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Is the Standard Treatment for Early Syphilis Sufficient to Prevent Cardiovascular and Neurologic Syphilis?
READERS’ COMMENTS Is the Standard Treatment for Early Syphilis Sufficient to Prevent Cardiovascular and Neurologic Syphilis? We read the study from Roberts et al1 about syphilis as a cause of thoracic aortic aneurysm that prompted us to make some considerations. We agree that syphilitic aortitis, far from disappeared, remains a major cause of thoracic aortic aneurism. Besides, coronary artery ostial stenosis, a less common manifestation of syphilitic aortitis, is still described in the study.2 Recently, we conducted a survey of the report of the last 5 years on the clinical presentation of neurosyphilis founding 286 affected patients (unpublished data). Regrettably, however, such cases are incompletely reported. In particular, most studies do not inform how early the patients did show cutaneous or mucosal symptoms of early infection, whether they had undergone a standard therapy nor the time elapsed before developing late complications. However, according to the study by Zhou et al and Drago et al3,4 and evidence that up to 5% of immunocompetent patients treated with benzathine penicillin G (BPG) experience treatment failure5 has wavered our confidence in BPG as the gold standard therapy for early and late latent syphilis. Trying to prevent long-term complications, we adopted in the last 5 years an enhanced therapy for early syphilis that uses doxycycline and ceftriaxone in addition to BPG. In fact, these treponemicidal antibiotics can penetrate all tissues more effectively than BPG6 and might be considered as a completion of the standard BPG therapy. We treated 47 patients: 12 had primary syphilis (PS), 9 had secondary syphilis (SS), 12 had early latent secondary syphilis (ELS), and 14 had late latent syphilis (LLS). Four patients were human immunodeficiency virus positive. Our treatment regimen was as follows: patients with PS, SS, and ELS received intramuscular BPG 2.4 million units (MU), according to the international guidelines, followed by intramuscular ceftriaxone 1 g/daily for 10 days and oral doxycycline 100 mg
twice daily for 20 days. Patients with LLS received intramuscular BPG 7.2 MU divided into 3 injections once a week for 3 consecutive weeks, followed by ceftriaxone and doxycycline as mentioned previously. A threefold-tofourfold decrease of venereal disease research laboratory titer within 1 year is considered a successful therapeutic achievement (serologic cure).7 All patients were followed up by 6 monthly visits with collection of careful clinical history, including risky sexual behaviors, physical examination, and serology. Echocardiography and neurologic examination were performed once a year. Cutaneous manifestations promptly remitted in all cases. At 12 months, all patients with PS, SS, ELS and LLS obtained serologic cure assessed by an at least fourfold decrease of venereal disease research laboratory and Treponema pallidum hemagglutination assay titers. Comparing our study with other reports of international relevance,8,9 we proved that our results are comparable to the main studies reported in the study, but serologic response to treatment was more significant and faster in our patients. During the followup, long-term complications have never been observed and no systemic alterations related to syphilis have been detected at echocardiography or at neurologic examination. These data are very encouraging considering that in another study, we found neurologic and cardiovascular abnormalities in patients with early syphilis overtreated for 2 consecutive years with a total of 60 MU of BPG already after 5 years of followup. In fact, 35% of them revealed neurologic alterations and 19% cardiovascular complications,4 confirming that BPG alone may be inadequate, in some patients, in preventing late complications. In addition, several patients have recently been described with early cardiovascular or neurologic complications.10,11 Our results show that the enhanced regimen composed by BPG, ceftriaxone, and doxycycline is highly effective in the treatment of syphilis obtaining in all the patients a faster and greater serologic response compared
Am J Cardiol 2015;-:1e2 0002-9149/15/$ - see front matter Ó 2015 Elsevier Inc. All rights reserved.
with BPG alone. In addition, none of our patients developed late complications related to syphilis during the 6 years of follow-up. We are aware that a larger cohort of patients with a longterm follow-up are required to evaluate the efficacy of the treatment we propose, but our encouraging preliminary results prompted us to bring this enhanced treatment to the attention of other sexually transmitted disease centers and scientific community. Finally, we emphasize that a significant percentage of reports about syphilis late complications (approximately 40%, personal unpublished data) were lacking information about past medical history, and in particular about sexual history, previous infections, previous genital ulcers, and their eventual therapy making difficult to evaluate the true effectiveness of BPG in preventing late complications.
Francesco Drago, MD Giulia Ciccarese, MD Giulia Merlo, MD Giulia Sartoris, MD Aurora Parodi, MD Genoa, Italy 26 October 2015
1. Roberts WC, Barbin CM, Weissenborn MR, Ko JM, Henry AC. Syphilis as a cause of thoracic aortic aneurysm. Am J Cardiol 2015;116:1298e1303. 2. Tewari S, Moorthy N. Cardiovascular syphilis with coronary stenosis and aneurysm. Indian Heart J 2014;66:735e736. 3. Zhou P, Gu X, Lu H, Guan Z, Qian Y. Re-evaluation of serological criteria for early syphilis treatment efficacy: progression to neurosyphilis despite therapy. Sex Transm Infect 2012;88:342e345. 4. Drago F, Parodi A, Rebora AE. Re-evaluation of serological criteria for early syphilis treatment efficacy: progression to neurosyphilis despite therapy: a reply. Sex Transm Infect 2012;88:509. 5. Ghanem KG, Erbelding EJ, Cheng WW, Rompalo AM. Doxycycline compared with benzathine penicillin for the treatment of early syphilis. Clin Infect Dis 2006;42:e45e49. 6. Nau R, Sörgel F, Eiffert H. Penetration of drugs through the blood-cerebrospinal fluid/ blood-brain barrier for treatment of central nervous system infections. Clin Microbiol Rev 2010;23:858e883. 7. Workowski KA, Berman S. Sexually transmitted diseases treatment guidelines, 2010. MMWR Recomm Rep 2010;59:1e110.
www.ajconline.org
2
The American Journal of Cardiology (www.ajconline.org)
8. Romanowski B, Sutherland R, Fick GH, Love EJ. Serologic response to treatment of infectious syphilis. Ann Intern Med 1991;114: 1005e1009. 9. Rolfs RT, Joesoef MR, Hendershot EF, Rompalo AM, Augenbraun MH, Chiu M, Bolan G, Johnson SC, French P, Steen E, Radolf JD, Larsen S. A randomized trial of
enhanced therapy for early syphilis in patients with and without human immunodeficiency virus infection. The Syphilis and HIV Study Group. N Engl J Med 1997;337: 307e314. 10. Zambon F, Silva FL, Cavalcante AF, Nakashima Y, Helal J Jr. Syphilitic retinitis and panuveitis simulating acute retinal
necrosis: case report. Arq Bras Oftalmol 2010;73:288e290. 11. Dietrich A, Gauglitz GG, Pfluger TT, Herzinger T, Braun-Falco M. Syphilitic aortitis in secondary syphilis. JAMA Dermatol 2014;150:790e791. http://dx.doi.org/10.1016/j.amjcard.2015.10.048
twice daily for 20 days. Patients with LLS received intramuscular BPG 7.2 MU divided into 3 injections once a week for 3 consecutive weeks, followed by ceftriaxone and doxycycline as mentioned previously. A threefold-tofourfold decrease of venereal disease research laboratory titer within 1 year is considered a successful therapeutic achievement (serologic cure).7 All patients were followed up by 6 monthly visits with collection of careful clinical history, including risky sexual behaviors, physical examination, and serology. Echocardiography and neurologic examination were performed once a year. Cutaneous manifestations promptly remitted in all cases. At 12 months, all patients with PS, SS, ELS and LLS obtained serologic cure assessed by an at least fourfold decrease of venereal disease research laboratory and Treponema pallidum hemagglutination assay titers. Comparing our study with other reports of international relevance,8,9 we proved that our results are comparable to the main studies reported in the study, but serologic response to treatment was more significant and faster in our patients. During the followup, long-term complications have never been observed and no systemic alterations related to syphilis have been detected at echocardiography or at neurologic examination. These data are very encouraging considering that in another study, we found neurologic and cardiovascular abnormalities in patients with early syphilis overtreated for 2 consecutive years with a total of 60 MU of BPG already after 5 years of followup. In fact, 35% of them revealed neurologic alterations and 19% cardiovascular complications,4 confirming that BPG alone may be inadequate, in some patients, in preventing late complications. In addition, several patients have recently been described with early cardiovascular or neurologic complications.10,11 Our results show that the enhanced regimen composed by BPG, ceftriaxone, and doxycycline is highly effective in the treatment of syphilis obtaining in all the patients a faster and greater serologic response compared
Am J Cardiol 2015;-:1e2 0002-9149/15/$ - see front matter Ó 2015 Elsevier Inc. All rights reserved.
with BPG alone. In addition, none of our patients developed late complications related to syphilis during the 6 years of follow-up. We are aware that a larger cohort of patients with a longterm follow-up are required to evaluate the efficacy of the treatment we propose, but our encouraging preliminary results prompted us to bring this enhanced treatment to the attention of other sexually transmitted disease centers and scientific community. Finally, we emphasize that a significant percentage of reports about syphilis late complications (approximately 40%, personal unpublished data) were lacking information about past medical history, and in particular about sexual history, previous infections, previous genital ulcers, and their eventual therapy making difficult to evaluate the true effectiveness of BPG in preventing late complications.
Francesco Drago, MD Giulia Ciccarese, MD Giulia Merlo, MD Giulia Sartoris, MD Aurora Parodi, MD Genoa, Italy 26 October 2015
1. Roberts WC, Barbin CM, Weissenborn MR, Ko JM, Henry AC. Syphilis as a cause of thoracic aortic aneurysm. Am J Cardiol 2015;116:1298e1303. 2. Tewari S, Moorthy N. Cardiovascular syphilis with coronary stenosis and aneurysm. Indian Heart J 2014;66:735e736. 3. Zhou P, Gu X, Lu H, Guan Z, Qian Y. Re-evaluation of serological criteria for early syphilis treatment efficacy: progression to neurosyphilis despite therapy. Sex Transm Infect 2012;88:342e345. 4. Drago F, Parodi A, Rebora AE. Re-evaluation of serological criteria for early syphilis treatment efficacy: progression to neurosyphilis despite therapy: a reply. Sex Transm Infect 2012;88:509. 5. Ghanem KG, Erbelding EJ, Cheng WW, Rompalo AM. Doxycycline compared with benzathine penicillin for the treatment of early syphilis. Clin Infect Dis 2006;42:e45e49. 6. Nau R, Sörgel F, Eiffert H. Penetration of drugs through the blood-cerebrospinal fluid/ blood-brain barrier for treatment of central nervous system infections. Clin Microbiol Rev 2010;23:858e883. 7. Workowski KA, Berman S. Sexually transmitted diseases treatment guidelines, 2010. MMWR Recomm Rep 2010;59:1e110.
www.ajconline.org
2
The American Journal of Cardiology (www.ajconline.org)
8. Romanowski B, Sutherland R, Fick GH, Love EJ. Serologic response to treatment of infectious syphilis. Ann Intern Med 1991;114: 1005e1009. 9. Rolfs RT, Joesoef MR, Hendershot EF, Rompalo AM, Augenbraun MH, Chiu M, Bolan G, Johnson SC, French P, Steen E, Radolf JD, Larsen S. A randomized trial of
enhanced therapy for early syphilis in patients with and without human immunodeficiency virus infection. The Syphilis and HIV Study Group. N Engl J Med 1997;337: 307e314. 10. Zambon F, Silva FL, Cavalcante AF, Nakashima Y, Helal J Jr. Syphilitic retinitis and panuveitis simulating acute retinal
necrosis: case report. Arq Bras Oftalmol 2010;73:288e290. 11. Dietrich A, Gauglitz GG, Pfluger TT, Herzinger T, Braun-Falco M. Syphilitic aortitis in secondary syphilis. JAMA Dermatol 2014;150:790e791. http://dx.doi.org/10.1016/j.amjcard.2015.10.048