidelines (78). Specialist consultation on PEP regimens is recommended if HIV exposure during the assault was possible and if PEP is being considered. The sooner PEP is initiated after the exposure, the higher the likelihood that it will prevent HIV transmission if HIV exposure occurred; however, distress after an assault also might prevent the survivor from accurately weighing exposure risks and benefits of PEP and from making an informed decision to start such therapy. If use of PEP is judged to be warranted, the survivor should be offered a 3–5-day supply of PEP, and a follow-up visit should be scheduled several days later to allow for additional counseling.

Recommendations for Postexposure Assessment of Adolescent and Adult Survivors Within 72 Hours of Sexual Assault§§

• Assess risk for HIV infection in the assailant.

• Evaluate characteristics of the assault event that might increase risk for HIV transmission.

• Consult with a specialist in HIV treatment, if PEP is being considered.

• If the survivor appears to be at risk for HIV transmission from the assault, discuss antiretroviral prophylaxis, including toxicity and lack of proven benefit.

• If the survivor chooses to start antiretroviral PEP (78), provide enough medication to last until the next return visit; reevaluate the survivor 3–7 days after initial assessment and assess tolerance of medications.

• If PEP is started, perform CBC and serum chemistry at baseline (initiation of PEP should not be delayed, pending results).

• Perform HIV antibody test at original assessment; repeat at 6 weeks, 3 months, and 6 months.

Sexual Assault or Abuse of Children

Recommendations in this report are limited to the identification and treatment of STDs. Management of the psychosocial aspects of the sexual assault or abuse of children is beyond the scope of these recommendations.

The identification of sexually transmissible agents in children beyond the neonatal period suggests sexual abuse. The significance of the identification of a sexually transmitted agent in such children as evidence of possible child sexual abuse varies by pathogen. Postnatally acquired gonorrhea; syphilis; and nontransfusion, nonperinatally acquired HIV are usually diagnostic of sexual abuse. Sexual abuse should be suspected when genital herpes is diagnosed. The investigation of sexual abuse among children who have an infection that could have been transmitted sexually should be conducted in compliance with recommendations by clinicians who have experience and training in all elements of the evaluation of child abuse, neglect, and assault. The social significance of an infection that might have been acquired sexually and the recommended action regarding reporting of suspected child sexual abuse varies by the specific organism, as do the recommendations regarding reporting of suspected child sexual abuse (Table 6). In all cases in which an STD has been diagnosed in a child, efforts should be made to detect evidence of sexual abuse, including conducting diagnostic testing for other commonly occurring STDs (484—486).

The general rule that sexually transmissible infections beyond the neonatal period are evidence of sexual abuse has exceptions. For example, rectal or genital infection with C. trachomatis among young children might be the result of perinatally acquired infection and has, in some cases, persisted for as long as 2–3 years. Genital warts have been diagnosed in children who have been sexually abused, but also in children who have no other evidence of sexual abuse (487,488). BV has been diagnosed in children who have been abused, but its presence alone does not prove sexual abuse. In addition, most HBV infections in children result from household exposure to persons who have chronic HBV infection.

The possibility of sexual abuse should be strongly considered if no conclusive explanation for nonsexual transmission of an STD can be identified.

Reporting

All U.S. states and territories have laws that require the reporting of child abuse. Although the exact requirements differ by state, if a health-care provider has reasonable cause to suspect child abuse, a report must be made. Health-care providers should contact their state or local child-protection service agency regarding child-abuse reporting requirements in their states.

Evaluating Children for Sexually Transmitted Diseases

Examinations of children for sexual assault or abuse should be conducted in a manner designed to minimize pain and trauma to the child. Collection of vaginal specimens in prepubertal children can be very uncomfortable and should be performed by an experienced clinician to avoid psychological and physical trauma to the child. The decision to obtain genital or other specimens from a child to conduct an STD evaluation must be made on an individual basis. The following situations place children at high-risk for STDs and constitute a strong indication for testing.

• The child has or has had symptoms or signs of an STD or of an infection that can be sexually transmitted, even in the absence of suspicion of sexual abuse. Among the signs that are associated with a confirmed STD diagnosis are vaginal discharge or pain, genital itching or odor, urinary symptoms, and genital ulcers or lesions.

• A suspected assailant is known to have an STD or to be at high risk for STDs (e.g., has multiple sex partners or a history of STDs).

• A sibling or another child or adult in the household or child’s immediate environment has an STD.

• The patient or parent requests testing.

• Evidence of genital, oral, or anal penetration or ejaculation is present.

If a child has symptoms, signs, or evidence of an infection that might be sexually transmitted, the child should be tested for other common STDs before the initiation of any treatment that could interfere with the diagnosis of those other STDs. Because of the legal and psychosocial consequences of a false-positive diagnosis, only tests with high specificities should be used. The potential benefit to the child of a reliable diagnosis of an STD justifies deferring presumptive treatment until specimens for highly specific tests are obtained by providers with experience in the evaluation of sexually abused and assaulted children.

The scheduling of an examination should depend on the history of assault or abuse. If the initial exposure was recent, the infectious agents acquired through the exposure might not have produced sufficient concentrations of organisms to result in positive test results. A follow-up visit approximately 2 weeks after the most recent sexual exposure can include a repeat physical examination and collection of additional specimens. To allow sufficient time for antibodies to develop, another follow-up visit approximately 12 weeks after the most recent sexual exposure might be necessary to collect sera. A single examination might be sufficient if the child was abused for an extended period and if a substantial amount of time elapsed between the last suspected episode of abuse and the medical evaluation.

The following recommendations for scheduling examinations serve as a general guide. The exact timing and nature of follow-up examinations should be determined on an individual basis and should be performed to minimize the possibility for psychological trauma and social stigma. Compliance with follow-up appointments might be improved when law enforcement personnel or child protective services are involved.

Initial and 2-Week Follow-Up Examinations

During the initial examination and 2-week follow-up examination (if indicated), the following should be performed.

• Visual inspection of the genital, perianal, and oral areas for genital discharge, odor, bleeding, irritation, warts, and ulcerative lesions. The clinical manifestations of some STDs are different in children than in adults. For example, typical vesicular lesions might not be present in the presence of HSV infection. Because this infection can be indicative of sexual abuse, specimens should be obtained from all vesicular or ulcerative genital or perianal lesions compatible with genital herpes and then sent for viral culture.

• Specimen collection for N. gonorrhoeae culture from the pharynx and anus in boys and girls, the vagina in girls, and the urethra in boys. Cervical specimens are not recommended for prepubertal girls. For boys with a urethral discharge, a meatal specimen discharge is an adequate substitute for an intraurethral swab specimen. Because of the legal implications of a diagnosis of N. gonorrhoeae infection in a child, if culture for the isolation of N. gonorrhoeae is done, only standard culture procedures should be performed. Gram stains are inadequate to evaluate prepubertal children for gonorrhea and should not be used to diagnose or exclude gonorrhea. Specimens from the vagina, urethra, pharynx, or rectum should be streaked onto selective media for isolation of N. gonorrhoeae, and all presumptive isolates of N. gonorrhoeae should be identified definitively by at least two tests that involve different principles (e.g., biochemical, enzyme substrate, or serologic). Isolates should be preserved to enable additional or repeated testing.

• Cultures for C. trachomatis from specimens collected from the anus in both boys and girls and from the vagina in girls. The likelihood of recovering C. trachomatis from the urethra of prepubertal boys is too low to justify the trauma involved in obtaining an intraurethral specimen. However, a meatal specimen should be obtained if urethral discharge is present. Pharyngeal specimens for C. trachomatis are not recommended for children of either sex because the yield is low, perinatally acquired infection might persist beyond infancy, and culture systems in some laboratories do not distinguish between C. trachomatis and C. pneumoniae. Only standard culture systems for the isolation of C. trachomatis should be used. The isolation of C. trachomatis should be confirmed by microscopic identification of inclusions by staining with fluorescein-conjugated monoclonal antibody specific for C. trachomatis; EIAs are not acceptable confirmatory methods. Isolates should be preserved. Nonculture tests for chlamydia (e.g., nonamplified probes, EIAs, and DFA) are not sufficiently specific for use in circumstances involving possible child abuse or assault. NAATs can be used for detection of C. trachomatis in vaginal specimens or urine from girls. All specimens should be retained for additional testing if necessary. No data are available regarding the use of NAATs in boys or for extragenital specimens (e.g., those obtained from the rectum) in boys and girls. Culture remains the preferred method for extragenital sites.

• Culture and wet mount of a vaginal swab specimen for T. vaginalis infection and BV.

• Collection of serum samples to be evaluated immediately, preserved for subsequent analysis, and used as a baseline for comparison with follow-up serologic tests. Sera should be tested immediately for antibodies to sexually transmitted agents. Agents for which suitable tests are available include T. pallidum, HIV, and HBV. Decisions regarding the agents for which to perform serologic tests should be made on a case-by-case basis.

Data on use of NAATs for detection of N. gonorrhoeae in children are limited, and performance is test dependent (197,486). Consultation with an expert is necessary before using NAATs in this context to minimize the possibility of cross-reaction with nongonococcal Neisseria species and other commensals (e.g., N. meningitidis, N. sicca, N. lactamica, N. cinerea, and Moraxella catarrhalis). NAATs can be used as an alternative to culture with vaginal specimens or urine from girls, whereas culture remains the preferred method for urethral specimens or urine from boys and for extragenital specimens (pharynx and rectum) from all children. All positive specimens should be retained for additional testing.

HIV infection has been reported in children whose only known risk factor was sexual abuse. Serologic testing for HIV infection should be considered for abused children. The decision to test for HIV infection should be made on a case-by-case basis, depending on the likelihood of infection among assailant(s). Although data are insufficient concerning the efficacy and safety of PEP among both children and adults, treatment is well tolerated by infants and children (with and without HIV infection), and children have a minimal risk for serious adverse reactions because of the short period recommended for prohylaxis. (78,138). In considering whether to offer antiretroviral PEP, health-care providers should consider whether the child can be treated soon after the sexual exposure (i.e., within 72 hours), the likelihood that the assailant is infected with HIV, and the likelihood of high compliance with the prophylactic regimen. The potential benefit of treating a sexually abused child should be weighed against the risk for adverse reactions. If antiretroviral PEP is being considered, a provider specializing in evaluating or treating HIV-infected children should be consulted.

Recommendations for HIV-Related Postexposure Assessment of Children within 72 Hours of Sexual Assault

• Review HIV/AIDS local epidemiology and assess risk for HIV infection in the assailant.

• Evaluate circumstances of assault that might affect risk for HIV transmission.

• Consult with a specialist in treating HIV-infected children if PEP is considered.

• If the child appears to be at risk for HIV transmission from the assault, discuss PEP with the caregiver(s), including its toxicity and unknown efficacy.

• If caregivers choose for the child to receive antiretroviral PEP (rx,142,489), provide enough medication to last until the return visit at 3–7 days after the initial assessment, at which time the child should be reevaluated and tolerance of medication assessed; dosages should not exceed those for adults.

• Perform HIV antibody test at original assessment, 6 weeks, 3 months, and 6 months.

Follow-Up Examination After Assault

In circumstances in which transmission of syphilis, HIV, or hepatitis B is a concern but baseline tests are negative, an examination approximately 6 weeks, 3 months, and 6 months after the last suspected sexual exposure is recommended to allow time for antibodies to infectious agents to develop. In addition, results of HBsAg testing must be interpreted carefully, because HBV can be transmitted nonsexually. Decisions regarding which tests should be performed must be made on an individual basis.

Presumptive Treatment

The risk of a child acquiring an STD as a result of sexual abuse or assault has not been well studied. Presumptive treatment for children who have been sexually assaulted or abused is not recommended because 1) the incidence of most STDs in children is low after abuse/assault, 2) prepubertal girls appear to be at lower risk for ascending infection than adolescent or adult women, and 3) regular follow-up of children usually can be ensured. However, some children or their parent(s) or guardian(s) might be concerned about the possibility of infection with an STD, even if the risk is perceived to be low by the health-care provider. Such concerns might be an appropriate indication for presumptive treatment in some settings and might be considered after all specimens for diagnostic tests relevant to the investigation have been collected.

Terms and Abbreviations Used in This Report

AIDS Acquired immunodeficiency syndrome

ALT Alanine aminotransferase

anti-HBc Antibody to hepatitis B core antigen

anti-HCV Hepatitis C antibodies

ASC-US Atypical squamous cells of undetermined significance

BCA Bichloroacetic acid

BV Bacterial vaginosis

CBC Complete blood count

CI Confidence interval

CIN Cervical intraepithelial neoplasia

CLD Chronic liver disease

CLIA Clinical Laboratory Improvement  Amendments

CNS Central nervous system

CSF Cerebrospinal fluid

DFA Direct fluorescent antibody

DGI Disseminated gonococcal infection

dL Deciliter

DNA Deoxyribonucleic acid

EC Emergency contraception

EIA Enzyme immunoassay

ELISA Enzyme-linked immunosorbent assay

EPT Expedited partner therapy

FDA Food and Drug Administration

FTA-ABS Fluorescent treponemal antibody absorbed

gG Glycoprotein G

GNID Gram-negative intracellular diplococci

HAART Highly active antiretroviral therapy

HAV Hepatitis A virus

HBIG Hepatitis B immune globulin

HBsAg Hepatitis B surface antigen

HBV Hepatitis B virus

HCC hepatocellular carcinoma

HCV Hepatitis C virus

HIV Human immunodeficiency virus

HPV Human papillomavirus

HSV Herpes simplex virus

IFA Immunofluorescence assay

IgE Immunoglobulin E

Ig Immune globulin

IgG Immunoglobulin G

IgM Immunoglobulin M

IM Intramuscularly

IUD Intrauterine device

IV Intravenous or intravenously

KOH Potassium hydroxide

LGV Lymphogranuloma venereum

MAC Mycobacterium avium complex

MIC Minimum inhibitory concentration

MSM Men who have sex with men

N-9 Nonoxynol-9

NAAT Nucleic acid amplification test

NGU Nongonococcal urethritis

Pap Papanicolaou

PCR Polymerase chain reaction

PEP Postexposure prophylaxis

PID Pelvic inflammatory disease

PO By mouth

PPV Positive predictive value

QRNG Quinolone-resistant Neisseria gonorrhoeae

RNA Ribonucleic acid

RPR Rapid plasma reagin

RT-PCR Reverse transcriptase polymerase chain  reaction

RVVC Recurrent vulvovaginal candidiasis

SIL Squamous intraepithelial lesion

STD Sexually transmitted disease

TCA Trichloroacetic acid

TE Toxoplasmic encephalitis

TP-PA Treponema pallidum particle agglutation

VDRL Venereal Disease Research Laboratory

VVC Vulvovaginal candidiasis

WB Western blot

WBC White blood count

WSW Women who have sex with women

References

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