Treatment of syphilis: A systematic review

JAMA - Journal of the American Medical Association

Volumn 312, Issue 18, 2014, Pages 1905-1917

  Clement, Meredith E ^a   Okeke, N Lance ^a   Hicks, Charles B ^b  

^a DUKE UNIVERSITY MEDICAL CENTER   (United States)

^b UNIVERSITY OF CALIFORNIA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

AZITHROMYCIN; BENZATHINE PENICILLIN; CEFTRIAXONE; DOXYCYCLINE; PENICILLIN DERIVATIVE; PENICILLIN G; PROBENECID; TETRACYCLINE; ANTIINFECTIVE AGENT;

AGE DISTRIBUTION; ARTICLE; CONTINUOUS INFUSION; DISEASE COURSE; DISEASE SEVERITY; DRUG EFFICACY; DRUG SAFETY; EVIDENCE BASED PRACTICE; HEALTH CARE QUALITY; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS INFECTION; INCIDENCE; NONHUMAN; PREGNANCY; RACE DIFFERENCE; SEROLOGY; SEX DIFFERENCE; SINGLE DRUG DOSE; SYPHILIS; SYSTEMATIC REVIEW; UNITED STATES; ADULT; FEMALE; INTRAMUSCULAR DRUG ADMINISTRATION; MALE;

ADULT; ANTI-BACTERIAL AGENTS; FEMALE; HUMANS; INJECTIONS, INTRAMUSCULAR; MALE; PENICILLIN G BENZATHINE; PREGNANCY; SYPHILIS;

EID: 84918772772     PISSN: 00987484     EISSN: 15383598     Source Type: Journal    
DOI: 10.1001/jama.2014.13259     Document Type: Article

References (102)

1. Centers for Disease Control and Prevention. Syphilis fact sheet. http://www.cdc.gov/std/syphilis/STDFact-Syphilis-detailed.htm. Accessed January 19, 2014.
2. Golden MR, Marra CM, Holmes KK. Update on syphilis. JAMA. 2003;290(11):1510-1514.
3. Gomez GB, Kamb ML, Newman LM, et al. Untreated maternal syphilis and adverse outcomes of pregnancy. BullWorld Health Organ. 2013;91(3): 217-226.
4. Ingraham NR Jr. The value of penicillin alone in the prevention and treatment of congenital syphilis. Acta Derm Venereol Suppl (Stockh). 1950;31 (suppl 24):60-87.
5. Tobian AA, Quinn TC. Herpes simplex virus type 2 and syphilis infections with HIV. Curr Opin HIV AIDS. 2009;4(4):294-299.
6. Patton ME, Su JR, Nelson R, Weinstock H; Centers for Disease Control and Prevention. Primary and secondary syphilis-United States, 2005-2013. MMWR Morb Mortal Wkly Rep. 2014;63(18):402-406.
7. Workowski KA, Berman S; Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines, 2010. MMWR RecommRep. 2010;59(RR-12):1-110.
8. Cohen SE, Klausner JD, Engelman J, Philip S. Syphilis in the modern era. Infect Dis Clin North Am. 2013;27(4):705-722.
9. Centers for Disease Control and Prevention. STD Surveillance Case Definitions Effective January 2014. http://www.cdc.gov/std/stats /CaseDefinitions-2014.pdf. Accessed August 17, 2014.
10. Rolfs RT, Joesoef MR, Hendershot EF, et al; Syphilis and HIV Study Group. A randomized trial of enhanced therapy for early syphilis in patients with and without human immunodeficiency virus infection. N Engl J Med. 1997;337(5):307-314.
11. Riedner G, Rusizoka M, Todd J, et al. Single-dose azithromycin vs penicillin G benzathine for the treatment of early syphilis. N Engl J Med. 2005;353(12):1236-1244.
12. Hook EW III, Behets F, Van Damme K, et al. A phase III equivalence trial of azithromycin vs benzathine penicillin for treatment of early syphilis. J Infect Dis. 2010;201(11):1729-1735.
13. Li J, Zheng H-Y. Early syphilis: serological treatment response to doxycycline/tetracycline vs benzathine penicillin. J Infect Dev Ctries. 2014;8(2):228-232.
14. Ghanem KG, Erbelding EJ, Cheng WW, Rompalo AM. Doxycycline compared with benzathine penicillin for the treatment of early syphilis. Clin Infect Dis. 2006;42(6):e45-e49.
15. Wong T, Singh AE, De P. Primary syphilis: serological treatment response to doxycycline/tetracycline vs benzathine penicillin. Am J Med. 2008;121(10):903-908.
16. Psomas KC, Brun M, Causse A, Atoui N, Reynes J, Le Moing V. Efficacy of ceftriaxone and doxycycline in the treatment of early syphilis. Med Mal Infect. 2012;42(1):15-19.
17. Long CM, Klausner JD, Leon S, et al; NIMH Collaborative HIV/STD Prevention Trial Group. Syphilis treatment and HIV infection in a population-based study of persons at high risk for sexually transmitted disease/HIV infection in Lima, Peru. Sex Transm Dis. 2006;33(3):151-155.
18. Onoda Y. Therapeutic effect of oral doxycycline on syphilis [in Japanese]. Jpn J Antibiot. 1980;33(1):18-28.
19. Harshan V, Jayakumar W. Doxycycline in early syphilis: a long term follow up. Indian J Dermatol. 1982;27(4):119-124.
20. Spornraft-Ragaller P, Abraham S, Lueck C, Meurer M. Response of HIV-infected patients with syphilis to therapy with penicillin or intravenous ceftriaxone. Eur J Med Res. 2011;16(2):47-51.
21. Schöfer H, Vogt HJ, Milbradt R. Ceftriaxone for the treatment of primary and secondary syphilis. Chemotherapy. 1989;35(2):140-145.
22. Hook EW III, Roddy RE, Handsfield HH. Ceftriaxone therapy for incubating and early syphilis. J Infect Dis. 1988;158(4):881-884.
23. Moorthy TT, Lee CT, Lim KB, Tan T. Ceftriaxone for treatment of primary syphilis in men. Sex Transm Dis. 1987;14(2):116-118.
24. Hook EW III, Martin DH, Stephens J, et al. A randomized, comparative pilot study of azithromycin vs benzathine penicillin G for treatment of early syphilis. Sex Transm Dis. 2002;29(8):486-490.
25. Kiddugavu MG, Kiwanuka N, Wawer MJ, et al; Rakai Study Group. Effectiveness of syphilis treatment using azithromycin and/or benzathine penicillin in Rakai, Uganda. Sex Transm Dis. 2005;32(1):1-6.
26. Bai ZG, Wang B, Yang K, et al. Azithromycin vs penicillin G benzathine for early syphilis. Cochrane Database Syst Rev. 2012;6:CD007270.
27. Bai Z-G, Yang K-H, Liu Y-L, et al. Azithromycin vs benzathine penicillin G for early syphilis. Int J STD AIDS. 2008;19(4):217-221.
28. Tittes J, Aichelburg MC, Antoniewicz L, Geusau A. Enhanced therapy for primary and secondary syphilis. Int J STD AIDS. 2013;24(9):703-711.
29. Gibbons RJ, Smith S, Antman E; American College of Cardiology; American Heart Association. American College of Cardiology/American Heart Association clinical practice guidelines, I. Circulation. 2003;107(23):2979-2986.
30. Talwar S, Tutakne MA, Tiwari VD. VDRL titres in early syphilis before and after treatment. Genitourin Med. 1992;68(2):120-122.
31. Fiumara NJ. Treatment of primary and secondary syphilis. J AmAcad Dermatol. 1986;14(3):487-491.
32. Durst RD Jr, Sibulkin D, Trunnell TN, Allyn B. Dose-related seroreversal in syphilis. Arch Dermatol. 1973;108(5):663-664.
33. Jefferiss FJG, Willcox RR. Treatment of early syphilis with penicillin alone. Br J Vener Dis. 1963;39(3):143-148.
34. Smith CA, Kamp M, Olansky S, Price EV. Benzathine penicillin G in the treatment of syphilis. BullWorld Health Organ. 1956;15(6):1087-1096.
35. Sternberg TH, Leifer W. Treatment of early syphilis with penicillin. JAMA. 1947;133(1):1-5. doi:10 .1001/jama.1947.02880010003001.
36. Schroeter AL, Lucas JB, Price EV, Falcone VH. Treatment for early syphilis and reactivity of serologic tests. JAMA. 1972;221(5):471-476.
37. Smith NH, Musher DM, Huang DB, et al. Response of HIV-infected patients with asymptomatic syphilis to intensive intramuscular therapy with ceftriaxone or procaine penicillin. Int J STD AIDS. 2004;15(5):328-332.
38. Dowell ME, Ross PG, Musher DM, et al. Response of latent syphilis or neurosyphilis to ceftriaxone therapy in persons infected with human immunodeficiency virus. Am J Med. 1992;93(5):481-488.
39. Association of Public Health Laboratories. Laboratory Diagnostic Testing for Treponema pallidum: Expert Consultation Meeting Summary Report. January 2009. http://www.aphl.org/aphlprograms/infectious/std/Documents/ID -2009Jan-Laboratory-Guidelines-Treponema-pallidum-Meeting-Report.pdf. Accessed October 19, 2013.
40. Holman KM, Wolff M, Seña AC, et al. Rapid plasma reagin titer variation in the 2 weeks after syphilis therapy. Sex Transm Dis. 2012;39(8):645-647.
41. Ghanem KG, Erbelding EJ, Wiener ZS, Rompalo AM. Serological response to syphilis treatment in HIV-positive and HIV-negative patients attending sexually transmitted diseases clinics. Sex Transm Infect. 2007;83(2):97-101.
42. Manavi K, McMillan A. The outcome of treatment of early latent syphilis and syphilis with undetermined duration in HIV-infected and HIV-uninfected patients. Int J STD AIDS. 2007;18(12):814-818.
43. González-López JJ, Guerrero MLF, Luján R, et al. Factors determining serologic response to treatment in patients with syphilis. Clin Infect Dis. 2009;49(10):1505-1511.
44. Knaute DF, Graf N, Lautenschlager S, et al. Serological response to treatment of syphilis according to disease stage and HIV status. Clin Infect Dis. 2012;55(12):1615-1622.
45. Ghanem KG, Workowski KA. Management of adult syphilis. Clin Infect Dis. 2011;53(suppl 3):S110-S128.
46. Seña AC, Wolff M, Behets F, et al. Response to therapy following retreatment of serofast early syphilis patients with benzathine penicillin. Clin Infect Dis. 2013;56(3):420-422.
47. Agmon-Levin N, Elbirt D, Asher I, et al. Syphilis and HIV co-infection in an Israeli HIV clinic. Int J STD AIDS. 2010;21(4):249-252.
48. Tong M-L, Lin L-R, Liu G-L, et al. Factors associated with serological cure and the serofast state of HIV-negative patients with primary, secondary, latent, and tertiary syphilis. PLoS One. 2013;8(7):e70102.
49. Dionne-Odom J, Karita E, Kilembe W, et al. Syphilis treatment response among HIV-discordant couples in Zambia and Rwanda. Clin Infect Dis. 2013;56(12):1829-1837.
50. Seña AC, Wolff M, Martin DH, et al. Predictors of serological cure and serofast state after treatment in HIV-negative persons with early syphilis. Clin Infect Dis. 2011;53(11):1092-1099.
51. Lewis DA, Lukehart SA. Antimicrobial resistance in Neisseria gonorrhoeae and Treponema pallidum. Sex Transm Infect. 2011;87(suppl 2):ii39-ii43.
52. Nell EE. Comparative sensitivity of treponemes of syphilis, yaws, and bejel to penicillin in vitro, with observations on factors affecting its treponemicidal action. Am J Syph Gonorrhea Vener Dis. 1954;38(2):92-106.
53. Norris SJ, Edmondson DG. In vitro culture system to determineMICs and MBCs of antimicrobial agents against Treponema pallidum subsp pallidum (Nichols strain). Antimicrob Agents Chemother. 1988;32(1):68-74.
54. Idsoe O, Guthe T, Willcox RR. Penicillin in the treatment of syphilis. BullWorld Health Organ. 1972;47(suppl):1-68.
55. Rolfs RT. Treatment of syphilis, 1993. Clin Infect Dis. 1995;20(suppl 1):S23-S38.
56. Lukehart SA, Godornes C, Molini BJ, et al. Macrolide resistance in Treponema pallidum in the United States and Ireland. N Engl J Med. 2004;351(2):154-158.
57. Pichichero ME, Casey JR. Safe use of selected cephalosporins in penicillin-allergic patients. Otolaryngol Head Neck Surg. 2007;136(3):340-347.
58. Klausner JD, Kohn RP, Kent CK. Azithromycin vs penicillin for early syphilis. N Engl J Med. 2006;354(2):203-205.
59. Marra CM, Colina AP, Godornes C, et al. Antibiotic selectionmay contribute to increases in macrolide-resistant Treponema pallidum. J Infect Dis. 2006;194(12):1771-1773.
60. Van Damme K, Behets F, Ravelomanana N, et al. Evaluation of azithromycin resistance in Treponema pallidum specimens from Madagascar. Sex Transm Dis. 2009;36(12):775-776.
61. A2058G Prevalence Workgroup. Prevalence of the 23S rRNA A2058G point mutation and molecular subtypes in Treponema pallidum in the United States, 2007 to 2009. Sex Transm Dis. 2012;39(10):794-798.
62. Centers for Disease Control and Prevention. Azithromycin treatment failures in syphilis infections-San Francisco, California, 2002-2003. MMWR Morb Mortal Wkly Rep. 2004;53(9):197-198.
63. Yang C-J, Lee N-Y, Lin Y-H, et al. Jarisch-Herxheimer reaction after penicillin therapy among patients with syphilis in the era of the HIV infection epidemic. Clin Infect Dis. 2010;51(8):976-979.
64. Pound MW, May DB. Proposed mechanisms and preventative options of Jarisch-Herxheimer reactions. J Clin Pharm Ther. 2005;30(3):291-295.
65. Cernadas JR, Brockow K, Romano A, et al; European Network of Drug Allergy and the EAACI Interest Group on Drug Hypersensitivity. General considerations on rapid desensitization for drug hypersensitivity-a consensus statement. Allergy. 2010;65(11):1357-1366.
66. National Library of Medicine. Bicillin L-A (penicillin G benzathine) injection. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=012d46f1-d0a0-4676-a879-cd320297ab16. Accessed May 24, 2014.
67. National Library of Medicine. Penicillin G procaine injection. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=07fe2b47-34ac-4a20-be67-3c788c77b207#nlm34090-1. Accessed May 24, 2014.
68. National Library of Medicine. Penicillin G sodium injection. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=23b6d4a3-b273-4e10-9da9-1376933fdbdf. Accessed May 24, 2014.
69. Mohr JA, Griffiths W, Jackson R, et al. Neurosyphilis and penicillin levels in cerebrospinal fluid. JAMA. 1976;236(19):2208-2209.
70. Dunlop EM, Al-Egaily SS, Houang ET. Production of treponemicidal concentration of penicillin in cerebrospinal fluid. BMJ (Clin Res Ed). 1981;283(6292):646.
71. Hellerstrom S, Skog E. Outcome of penicillin therapy of syphilis. Acta Derm Venereol. 1962;42:179-194.
72. Gentile JH, Viviani C, Sparo MD, Arduino RC. Syphilitic meningomyelitis treated with ceftriaxone. Clin Infect Dis. 1998;26(2):528.
73. Hook EW III, Baker-Zander SA, Moskovitz BL, et al. Ceftriaxone therapy for asymptomatic neurosyphilis. Sex Transm Dis. 1986;13(3)(suppl):185-188.
74. Shann S, Wilson J. Treatment of neurosyphilis with ceftriaxone. Sex Transm Infect. 2003;79(5):415-416.
75. Su J, Weinstock H. Epidemiology of co-infection with HIV and syphilis in 34 states, United States-2009. In: Proceedings of the 2011 National HIV Prevention Conference; August 14-17, 2011; Atlanta, GA.
76. Blank LJ, Rompalo AM, Erbelding EJ, et al. Treatment of syphilis in HIV-infected subjects. Sex Transm Infect. 2011;87(1):9-16.
77. Goeman J, Kivuvu M, Nzila N, et al. Similar serological response to conventional therapy for syphilis among HIV-positive and HIV-negative women. Genitourin Med. 1995;71(5):275-279.
78. Jinno S, Anker B, Kaur P, et al. Predictors of serological failure after treatment in HIV-infected patients with early syphilis in the emerging era of universal antiretroviral therapy use. BMC Infect Dis. 2013;13:605.
79. Pialoux G, Vimont S, Moulignier A, et al. Effect of HIV infection on the course of syphilis. AIDS Rev. 2008;10(2):85-92.
80. Musher DM, Hamill RJ, Baughn RE. Effect of human immunodeficiency virus (HIV) infection on the course of syphilis and on the response to treatment. Ann Intern Med. 1990;113(11):872-881.
81. Gordon SM, Eaton ME, George R, et al. The response of symptomatic neurosyphilis to high-dose intravenous penicillin G in patients with human immunodeficiency virus infection. N Engl J Med. 1994;331(22):1469-1473.
82. Musher DM. Syphilis, neurosyphilis, penicillin, and AIDS. J Infect Dis. 1991;163(6):1201-1206.
83. Ghanem KG, Moore RD, Rompalo AM, et al. Antiretroviral therapy is associated with reduced serologic failure rates for syphilis among HIV-infected patients. Clin Infect Dis. 2008;47(2):258-265.
84. Ghanem KG, Moore RD, Rompalo AM, et al. Neurosyphilis in a clinical cohort of HIV-1-infected patients. AIDS. 2008;22(10):1145-1151.
85. Buchacz K, Patel P, Taylor M, et al. Syphilis increases HIV viral load and decreases CD4 cell counts in HIV-infected patients with new syphilis infections. AIDS. 2004;18(15):2075-2079.
86. Palacios R, Jiménez-Oñate F, Aguilar M, et al. Impact of syphilis infection on HIV viral load and CD4 cell counts in HIV-infected patients. J Acquir Immune Defic Syndr. 2007;44(3):356-359.
87. Kofoed K, Gerstoft J, Mathiesen LR, Benfield T. Syphilis and human immunodeficiency virus (HIV)-1 coinfection. Sex Transm Dis. 2006;33(3):143-148.
88. Flood JM, Weinstock HS, Guroy ME, et al. Neurosyphilis during the AIDS epidemic, San Francisco, 1985-1992. J Infect Dis. 1998;177(4):931-940.
89. Schöfer H, Imhof M, Thoma-Greber E, et al; German AIDS Study Group. Active syphilis in HIV infection. Genitourin Med. 1996;72(3):176-181.
90. Marra CM, Longstreth WT Jr, Maxwell CL, Lukehart SA. Resolution of serum and cerebrospinal fluid abnormalities after treatment of neurosyphilis. Sex Transm Dis. 1996;23(3):184-189.
91. Malone JL, Wallace MR, Hendrick BB, et al. Syphilis and neurosyphilis in a human immunodeficiency virus type 1 seropositive population. Am J Med. 1995;99(1):55-63.
92. Marra CM, Boutin P, McArthur JC, et al. A pilot study evaluating ceftriaxone and penicillin G as treatment agents for neurosyphilis in human immunodeficiency virus-infected individuals. Clin Infect Dis. 2000;30(3):540-544.
93. Marra CM, Maxwell CL, Tantalo L, et al. Normalization of cerebrospinal fluid abnormalities after neurosyphilis therapy. Clin Infect Dis. 2004;38(7):1001-1006.
94. Hawkes SJ, Gomez GB, Broutet N. Early antenatal care: does it make a difference to outcomes of pregnancy associated with syphilis? PLoS One. 2013;8(2):e56713.
95. Qin J, Yang T, Xiao S, et al. Reported estimates of adverse pregnancy outcomes among women with and without syphilis. PLoS One. 2014;9(7): e102203.
96. Blencowe H, Cousens S, Kamb M, et al. Lives Saved Tool supplement detection and treatment of syphilis in pregnancy to reduce syphilis related stillbirths and neonatal mortality. BMC Public Health. 2011;11(suppl 3):S9.
97. Alexander JM, Sheffield JS, Sanchez PJ, et al. Efficacy of treatment for syphilis in pregnancy. Obstet Gynecol. 1999;93(1):5-8.
98. Watson-Jones D, Gumodoka B, Weiss H, et al. Syphilis in pregnancy in Tanzania, II. J Infect Dis. 2002;186(7):948-957.
99. Berman SM. Maternal syphilis. BullWorld Health Organ. 2004;82(6):433-438.
100. Walker GJ. Antibiotics for syphilis diagnosed during pregnancy. Cochrane Database Syst Rev. 2001;(3):CD001143.
101. Zhou P, Gu Z, Xu J, et al. A study evaluating ceftriaxone as a treatment agent for primary and secondary syphilis in pregnancy. Sex Transm Dis. 2005;32(8):495-498.
102. Parkes R, Renton A, Meheus A, Laukamm-Josten U. Review of current evidence and comparison of guidelines for effective syphilis treatment in Europe. Int J STD AIDS. 2004;15(2):73-88.