Oral doxycycline for syphilitic uveitis: a case report highlighting potential efficacy

Oral doxycycline for syphilitic uveitis: a case report highlighting potential efficacy Sir, Uveitis is the most common ocular manifestation in acquired syphilis.1 A course of intravenous penicillin G for 10–14 days is recommended for ophthalmic syphilis.2 Despite its theoretical optimal adherence, the intravenous penicillin regimen is time-consuming, uncomfortable and requires continuous intravenous administration. Alternative treatments are consequently required. We report here a case of syphilitic uveitis successfully treated with oral doxycycline only. An MSM, 56 kg, consulted at our institution for chronic visual discomfort, blurred vision and right-eye redness that started 1 year before. He had a medical history of psoriasis without arthritis treated with acitretin. Ocular examination evidenced panuveitis with episcleritis. Neurological examination was normal. Muco-cutaneous examination only revealed chronic psoriasis plaques. The blood Venereal Disease Research Laboratory (VDRL) test was positive (128 IU). The Treponema pallidum haemagglutination assay (TPHA) was also positive. HIV serology was negative. He refused hospitalization, lumbar puncture or intravenous penicillin G treatment. Hence he was given only oral doxycycline at 200 mg/day, divided into two equal doses, for 28 days. Post-treatment fundus and anterior chamber examination showed a complete regression of the uveitis, and VDRL follow-up (16 IU) 6 months later confirmed the favourable outcome. The patient did not relapse after 2 years of follow-up. This case report highlights the potential usefulness of oral doxycycline for the treatment of syphilitic uveitis. Ocular involvement is reported during early and late syphilis. Ocular manifestations include conjunctivitis, uveitis, scleritis, episcleritis, chorioretinitis, iritis and iridocyclitis.3 Uveitis, as in our patient, is the most common ocular manifestation of syphilis in both HIV-positive and HIV-negative patients.1 In a review of 143 cases of ocular syphilis, posterior uveitis was the most frequent presentation (55.2%), followed by panuveitis (25.2%) and anterior uveitis (19.6%).4 Ocular neuroepithelial structure involvement, including retinitis or optic neuritis, is considered as neurosyphilis. Intravenous penicillin G for 10–14 days is the gold standard treatment for syphilitic uveitis as well as for neurosyphilis.2 Alternative treatments include the combination of procaine penicillin plus probenecid (not available in France) or ceftriaxone (recommended in case of penicillin allergy).2 However, limited data suggest that either intramuscular or intravenous ceftriaxone at 2 g daily for 10–14 days could be efficient.5,6 Doxycycline has not been adequately evaluated for the treatment of ocular syphilis but our case report suggests it could be efficient. Doxycycline, a derivative of tetracycline, has long been known to have spirochaetocidal activity. A daily dose of 200 mg (in two equal doses), given orally, is effective in early and late syphilis. Onoda7 reported in 1979 a response rate of 100% for primary, 90% for early, 68% for late and 90% for congenital syphilis in adults with this regimen in an open study. Several controlled studies have since found similarly high rates of success between doxycycline/tetracycline and benzathine penicillin in the treatment of early syphilis.8–10 Penetration of oral doxycycline (200 mg twice a day) into the CSF has been evaluated in five patients with latent syphilis or neurosyphilis. Drug levels in serum ranged from 3.6 to 8.6 mg/L (mean of 5.8 mg/L), whereas the mean doxycycline level in CSF was 1.3 mg/L (0.8–2.0 mg/L). The CSF penetration rate ranged from 11% to 56%, with a mean of 26%.11 In another study, 100 mg daily doses of doxycycline for 2–10 days were associated with a spinal fluid level of 0.1–0.76 mg/L, the mean value (0.37 mg/L) corresponding to a 14% CSF penetration rate.12 These results are consistent with those from a study of CSF penetration rates of doxycycline in patients with Lyme neuroborreliosis. Twelve patients were treated orally with 100 mg of doxycycline twice a day. The mean concentration in serum 5–8 days after the therapy started was 4.7 mg/L 2–3 h after the last drug administration. The corresponding level for CSF was 0.6 mg/L. Penetration into the CSF varied from 8% to 35% of concentration in plasma, with a mean of 15%.13 There is no controlled study evaluating the efficacy of doxycycline in ocular syphilis. Only two cases of syphilitic uveitis in which treatment included oral doxycycline have been reported. Both patients were previously treated with intravenous penicillin G for 4 weeks.14 Therefore, the good outcome could be due to either penicillin or doxycycline. Poor data are available concerning doxycycline ocular penetration. Norris and Edmonson15 determined a tetracycline MIC of 0.2 mg/L for T. pallidum using an in vitro culture procedure. Clinical relevance of such pharmacokinetic data should be tested in a therapeutic trial. Oral doxycycline could improve the clinical management of patients diagnosed with ophthalmological syphilis (with no evidence for neurosyphilis), avoiding the intravenous route, and in a more cost-effective way. However, comparative studies are needed to assert this efficacy, including in HIV-positive patients. The duration of 28 days we chose was empirical and should be investigated pharmacokinetically. Funding This study was carried out as part of our routine work. Transparency declarations None to declare. References 1 Aldave AJ , King JA , Cunningham ET Jr. Ocular syphilis . Curr Opin Ophthalmol 2001 ; 6 : 433 – 41 . Google Scholar CrossRef Search ADS 2 Workowski KA , Bolan GA ; Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines, 2015 . MMWR Recomm Rep 2015 ; 64 : 1 – 137 . Google Scholar CrossRef Search ADS PubMed 3 Watson PG , Hazelman BL. The Sclera and Systemic Disorders . Philadelphia, PA, USA : WB Saunders , 1976 . 4 Amaratunge BC , Camuglia JE , Hall AJ. Syphilitic uveitis: a review of clinical manifestations and treatment outcomes of syphilitic uveitis in human immunodeficiency virus-positive and negative patients . Clin Exp Ophthalmol 2010 ; 38 : 68 – 74 . Google Scholar CrossRef Search ADS PubMed 5 Hook EW 3rd , Baker-Zander SA , Moskovitz BL et al. Ceftriaxone therapy for asymptomatic neurosyphilis. Case report and Western blot analysis of serum and cerebrospinal fluid IgG response to therapy . Sex Transm Dis 1986 ; 13 : 185 – 8 . Google Scholar CrossRef Search ADS PubMed 6 Shann S , Wilson J. Treatment of neurosyphilis with ceftriaxone . Sex Transm Infect 2003 ; 79 : 415 – 6 . Google Scholar CrossRef Search ADS PubMed 7 Onoda Y. Therapeutic effect of oral doxycycline on syphilis . Br J Vener Dis 1979 ; 55 : 110 – 5 . Google Scholar PubMed 8 Ghanem KG , Erbelding EJ , Cheng WW et al. Doxycycline compared with benzathine penicillin for the treatment of early syphilis . Clin Infect Dis 2006 ; 42 : 45 – 9 . Google Scholar CrossRef Search ADS 9 Wong T , Singh AE , De P. Primary syphilis: serological treatment response to doxycycline/tetracycline versus benzathine penicillin . Am J Med 2008 ; 121 : 903 – 8 . Google Scholar CrossRef Search ADS PubMed 10 Li J , Zheng HY. Early syphilis: serological treatment response to doxycycline/tetracycline versus benzathine penicillin . J Infect Dev Ctries 2014 ; 8 : 228 – 32 . Google Scholar CrossRef Search ADS PubMed 11 Yim CW , Flynn NM , Fitzgerald FT. Penetration of oral doxycycline into the cerebrospinal fluid of patients with latent or neurosyphilis . Antimicrob Agents Chemother 1985 ; 28 : 347 – 8 . Google Scholar CrossRef Search ADS PubMed 12 Andersson H , Alestig K. The penetration of doxycycline into CSF . Scand J Infect Dis Suppl 1976 ; 9 : 17 – 9 . 13 Dotevall L , Hagberg L. Penetration of doxycycline into cerebrospinal fluid in patients treated for suspected Lyme neuroborreliosis . Antimicrob Agents Chemother 1989 ; 33 : 1078 – 80 . Google Scholar CrossRef Search ADS PubMed 14 Pan SW , Yusof NS , Hitam WH et al. Syphilitic uveitis: report of 3 cases . Int J Ophthalmol 2010 ; 3 : 361 – 4 . Google Scholar PubMed 15 Norris SJ , Edmondson DG. In vitro culture system to determine MICs and MBCs of antimicrobial agents against Treponema pallidum subsp. pallidum (Nichols strain) . Antimicrob Agents Chemother 1988 ; 32 : 68 – 74 . Google Scholar CrossRef Search ADS PubMed © The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Antimicrobial Chemotherapy Oxford University Press

Oral doxycycline for syphilitic uveitis: a case report highlighting potential efficacy

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Oxford University Press
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© The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.
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0305-7453
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1460-2091
D.O.I.
10.1093/jac/dky102
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Abstract

Sir, Uveitis is the most common ocular manifestation in acquired syphilis.1 A course of intravenous penicillin G for 10–14 days is recommended for ophthalmic syphilis.2 Despite its theoretical optimal adherence, the intravenous penicillin regimen is time-consuming, uncomfortable and requires continuous intravenous administration. Alternative treatments are consequently required. We report here a case of syphilitic uveitis successfully treated with oral doxycycline only. An MSM, 56 kg, consulted at our institution for chronic visual discomfort, blurred vision and right-eye redness that started 1 year before. He had a medical history of psoriasis without arthritis treated with acitretin. Ocular examination evidenced panuveitis with episcleritis. Neurological examination was normal. Muco-cutaneous examination only revealed chronic psoriasis plaques. The blood Venereal Disease Research Laboratory (VDRL) test was positive (128 IU). The Treponema pallidum haemagglutination assay (TPHA) was also positive. HIV serology was negative. He refused hospitalization, lumbar puncture or intravenous penicillin G treatment. Hence he was given only oral doxycycline at 200 mg/day, divided into two equal doses, for 28 days. Post-treatment fundus and anterior chamber examination showed a complete regression of the uveitis, and VDRL follow-up (16 IU) 6 months later confirmed the favourable outcome. The patient did not relapse after 2 years of follow-up. This case report highlights the potential usefulness of oral doxycycline for the treatment of syphilitic uveitis. Ocular involvement is reported during early and late syphilis. Ocular manifestations include conjunctivitis, uveitis, scleritis, episcleritis, chorioretinitis, iritis and iridocyclitis.3 Uveitis, as in our patient, is the most common ocular manifestation of syphilis in both HIV-positive and HIV-negative patients.1 In a review of 143 cases of ocular syphilis, posterior uveitis was the most frequent presentation (55.2%), followed by panuveitis (25.2%) and anterior uveitis (19.6%).4 Ocular neuroepithelial structure involvement, including retinitis or optic neuritis, is considered as neurosyphilis. Intravenous penicillin G for 10–14 days is the gold standard treatment for syphilitic uveitis as well as for neurosyphilis.2 Alternative treatments include the combination of procaine penicillin plus probenecid (not available in France) or ceftriaxone (recommended in case of penicillin allergy).2 However, limited data suggest that either intramuscular or intravenous ceftriaxone at 2 g daily for 10–14 days could be efficient.5,6 Doxycycline has not been adequately evaluated for the treatment of ocular syphilis but our case report suggests it could be efficient. Doxycycline, a derivative of tetracycline, has long been known to have spirochaetocidal activity. A daily dose of 200 mg (in two equal doses), given orally, is effective in early and late syphilis. Onoda7 reported in 1979 a response rate of 100% for primary, 90% for early, 68% for late and 90% for congenital syphilis in adults with this regimen in an open study. Several controlled studies have since found similarly high rates of success between doxycycline/tetracycline and benzathine penicillin in the treatment of early syphilis.8–10 Penetration of oral doxycycline (200 mg twice a day) into the CSF has been evaluated in five patients with latent syphilis or neurosyphilis. Drug levels in serum ranged from 3.6 to 8.6 mg/L (mean of 5.8 mg/L), whereas the mean doxycycline level in CSF was 1.3 mg/L (0.8–2.0 mg/L). The CSF penetration rate ranged from 11% to 56%, with a mean of 26%.11 In another study, 100 mg daily doses of doxycycline for 2–10 days were associated with a spinal fluid level of 0.1–0.76 mg/L, the mean value (0.37 mg/L) corresponding to a 14% CSF penetration rate.12 These results are consistent with those from a study of CSF penetration rates of doxycycline in patients with Lyme neuroborreliosis. Twelve patients were treated orally with 100 mg of doxycycline twice a day. The mean concentration in serum 5–8 days after the therapy started was 4.7 mg/L 2–3 h after the last drug administration. The corresponding level for CSF was 0.6 mg/L. Penetration into the CSF varied from 8% to 35% of concentration in plasma, with a mean of 15%.13 There is no controlled study evaluating the efficacy of doxycycline in ocular syphilis. Only two cases of syphilitic uveitis in which treatment included oral doxycycline have been reported. Both patients were previously treated with intravenous penicillin G for 4 weeks.14 Therefore, the good outcome could be due to either penicillin or doxycycline. Poor data are available concerning doxycycline ocular penetration. Norris and Edmonson15 determined a tetracycline MIC of 0.2 mg/L for T. pallidum using an in vitro culture procedure. Clinical relevance of such pharmacokinetic data should be tested in a therapeutic trial. Oral doxycycline could improve the clinical management of patients diagnosed with ophthalmological syphilis (with no evidence for neurosyphilis), avoiding the intravenous route, and in a more cost-effective way. However, comparative studies are needed to assert this efficacy, including in HIV-positive patients. The duration of 28 days we chose was empirical and should be investigated pharmacokinetically. Funding This study was carried out as part of our routine work. Transparency declarations None to declare. References 1 Aldave AJ , King JA , Cunningham ET Jr. Ocular syphilis . Curr Opin Ophthalmol 2001 ; 6 : 433 – 41 . Google Scholar CrossRef Search ADS 2 Workowski KA , Bolan GA ; Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines, 2015 . MMWR Recomm Rep 2015 ; 64 : 1 – 137 . Google Scholar CrossRef Search ADS PubMed 3 Watson PG , Hazelman BL. The Sclera and Systemic Disorders . Philadelphia, PA, USA : WB Saunders , 1976 . 4 Amaratunge BC , Camuglia JE , Hall AJ. Syphilitic uveitis: a review of clinical manifestations and treatment outcomes of syphilitic uveitis in human immunodeficiency virus-positive and negative patients . Clin Exp Ophthalmol 2010 ; 38 : 68 – 74 . Google Scholar CrossRef Search ADS PubMed 5 Hook EW 3rd , Baker-Zander SA , Moskovitz BL et al. Ceftriaxone therapy for asymptomatic neurosyphilis. Case report and Western blot analysis of serum and cerebrospinal fluid IgG response to therapy . Sex Transm Dis 1986 ; 13 : 185 – 8 . Google Scholar CrossRef Search ADS PubMed 6 Shann S , Wilson J. Treatment of neurosyphilis with ceftriaxone . Sex Transm Infect 2003 ; 79 : 415 – 6 . Google Scholar CrossRef Search ADS PubMed 7 Onoda Y. Therapeutic effect of oral doxycycline on syphilis . Br J Vener Dis 1979 ; 55 : 110 – 5 . Google Scholar PubMed 8 Ghanem KG , Erbelding EJ , Cheng WW et al. Doxycycline compared with benzathine penicillin for the treatment of early syphilis . Clin Infect Dis 2006 ; 42 : 45 – 9 . Google Scholar CrossRef Search ADS 9 Wong T , Singh AE , De P. Primary syphilis: serological treatment response to doxycycline/tetracycline versus benzathine penicillin . Am J Med 2008 ; 121 : 903 – 8 . Google Scholar CrossRef Search ADS PubMed 10 Li J , Zheng HY. Early syphilis: serological treatment response to doxycycline/tetracycline versus benzathine penicillin . J Infect Dev Ctries 2014 ; 8 : 228 – 32 . Google Scholar CrossRef Search ADS PubMed 11 Yim CW , Flynn NM , Fitzgerald FT. Penetration of oral doxycycline into the cerebrospinal fluid of patients with latent or neurosyphilis . Antimicrob Agents Chemother 1985 ; 28 : 347 – 8 . Google Scholar CrossRef Search ADS PubMed 12 Andersson H , Alestig K. The penetration of doxycycline into CSF . Scand J Infect Dis Suppl 1976 ; 9 : 17 – 9 . 13 Dotevall L , Hagberg L. Penetration of doxycycline into cerebrospinal fluid in patients treated for suspected Lyme neuroborreliosis . Antimicrob Agents Chemother 1989 ; 33 : 1078 – 80 . Google Scholar CrossRef Search ADS PubMed 14 Pan SW , Yusof NS , Hitam WH et al. Syphilitic uveitis: report of 3 cases . Int J Ophthalmol 2010 ; 3 : 361 – 4 . Google Scholar PubMed 15 Norris SJ , Edmondson DG. In vitro culture system to determine MICs and MBCs of antimicrobial agents against Treponema pallidum subsp. pallidum (Nichols strain) . Antimicrob Agents Chemother 1988 ; 32 : 68 – 74 . Google Scholar CrossRef Search ADS PubMed © The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

Journal

Journal of Antimicrobial ChemotherapyOxford University Press

Published: Mar 23, 2018

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