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1993 Sexually Transmitted Diseases Treatment Guidelines
09/24/1993 SUGGESTED CITATION Centers for Disease Control and Prevention. 1993 Sexually transmitted diseases treatment guidelines. MMWR 1993;42(No. RR-14): {inclusive page numbers}. CIO Responsible for this publication: National Center for Prevention Services, Division of Sexually Transmitted Diseases and HIV Prevention DISEASES CHARACTERIZED BY GENITAL ULCERS Management of the Patient with Genital Ulcers In the United States, most patients with genital ulcers have genital herpes, syphilis, or chancroid. The relative frequency of each varies by geographic area and patient population, but in most areas of the United States genital herpes is the most common of these diseases. More than one of these diseases may be present among at least 3%-10% of patients with genital ulcers. Each disease has been associated with an increased risk for HIV infection. A diagnosis based only on history and physical examination is often inaccurate. Therefore, evaluation of all persons with genital ulcers should include a serologic test for syphilis and possibly other tests. Although ideally all of these tests should be conducted for each patient with a genital ulcer, use of such tests (other than a serologic test for syphilis) may be based on test availability and clinical or epidemiologic suspicion. Specific tests for the evaluation of genital ulcers are listed below: -- Darkfield examination or direct immunofluorescence test for Treponema pallidum, -- Culture or antigen test for HSV, and -- Culture for Haemophilus ducreyi. HIV testing should be considered in the management of patients with genital ulcers, especially for those with syphilis or chancroid. A health-care provider often must treat a patient before test results are available (even after complete testing, at least one quarter of patients with genital ulcers have no laboratory-confirmed diagnosis). In that circumstance, the clinician should treat for the diagnosis considered most likely. Many experts recommend treatment for both chancroid and syphilis if the diagnosis is unclear or if the patient resides in a community in which chancroid morbidity is notable (especially when diagnostic capabilities for chancroid and syphilis are not ideal). Chancroid Chancroid is endemic in many areas of the United States and also occurs in discrete outbreaks. Chancroid has been well established as a co-factor for HIV transmission and a high rate of HIV infection among patients with chancroid has been reported in the United States and in other countries. As many as 10% of patients with chancroid may be coinfected with T. pallidum or HSV. Definitive diagnosis of chancroid requires identification of H. ducreyi on special culture media that are not commercially available; even using these media, sensitivity is no higher than 80% and is usually lower. A probable diagnosis, for both clinical and surveillance purposes, may be made if the person has one or more painful genital ulcers, and a) no evidence of T. pallidum infection by darkfield examination of ulcer exudate or by a serologic test for syphilis performed at least 7 days after onset of ulcers, and b) either the clinical presentation of the ulcer(s) is not typical of disease caused by HSV or the HSV test results are negative. The combination of a painful ulcer with tender inguinal adenopathy (which occurs among one-third of patients) is suggestive of chancroid, and when accompanied by suppurative inguinal adenopathy is almost pathognomonic. Treatment Successful treatment cures infection, resolves clinical symptoms, and prevents transmission to others. In extensive cases, scarring may result despite successful therapy. Recommended Regimens Azithromycin 1 g orally in a single dose or Ceftriaxone 250 mg intramuscularly (IM) in a single dose or Erythromycin base 500 mg orally 4 times a day for 7 days. All three regimens are effective for the treatment of chancroid among patients without HIV infection. Azithromycin and ceftriaxone offer the advantage of single-dose therapy. Antimicrobial resistance to ceftriaxone and azithromycin has not been reported. Although two isolates resistant to erythromycin were reported from Asia a decade ago, similar isolates have not been reported. Alternative Regimens Amoxicillin 500 mg plus clavulanic acid 125 mg orally 3 times a day for 7 days, or Ciprofloxacin 500 mg orally 2 times a day for 3 days. NOTE: Ciprofloxacin is contraindicated for pregnant and lactating women, children, and adolescents less than or equal to 17 years of age. These regimens have not been evaluated as extensively as the recommended regimens; neither has been studied in the United States. Other Management Considerations Patients should be tested for HIV infection at the time of diagnosis. Patients also should be tested 3 months later for both syphilis and HIV, if initial results are negative. Follow-Up Patients should be re-examined 3-7 days after initiation of therapy. If treatment is successful, ulcers improve symptomatically within 3 days and improve objectively within 7 days after therapy. If no clinical improvement is evident, the clinician must consider whether a) the diagnosis is correct, b) coinfection with another STD agent exists, c) the patient is infected with HIV, d) treatment was not taken as instructed, or e) the H. ducreyi strain causing infection is resistant to the prescribed antimicrobial. The time required for complete healing is related to the size of the ulcer; large ulcers may require greater than or equal to 2 weeks. Clinical resolution of fluctuant lymphadenopathy is slower than that of ulcers and may require needle aspiration through adjacent intact skin -- even during successful therapy. Management of Sex Partners Persons who had sexual contact with a patient who has chancroid within the 10 days before onset of the patient's symptoms should be examined and treated. The examination and treatment should be administered even in the absence of symptoms. Special Considerations Pregnancy - The safety of azithromycin for pregnant and lactating women has not been established. Ciprofloxacin is contraindicated during pregnancy. No adverse effects of chancroid on pregnancy outcome or on the fetus have been reported. HIV Infection - Patients coinfected with HIV should be closely monitored. These patients may require courses of therapy longer than those recommended in this report. Healing may be slower among HIV-infected persons and treatment failures do occur, especially after shorter-course treatment regimens. Since data on therapeutic efficacy with the recommended ceftriaxone and azithromycin regimens among patients infected with HIV are limited, those regimens should be used among persons known to be infected with HIV only if follow-up can be assured. Some experts suggest using the erythromycin 7-day regimen for treating HIV-infected persons. Genital Herpes Simplex Virus Infections Genital herpes is a viral disease that may be recurrent and has no cure. Two serotypes of HSV have been identified: HSV-1 and HSV-2; most cases of genital herpes are caused by HSV-2. On the basis of serologic studies, approximately 30 million persons in the United States may have genital HSV infection. Most infected persons never recognize signs suggestive of genital herpes; some will have symptoms shortly after infection and then never again. A minority of the total infected U.S. population will have recurrent episodes of genital lesions. Some cases of first clinical episode genital herpes are manifested by extensive disease that requires hospitalization. Many cases of genital herpes are acquired from persons who do not know that they have a genital infection with HSV or who were asymptomatic at the time of the sexual contact. Randomized trials show that systemic acyclovir provides partial control of the symptoms and signs of herpes episodes when used to treat first clinical episodes, or when used as suppressive therapy. However, acyclovir neither eradicates latent virus nor affects subsequent risk, frequency, or severity of recurrences after administration of the drug is discontinued. Topical therapy with acyclovir is substantially less effective than the oral drug and its use is discouraged. Episodes of HSV infection among HIV-infected patients may require more aggressive therapy. Immunocompromised persons may have prolonged episodes with extensive disease. For these persons, infections caused by acyclovir-resistant strains require selection of alternate antiviral agents. First Clinical Episode of Genital Herpes Recommended Regimen - Acyclovir 200 mg orally 5 times a day for 7-10 days or until clinical resolution is attained. First Clinical Episode of Herpes Proctitis Recommended Regimen - Acyclovir 400 mg orally 5 times a day for 10 days or until clinical resolution is attained. Recurrent Episodes When treatment is instituted during the prodrome or within 2 days of onset of lesions, some patients with recurrent disease experience limited benefit from therapy. However, since early treatment can seldom be administered, most immunocompetent patients with recurrent disease do not benefit from acyclovir treatment, and it is not generally recommended. Recommended Regimen - Acyclovir 200 mg orally 5 times a day for 5 days, or Acyclovir 400 mg orally 3 times a day for 5 days, or Acyclovir 800 mg orally 2 times a day for 5 days. Daily Suppressive Therapy Daily suppressive therapy reduces the frequency of HSV recurrences by at least 75% among patients with frequent recurrences (i.e., <M>six or more recurrences per year). Suppressive treatment with oral acyclovir does not totally eliminate symptomatic or asymptomatic viral shedding or the potential for transmission. Safety and efficacy have been documented among persons receiving daily therapy for as long as 5 years. Acyclovir-resistant strains of HSV have been isolated from some persons receiving suppressive therapy, but these strains have not been associated with treatment failure among immunocompetent patients. After 1 year of continuous suppressive therapy, acyclovir should be discontinued to allow assessment of the patient's rate of recurrent episodes. Recommended Regimen - Acyclovir 400 mg orally 2 times a day. Alternative Regimen - Acyclovir 200 mg orally 3-5 times a day. The goal of the alternative regimen is to identify for each patient the lowest dose that provides relief from frequently recurring symptoms. Severe Disease Intravenous (IV) therapy should be provided for patients with severe disease or complications necessitating hospitalization (e.g., disseminated infection that includes encephalitis, pneumonitis, or hepatitis). Recommended Regimen - Acyclovir 5-10 mg/kg body weight IV every 8 hours for 5-7 days or until clinical resolution is attained. Other Management Considerations Other considerations for managing patients with genital HSV infection are as follows: -- Patients should be advised to abstain from sexual activity while lesions are present. -- Patients with genital herpes should be told about the natural history of the disease, with emphasis on the potential for recurrent episodes, asymptomatic viral shedding, and sexual transmission. Sexual transmission of HSV has been documented to occur during periods without evidence of lesions. Many cases are transmitted during such asymptomatic periods. The use of condoms should be encouraged during all sexual exposures. The risk for neonatal infection should be explained to all patients -- male and female -- with genital herpes. Women of childbearing age who have genital herpes should be advised to inform health-care providers who care for them during pregnancy about their HSV infection. Management of Sex Partners Sex partners of patients who have genital herpes are likely to benefit from evaluation and counseling. Symptomatic sex partners should be managed in the same manner as any patient with genital lesions. However, the majority of persons with genital HSV infection do not have a history of typical genital lesions. These asymptomatic persons may benefit from evaluation and counseling; thus, even asymptomatic partners should be queried about histories of typical and atypical genital lesions and encouraged to examine themselves for lesions in the future. Commercially available HSV type-specific antibody tests have not demonstrated adequate performance characteristics; their use is not currently recommended. Sensitive and specific type-specific serum antibody assays now utilized in research settings might contribute to future intervention strategies. Should tests with adequate sensitivity and specificity become commercially available, it might be possible to accurately identify asymptomatic persons infected with HSV-2, to focus counseling on how to detect lesions by self-examination, and to reduce the risk for transmission to sex partners. Special Considerations Allergy, Intolerance, or Adverse Reactions - Effective alternatives to therapy with acyclovir are not available. HIV Infection - Lesions caused by HSV are relatively common among patients infected with HIV. Intermittent or suppressive therapy with oral acyclovir may be needed. The acyclovir dosage for HIV-infected persons is controversial, but experience strongly suggests that immunocompromised patients benefit from increased dosage. Regimens such as 400 mg orally 3 to 5 times a day, as used for other immunocompromised persons, have been found useful. Therapy should be continued until clinical resolution is attained. For severe disease, IV acyclovir therapy may be required. If lesions persist among patients undergoing acyclovir treatment, resistance to acyclovir should be suspected. These patients should be managed in consultation with an expert. For severe disease because of proven or suspected acyclovir-resistant strains, hospitalization should be considered. Foscarnet, 40 mg/kg body weight IV every 8 hours until clinical resolution is attained, appears to be the best available treatment. Pregnancy - The safety of systemic acyclovir therapy among pregnant women has not been established. Burroughs Wellcome Co., in cooperation with CDC, maintains a registry to assess the effects of the use of acyclovir during pregnancy. Women who receive acyclovir during pregnancy should be reported to this registry (1-800-722-9292, ext. 58465). Current registry findings do not indicate an increase in the number of birth defects identified among the prospective reports when compared with those expected in the general population. Moreover, no consistent pattern of abnormalities emerges among retrospective reports. These findings provide some assurance in counseling women who have had inadvertent prenatal exposure to acyclovir. However, accumulated case histories comprise a sample of insufficient size for reaching reliable and definitive conclusions regarding the risks of acyclovir treatment to pregnant women and to their fetuses. In the presence of life-threatening maternal HSV infection (e.g., disseminated infection that includes encephalitis, pneumonitis, or hepatitis), acyclovir administered IV is indicated. Among pregnant women without life-threatening disease, systemic acyclovir should not be used to treat recurrences nor should it be used as suppressive therapy near-term (or at other times during pregnancy) to prevent reactivation. Perinatal Infections Most mothers of infants who acquire neonatal herpes lack histories of clinically evident genital herpes. The risk for transmission to the neonate from an infected mother appears highest among women with first episode genital herpes near the time of delivery, and is low ( less than or equal to 3%) among women with recurrent herpes. The results of viral cultures during pregnancy do not predict viral shedding at the time of delivery, and such cultures are not routinely indicated. At the onset of labor, all women should be carefully questioned about symptoms of genital herpes and should be examined. Women without symptoms or signs of genital herpes infection (or prodrome) may deliver their babies vaginally. Among women who have a history of genital herpes, or who have a sex partner with genital herpes, cultures of the birth canal at delivery may aid in decisions relating to neonatal management. Infants delivered through an infected birth canal (proven by virus isolation or presumed by observation of lesions) should be followed carefully, including virus cultures obtained 24-48 hours after birth. Available data do not support the routine use of acyclovir as anticipatory treatment for asymptomatic infants delivered through an infected birth canal. Treatment should be reserved for infants who develop evidence of clinical disease and for those with positive postpartum cultures. All infants with evidence of neonatal herpes should be treated with systemic acyclovir or vidarabine; refer to the Report of the Committee on Infectious Diseases, American Academy of Pediatrics (13). For ease of administration and to lower toxicity, acyclovir (30 mg/kg/day for 10-14 days) is the preferred drug. The care of these infants should be managed in consultation with an expert. Lymphogranuloma Venereum Lymphogranuloma venereum (LGV), a rare disease in the United States, is caused by serovars L1, L2, or L3 of C. trachomatis. The most common clinical manifestation of LGV among heterosexuals is tender inguinal lymphadenopathy that is most commonly unilateral. Women and homosexually active men may have proctocolitis or inflammatory involvement of perirectal or perianal lymphatic tissues resulting in fistulas and strictures. When patients seek care, most no longer have the self-limited genital ulcer that sometimes occurs at the site of inoculation. The diagnosis is usually made serologically and by exclusion of other causes of inguinal lymphadenopathy or genital ulcers. Treatment Treatment cures infection and prevents ongoing tissue damage, although tissue reaction can result in scarring. Buboes may require aspiration or incision and drainage through intact skin. Doxycycline is the preferred treatment. Recommended Regimen - Doxycycline 100 mg orally 2 times a day for 21 days. Alternative Regimens - Erythromycin 500 mg orally 4 times a day for 21 days or Sulfisoxazole 500 mg orally 4 times a day for 21 days or equivalent sulfonamide course. Follow-Up Patients should be followed clinically until signs and symptoms have resolved. Management of Sex Partners Persons who have had sexual contact with a patient who has LGV within the 30 days before onset of the patient's symptoms should be examined, tested for urethral or cervical chlamydial infection, and treated. Special Considerations Pregnancy - Pregnant and lactating women should be treated with the erythromycin regimen. HIV infection - Persons with HIV infection and LGV should be treated following the regimens previously cited. Syphilis General Principles Background - Syphilis is a systemic disease caused by T. pallidum. Patients with syphilis may seek treatment for signs or symptoms of primary infection (ulcer or chancre at site of infection), secondary infection (manifestations that include rash, mucocutaneous lesions, and adenopathy), or tertiary infection (cardiac, neurologic, ophthalmic, auditory, or gummatous lesions). Infections also may be detected during the latent stage by serologic testing. Patients with latent syphilis who are known to have been infected within the preceding year are considered to have early latent syphilis; others have late latent syphilis or syphilis of unknown duration. Theoretically, treatment for late latent syphilis (as well as tertiary syphilis) requires therapy of longer duration because organisms are dividing more slowly; however, the validity of this division and its timing are unproven. Diagnostic Considerations and Use of Serologic Tests - Darkfield examinations and direct fluorescent antibody tests of lesion exudate or tissue are the definitive methods for diagnosing early syphilis. Presumptive diagnosis is possible with the use of two types of serologic tests for syphilis: a) nontreponemal (e.g., Venereal Disease Research Laboratory {VDRL} and RPR, and b) treponemal (e.g., fluorescent treponemal antibody absorbed {FTA-ABS} and microhemagglutination assay for antibody to T. pallidum {MHA-TP}). The use of one type of test alone is not sufficient for diagnosis. Nontreponemal test antibody titers usually correlate with disease activity, and results should be reported quantitatively. A fourfold change in titer, equivalent to a change of two dilutions (e.g., from 1:16 to 1:4, or from 1:8 to 1:32), is necessary to demonstrate a substantial difference between two nontreponemal test results that were obtained using the same serologic test. A patient who has a reactive treponemal test usually will have a reactive test for a lifetime, regardless of treatment or disease activity (15%-25% of patients treated during the primary stage may revert to being serologically nonreactive after 2-3 years). Treponemal test antibody titers correlate poorly with disease activity and should not be used to assess response to treatment. Sequential serologic tests should be performed using the same testing method (e.g., VDRL or RPR) by the same laboratory. The VDRL and RPR are equally valid, but quantitative results from the two tests cannot be directly compared because RPR titers are often slightly higher than VDRL titers. Abnormal results of serologic testing (unusually high, unusually low, and fluctuating titers) have been observed among HIV-infected patients. For such patients, use of other tests (e.g., biopsy and direct microscopy) should be considered. However, serologic tests appear to be accurate and reliable for the diagnosis of syphilis and for evaluation of treatment response for the vast majority of HIV-infected patients. No single test can be used to diagnose neurosyphilis among all patients. The diagnosis of neurosyphilis can be made based on various combinations of reactive serologic test results, abnormalities of cerebrospinal fluid (CSF) cell count or protein, or a reactive VDRL-CSF (RPR is not performed on CSF) with or without clinical manifestations. The CSF leukocyte count is usually elevated ( greater than 5 WBC/mm3) when active neurosyphilis is present, and it is also a sensitive measure of the effectiveness of therapy. The VDRL-CSF is the standard serologic test for CSF; when reactive in the absence of substantial contamination of the CSF with blood, it is considered diagnostic of neurosyphilis. However, the VDRL-CSF may be nonreactive when neurosyphilis is present. Some experts recommend performing an FTA-ABS test on CSF. The CSF FTA-ABS is less specific (i.e., yields more false positives) for neurosyphilis than the VDRL-CSF; however, the test is believed to be highly sensitive. Treatment - Parenteral penicillin G is the preferred drug for treatment of all stages of syphilis. The preparation(s) used (i.e., benzathine, aqueous procaine, or aqueous crystalline), the dosage, and the length of treatment depend on the stage and clinical manifestations of disease. The efficacy of penicillin for the treatment of syphilis was well established through clinical experience before the value of randomized controlled clinical trials was recognized. Therefore, nearly all the recommendations for the treatment of syphilis are based on expert opinion reinforced by case series, open clinical trials, and 50 years of clinical experience. Parenteral penicillin G is the only therapy with documented efficacy for neurosyphilis or for syphilis during pregnancy. Patients with neurosyphilis and pregnant women with syphilis in any stage who report penicillin allergy should almost always be treated with penicillin, after desensitization, if necessary. Skin testing for penicillin allergy may be useful for some patients and in some settings (see Management of the Patient With a History of Penicillin Allergy). However, minor determinants needed for penicillin skin testing are not available commercially. The Jarisch-Herxheimer reaction is an acute febrile reaction -- accompanied by headache, myalgia, and other symptoms -- that may occur within the first 24 hours after any therapy for syphilis; patients should be advised of this possible adverse reaction. The Jarisch-Herxheimer reaction is common among patients with early syphilis. Antipyretics may be recommended, but there are no proven methods for preventing this reaction. The Jarisch-Herxheimer reaction may induce early labor or cause fetal distress among pregnant women. This concern should not prevent or delay therapy (see Syphilis During Pregnancy). Management of Sex Partners - Sexual transmission of T. pallidum occurs only when mucocutaneous syphilitic lesions are present; such manifestations are uncommon after the first year of infection. However, persons sexually exposed to a patient with syphilis in any stage should be evaluated clinically and serologically according to the following recommendations: -- Persons who were exposed to a patient with primary, secondary, or latent (duration less than 1 year) syphilis within the preceding 90 days might be infected even if seronegative, and therefore should be treated presumptively. -- Persons who were sexually exposed to a patient with primary, secondary, or latent (duration less than 1 year) syphilis greater than 90 days before examination should be treated presumptively if serologic test results are not available immediately, and the opportunity for follow-up is uncertain. -- For purposes of partner notification and presumptive treatment of exposed sex partners, patients who have syphilis of unknown duration and who have high nontreponemal serologic test titers ( greater than or equal to 1:32) may be considered to be infected with early syphilis. -- Long-term sex partners of patients with late syphilis should be evaluated clinically and serologically for syphilis. The time periods before treatment used for identifying at-risk sex partners are 3 months plus duration of symptoms for primary syphilis, 6 months plus duration of symptoms for secondary syphilis, and 1 year for early latent syphilis. Primary and Secondary Syphilis Treatment Four decades of experience indicate that parenteral penicillin G is effective in achieving local cure (healing of lesions and prevention of sexual transmission) and in preventing late sequelae. However, no adequately conducted comparative trials have been performed to guide the selection of an optimal penicillin regimen (i.e., dose, duration, and preparation). Substantially fewer data on nonpenicillin regimens are available. Recommended Regimen for Adults - Nonallergic patients with primary or secondary syphilis should be treated with the following regimen: Benzathine penicillin G, 2.4 million units IM in a single dose. NOTE: Recommendations for treating pregnant women and HIV-infected persons for syphilis are discussed in separate sections. Recommended Regimen for Children - After the newborn period, children diagnosed with syphilis should have a CSF examination to exclude a diagnosis of neurosyphilis, and birth and maternal medical records should be reviewed to assess whether the child has congenital or acquired syphilis (see Congenital Syphilis). Children with acquired primary or secondary syphilis should be evaluated (including consultation with child-protection services) and treated using the following pediatric regimen (see Sexual Assault or Abuse of Children). Benzathine penicillin G, 50,000 units/kg IM, up to the adult dose of 2.4 million units in a single dose. Other Management Considerations All patients with syphilis should be tested for HIV. In areas with high HIV prevalence, patients with primary syphilis should be retested for HIV after 3 months. Patients who have syphilis and who also have symptoms or signs suggesting neurologic disease (e.g., meningitis) or ophthalmic disease (e.g., uveitis) should be fully evaluated for neurosyphilis and syphilitic eye disease (including CSF analysis and ocular slit-lamp examination). Such patients should be treated appropriately according to the results of this evaluation. Invasion of CSF by T. pallidum with accompanying CSF abnormalities is common among adults who have primary or secondary syphilis. However, few patients develop neurosyphilis after treatment with the regimens described in this report. Therefore, unless clinical signs or symptoms of neurologic involvement are present (e.g., auditory, cranial nerve, meningeal, or ophthalmic manifestations), lumbar puncture is not recommended for routine evaluation of patients with primary or secondary syphilis. Follow-Up Treatment failures can occur with any regimen. However, assessing response to treatment is often difficult, and no definitive criteria for cure or failure exist. Serologic test titers may decline more slowly among patients with a prior syphilis infection. Patients should be re-examined clinically and serologically at 3 months and again at 6 months. Patients with signs or symptoms that persist or recur or who have a sustained fourfold increase in nontreponemal test titer compared with either the baseline titer or to a subsequent result, can be considered to have failed treatment or to be reinfected. These patients should be re-treated after evaluation for HIV infection. Unless reinfection is likely, lumbar puncture also should be performed. Failure of nontreponemal test titers to decline fourfold by 3 months after therapy for primary or secondary syphilis identifies persons at risk for treatment failure. Those persons should be evaluated for HIV infection. Optimal management of such patients is unclear if they are HIV negative. At a minimum, these patients should have additional clinical and serologic follow-up. If further follow-up cannot be assured, re-treatment is recommended. Some experts recommend CSF examination in such situations. When patients are re-treated, most experts recommend re-treatment with three weekly injections of benzathine penicillin G 2.4 million units IM, unless CSF examination indicates that neurosyphilis is present. Management of Sex Partners Refer to General Principles, Management of Sex Partners. Special Considerations Penicillin Allergy - Nonpregnant penicillin-allergic patients who have primary or secondary syphilis should be treated with the following regimen. Doxycycline 100 mg orally 2 times a day for 2 weeks or Tetracycline 500 mg orally 4 times a day for 2 weeks. There is less clinical experience with doxycycline than with tetracycline, but compliance is likely to be better with doxycycline. Therapy for a patient who cannot tolerate either doxycycline or tetracycline should be based upon whether the patient's compliance with the therapy regimen and with follow-up examinations can be assured. For nonpregnant patients whose compliance with therapy and follow-up can be assured, an alternative regimen is erythromycin 500 mg orally 4 times a day for 2 weeks. Various ceftriaxone regimens also may be considered. Patients whose compliance with therapy or follow-up cannot be assured should be desensitized, if necessary, and treated with penicillin. Skin testing for penicillin allergy may be useful in some situations (see Management of the Patient With a History of Penicillin Allergy). Erythromycin is less effective than other recommended regimens. Data on ceftriaxone are limited, and experience has been too brief to permit identification of late failures. Optimal dose and duration have not been established for ceftriaxone, but regimens that provide 8-10 days of treponemicidal levels in the blood should be used. Single dose ceftriaxone therapy is not effective for treating syphilis. Pregnancy - Pregnant patients who are allergic to penicillin should be treated with penicillin, after desensitization, if necessary (see Management of the Patient With a History of Penicillin Allergy and Syphilis During Pregnancy). HIV Infection - Refer to Syphilis Among HIV-Infected Patients. Latent Syphilis Latent syphilis is defined as those periods after infection with T. pallidum when patients are seroreactive, but show no other evidence of disease. Patients who have latent syphilis and who have acquired syphilis within the preceding year are classified as having early latent syphilis. Patients can be demonstrated to have acquired syphilis within the preceding year on the basis of documented seroconversion, a fourfold or greater increase in titer of a nontreponemal serologic test, history of symptoms of primary or secondary syphilis, or if they had a sex partner with primary, secondary, or latent syphilis (documented independently as duration less than 1 year). Nearly all others have latent syphilis of unknown duration and should be managed as if they had late latent syphilis. Treatment Treatment of latent syphilis is intended to prevent occurrence or progression of late complications. Although clinical experience supports belief in the effectiveness of penicillin in achieving those goals, limited evidence is available for guidance in choosing specific regimens. There is very little evidence to support the use of nonpenicillin regimens. Recommended Regimens for Adults - These regimens are for nonallergic patients with normal CSF examination (if performed). Early Latent Syphilis - Benzathine penicillin G, 2.4 million units IM in a single dose. Late Latent Syphilis or Latent Syphilis of Unknown Duration - Benzathine penicillin G, 7.2 million units total, administered as 3 doses of 2.4 million units IM each, at 1-week intervals. Recommended Regimens for Children - After the newborn period, children diagnosed with syphilis should have a CSF examination to exclude neurosyphilis, and birth and maternal medical records should be reviewed to assess whether the child has congenital or acquired syphilis (see Congenital Syphilis). Older children with acquired latent syphilis should be evaluated as described for adults and treated using the following pediatric regimens (see Sexual Assault or Abuse of Children). These regimens are for nonallergic children who have acquired syphilis and who have had a normal CSF examination. Early Latent Syphilis - Benzathine penicillin G, 50,000 units/kg IM, up to the adult dose of 2.4 million units in a single dose. Late Latent Syphilis or Latent Syphilis of Unknown Duration Benzathine penicillin G, 50,000 units/kg IM, up to the adult dose of 2.4 million units, for three total doses (total 150,000 units/kg up to adult total dose of 7.2 million units). Other Management Considerations All patients with latent syphilis should be evaluated clinically for evidence of tertiary disease (e.g., aortitis, neurosyphilis, gumma, and iritis). Recommended therapy for patients with latent syphilis may not be optimal therapy for the persons with asymptomatic neurosyphilis. However, the yield from CSF examination, in terms of newly diagnosed cases of neurosyphilis, is low. Patients with any one of the criteria listed below should have a CSF examination before treatment: -- Neurologic or ophthalmic signs or symptoms; -- Other evidence of active syphilis (e.g., aortitis, gumma, iritis); -- Treatment failure; -- HIV infection; -- Serum nontreponemal titer greater than or equal to 1:32, unless duration of infection is known to be less than 1 year; or -- Nonpenicillin therapy planned, unless duration of infection is known to be less than 1 year. If dictated by circumstances and patient preferences, CSF examination may be performed for persons who do not meet the criteria listed above. If a CSF examination is performed and the results show abnormalities consistent with CNS syphilis, the patient should be treated for neurosyphilis (see Neurosyphilis). -- All syphilis patients should be tested for HIV. Follow-Up Quantitative nontreponemal serologic tests should be repeated at 6 months and again at 12 months. Limited data are available to guide evaluation of the response to therapy for a patient with latent syphilis. If titers increase fourfold, or if an initially high titer ( greater than or equal to 1:32) fails to decline at least fourfold (two dilutions) within 12-24 months, or if the patient develops signs or symptoms attributable to syphilis, the patient should be evaluated for neurosyphilis and re-treated appropriately. Management of Sex Partners Refer to General Principles, Management of Sex Partners. Special Considerations Penicillin Allergy - For patients who have latent syphilis and who are allergic to penicillin, nonpenicillin therapy should be used only after CSF examination has excluded neurosyphilis. Nonpregnant, penicillin-allergic patients should be treated with the following regimens. Doxycycline 100 mg orally 2 times a day or Tetracycline 500 mg orally 4 times a day. Both drugs are administered for 2 weeks if duration of infection is known to have been less than 1 year; otherwise, for 4 weeks. Pregnancy - Pregnant patients who are allergic to penicillin should be treated with penicillin, after desensitization, if necessary (see Management of the Patient With a History of Penicillin Allergy and Syphilis During Pregnancy). HIV Infection - Refer to Syphilis Among HIV-Infected Patients. Late Syphilis Late (tertiary) syphilis refers to patients with gumma and patients with cardiovascular syphilis, but not to neurosyphilis. Nonallergic patients without evidence of neurosyphilis should be treated with the following regimen. Recommended Regimen - Benzathine penicillin G, 7.2 million units total, administered as 3 doses of 2.4 million units IM, at 1-week intervals. Other Management Considerations Patients with symptomatic late syphilis should undergo CSF examination before therapy. Some experts treat all patients who have cardiovascular syphilis with a neurosyphilis regimen. The complete management of patients with cardiovascular or gummatous syphilis is beyond the scope of these guidelines. These patients should be managed in consultation with experts. Follow-Up There is minimal evidence regarding follow-up of patients infected with late syphilis. Clinical response depends partly on the nature of the lesions. Management of Sex Partners Refer to General Principles, Management of Sex Partners. Special Considerations Penicillin Allergy - Patients allergic to penicillin should be treated according to treatment regimens recommended for late latent syphilis. Pregnancy - Pregnant patients who are allergic to penicillin should be treated with penicillin, after desensitization, if necessary (see Management of the Patient With a History of Penicillin Allergy and Syphilis During Pregnancy). HIV Infection - Refer to Syphilis Among HIV-Infected Patients. Neurosyphilis Treatment Central nervous system disease can occur during any stage of syphilis. A patient with clinical evidence of neurologic involvement (e.g., ophthalmic or auditory symptoms, cranial nerve palsies) with syphilis warrants a CSF examination. Although four decades of experience have confirmed the effectiveness of penicillin, the evidence to guide the choice of the best regimen is limited. Syphilitic eye disease is frequently associated with neurosyphilis, and patients with this disease should be treated according to neurosyphilis treatment recommendations. CSF examination should be performed on all such patients to identify those patients with CSF abnormalities who should have follow-up CSF examinations to assess response to treatment. Patients who have neurosyphilis or syphilitic eye disease (e.g., uveitis, neuroretinitis, or optic neuritis) and who are not allergic to penicillin should be treated with the following regimen. Recommended Regimen - 12-24 million units aqueous crystalline penicillin G daily, administered as 2-4 million units IV every 4 hours, for 10-14 days. If compliance with therapy can be assured, patients may be treated with the following alternative regimen. Alternative Regimen - 2.4 million units procaine penicillin IM daily, plus probenecid 500 mg orally 4 times a day, both for 10-14 days. The durations of these regimens are shorter than that of the regimen used for late syphilis in the absence of neurosyphilis. Therefore, some experts administer benzathine penicillin, 2.4 million units IM after completion of these neurosyphilis treatment regimens to provide a comparable total duration of therapy. Other Management Considerations Other considerations in the management of the patient with neurosyphilis are the following: -- All patients with syphilis should be tested for HIV. -- Many experts recommend treating patients with evidence of auditory disease caused by syphilis in the same manner as for neurosyphilis, regardless of the findings on CSF examination. Follow-Up If CSF pleocytosis was present initially, CSF examination should be repeated every 6 months until the cell count is normal. Follow-up CSF examinations also may be used to evaluate changes in the VDRL-CSF or CSF protein in response to therapy, though changes in these two parameters are slower and persistent abnormalities are of less certain importance. If the cell count has not decreased at 6 months, or if the CSF is not entirely normal by 2 years, re-treatment should be considered. Management of Sex Partners Refer to General Principles, Management of Sex Partners. Special Considerations Penicillin Allergy - No data have been collected systematically for evaluation of therapeutic alternatives to penicillin for treatment of neurosyphilis. Therefore, patients who report being allergic to penicillin should be treated with penicillin, after desensitization if necessary, or should be managed in consultation with an expert. In some situations, skin testing to confirm penicillin allergy may be useful (see Management of the Patient With a History of Penicillin Allergy). Pregnancy - Pregnant patients who are allergic to penicillin should be treated with penicillin, after desensitization if necessary (see Syphilis During Pregnancy). HIV Infection - Refer to Syphilis Among HIV-Infected Patients. Syphilis Among HIV-Infected Patients Diagnostic Considerations Unusual serologic responses have been observed among HIV-infected persons who also have syphilis. Most reports involved serologic titers that were higher than expected, but false-negative serologic test results or delayed appearance of seroreactivity have also been reported. Nevertheless, both treponemal and nontreponemal serologic tests for syphilis are accurate for the majority of patients with syphilis and HIV coinfection. When clinical findings suggest that syphilis is present, but serologic tests are nonreactive or confusing, it may be helpful to perform such alternative tests as biopsy of a lesion, darkfield examination, or direct fluorescent antibody staining of lesion material. Neurosyphilis should be considered in the differential diagnosis of neurologic disease among HIV-infected persons. Treatment Although adequate research-based evidence is not available, published case reports and expert opinion suggest that HIV-infected patients with early syphilis are at increased risk for neurologic complications and have higher rates of treatment failure with currently recommended regimens. The magnitude of these risks, although not precisely defined, is probably small. No treatment regimens have been demonstrated to be more effective in preventing development of neurosyphilis than those recommended for patients without HIV infection. Careful follow-up after therapy is essential. Primary and Secondary Syphilis Among HIV-Infected Patients Treatment Treatment with benzathine penicillin G 2.4 million units IM, as for patients without HIV infection, is recommended. Some experts recommend additional treatments, such as multiple doses of benzathine penicillin G as suggested for late syphilis, or other supplemental antibiotics in addition to benzathine penicillin G 2.4 million units IM. Other Management Considerations CSF abnormalities are common among HIV-infected patients who have primary or secondary syphilis, but these abnormalities are of unknown prognostic significance. Most HIV-infected patients respond appropriately to currently recommended penicillin therapy; however, some experts recommend CSF examination before therapy and modification of treatment accordingly. Follow-Up Patients should be evaluated clinically and serologically for treatment failure at 1 month and at 2, 3, 6, 9, and 12 months after therapy. Although of unproven benefit, some experts recommend performing CSF examination after therapy (i.e., at 6 months). HIV-infected patients who meet the criteria for treatment failure should undergo CSF examination and be retreated just as for patients without HIV infection. CSF examination and re-treatment also should be strongly considered for patients in whom the suggested fourfold decrease in nontreponemal test titer does not occur within 3 months for primary or secondary syphilis. Most experts would re-treat patients with benzathine penicillin G 7.2 million units (as 3 weekly doses of 2.4 million units each) if the CSF examination is normal. Special Considerations Penicillin Allergy - Penicillin regimens should be used to treat HIV-infected patients in all stages of syphilis. Skin testing to confirm penicillin allergy may be used (see Management of the Patient With a History of Penicillin Allergy), but data on the utility of that approach among immunocompromised patients are inadequate. Patients may be desensitized, then treated with penicillin. Latent Syphilis Among HIV-Infected Patients Diagnostic Considerations Patients who have both latent syphilis (regardless of apparent duration) and HIV infection should undergo CSF examination before treatment. Treatment A patient with latent syphilis, HIV infection, and a normal CSF examination can be treated with benzathine penicillin G 7.2 million units (as 3 weekly doses of 2.4 million units each). Special Considerations Penicillin Allergy Penicillin regimens should be used to treat all stages of syphilis among HIV- infected patients. Skin testing to confirm penicillin allergy may be used (see Management of the Patient With a History of Penicillin Allergy), but data on the utility of that approach in immunocompromised patients are inadequate. Patients may be desensitized, then treated with penicillin. Syphilis During Pregnancy All women should be screened serologically for syphilis during the early stages of pregnancy. In populations in which utilization of prenatal care is not optimal, RPR-card test screening and treatment, if that test is reactive, should be performed at the time a pregnancy is diagnosed. In communities and populations with high syphilis prevalence or for patients at high risk, serologic testing should be repeated during the third trimester and again at delivery. (Some states mandate screening at delivery for all women.) Any woman who delivers a stillborn infant after 20 weeks gestation should be tested for syphilis. No infant should leave the hospital without the serologic status of the infant's mother having been determined at least once during pregnancy. Diagnostic Considerations Seropositive pregnant women should be considered infected unless treatment history is clearly documented in a medical or health department record and sequential serologic antibody titers have appropriately declined. Treatment Penicillin is effective for preventing transmission to fetuses and for treating established infection among fetuses. Evidence is insufficient, however, to determine whether the specific, recommended penicillin regimens are optimal. Recommended Regimens - Treatment during pregnancy should be the penicillin regimen appropriate for the woman's stage of syphilis. Some experts recommend additional therapy (e.g., a second dose of benzathine penicillin 2.4 million units IM) 1 week after the initial dose, particularly for those women in the third trimester of pregnancy and for women who have secondary syphilis during pregnancy. Other Management Considerations Women who are treated for syphilis during the second half of pregnancy are at risk for premature labor or fetal distress, or both, if their treatment precipitates the Jarisch-Herxheimer reaction. These women should be advised to seek medical attention following treatment if they notice any change in fetal movements or if they have contractions. Stillbirth is a rare complication of treatment; however, since therapy is necessary to prevent further fetal damage, that concern should not delay treatment. All patients with syphilis should be tested for HIV. Follow-Up Serologic titers should be checked monthly until adequacy of treatment has been assured. The antibody response should be appropriate for the stage of disease. Management of Sex Partners Refer to General Principles, Management of Sex Partners. Special Considerations Penicillin Allergy - There are no proven alternatives to penicillin. A pregnant woman with a history of penicillin allergy should be treated with penicillin, after desensitization, if necessary. Skin testing may be helpful for some patients and in some settings (see Management of the Patient With a History of Penicillin Allergy). Tetracycline and doxycycline are contraindicated during pregnancy. Erythromycin should not be used because it cannot be relied upon to cure an infected fetus. Congenital Syphilis Diagnostic Considerations Who Should Be Evaluated - Infants should be evaluated for congenital syphilis if they were born to seropositive (nontreponemal test confirmed by treponemal test) women who meet the following criteria: -- Have untreated syphilis;* or -- Were treated for syphilis during pregnancy with erythromycin; or -- Were treated for syphilis less than 1 month before delivery; or -- Were treated for syphilis during pregnancy with the appropriate penicillin regimen, but nontreponemal antibody titers did not decrease sufficiently after therapy to indicate an adequate response ( greater than or equal to fourfold decrease); or -- Do not have a well-documented history of treatment for syphilis; or -- Were treated appropriately before pregnancy but had insufficient serologic follow-up to assure that they had responded appropriately to treatment and are not currently infected ( greater than or equal to fourfold decrease for patients treated for early syphilis; stable or declining titers less than or equal to 1:4 for other patients). No infant should leave the hospital without the serologic status of the infant's mother having been documented at least once during pregnancy. Serologic testing also should be performed at delivery in communities and populations at risk for congenital syphilis. Serologic tests can be nonreactive among infants infected late during their mother's pregnancy. * A woman treated with a regimen other than those recommended for treatment of syphilis (for pregnant women or otherwise) in these guidelines should be considered untreated. Evaluation of the Infant - The clinical and laboratory evaluation of infants born to women described above should include the following: -- A thorough physical examination for evidence of congenital syphilis; -- A quantitative nontreponemal serologic test for syphilis performed on the infant's sera (not on cord blood); -- CSF analysis for cells, protein, and VDRL; -- Long bone x-rays; -- Other tests as clinically indicated (e.g., chest x-ray, complete blood count, differential and platelet count, liver function tests); -- For infants who have no evidence of congenital syphilis on the above evaluation, determination of presence of specific antitreponemal IgM antibody by a testing method recognized by CDC as having either provisional or standard status; -- Pathologic examination of the placenta or amniotic cord using specific fluorescent antitreponemal antibody staining. Treatment Therapy Decisions - Infants should be treated for presumed congenital syphilis if they were born to mothers who, at delivery, had untreated syphilis or who had evidence of relapse or reinfection after treatment (see Congenital Syphilis, Diagnostic Considerations). Additional criteria for presumptively treating infants with congenital syphilis are as follows: -- Physical evidence of active disease; -- X-ray evidence of active disease; -- A reactive VDRL-CSF or, for infants born to seroreactive mothers, an abnormal ** CSF white blood cell count or protein, regardless of CSF serology; -- A serum quantitative nontreponemal serologic titer that is at least fourfold greater than the mother's titer ***; -- Specific antitreponemal IgM antibody detected by a testing method that has been given provisional or standard status by CDC; -- If they meet the previously cited criteria for "Who Should Be Evaluated," but have not been fully evaluated (see Congenital Syphilis, Diagnostic Considerations). NOTE: Infants with clinically evident congenital syphilis should have an ophthalmologic examination. ** In the immediate newborn period, interpretation of CSF test results may be difficult; normal values vary with gestational age and are higher in preterm infants. Other causes of elevated values also should be considered when an infant is being evaluated for congenital syphilis. Though values as high as 25 white blood cells(WBC)/mm3 and 150 mg protein/dL occur among normal neonates, some experts recommend that lower values (5 WBC/mm3 and 40 mg/dL) be considered the upper limits of normal. The infant should be treated if test results cannot exclude infection. *** The absence of a fourfold greater titer for an infant cannot be used as evidence against congenital syphilis. Recommended Regimens - Aqueous crystalline penicillin G, 100,000-150,000 units/kg/day (administered as 50,000 units/kg IV every 12 hours during the first 7 days of life and every 8 hours thereafter) for 10-14 days, or Procaine penicillin G, 50,000 units/kg IM daily in a single dose for 10-14 days. If more than 1 day of therapy is missed, the entire course should be restarted. An infant whose complete evaluation was normal and whose mother was a) treated for syphilis during pregnancy with erythromycin, or b) treated for syphilis less than 1 month before delivery, or c) treated with an appropriate regimen before or during pregnancy but did not yet have an adequate serologic response should be treated with benzathine penicillin G, 50,000 units/kg IM in a single dose. In some cases, infants with a normal complete evaluation for whom follow-up can be assured can be followed closely without treatment. Treatment of Older Infants and Children with Congenital Syphilis After the newborn period, children diagnosed with syphilis should have a CSF examination to exclude neurosyphilis and records should be reviewed to assess whether the child has congenital or acquired syphilis (see Primary and Secondary Syphilis and Latent Syphilis). Any child who is thought to have congenital syphilis (or who has neurologic involvement) should be treated with aqueous crystalline penicillin G, 200,000-300,000 units/kg/day IV or IM (administered as 50,000 units/kg every 4-6 hours) for 10-14 days. Follow-Up A seroreactive infant (or an infant whose mother was seroreactive at delivery) who is not treated for congenital syphilis during the perinatal period should receive careful follow-up examinations at 1 month and at 2, 3, 6, and 12 months after therapy. Nontreponemal antibody titers should decline by 3 months of age and should be nonreactive by 6 months of age if the infant was not infected and the titers were the result of passive transfer of antibody from the mother. If these titers are found to be stable or increasing, the child should be re-evaluated, including CSF examination, and fully treated. Passively transferred treponemal antibodies may be present for as long as 1 year. If they are present greater than 1 year, the infant should be re-evaluated and treated for congenital syphilis. Treated infants also should be followed every 2-3 months to assure that nontreponemal antibody titers decline; these infants should have become nonreactive by 6 months of age (response may be slower for infants treated after the neonatal period). Treponemal tests should not be used to evaluate response to treatment because test results can remain positive despite effective therapy if the child was infected. Infants with CSF pleocytosis should undergo CSF examination every 6 months, or until the cell count is normal. If the cell count is still abnormal after 2 years, or if a downward trend is not present at each examination, the child should be re-treated. The VDRL-CSF also should be checked at 6 months; if still reactive, the infant should be re-treated. Follow-up of children treated for congenital syphilis after the newborn period should be the same as that prescribed for congenital syphilis among neonates. Special Considerations Penicillin Allergy - Children who require treatment for syphilis after the newborn period, but who have a history of penicillin allergy, should be treated with penicillin after desensitization, if necessary. Skin testing may be helpful in some patients and settings (see Management of the Patient With a History of Penicillin Allergy). HIV Infection - Mothers of infants with congenital syphilis should be tested for HIV. Infants born to mothers who have HIV infection should be referred for evaluation and appropriate follow-up. No data exist to suggest that infants with congenital syphilis whose mothers are coinfected with HIV require different evaluation, therapy, or follow-up for syphilis than is recommended for all infants. Management of the Patient With a History of Penicillin Allergy No proven alternatives to penicillin are available for treating neurosyphilis, congenital syphilis, or syphilis among pregnant women. Penicillin also is recommended for use, whenever possible, with HIV-infected patients. Unfortunately, 3%-10% of the adult population in the United States have experienced urticaria, angioedema, or anaphylaxis (upper airway obstruction, bronchospasm, or hypotension) with penicillin therapy. Re-administration of penicillin can cause severe immediate reactions among these patients. Because anaphylactic reactions to penicillin can be fatal, every effort should be made to avoid administering penicillin to penicillin-allergic patients, unless the anaphylactic sensitivity has been removed by acute desensitization. However, only approximately 10% of persons who report a history of severe allergic reactions to penicillin are still allergic. With the passage of time after an allergic reaction to penicillin, most persons who have experienced a severe reaction stop expressing penicillin-specific IgE. These persons can be treated safely with penicillin. Many studies have found that skin testing with the major and minor determinants can reliably identify persons at high risk for penicillin reactions. Although these reagents are easily generated and have been available in academic centers for greater than 30 years, currently only penicilloyl-poly-L-lysine (Pre-Pen, the major determinant) and penicillin G are available commercially. Experts estimate that testing with only the major determinant and penicillin G detects 90%-97% of the currently allergic patients. However, because skin testing without the minor determinants would still miss 3%-10% of allergic patients, and serious or fatal reactions can occur among these minor determinant positive patients, experts suggest caution when the full battery of skin test reagents listed in the table is not available. Recommendations If the full battery of skin-test reagents is available, including the major and minor determinants (see Penicillin Allergy Skin Testing), patients who report a history of penicillin reaction and are skin-test negative can receive conventional penicillin therapy. Skin-test positive patients should be desensitized. If the full battery of skin-test reagents, including the minor determinants, is not available, the patient should be skin tested using penicilloyl (the major determinant, Pre-Pen) and penicillin G. Those with positive tests should be desensitized. Some experts believe that persons with negative tests, in that situation, should be regarded as probably allergic and should be desensitized. Others suggest that those with negative skin tests can be test-dosed gradually with oral penicillin in a monitored setting in which treatment for anaphylactic reaction is possible. Penicillin Allergy Skin Testing Patients at high risk for anaphylaxis (i.e., a history of penicillin-related anaphylaxis, asthma or other diseases that would make anaphylaxis more dangerous, or therapy with beta-adrenergic blocking agents) should be tested with 100-fold dilutions of the full-strength skin-test reagents before testing with full-strength reagents. In these situations, patients should be tested in a monitored setting in which treatment for an anaphylactic reaction is possible. If possible, the patient should not have taken antihistamines (e.g., chlorpheniramine maleate or terfenadine during the past 24 hours, diphenhydramine HCl or hydroxyzine during the past 4 days, or astemizole during the past 3 weeks). Reagents (Adapted from Beall {14})* Major Determinant - -- Benzylpenicilloyl poly-L-lysine (Pre-Pen {Taylor Pharmacal Company, Decatur, Illinois}) (6 x 10-5M). Minor Determinant Precursors ** -- Benzylpenicillin G (10-2M, 3.3 mg/mL, 6000 U/mL), -- Benzylpenicilloate (10-2M, 3.3 mg/mL), -- Benzylpenilloate (or penicilloyl propylamine)(10-2M, 3.3 mg/mL). Positive Control - -- Commercial histamine for epicutaneous skin testing (1 mg/mL). Negative Control - -- Diluent used to dissolve other reagents, usually phenol saline. Procedures - Dilute the antigens 100-fold for preliminary testing if the patient has had a life-threatening reaction, or 10-fold if the patient has had another type of immediate, generalized reaction within the past year. Epicutaneous (prick) tests. Duplicate drops of skin-test reagent are placed on the volar surface of the forearm. The underlying epidermis is pierced with a 26-gauge needle without drawing blood. An epicutaneous test is positive if the average wheal diameter after 15 minutes is 4 mm larger than that of negative controls; otherwise, the test is negative. The histamine controls should be positive to assure that results are not falsely negative because of the effect of antihistaminic drugs. Intradermal test. If epicutaneous tests are negative, duplicate 0.02 mL intradermal injections of negative control and antigen solutions are made into the volar surface of the forearm using a 26- or 27-gauge needle on a syringe. The crossed diameters of the wheals induced by the injections should be recorded. An intradermal test is positive if the average wheal diameter 15 minutes after injection is 2 mm or larger than the initial wheal size and also is at least 2 mm larger than the negative controls. Otherwise, the tests are negative. Desensitization Patients who have a positive skin test to one of the penicillin determinants can be desensitized. This is a straightforward, relatively safe procedure that can be done orally or IV. Although the two approaches have not been compared, oral desensitization is thought to be safer, simpler, and easier. Patients should be desensitized in a hospital setting because serious IgE-mediated allergic reactions, although unlikely, can occur. Desensitization can usually be completed in about 4 hours, after which the first dose of penicillin is given Table_1. STD programs should have a referral center where patients with positive skin tests can be desensitized. After desensitization, patients must be maintained on penicillin continuously for the duration of the course of therapy. * Reprinted with permission from G.N. Beall in Annals of Internal Medicine. ** Aged penicillin is not an adequate source of minor determinants. Penicillin G should be freshly prepared or should come from a fresh-frozen source.
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