Syphilis PDF - Red Book 2018

SYPHILIS 773 people, because excretion of larvae in feces is highly vari...

SYPHILIS 773 people, because excretion of larvae in feces is highly variable and often of low intensity. At least 3 consecutive stool specimens should be examined microscopically for character- istic larvae (not eggs), but stool concentration techniques may be required to establish the diagnosis. The use of culture methods to visualize tracks of larval migration on agar me- dia may have greater sensitivity than fecal microscopy, but these techniques are not avail- able in all laboratories; examination of duodenal contents obtained using the string test (Entero-Test) or a direct aspirate through a flexible endoscope also may demonstrate lar- vae. Eosinophilia (blood eosinophil count greater than 500/µL) is common in chronic infection, but its absence does not eliminate infection from consideration. When eosino- philia is absent in hyperinfection syndrome, it may predict poor outcome. Serodiagnosis by enzyme immunoassay is more sensitive, although variable among different commercial assays, and cross-reaction with other nematode species is possible; newer methods such as a luciferase immunoprecipitation system technique with recombinant antigen are even All rights reserved. May not be reproduced in any form without permission from the publisher, except fair uses permitted under U.S. or applicable copyright law. more sensitive and specific but currently only available in reference laboratories. Because infection can persist for decades, a positive serologic test result in the absence of previous treatment should be considered evidence of current infection. In disseminated strongyloidiasis, filariform larvae may be isolated from other speci- mens such as sputum or bronchoalveolar lavage fluid, spinal fluid, or in skin biopsies. Gram-negative bacillary meningitis and bacteremia are commonly associated findings in disseminated disease and carry a high mortality rate. TREATMENT: Ivermectin is the treatment of choice for both chronic (asymptomatic) strongyloidiasis and hyperinfection with disseminated disease. Ivermectin is approved by the US Food and Drug Administration for the treatment of intestinal strongyloidiasis. An alternative agent is albendazole, although it is associated with lower cure rates (see Drugs for Parasitic Infections, p 985). Mebendazole is not recommended. Prolonged or repeated treatment may be necessary in people with hyperinfection and disseminated strongyloidi- asis, and relapse can occur. ISOLATION OF THE HOSPITALIZED PATIENT: Standard precautions are recommended. CONTROL MEASURES: Sanitary disposal of human waste is effective at interrupting transmission of S stercoralis. Serodiagnosis should be considered in all people with unex- plained eosinophilia. Any individual at risk epidemiologically for strongyloidiasis who will undergo a solid organ or hematopoietic stem cell transplant or immunosuppressant ther- apy, particularly with corticosteroids, either should be tested by serology (with treatment if positive), or presumptively treated for strongyloidiasis before the initiation of immuno- suppression. Syphilis CLINICAL MANIFESTATIONS: Copyright 2018. American Academy of Pediatrics. Congenital Syphilis. Intrauterine infection with Treponema pallidum can result in stillbirth, hydrops fetalis, or preterm birth or may be asymptomatic at birth. Infected infants can have hepatosplenomegaly; snuffles (copious nasal secretions); lymphadenopathy; mucocu- taneous lesions; pneumonia; osteochondritis, periostitis, and pseudoparalysis; edema; rash (maculopapular consisting of small dark red-copper spots that is most severe on the hands and feet); hemolytic anemia; or thrombocytopenia at birth or within the first 4 to 8 weeks of age. Skin lesions or moist nasal secretions of congenital syphilis are highly infectious. However, organisms rarely are found in lesions more than 24 hours after treatment has EBSCO Publishing : eBook Academic Collection (EBSCOhost) - printed on 8/17/2021 6:26 AM via UNIV OF SOUTH ALABAMA AN: 1809323 ; Kimberlin, David W., Brady, Michael T., Jackson, Mary Anne, Long, Sarah S..; Red Book 2018 : Report of the Committee on Infectious Diseases Account: s4595122.main.emed  774 SYPHILIS begun. Untreated infants, regardless of whether they have manifestations in early infancy, may develop late manifestations, which usually appear after 2 years of age and involve the central nervous system (CNS), bones and joints, teeth, eyes, and skin. Some consequences of intrauterine infection may not become apparent until many years after birth, such as interstitial keratitis (5–20 years of age), eighth cranial nerve deafness (10–40 years of age), Hutchinson teeth (peg-shaped, notched central incisors), anterior bowing of the shins, frontal bossing, mulberry molars, saddle nose, rhagades (perioral fissures), and Clutton joints (symmetric, painless swelling of the knees). The first 3 manifestations are referred to as the Hutchinson triad. Late manifestations can be prevented by treatment of early infec- tion. Acquired Syphilis. Infection with T pallidum in childhood or adulthood can be divided into 3 stages. The primary stage (or “primary syphilis”) appears as one or more painless indurated ulcers (chancres) of the skin or mucous membranes at the site of inoculation. Lesions most commonly appear on the genitalia but may appear elsewhere, depending on the sexual contact responsible for transmission (eg, oral, anal). These lesions appear, on average, 3 weeks after exposure (10–90 days) and heal spontaneously in a few weeks. Adjacent lymph nodes frequently are enlarged but are nontender. Chancres sometimes are not recognized clinically and sometimes still are present during the secondary stage of syphilis. The secondary stage (or “secondary syphilis”), beginning 1 to 2 months later, is characterized by fever, sore throat, muscle aches, rash, mucocutaneous lesions, and generalized lymphadenopathy. The polymorphic maculopapular rash is generalized and typically includes the palms and soles. In moist areas around the vulva or anus, hy- pertrophic papular lesions (condyloma lata) can occur and can be confused with condy- loma acuminata secondary to human papillomavirus (HPV) infection. Malaise, spleno- megaly, headache, alopecia, and arthralgia also can be present. Secondary syphilis can be mistaken for other conditions, because its signs and symptoms are nonspecific. This stage also resolves spontaneously without treatment in approximately 3 to 12 weeks, leaving the infected person completely asymptomatic. A variable latent period follows but sometimes is interrupted during the first few years by recurrences of symptoms of secondary syphilis. Latent syphilis is defined as the period after infection when patients are seroreactive but demonstrate no clinical manifestations of disease. Latent syphilis acquired within the preceding year is referred to as early latent syphilis; all other cases of latent syphilis are late latent syphilis (greater than 1 year’s duration). Patients who have latent syphi- lis of unknown duration should be managed clinically as if they have late latent syphilis. The tertiary stage of infection occurs 15 to 30 years after the initial infection and can include gumma formation (soft, noncancerous growths that can destroy tissue) or cardio- vascular involvement (including aortitis). Neurosyphilis, defined as infection of the central nervous system (CNS) with T pallidum, can occur at any stage of infection, especially in people infected with human immunodeficiency virus (HIV) and neonates with congenital syphilis. Manifestations of neurosyphilis include syphilitic meningitis, uveitis, seizures, optic atrophy, and (typically years after infection) dementia and posterior spinal cord de- generation (tabes dorsalis, including a characteristic high-stepping gait with the feet slap- ping the ground with each step because of loss of proprioception). ETIOLOGY: T pallidum subspecies pallidum (T pallidum) is a thin, motile spirochete that is extremely fastidious, surviving only briefly outside the host. The organism has not been cultivated successfully on artificial media. It is the causative agent of venereal syphilis and is very closely related to 3 other organisms causing nonvenereal human disease in distinct EBSCOhost - printed on 8/17/2021 6:26 AM via UNIV OF SOUTH ALABAMA. All use subject to https://www.ebsco.com/terms-of-use  SYPHILIS 775 geographic regions of the world: T pallidum subspecies pertenue, which causes yaws; T pal- lidum subspecies endemica, which causes endemic syphilis; and Treponema carateum, which causes pinta. The genus Treponema, along with the genus Borrelia, are currently classified in the family Spirochaetaceae. EPIDEMIOLOGY: Syphilis, which is rare in much of the industrialized world, persists in the United States and in resource-limited countries. In 2000 and 2001, the rate of prima- ry and secondary syphilis was the lowest since reporting began in 1941. The rate of pri- mary and secondary syphilis has increased almost every year since then, although initially mostly among men who have sex with men. In 2014, the rate of primary and secondary syphilis increased in every region of the United States in both men and women, with a concomitant increase in cases of congenital syphilis. 1 In adults, infection with HIV is common among individuals with syphilis, particularly among men who have sex with men. Primary and secondary rates of syphilis are highest in black, non-Hispanic people and in males compared with females. Congenital syphilis is contracted from an infected mother via transplacental transmis- sion of T pallidum at any time during pregnancy, or possibly at birth from contact with maternal lesions. Among women with untreated early syphilis, as many as 40% of preg- nancies result in spontaneous abortion, stillbirth, or perinatal death. Infection can be transmitted to the fetus at any stage of maternal disease. The rate of transmission is 60% to 100% during primary and secondary syphilis and slowly decreases with later stages of maternal infection (approximately 40% with early latent infection and 8% with late latent infection). Acquired syphilis almost always is contracted through direct sexual contact with ul- cerative lesions of the skin or mucous membranes of infected people. Open, moist lesions of the primary or secondary stages are highly infectious. Relapses of secondary syphilis with infectious mucocutaneous lesions have been observed 4 years after primary infection. Syphilis acquired beyond the neonatal period should be considered highly suggestive of sexual abuse in infants and prepubertal children once rare vertical transmission is ex- cluded (see Screening Sexually Victimized Children for STIs, p 58). The possibility of nonvenereal endemic syphilis should also be considered in children who have recently emigrated from areas with endemic infection. Health care providers are required to re- port suspected sexual abuse to the state child protective services agency. This mandate does not require that the provider is certain that abuse has occurred but only that there is “reasonable cause to suspect abuse.” The incubation period for acquired primary syphilis typically is 3 weeks but rang- es from 10 to 90 days. DIAGNOSTIC TESTS: Definitive diagnosis is made when spirochetes are identified by mi- croscopic darkfield examination of lesion exudate, nasal discharge, or tissue, such as pla- centa, umbilical cord, or autopsy specimens. T pallidum can be detected by polymerase chain reaction (PCR) assay, but clinical diagnostic PCR assays cleared by the US Food and Drug Administration (FDA) are not yet available. Direct fluorescent antibody (DFA) tests no longer are available in the United States. Specimens should be scraped from moist mucocutaneous lesions or aspirated from a regional lymph node. Specimens from mouth lesions can contain nonpathogenic treponemes that can be difficult to distinguish 1 Bowen V, Su J, Torrone E, Kidd S, Weinstock H. Increase in incidence of congenital syphilis—United States, 2012–2014. MMWR Morb Mortal Wkly Rep. 2015;64(44):1241–1245 EBSCOhost - printed on 8/17/2021 6:26 AM via UNIV OF SOUTH ALABAMA. All use subject to https://www.ebsco.com/terms-of-use  776 SYPHILIS from T pallidum by darkfield microscopy. Although such testing can provide a definitive diagnosis, serologic testing also is necessary. Presumptive diagnosis requires the use of both nontreponemal and treponemal sero- logic tests. Nontreponemal tests for syphilis include the Venereal Disease Research La- boratory (VDRL) slide test and the rapid plasma reagin (RPR) test. These tests are inex- pensive, are performed rapidly, and provide semiquantitative results through serial twofold dilutions that can help define disease activity and monitor response to therapy. However, nontreponemal test results may be falsely negative (ie, nonreactive) in early primary syphilis, latent acquired syphilis of long duration, and late congenital syphilis. Occasionally, a nontreponemal test performed on serum samples containing high concen- trations of antibody against T pallidum will be weakly reactive or falsely negative, a reac- tion termed the prozone phenomenon; diluting serum results in a positive test. RPR titers generally are higher than VDRL titers; therefore, when nontreponemal tests are used to monitor treatment response, the same test must be used throughout the follow-up period, preferably performed by the same laboratory, to ensure comparability of results. A reactive nontreponemal test result from a patient with typical lesions indicates a presumptive diagnosis of syphilis but must be confirmed by one of the specific treponemal tests to exclude a false-positive test result. False-positive nontreponemal results can be caused by certain viral infections (eg, Epstein-Barr virus infection, hepatitis, varicella, measles), lymphoma, tuberculosis, malaria, endocarditis, connective tissue disease, preg- nancy, abuse of injection drugs, laboratory or technical error, or Wharton jelly contami- nation when umbilical cord blood specimens are used. Treatment should not be delayed while awaiting the results of the treponemal test results if the patient is symptomatic or at high risk of infection. A sustained fourfold or greater decrease in titer, equivalent to a change of 2 dilutions (eg, from 1:32 to 1:8), of the nontreponemal test result after treat- ment usually demonstrates adequate therapy, whereas a sustained fourfold or greater increase in titer (eg, from 1:8 to 1:32) after treatment suggests reinfection or relapse. The nontreponemal test titer usually decreases fourfold within 6 to 12 months after therapy for primary or secondary syphilis and usually becomes nonreactive within 1 year after suc- cessful therapy if the infection (primary or secondary syphilis) was treated early. The pa- tient usually becomes seronegative within 2 years even if the initial titer was high or the infection was congenital. Some people will continue to have low stable nontreponemal antibody titers (eg, VDRL titer 1:2 or less, RPR titer 1:4 or less) despite effective therapy. This serofast state is more common in patients treated for latent or tertiary syphilis. Treponemal tests in use include the T pallidum particle agglutination (TP-PA) test, T pallidum enzyme immunoassay (TP-EIA), T pallidum chemiluminescent assay (TP-CIA), and fluorescent treponemal antibody absorption (FTA-ABS) test. Most people who have reactive treponemal test results remain reactive for life, even after successful therapy. However, 15% to 25% of patients treated during the primary stage revert to being sero- logically nonreactive on treponemal testing after 2 to 3 years. Treponemal tests also are not 100% specific for syphilis; positive reactions occur variably in patients with other spi- rochetal diseases, such as yaws, pinta, leptospirosis, rat-bite fever, relapsing fever, and Lyme disease. Nontreponemal tests can be used to differentiate Lyme disease from syphi- lis, because the VDRL test is nonreactive in Lyme disease. In most cases, if a patient has a positive RPR or VDRL in low titer and has a negative treponemal test result, the nontreponemal antibody test result will be a false positive. However, in patients with early syphilis, the nontreponemal test may become positive EBSCOhost - printed on 8/17/2021 6:26 AM via UNIV OF SOUTH ALABAMA. All use subject to https://www.ebsco.com/terms-of-use  SYPHILIS 777 before the treponemal test. Therefore, retesting in 2 to 4 weeks and again later if clinically indicated should be considered in persons at increased risk for syphilis, including preg- nant women. The Centers for Disease Control and Prevention (CDC) 1 and the US Preventive Ser- vices Task Force (USPSTF) 2 recommend syphilis serologic screening with a nontrepo- nemal test to identify people with possible untreated infection; this screening is followed by confirmation using one of the several available treponemal tests (“conventional diag- nostic” approach). However, because of cost issues, some clinical laboratories and blood banks have begun to screen samples using treponemal tests (eg, TP-EIA or TP-CIA) first rather than beginning with a nontreponemal test. This “reverse-sequence screening” approach can be associated with high rates of false-positive results, especially in low- prevalence populations. When the reverse-sequence algorithm is used, people with a positive TP-EIA/TP-CIA result and a negative nontreponemal test result (discordant result) should have a second treponemal test targeting a different T pallidum antigen per- formed to confirm the results of the original test. If the second treponemal test result is negative and the person is at low risk for syphilis, the original treponemal test result likely was a false positive. All patients who have syphilis should be tested for HIV infection and other sexually transmitted infections (STIs). Point-of-care syphilis tests have been developed, primarily for use in adults in the developing world (http://apps.who.int/iris/bitstream/ 10665/43590/1/TDR_SDI_06.1_eng.pdf). Cerebrospinal Fluid Tests. Cerebrospinal fluid (CSF) abnormalities in patients with neuro- syphilis can include increased protein concentration, increased white blood cell (WBC) count, and/or a reactive CSF-VDRL test result. Outside the neonatal period, the CSF- VDRL is highly specific but is insensitive; therefore, a negative CSF-VDRL result does not exclude a diagnosis of neurosyphilis. Conversely, a reactive CSF-VDRL test in a neo- nate can be the result of nontreponemal IgG antibodies that cross the blood-brain barri- er. The CSF leukocyte count usually is elevated in neurosyphilis (>5 WBCs/mm3). CSF cell counts as high as 25 WBCs/mm3 and/or protein concentration up to 150 mg/dL may occur among normal, noninfected term neonates and can be even higher in preterm neonates; however, lower values (ie, 5 WBCs/mm3 and protein of 40 mg/dL) should be considered the upper limits of normal when assessing a term infant for congenital syphilis. A positive CSF FTA-ABS result can support the diagnosis of neurosyphilis but by itself cannot establish the diagnosis. Fewer data exist for the TP-PA or RPR test for CSF, and these tests should not be used for CSF evaluation. Testing During Pregnancy. Prevention of congenital syphilis depends on the identification and adequate treatment of pregnant women with syphilis. All women should be screened serologically for syphilis early in pregnancy. False-negative test results are possible in recent infection, and syphilis may be acquired later in pregnancy. Therefore, in commu- nities and populations in which the prevalence of syphilis is high, and for women at high risk for infection, serologic testing also should be performed at 28 to 32 weeks’ gestation and again at delivery. A nontreponemal test (RPR or VDRL) is recommended for 1Centersfor Disease Control and Prevention. Sexually transmitted diseases treatment guidelines, 2015. MMWR Recomm Rep. 2015;64(RR-3):34–51 2 US Preventive Services Task Force. Screening for syphilis infection in non-pregnant adults and adolescents. JAMA. 2016;315(21):2321–2327 EBSCOhost - printed on 8/17/2021 6:26 AM via UNIV OF SOUTH ALABAMA. All use subject to https://www.ebsco.com/terms-of-use  778 SYPHILIS screening, followed by a treponemal test if the screening result is positive. In most cases, if the treponemal antibody test result is negative, the nontreponemal test result is falsely positive and no further evaluation is necessary. However, retesting in 2 to 4 weeks, and again later if clinically indicated, should be considered for pregnant women who are at high risk of syphilis. If the reverse-sequence screening algorithm is used, pregnant women with reactive treponemal EIA/CIA screening test results should have confirmatory testing with a quan- titative nontreponemal test. If the nontreponemal test result is negative (discordant result), a second treponemal test using a different T pallidum antigen should be obtained to de- termine whether the initial treponemal test result was a false positive. If the second trepo- nemal test result is positive, it may be attributable to a prior infection adequately treated in the past or to untreated syphilis in a late stage. For women treated for syphilis during pregnancy, follow-up nontreponemal serologic testing is necessary to assess the effectiveness of therapy. Treated pregnant women with syphilis should have quantitative nontreponemal serologic tests repeated at 28 to 32 weeks of gestation, at delivery, and according to recommendations for the stage of disease. Sero- logic titers may be repeated monthly in women at high risk of reinfection or in geographic areas where the prevalence of syphilis is high. Sonographic evaluation of the fetus should be performed when syphilis is diagnosed during the second half of pregnancy. Pathologic examination of the placenta and/or um- bilical cord at delivery also should be performed. Any woman who delivers a stillborn infant after 20 weeks’ gestation should be tested for syphilis. Evaluation of Infants for Congenital Infection During the Newborn Period to 1 Month of Age. No newborn infant should be discharged from the hospital without determination of the mother’s serologic status for syphilis. All infants born to seropositive mothers require a careful examination and a nontreponemal test obtained from the infant. The test per- formed on the infant should be the same as that performed on the mother to enable com- parison of titer results. A negative maternal RPR or VDRL test result at delivery does not rule out the possibility of the infant having congenital syphilis, although such a situation is rare. The diagnostic approach to infants being evaluated for congenital syphilis is pre- sented in Fig 3.10 (p 781), with treatment recommendations provided in Table 3.76 (p 782). Other causes of elevated CSF laboratory values should be considered when an infant is being evaluated for congenital syphilis. Infants born to mothers who have syphilis and HIV infection do not require different evaluation, therapy, or follow-up for syphilis than is recommended for all infants. 1 Evaluation of Infants >1 Month of Age and Children. Infants and children identified as having reactive serologic tests for syphilis should have maternal serologic test results and records reviewed to assess whether they have congenital or acquired syphilis. The recommended evaluation for congenital syphilis includes a CSF examination plus other tests as clinically indicated. CSF examination also should be performed in patients with neurologic or 1Guidelines for prevention and treatment of opportunistic infections in HIV-exposed and HIV-infected chil- dren. Recommendations from the National Institutes of Health, Centers for Disease Control and Prevention, the HIV Medicine Association of the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the American Academy of Pediatrics. Pediatr Infect Dis J. 2013;32(Suppl 2):i-KK4. Available at: http://aidsinfo.nih.gov/guidelines/html/5/pediatric-oi-prevention-and-treatment- guidelines/0 EBSCOhost - printed on 8/17/2021 6:26 AM via UNIV OF SOUTH ALABAMA. All use subject to https://www.ebsco.com/terms-of-use  SYPHILIS 779 Fig 3.10. Algorithm for diagnostic approach of infants born to mothers with reactive serologic tests for syphilis. RPR indicates rapid plasma reagin; VDRL, Venereal Disease Research Laboratory. a Treponema pallidum particle agglutination (TP-PA) (which is the preferred treponemal test), fluorescent treponemal antibody absorption (FTA-ABS), or microhemagglutination test for antibodies to T pallidum (MHA-TP). b Test for human immunodeficiency virus (HIV) antibody. Infants of HIV-infected mothers do not require different evaluation or treatment for syphilis. c A fourfold change in titer is the same as a change of 2 dilutions. For example, a titer of 1:64 is fourfold greater than a titer of 1:16, and a titer of 1:4 is fourfold lower than a titer of 1:16. When comparing titers, the same type of nontreponemal test should be used (eg, if the initial test was an RPR, the follow-up test should also be an RPR). d Stable VDRL titers 1:2 or less or RPR 1:4 or less beyond 1 year after successful treatment are considered low serofast. e Complete blood cell (CBC) and platelet count; cerebrospinal fluid (CSF) examination for cell count, protein, and quantitative VDRL; other tests as clinically indicated (eg, chest radiographs, long-bone radiographs, eye examination, liver function tests, neuroimaging, and auditory brainstem response). EBSCOhost - printed on 8/17/2021 6:26 AM via UNIV OF SOUTH ALABAMA. All use subject to https://www.ebsco.com/terms-of-use  780 SYPHILIS ophthalmic signs or symptoms (eg, iritis, uveitis), evidence of active tertiary syphilis (eg, aortitis, gumma), or treatment failure. Some experts recommend performing a CSF ex- amination on all patients who have latent syphilis and a nontreponemal serologic test result of 1:32 or greater or in patients who are HIV infected and have a serum CD4+ T- lymphocyte count of 350 or less, because the risk of asymptomatic neurosyphilis in these circumstances is increased approximately threefold. However, among people with HIV infection and syphilis, CSF examination has not been associated with improved clinical outcomes in the absence of neurologic signs and symptoms. TREATMENT 1: Parenteral penicillin G remains the preferred drug for treatment of syphilis at any stage. Recommendations for penicillin G use and duration of therapy vary, de- pending on the stage of disease and clinical manifestations. Parenteral penicillin G is the only documented effective therapy for patients who have neurosyphilis, congenital syphi- lis, or syphilis during pregnancy and is recommended for people with HIV infection. Penicillin Allergy. Infants and children with a history of penicillin allergy or who develop presumed penicillin allergy during treatment should be desensitized and then treated with penicillin whenever possible. Table 3.76. Evaluation and Treatment of Infants With Possible, Probable, or Confirmed Congenital Syphilis Recommended Category Findings Evaluation Treatment Proven or Abnormal physical exami- CSF analysis (CSF Aqueous crystalline peni- highly nation consistent with VDRL, cell count, and cillin G, 50 000 U/kg, probable congenital syphilis protein) IV, every 12 hours (1 wk congenital or younger), then every syphilis OR CBC count with differen- 8 h for infants older tial and platelet count than 1 wk, for a total of A serum quantitative non- 10 days of therapya treponemal serologic titer Other tests (as clinically (preferred) that is fourfold higher indicated): than the mother’s titer Long-bone radiography OR Chest radiography OR Transaminases Procaine penicillin G, Neuroimaging 50 000 U/kg, IM, as A positive result of darkfield Ophthalmologic single daily dose for 10 test or PCR assay of le- examination days sions or body fluid(s) Auditory brain stem response Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines, 2015. MMWR 1 Recomm Rep. 2015;64(RR-3):34–51 EBSCOhost - printed on 8/17/2021 6:26 AM via UNIV OF SOUTH ALABAMA. All use subject to https://www.ebsco.com/terms-of-use  SYPHILIS 781 Table 3.76. Evaluation and Treatment of Infants With Possible, Probable, or Confirmed Congenital Syphilis, continued Recommended Category Findings Evaluation Treatment Possible Normal infant exami- CSF analysis (CSF Aqueous crystalline penicil- congenital nation VDRL, CBC lin G, 50 000 U/kg, IV, syphilis count, and protein) every 12 h (1 wk or AND younger), then every 8 h CBC count with dif- for infants older than 1 A serum quantitative ferential and plate- wk, for a total of 10 days nontreponemal sero- let count of therapya (preferred) logic titer equal to or less than fourfold the Long-bone radiog- OR maternal titer raphy Procaine penicillin G, AND ONE OF THE These evaluations 50 000 U/kg, IM, as sin- FOLLOWING: may not be neces- gle daily dose for 10 days sary if 10 days of Mother was not treat- parenteral therapy OR ed, was inadequately is administered treated, or had no Benzathine penicillin G, documentation of 50 000 U/kg, IM, single receiving treatment; dose (recommended by some experts, but only if OR all components of the evaluation are obtained Mother was treated and are normal, includ- with erythromycin or ing normal CSF resultsb a regimen other than and follow-up is certain those recommended (some experts) in the guideline (ie, a nonpenicillin regi- men) OR Mother received rec- ommended treat- ment 4 wk before 3 mo of age and should delivery be nonreactive by 6 mo of age whether the infant AND was infected and ade- quately treated or was Mother has no evi- not infected and initially dence of reinfection seropositive because of or relapse transplacentally acquired maternal antibody. Pa- tients with increasing ti- ters or with persistent stable titers 6 to 12 mo after initial treatment should be reevaluated, including a CSF exami- nation, and treated with a 10-day course of paren- teral penicillin G, even if they were treated previ- ously. EBSCOhost - printed on 8/17/2021 6:26 AM via UNIV OF SOUTH ALABAMA. All use subject to https://www.ebsco.com/terms-of-use  SYPHILIS 783 Table 3.76. Evaluation and Treatment of Infants With Possible, Probable, or Confirmed Congenital Syphilis, continued Recommended Category Findings Evaluation Treatment Congenital Normal infant exami- Not recommended No treatment required, but syphilis is nation infants with reactive non- unlikely treponemal tests should AND be followed serologically to ensure test result re- A serum quantitative turns to negative nontreponemal sero- logic titer equal to or Benzathine penicillin G, less than fourfold the 50 000 U/kg, IM, single maternal titer dose can be considered if follow-up is uncertain AND and infant has a reactive test (some experts) Mother was treated adequately before Neonates with a negative pregnancy nontreponemal test result at birth and whose moth- AND ers were seroreactive at delivery should be retest- Mother’s nontrepo- ed at 3 mo to rule out se- nemal serologic titer rologically negative incu- remained low and bating congenital syphilis stable (ie, serofast) at the time of birth before and during pregnancy and at de- livery (eg, VDRL ≤1:2; RPR ≤1:4) PCR indicates polymerase chain reaction; CSF, cerebrospinal fluid; CBC, complete blood cell count; VDRL, Venereal Disease Research Laboratory; IV, intravenously; IM, intramuscularly; RPR, rapid plasma reagin, Adapted and modified from Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines, 2015. MMWR Recomm Rep. 2015;64(RR-3):45–47. a If 24 hours or more of therapy is missed, the entire course must be restarted. b If CSF is not obtained or uninterpretable (eg, bloody tap), a 10-day course is recommended. Congenital Syphilis: Newborn Period to 1 Month of Age. The management of congenital syphilis is based on whether the infant has proven or probable congenital syphilis, has possible congenital syphilis, or is considered less likely or unlikely to have syphilis. The treatment of infants with congenital syphilis is detailed in Table 3.76 (p 782), with the diagnostic approach to such infants presented in Fig 3.10. If more than 1 day of therapy is missed, the entire course should be restarted. Data supporting use of other antimicrobial agents (eg, ampicillin) for treatment of congenital syphilis are not available. When possible, a full 10-day course of penicillin is preferred, even if ampicillin initially was provided for EBSCOhost - printed on 8/17/2021 6:26 AM via UNIV OF SOUTH ALABAMA. All use subject to https://www.ebsco.com/terms-of-use  784 SYPHILIS possible sepsis. Use of agents other than penicillin requires close serologic follow-up to assess adequacy of therapy. Congenital Syphilis: Infants ≥1 Month of Age and Children. Infants older than 1 month who pos- sibly have congenital syphilis should be treated with intravenous aqueous crystalline peni- cillin (200 000–300 000 U/kg/day, intravenously, administered as 50 000 U/kg, every 4– 6 hours for 10 days). This regimen also should be used to treat children older than 2 years who have late and previously untreated congenital syphilis. Some experts suggest giving such patients a single dose of penicillin G benzathine (50 000 U/kg, intramuscularly, not to exceed 2.4 million U) after the 10-day course of intravenous aqueous crystalline peni- cillin. If the patient has no clinical manifestations of disease, the CSF examination is nor- mal, and the result of the CSF-VDRL test is negative, some experts would treat with 3 weekly doses of penicillin G benzathine (50 000 U/kg, intramuscularly, not to exceed 2.4 million U). Syphilis in Pregnancy. Regardless of stage of pregnancy, women should be treated with pen- icillin according to the dosage schedules appropriate for the stage of syphilis as recom- mended for nonpregnant patients (see Table 3.77, p 784). For penicillin-allergic patients, no proven alternative therapy has been established. A pregnant woman with a history of penicillin allergy should have skin testing, if available, to evaluate for true allergy, and should be treated with penicillin if allergy is not confirmed; if allergy is confirmed, the woman should undergo desensitization followed by treatment with penicillin. Erythromy- cin, azithromycin, or any other nonpenicillin treatment of syphilis during pregnancy can- not be considered reliable to cure infection in the fetus. Tetracycline is not recommended for pregnant women because of potential adverse effects on the fetus. Early Acquired Syphilis (Primary, Secondary, Early Latent Syphilis). A single intramuscular dose of penicillin G benzathine is the preferred treatment for children and adults (see Table 3.77). For nonpregnant patients who are allergic to penicillin, doxycycline or (if ≥8 years of age) tetracycline should be given for 14 days. Clinical studies (along with biologic and pharmacologic considerations) suggest that ceftriaxone at 1 g, once daily, either intramus- cularly or intravenously, for 10 to 14 days (for adolescents and adults) is effective for early-acquired syphilis, but the optimal dose and duration of therapy have not been de- fined. Single-dose therapy with ceftriaxone is not effective. Azithromycin can be effective as a single oral dose of 2 g; however, azithromycin treatment failures have been reported, and resistance to azithromycin has been documented. Close follow-up of people receiving any alternative therapy is essential. When follow-up cannot be ensured, especially for children younger than 8 years, consideration must be given to hospitalization and desen- sitization followed by administration of penicillin G. Syphilis of More Than 1 Year’s Duration (Late Latent Syphilis and Late Syphilis). Penicillin G ben- zathine should be administered intramuscularly, weekly, for 3 successive weeks (see Table 3.77, p 784). In patients who are allergic to penicillin, tetracycline or doxycycline (both if ≥8 years of age) for 4 weeks should be given only with close serologic and clinical follow- up. Doxycycline can be used for short durations (ie, 21 days or less) without regard to patient age, but for the longer treatment durations required for treatment of late latent and late syphilis, doxycycline is not recommended for children younger than 8 years (see Tetracyclines, p 905). Limited clinical studies suggest that ceftriaxone might be effective, but the optimal dose and duration have not been defined. EBSCOhost - printed on 8/17/2021 6:26 AM via UNIV OF SOUTH ALABAMA. All use subject to https://www.ebsco.com/terms-of-use  SYPHILIS 785 Table 3.77. Recommended Treatment for Syphilis in People Older Than 1 Month Status Children Adults Primary, Penicillin G benzathine,b Penicillin G benzathine, 2.4 million U, IM, in secondary, 50 000 U/kg, IM, a single dose and early up to the adult dose of 2.4 OR latent million U in a single dose If allergic to penicillin and not pregnant, syphilisa Doxycycline, 100 mg, orally, twice a day for 14 days OR Tetracycline, 500 mg, orally, 4 times/day for 14 days (≥8 y only) Late latent Penicillin G benzathine, Penicillin G benzathine, 7.2 million U total, syphilisc 50 000 U/kg, IM, administered as 3 doses of up to the adult dose of 2.4 2.4 million U, IM, each at 1-wk intervals million U, administered as OR 3 single doses at 1-wk If allergic to penicillin and not pregnant, intervals (total 150 000 Doxycycline, 100 mg, orally, twice a day for U/kg, up to the 4 wk (≥8 y only) adult dose of 7.2 million U) OR Tetracycline, 500 mg, orally, 4 times/day for 4 wk (≥8 y only) Tertiary … Penicillin G benzathine, 7.2 million U total, administered as 3 doses of 2.4 million U, IM, at 1-wk intervals If allergic to penicillin and not pregnant, consult an infectious diseases expert Neurosyphilisd Aqueous crystalline penicillin Aqueous crystalline penicillin G, 18–24 mil- G, lion U per day, administered as 3–4 million 200 000–300 000 U, IV, every 4 h for 10–14 dayse U/kg/day, IV, adminis- OR tered as 50 000 U/kg eve- Penicillin G procaine,c 2.4 million U, IM, ry 4–6 h for 10–14 days, in once daily PLUS probenecid, doses not to exceed the 500 mg, orally, 4 times/day, both for 10–14 adult dose dayse IV indicates intravenously; IM, intramuscularly. a Early latent syphilis is defined as being acquired within the preceding year. b Penicillin G benzathine and penicillin G procaine are approved for intramuscular administration only. c Late latent syphilis is defined as syphilis beyond 1 year’s duration. d Patients who are allergic to penicillin should be desensitized. e Some experts administer penicillin G benzathine, 2.4 million U, IM, once per week for up to 3 weeks after completion of these neurosyphilis treatment regimens. Neurosyphilis. For children, intravenous aqueous crystalline penicillin G for 10 to 14 days is recommended. Some experts recommend additional subsequent therapy with intra- muscular penicillin G benzathine, 50 000 U/kg per dose (not to exceed 2.4 million U), for EBSCOhost - printed on 8/17/2021 6:26 AM via UNIV OF SOUTH ALABAMA. All use subject to https://www.ebsco.com/terms-of-use  786 SYPHILIS up to 3 single weekly doses (see Table 3.77). A patient with a history of penicillin allergy should have skin testing to evaluate for true allergy and treated with penicillin if allergy is not confirmed; if allergy is confirmed, the patient should undergo desensitization followed by treatment with penicillin. Other Considerations. Mothers of infants with congenital syphilis should be tested for other STIs, including Neisseria gonorrhoeae, Chlamydia trachomatis, HIV, and hepatitis B. If injection drug use is suspected, the mother also may be at risk of hepatitis C virus infection. All patients with syphilis should be tested for other STIs, including N gonorrhoeae, C tra- chomatis, HIV, and hepatitis B. Patients who have primary syphilis should be retested for HIV after 3 months if the first HIV test result is negative. Immunization status for hepatitis B and human papillomavirus (HPV) should be reviewed and vaccines should be administered if not up to date. For people with HIV infection and syphilis, careful follow-up is essential. People with HIV infection who have early syphilis may be at increased risk of neurologic complica- tions and higher rates of treatment failure with currently recommended regimens. 1 All recent sexual contacts of people with acquired syphilis should be evaluated for oth- er STIs as well as syphilis (see Control Measures, p 788). Partners who were exposed within 90 days preceding the diagnosis of primary, secondary, or early latent syphilis in the index patient should be treated presumptively for syphilis, even if they are sero- negative. Children with acquired primary, secondary, or latent syphilis should be evaluated for possible sexual assault or abuse. Follow-up and Management. Congenital Syphilis. All infants who have reactive serologic tests for syphilis or were born to mothers who were seroreactive at delivery should receive careful follow-up evaluations during regularly scheduled well-child care visits at 2, 4, 6, and 12 months of age. Sero- logic nontreponemal tests should be performed every 2 to 3 months until the nontrepo- nemal test becomes nonreactive. Nontreponemal antibody titers should decrease by 3 months of age and should be nonreactive by 6 months of age, whether the infant was in- fected and adequately treated or was not infected and initially seropositive because of transplacentally acquired maternal antibody. The serologic response after therapy may be slower for infants treated after the neonatal period. Patients with increasing titers or with persistent stable titers 6 to 12 months after initial treatment should be reevaluated, includ- ing a CSF examination, and treated with a 10-day course of parenteral penicillin G, even if they were treated previously. Neonates with a negative nontreponemal test at birth whose mothers were seroreactive at delivery should be retested at 3 months to rule out seronegative incubating congenital syphilis. Treponemal tests should not be used to evaluate treatment response, because results for an infected child can remain positive despite effective therapy. Passively transferred 1Guidelines for prevention and treatment of opportunistic infections in HIV-exposed and HIV-infected chil- dren. Recommendations from the National Institutes of Health, Centers for Disease Control and Prevention, the HIV Medicine Association of the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the American Academy of Pediatrics. Pediatr Infect Dis J. 2013;32(Suppl 2):i-KK4. Available at: http://aidsinfo.nih.gov/guidelines/html/5/pediatric-oi-prevention-and-treatment- guidelines/0 EBSCOhost - printed on 8/17/2021 6:26 AM via UNIV OF SOUTH ALABAMA. All use subject to https://www.ebsco.com/terms-of-use  SYPHILIS 787 maternal treponemal antibodies can persist in an infant until 15 months of age. A reactive treponemal test after 18 months of age is diagnostic of congenital syphilis. If the nontrep- onemal test is nonreactive at this time, no further evaluation or treatment is necessary. If the nontreponemal test is reactive at 18 months of age, the infant should be evaluated (or reevaluated) fully and treated for congenital syphilis. Treated infants with congenital neurosyphilis should undergo repeated clinical evalu- ation and CSF examination at 6-month intervals until their CSF examination is normal. A reactive CSF VDRL test or abnormal CSF indices that cannot be attributed to another ongoing illness at the 6-month interval are indications for retreatment. Neuroimaging studies, such as magnetic resonance imaging, should be considered in these children. Acquired Syphilis. People with acquired syphilis should have clinical and serologic evalu- ations following treatment to evaluate for persistence or recurrence of symptoms or an inadequate serologic response following therapy. People with primary or secondary syphi- lis should have clinical and serologic evaluations performed at 6 and 12 months after treatment. If signs or symptoms persist or recur, or a fourfold or greater increase in non- treponemal titers occurs, treatment failure or reinfection may be responsible. CSF analy- sis, HIV testing, and retreatment based on CSF findings are indicated. Failure of non- treponemal titers to decline fourfold within 6 to 12 months may also indicate treatment failure. Following treatment, people with latent syphilis should experience a fourfold or greater decline in nontreponemal titers within 12 to 24 months. If titers increase at least fourfold or initial high titers fail to fall fourfold, or symptoms of syphilis develop, reevalua- tion, including a CSF examination, is warranted. Additional guidance can be found in the current CDC guidelines for the management of sexually transmitted diseases. 1 In all these instances, retreatment should be performed with 3 weekly injections of penicillin G benzathine, 50 000 U/kg up to the adult dose of 2.4 million U, intramuscu- larly, unless CSF examination indicates that neurosyphilis is present, at which time treat- ment for neurosyphilis should be initiated. Retreated patients should be treated with the schedules recommended for patients with syphilis for more than 1 year, and only 1 re- treatment course is indicated. The possibility of reinfection or concurrent HIV infection should always be considered when retreating patients with early syphilis, and repeat HIV testing should be performed in such cases. Patients with neurosyphilis associated with acquired syphilis must have periodic sero- logic testing, clinical evaluation at 6-month intervals, and repeat CSF examinations. If the CSF white blood cell count has not decreased after 6 months or if the CSF white blood cell count or protein concentration is not normal after 2 years, retreatment should be considered. CSF abnormalities may persist for extended periods of time in people with HIV infection with neurosyphilis. Close follow-up is warranted. ISOLATION OF THE HOSPITALIZED PATIENT: Standard precautions are recommended for all patients, including infants with suspected or proven congenital syphilis. Because moist open lesions, secretions, and possibly blood are contagious in all patients with syphi- lis, gloves should be worn when caring for patients with congenital, primary, and second- ary syphilis with skin and mucous membrane lesions until 24 hours of treatment has been completed. 1 Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines, 2015. MMWR Recomm Rep. 2015;64(RR-3):34–51 EBSCOhost - printed on 8/17/2021 6:26 AM via UNIV OF SOUTH ALABAMA. 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