Lauren C Tantalo, Nicole A P Lieberman, Clara Pérez-Mañá, Clara Suñer, Marti Vall Mayans, Maria Ubals, Camila González-Beiras, Alicia Rodríguez-Gascón, Andrés Canut, Fernando González-Candelas, John Mueller, Kenneth Tapia, Alexander L Greninger, Lorenzo Giacani, Oriol Mitjà
Antimicrobial susceptibility of Treponema pallidum subspecies pallidum: an in-vitro study.
Lancet Microbe. 2023 Dec;4(12):e994-e1004. doi: 10.1016/S2666-5247(23)00219-7. Epub 2023 Oct 9.
Abstract/Text
BACKGROUND: The increasing incidence of syphilis and the limitations of first-line treatment with penicillin, particularly in neurosyphilis, neonatal syphilis, and pregnancy, highlight the need to expand the therapeutic repertoire for effective management of this disease. We assessed the in-vitro efficacy of 18 antibiotics from several classes on Treponema pallidum subspecies pallidum (T pallidum), the syphilis bacteria.
METHODS: Using the in-vitro culture system for T pallidum, we exposed the pathogen to a concentration range of each tested antibiotic. After a 7-day incubation, the treponemal burden was evaluated by quantitative PCR targeting the T pallidum tp0574 gene. The primary outcome was the minimum inhibitory concentration (MIC) at which the quantitative PCR values were not significantly higher than the inoculum wells. We also investigated the susceptibility of macrolide-resistant strains to high concentrations of azithromycin, and the possibility of developing resistance to linezolid, a proposed candidate for syphilis treatment.
FINDINGS: Amoxicillin, ceftriaxone, several oral cephalosporins, tedizolid, and dalbavancin exhibited anti-treponemal activity at concentrations achievable in human plasma following regular dosing regimens. The experiments revealed a MIC for amoxicillin at 0·02 mg/L, ceftriaxone at 0·0025 mg/L, cephalexin at 0·25 mg/L, cefetamet and cefixime at 0·0313 mg/L, cefuroxime at 0·0156 mg/L, tedizolid at 0·0625 mg/L, spectinomycin at 0·1 mg/L, and dalbavancin at 0·125 mg/L. The MIC for zoliflodacin and balofloxacin was 2 mg/L. Ertapenem, isoniazid, pyrazinamide, and metronidazole had either a poor or no effect. Azithromycin concentrations up to 2 mg/L (64 times the MIC) were ineffective against strains carrying mutations associated to macrolide resistance. Exposure to subtherapeutic doses of linezolid for 10 weeks did not induce phenotypic or genotypic resistance.
INTERPRETATION: Cephalosporins and oxazolidinones are potential candidates for expanding the current therapeutic repertoire for syphilis. Our findings warrant testing efficacy in animal models and, if successful, clinical assessment of efficacy.
FUNDING: European Research Council.
Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.
Kimberly A Workowski, Gail A Bolan, Centers for Disease Control and Prevention
Sexually transmitted diseases treatment guidelines, 2015.
MMWR Recomm Rep. 2015 Jun 5;64(RR-03):1-137.
Abstract/Text
These guidelines for the treatment of persons who have or are at risk for sexually transmitted diseases (STDs) were updated by CDC after consultation with a group of professionals knowledgeable in the field of STDs who met in Atlanta on April 30-May 2, 2013. The information in this report updates the Sexually Transmitted Diseases Treatment Guidelines, 2010 (MMWR Recomm Rep 2010;59 [No. RR-12]). These updated guidelines discuss 1) alternative treatment regimens for Neisseria gonorrhoeae; 2) the use of nucleic acid amplification tests for the diagnosis of trichomoniasis; 3) alternative treatment options for genital warts; 4) the role of Mycoplasma genitalium in urethritis/cervicitis and treatment-related implications; 5) updated HPV vaccine recommendations and counseling messages; 6) the management of persons who are transgender; 7) annual testing for hepatitis C in persons with HIV infection; 8) updated recommendations for diagnostic evaluation of urethritis; and 9) retesting to detect repeat infection. Physicians and other health-care providers can use these guidelines to assist in the prevention and treatment of STDs.
Sam Ratnam
The laboratory diagnosis of syphilis.
Can J Infect Dis Med Microbiol. 2005 Jan;16(1):45-51.
Abstract/Text
Syphilis has several clinical manifestations, making laboratory testing a very important aspect of diagnosis. In North America, many unsuspected cases are discovered by laboratory testing. The etiological agent, Treponema pallidum, cannot be cultured, and there is no single optimal alternative test. Serological testing is the most frequently used approach in the laboratory diagnosis of syphilis. The present paper discusses the various serological and alternative tests currently available along with their limitations, and relates their results to the likely corresponding clinical stage of the disease. The need to use multiple tests is discussed, and the importance of quality control is noted. The complexity of syphilis serology means that the services of reference laboratories and clinical experts are often needed.
Rita Castro, Emília Simões Prieto, Filomena da Luz Martins Pereira
Nontreponemal tests in the diagnosis of neurosyphilis: an evaluation of the Venereal Disease Research Laboratory (VDRL) and the Rapid Plasma Reagin (RPR) tests.
J Clin Lab Anal. 2008;22(4):257-61. doi: 10.1002/jcla.20254.
Abstract/Text
The Venereal Disease Research Laboratory (VDRL) test has long been considered the best serological test for the diagnosis of neurosyphilis. The goal of this study was to find out if the Rapid Plasma Reagin (RPR) could be an alternative to the VDRL. Cerebrospinal fluid (CSF) and sera samples from patients in the following stages of syphilis were tested: 8 had symptomatic and 16 asymptomatic neurosyphilis, 4 were in the primary stage, 6 had secondary syphilis, and 92 were in the latent stage. We have also studied 61 samples from individuals with treated syphilis and 126 with other neurological diseases than neurosyphilis. All the CSF samples were studied with both RPR and VDRL tests. RPR and VDRL test results were mostly concordant. The specificity of these tests for current neurosyphilis was 99% for the VDRL and 99.3% for the RPR, whereas the sensitivity was 70.8 and 75%, respectively, for the VDRL and RPR. In view of these results it seems to us that the RPR could be an alternative to the VDRL in the diagnosis of neurosyphilis.
Christina M Marra, Clare L Maxwell, Stacy L Smith, Sheila A Lukehart, Anne M Rompalo, Molly Eaton, Bradley P Stoner, Michael Augenbraun, David E Barker, James J Corbett, Mark Zajackowski, Charles Raines, Judith Nerad, Romina Kee, Scott H Barnett
Cerebrospinal fluid abnormalities in patients with syphilis: association with clinical and laboratory features.
J Infect Dis. 2004 Feb 1;189(3):369-76. doi: 10.1086/381227. Epub 2004 Jan 27.
Abstract/Text
OBJECTIVE: To define clinical and laboratory features that identify patients with neurosyphilis.
METHODS: Subjects (n=326) with syphilis but no previous neurosyphilis who met 1993 Centers for Disease Control and Prevention criteria for lumbar puncture underwent standardized history, neurological examination, venipuncture, and lumbar puncture. Neurosyphilis was defined as a cerebrospinal fluid (CSF) white blood cell count >20 cells/ microL or reactive CSF Venereal Disease Research Laboratory (VDRL) test result.
RESULTS: Sixty-five subjects (20.1%) had neurosyphilis. Early syphilis increased the odds of neurosyphilis in univariate but not multivariate analyses. In multivariate analyses, serum rapid plasma reagin (RPR) titer > or =1 : 32 increased the odds of neurosyphilis 10.85-fold in human immunodeficiency virus (HIV)-uninfected subjects and 5.98-fold in HIV-infected subjects. A peripheral blood CD4+ T cell count < or =350 cells/ microL conferred 3.10-fold increased odds of neurosyphilis in HIV-infected subjects. Similar results were obtained when neurosyphilis was more stringently defined as a reactive CSF VDRL test result.
CONCLUSION: Serum RPR titer helps predict the likelihood of neurosyphilis. HIV-induced immune impairment may increase the risk of neurosyphilis.
Matthew R Golden, Christina M Marra, King K Holmes
Update on syphilis: resurgence of an old problem.
JAMA. 2003 Sep 17;290(11):1510-4. doi: 10.1001/jama.290.11.1510.
Abstract/Text
Ryutaro Tanizaki, Takeshi Nishijima, Takahiro Aoki, Katsuji Teruya, Yoshimi Kikuchi, Shinichi Oka, Hiroyuki Gatanaga
High-dose oral amoxicillin plus probenecid is highly effective for syphilis in patients with HIV infection.
Clin Infect Dis. 2015 Jul 15;61(2):177-83. doi: 10.1093/cid/civ270. Epub 2015 Mar 31.
Abstract/Text
BACKGROUND: Intramuscular benzathine penicillin G (BPG) is widely used for the treatment of syphilis. However, BPG is not available in some countries. This study examined the effectiveness and safety of high-dose oral amoxicillin plus probenecid for the treatment of syphilis in patients with human immunodeficiency virus type 1 (HIV-1).
METHODS: This retrospective observational study included 286 HIV-infected male patients with syphilis (median age, 36 years; median CD4 count, 389 cells/µL) who were treated with oral amoxicillin 3 g plus probenecid. Syphilis was diagnosed by both serum rapid plasma reagin (RPR) titers ≥8 and positive Treponema pallidum hemagglutination test. Patients with neurosyphilis diagnosed by cerebrospinal fluid examination were excluded. Successful treatment was defined as a at least 4-fold decrement in RPR titer.
RESULTS: The overall treatment efficacy was 95.5% (95% confidence interval [CI], 92.4%-97.7%; 273/286 patients), and efficacy for primary, secondary, early latent, late latent, and unknown duration syphilis was 93.8% (95% CI, 68.1%-99.8%; 15/16), 97.3% (95% CI, 92.9%-99.2%; 142/146), 100% (95% CI, 90.5%-100%; 37/37), 85.7% (95% CI, 58.6%-96.4%; 18/21), and 92.4% (95% CI, 81.9%-97.3%; 61/66), respectively. Treatment duration was mostly 14-16 days (49.7%) or 28-30 days (34.3%), with efficacy of 94.4% (134/142) and 95.9% (94/98), respectively; 96.3% of successfully treated patients achieved a ≥4-fold decrement in RPR titer within 12 months. Adverse events were noted in 28 (9.8%) patients, and 25 of these (89.3%) were successfully treated. Only 6% of patients underwent lumbar puncture.
CONCLUSIONS: The combination of oral amoxicillin 3 g plus probenecid was highly effective and tolerable for the treatment of syphilis in patients with HIV-1 infection.
© The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.
Naokatsu Ando, Daisuke Mizushima, Kazumi Omata, Takashi Nemoto, Natsumi Inamura, Saori Hiramoto, Misao Takano, Takahiro Aoki, Koji Watanabe, Haruka Uemura, Daisuke Shiojiri, Yasuaki Yanagawa, Junko Tanuma, Katsuji Teruya, Yoshimi Kikuchi, Hiroyuki Gatanaga, Shinichi Oka
Combination of Amoxicillin 3000 mg and Probenecid Versus 1500 mg Amoxicillin Monotherapy for Treating Syphilis in Patients With Human Immunodeficiency Virus: An Open-Label, Randomized, Controlled, Non-Inferiority Trial.
Clin Infect Dis. 2023 Sep 11;77(5):779-787. doi: 10.1093/cid/ciad278.
Abstract/Text
BACKGROUND: Amoxicillin plus probenecid is an alternative to intramuscular benzathine penicillin G for treating syphilis in the United Kingdom. Low-dose amoxicillin is an alternative treatment option used in Japan.
METHODS: We conducted an open-label, randomized, controlled, non-inferiority trial between 31 August 2018, and 3 February 2022, to compare 1500 mg low-dose amoxicillin monotherapy with the combination of 3000 mg amoxicillin and probenecid (non-inferiority margin 10%). Patients with human immunodeficiency virus (HIV) infection and syphilis were eligible. The primary outcome was the cumulative serological cure rate within 12 months post-treatment, measured using the manual rapid plasma reagin card test. Secondary outcomes included safety assessment.
RESULTS: A total of 112 participants were randomized into 2 groups. Serological cure rates within 12 months were 90.6% and 94.4% with the low-dose amoxicillin and combination regimens, respectively. Serological cure rates for early syphilis within 12 months were 93.5% and 97.9% with the low-dose amoxicillin and combination regimens, respectively. Non-inferiority of low-dose amoxicillin compared with amoxicillin plus probenecid overall and for early syphilis was not confirmed. No significant side effects were detected.
CONCLUSIONS: This is the first randomized controlled trial to demonstrate a high efficacy of amoxicillin-based regimens for treating syphilis in patients with HIV infection, and the non-inferiority of low-dose amoxicillin compared with amoxicillin plus probenecid was not seen. Therefore, amoxicillin monotherapy could be a good alternative to intramuscular benzathine penicillin G with fewer side effects. However, further studies comparing with benzathine penicillin G in different populations and with larger sample sizes are needed.
TRIALS REGISTRATION: (UMIN000033986).
© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
A R Salkind, P G Cuddy, J W Foxworth
The rational clinical examination. Is this patient allergic to penicillin? An evidence-based analysis of the likelihood of penicillin allergy.
JAMA. 2001 May 16;285(19):2498-505.
Abstract/Text
CONTEXT: Clinicians frequently withhold antibiotics that contain penicillin based on patients' self-reported clinical history of an adverse reaction to penicillin and the clinicians' own misunderstandings about the characteristics of a true penicillin allergy.
OBJECTIVES: To determine the likelihood of true penicillin allergy with consideration of clinical history and to evaluate the diagnostic value added by appropriate skin testing.
DATA SOURCES: MEDLINE was searched for relevant English-language articles dated 1966 to October 2000. Bibliographies were searched to identify additional articles.
STUDY SELECTION: We included original studies describing the precision of skin testing in diagnosis of penicillin allergy. We excluded studies that did not use both minor and major determinants, provide an explicit definition of penicillin allergy, or list the specific criteria necessary for a positive skin test result. Fourteen studies met the inclusion criteria.
DATA EXTRACTION: Three authors independently reviewed and abstracted data from all articles and reached consensus about any discrepancies.
DATA SYNTHESIS: Patients' self-reported history has low accuracy for diagnosis of true penicillin allergy. By evaluating studies comparing clinical history to the skin test for penicillin allergy among patients with and without a positive history for penicillin allergy, positive and negative likelihood ratios were calculated. History of penicillin allergy had a positive likelihood ratio of 1.9 (95% confidence interval [CI], 1.5-2.5), while absence of history of penicillin allergy had a negative likelihood ratio of 0.5 (95% CI, 0.4-0.6).
CONCLUSIONS: Only 10% to 20% of patients reporting a history of penicillin allergy are truly allergic when assessed by skin testing. Taking a detailed history of a patient's reaction to penicillin may allow clinicians to exclude true penicillin allergy, allowing these patients to receive penicillin. Patients with a concerning history of type I penicillin allergy who have a compelling need for a drug containing penicillin should undergo skin testing. Virtually all patients with a negative skin test result can take penicillin without serious sequelae.
Khalil G Ghanem, Emily J Erbelding, Walter W Cheng, Anne M Rompalo
Doxycycline compared with benzathine penicillin for the treatment of early syphilis.
Clin Infect Dis. 2006 Mar 15;42(6):e45-9. doi: 10.1086/500406. Epub 2006 Feb 8.
Abstract/Text
BACKGROUND: Doxycycline is the preferred recommended second-line agent for the treatment of syphilis, although efficacy data from controlled trials are lacking. We compared the serological responses of patients with early syphilis treated with doxycycline with the responses of patients treated with benzathine penicillin G (BPG).
METHODS: All patients who received a diagnosis of early syphilis attending 2 public sexually transmitted disease clinics in Baltimore, Maryland, who were treated with doxycycline (100 mg orally, twice daily for 14 days) between October 1993 and June 2000 were eligible. Patients treated with BPG (a single dose of 2.4 million units intramuscularly) were selected as the control group. Inclusion criteria included a clinician-recorded diagnosis of primary, secondary, or early latent syphilis with reactive serological test results at the time of diagnosis and at least 1 follow-up serological test titer. Serological failure was defined as lack of a 4-fold drop in rapid plasma reagin titer 270-400 days after treatment, or a 4-fold increase in titer 30-400 days after therapy.
RESULTS: During the study period, 1558 patients were treated for early syphilis, and 87 received doxycycline. Of those treated with doxycycline, 34 met the inclusion criteria. Seventy-three patients from a randomly selected group of 200 age-matched individuals treated with BPG met the inclusion criteria. There were 4 patients with serological failure in the BPG group (5.5%; 95% confidence interval [CI], 1.6%-13.8%) and 0 patients with serological failure in the doxycycline group (0%; 95% CI, 0%-10.3%; P=.2). The median times to successful serological responses for patients in the doxycycline and BPG groups were 106 days (95% CI, 75-149 days) and 137 days (95% CI, 111-172 days), respectively (P=.6).
CONCLUSION: Doxycycline appears to be an effective agent for the treatment of early syphilis.
Tom Wong, Ameeta E Singh, Prithwish De
Primary syphilis: serological treatment response to doxycycline/tetracycline versus benzathine penicillin.
Am J Med. 2008 Oct;121(10):903-8. doi: 10.1016/j.amjmed.2008.04.042.
Abstract/Text
BACKGROUND: Benzathine penicillin G is the treatment of choice for infectious syphilis, but tetracycline and doxycycline are believed to be effective second-line treatments. The objective of this study was to assess the serological response from treatment of primary syphilis with benzathine penicillin compared with doxycycline or tetracycline.
METHODS: We examined rapid plasma reagin serological test results of all first-time primary syphilis patients in Alberta, Canada from 1980 to 2001 and compared treatment with single dose of penicillin with 14-day course of oral doxycycline (100 mg twice a day) or oral tetracycline (500 mg 4 times a day). Serological treatment success was defined as a minimum 4-fold decrease in baseline rapid plasma reagin test antibody titer within 6 months, or > or =8-fold decrease within 12 months, or > or =16-fold decrease by 24 months. The median time to successful response was estimated, and factors associated with treatment success were identified by unadjusted logistic regression.
RESULTS: Of the 445 primary syphilis cases with available treatment outcome data, 420 (94.4%) received penicillin and 25 (5.6%) received doxycycline/tetracycline. The serological treatment success rate was 97.4% in the penicillin group (409/420) and 100% in the doxycycline/tetracycline group (25/25), and not significantly different. The estimated median time to serological treatment success was 72.0 days (mean=101.7, range 10-603) in penicillin and 43.0 days (mean=78.6, range 15-334) in doxycycline/tetracycline-treated patients; however, this difference was not statistically significant (P=0.16).
CONCLUSION: Doxycycline/tetracycline had a similarly high serological treatment success rate when compared with penicillin in the treatment of primary syphilis.
Gabriele Riedner, Mary Rusizoka, Jim Todd, Leonard Maboko, Michael Hoelscher, Donan Mmbando, Eleuter Samky, Eligius Lyamuya, David Mabey, Heiner Grosskurth, Richard Hayes
Single-dose azithromycin versus penicillin G benzathine for the treatment of early syphilis.
N Engl J Med. 2005 Sep 22;353(12):1236-44. doi: 10.1056/NEJMoa044284.
Abstract/Text
BACKGROUND: Pilot studies suggest that a single, 2-g oral dose of azithromycin may be an alternative to a 2.4-MU intramuscular dose of penicillin G benzathine in the prevention and treatment of syphilis. We evaluated the efficacy of treatment with azithromycin in a developing country.
METHODS: A total of 328 subjects, 25 with primary and 303 with high-titer (a titer of at least 1:8 on a rapid plasmin reagin [RPR] test) latent syphilis, were recruited through screening of high-risk populations in Mbeya, Tanzania, and randomly assigned to receive 2 g of azithromycin orally (163 subjects) or 2.4 million units of penicillin G benzathine intramuscularly (165 subjects). The primary outcome was treatment efficacy, with cure defined serologically (a decline in the RPR titer of at least two dilutions by nine months after treatment) and, in primary syphilis, by epithelialization of ulcers within one or two weeks.
RESULTS: The average age of participants was 27.0 years, 235 (71.6 percent) were female, and 171 (52.1 percent) were seropositive for human immunodeficiency virus. Cure rates were 97.7 percent (95 percent confidence interval, 94.0 to 99.4) in the azithromycin group and 95.0 percent (95 percent confidence interval, 90.6 to 97.8) in the penicillin G benzathine group (95 percent confidence interval for the difference, -1.7 to 7.1 percent), achieving prespecified criteria for equivalence. Cure rates were also similar three and six months after treatment in the two groups and in all subgroups. Cure rates at three months were 59.4 percent (95 percent confidence interval, 51.8 to 67.1) in the azithromycin group and 59.5 percent (95 percent confidence interval, 51.8 to 67.3) in the penicillin G benzathine group and at six months were 85.5 percent (95 percent confidence interval, 79.4 to 90.6) and 81.5 percent (95 percent confidence interval, 74.8 to 87.4), respectively.
CONCLUSIONS: Single-dose oral azithromycin is effective in treating syphilis and may be particularly useful in developing countries in which the use of penicillin G benzathine injections is problematic. However, recent reports of azithromycin-resistant Treponema pallidum in the United States indicate the importance of continued monitoring for resistance.
Copyright 2005 Massachusetts Medical Society.
Yuping Cao, Xiaohong Su, Qianqiu Wang, Huazhong Xue, Xiaofeng Zhu, Chuanfu Zhang, Juan Jiang, Shuzhen Qi, Xiangdong Gong, Xiaofang Zhu, Min Pan, Hong Ren, Wenlong Hu, Zhiping Wei, Meihua Tian, Weida Liu
A Multicenter Study Evaluating Ceftriaxone and Benzathine Penicillin G as Treatment Agents for Early Syphilis in Jiangsu, China.
Clin Infect Dis. 2017 Oct 30;65(10):1683-1688. doi: 10.1093/cid/cix611.
Abstract/Text
Background: The aim of this study was to assess the efficacy of ceftriaxone and benzathine penicillin G (BPG) in nonpregnant, immunocompetent adults with early syphilis because there is a lack of clinical evidence supporting ceftriaxone as an alternative treatment for early syphilis without an human immunodeficiency virus coinfection.
Methods: A randomized, open-label controlled study evaluating the efficacy of ceftriaxone and BPG was conducted in 4 hospitals in Jiangsu Province. Treatment comprised either ceftriaxone (1.0 g, given intravenously, once daily for 10 days) or BPG (2.4 million units, given intramuscularly, once weekly for 2 weeks). A serological response was defined as a ≥4-fold decline in the rapid plasma reagin (RPR) titer.
Results: In all, 301 patients with early syphilis were enrolled in this study; 230 subjects completed the follow-ups. The serological response at 6 months of follow up was observed in 90.2% in ceftriaxone group and 78.0% in BPG group (P = .01). There was no significant difference between treatment groups in patients with primary or early latent syphilis, but among patients with secondary syphilis the difference was highly significant (95.8% vs 76.2%; P < .01). Moreover, patients exhibiting a Jarisch-Herxheimer reaction after treatment might have a shorter period before a serological response (P = .03).
Conclusions: In this study, ceftriaxone regimen was noninferior to the BPG regimen in nonpregnant, immunocompetent patients with early syphilis.
Clinical Trials Registration: ChiCTR-TQR-13003624.
© The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.
Pingyu Zhou, Kang Li, Haikong Lu, Yihong Qian, Xin Gu, Weiming Gong, Joseph D Tucker, Myron S Cohen
Azithromycin treatment failure among primary and secondary syphilis patients in Shanghai.
Sex Transm Dis. 2010 Nov;37(11):726-9. doi: 10.1097/OLQ.0b013e3181e2c753.
Abstract/Text
BACKGROUND: Azithromycin has been used to treat primary and secondary syphilis and as prophylaxis for sexual partners. We evaluated syphilis treatment failure in patients who received azithromycin therapy.
METHODS: Patients who did not respond to azithromycin therapy were referred to Shanghai Skin Disease and sexually transmitted disease hospital. Treatment failure was defined as follows: (1) persistent ulcers or cutaneous or mucosal lesions 1 month after therapy; or (2) detection of spirochetes in dark-field microscopy examination of a lesion at least 1 week after treatment; or (3) failure of rapid plasma reagin titers to decrease 4-fold at 3 months after treatment.
RESULTS: A total of 132 patients with primary and secondary syphilis who failed azithromycin therapy were referred to our hospital between January 2001 and October 2008. Of 132 patients, 42 (31.8%) had primary syphilis and 90 (68.2%) had secondary syphilis. Twenty-six patients with primary syphilis developed multiple lesions or secondary syphilis, or persistent ulcers despite using azithromycin. The skin or mucosal lesions did not resolve in 37 patients with secondary syphilis after azithromycin treatment. Ten patients had a positive dark-field examination for Treponema pallidum (T. pallidum) after treatment. The serum rapid plasma reagin titers studied in all cases had failed to decrease 4-fold at 3 months after therapy. The doses of azithromycin used for treatment ranged from 4 to 30 g.
CONCLUSIONS: The failure of azithromycin to cure a substantial number of patients with primary and secondary syphilis in Shanghai suggests that azithromycin has limited therapeutic value in this setting.
Takeshi Nishijima, Kei Kawana, Ichio Fukasawa, Naoko Ishikawa, Melanie M Taylor, Hiroshige Mikamo, Kiyoko Kato, Jo Kitawaki, Tomoyuki Fujii, Women’s Health Care Committee, Japan Society of Obstetrics and Gynecology
Effectiveness and Tolerability of Oral Amoxicillin in Pregnant Women with Active Syphilis, Japan, 2010-2018.
Emerg Infect Dis. 2020 Jun;26(6):1192-1200. doi: 10.3201/eid2606.191300.
Abstract/Text
We conducted a nationwide retrospective study in Japan to evaluate the effectiveness of oral amoxicillin or ampicillin as alternatives to injectable benzathine penicillin G for treating pregnant women with syphilis and preventing congenital syphilis (CS). We investigated 80 pregnant women with active syphilis treated with amoxicillin or ampicillin during 2010-2018. Overall, 21% (15/71) had pregnancies resulting in CS cases, and 3.8% (3/80) changed therapies because of side effects. Among 26 patients with early syphilis, no CS cases occurred, but among 45 with late syphilis, 15 (33%) CS cases occurred. Among 57 patients who started treatment >60 days before delivery, 8 (14%) had CS pregnancy outcomes. We found oral amoxicillin potentially ineffective for preventing CS cases among pregnant women with late syphilis but potentially effective in those with early syphilis. Prospective studies are needed to definitively evaluate the efficacy of amoxicillin for the treatment of pregnant women with syphilis to prevent CS.
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 Oct;39(10):794-8. doi: 10.1097/OLQ.0b013e31826f36de.
Abstract/Text
BACKGROUND: The 23S rRNA A2058G point mutation in Treponema pallidum is associated with macrolide antibiotic treatment failure. Its prevalence and potential association with a molecular subtype within the United States are unknown.
METHODS: During 2007 to 2009, 11 clinics across the United States sent samples from genital ulcers to the Centers for Disease Control and Prevention. Molecular techniques were used to identify T. pallidum DNA sequences, the A2058G mutation, and subtype of T. pallidum. Accompanying epidemiologic information was abstracted from medical records.
RESULTS: A total of 141 samples with T. pallidum were collected from individuals whose median age was 33 years (range, 13-68 years): 118 were male (69% reported as men having sex with men [MSM]). The A2058G mutation was carried in 75 samples (53%) with T. pallidum, with samples from MSM (versus women and other men) more likely carrying the A2058G mutation (65/82 samples versus 8/57 samples; prevalence ratio, 5.7; 95% confidence interval, 2.9-10.8). Of 98 strain-typed samples, 61 (62%) were the 14d9 subtype of T. pallidum, which was also associated with samples with T. pallidum from MSM (prevalence ratio, 3.5; 95% confidence interval, 1.9-6.5). However, among T. pallidum from MSM, the A2058G mutation was not associated with the 14d9 subtype.
CONCLUSIONS: The A2058G mutation and 14d9 subtype of T. pallidum were present throughout the United States. Both were more commonly found in T. pallidum from MSM compared with women or other men but were not associated with each other. Treating syphilis with azithromycin should be done cautiously and only when treatment with penicillin or doxycycline is not feasible.
E C Tramont
Persistence of Treponema pallidum following penicillin G therapy. Report of two cases.
JAMA. 1976 Nov 8;236(19):2206-7.
Abstract/Text
The isolation of Treponema pallidum from cerebrospinal fluid (CSF) obtained from two adult patients, both of whom had normal CSF values except for positive fluorescent treponemal antibody-absorption (FTA-ABS) tests and both of whom had received currently recommended courses of penicillin, raises important considerations in the treatment of neurosyphilis in adults.
R E Morrison, S M Harrison, E C Tramont
Oral amoxycillin, an alternative treatment for neurosyphilis.
Genitourin Med. 1985 Dec;61(6):359-62.
Abstract/Text
A serum amoxycillin concentration of 0.11 g/l was established as being treponemicidal in a rabbit model with orchitis. Seventeen patients treated with amoxycillin 2 g by mouth three times a day plus 500 mg probenecid twice a day attained treponemicidal CSF amoxycillin concentrations. Thus amoxycillin by mouth offers an effective alternative method for treating patients with neurosyphilis.
Motoyuki Tsuboi, Takeshi Nishijima, Takahiro Aoki, Katsuji Teruya, Yoshimi Kikuchi, Hiroyuki Gatanaga, Shinichi Oka
Usefulness of Automated Latex Turbidimetric Rapid Plasma Reagin Test for Diagnosis and Evaluation of Treatment Response in Syphilis in Comparison with Manual Card Test: a Prospective Cohort Study.
J Clin Microbiol. 2018 Nov;56(11). doi: 10.1128/JCM.01003-18. Epub 2018 Oct 25.
Abstract/Text
The usefulness of an automated latex turbidimetric rapid plasma reagin (RPR) assay, compared to the conventional manual card test (serial 2-fold dilution method), for the diagnosis of syphilis and evaluation of treatment response remains unknown. We conducted (i) a cross-sectional study and (ii) a prospective cohort study to elucidate the correlation between automated and manual tests and whether a 4-fold decrement is a feasible criterion for successful treatment with the automated test, respectively, in HIV-infected patients, from October 2015 to November 2017. Study i included 518 patients. The results showed strong correlation between the two tests (r = 0.931; P < 0.001). With a manual test titer of ≥1:8 plus a positive Treponema pallidum particle agglutination (TPPA) test as the reference standard for diagnosis, the optimal cutoff value for the automated test was 6.0 RPR units (area under the curve [AUC], 0.998), with positive predictive value (PPV) of 92.5% and negative predictive value (NPV) of 99.4%. Study ii enrolled 66 men with syphilis. Their RPR values were followed up until after 12 months of treatment. At 12 months, 77.3% and 78.8% of the patients achieved a 4-fold decrement in RPR titer by the automated and manual test, respectively. The optimal decrement rate in RPR titer by the automated test for a 4-fold decrement by manual card test was 76.54% (AUC, 0.96) (PPV, 96.1%; NPV, 80.0%). The automated RPR test is a good alternative to the manual test for the diagnosis of syphilis and evaluation of treatment response and is more rapid and can handle more specimens than the manual test without interpersonal variation in interpretation.
Copyright © 2018 American Society for Microbiology.
A F Luger, B L Schmidt, M Kaulich
Significance of laboratory findings for the diagnosis of neurosyphilis.
Int J STD AIDS. 2000 Apr;11(4):224-34. doi: 10.1258/0956462001915750.
Abstract/Text
Our objective is to assess the specificity and sensitivity, and thus elaborate the relevance, of different laboratory findings for the diagnosis of neurosyphilis. One hundred and fourteen HIV-negative pairs of serum and cerebrospinal fluid (CSF) samples were examined by the Venereal Disease Research Laboratory (VDRL) test, a fluorescent treponemal antibody-absorption (FTA-ABS) test, microhaemagglutination assay with Treponema pallidum antigen (MHA-TP) test (serum) and Treponema pallidum haemagglutination assay (TPHA) test (CSF); further, albumin, total protein, and total IgG were determined and, in the CSF, cell count was performed. The donors were 60 patients with active neurosyphilis and 54 healthy persons with a former history of syphilis and with persisting positive results in the T. pallidum haemagglutination tests (serum: MHA-TP, CSF: TPHA), who supplied specimens for control. Albumin quotient, IgG index, TPHA index, modified TPHA index, Intrathecally produced T. pallidum Antigen (ITpA) index, its 2 modifications and, in 12 samples, the adenovirus group antibody (AVGA)/TPHA index were ascertained. The specificity and sensitivity of the TPHA index were 100% and 98.3%, of the modified TPHA index 50.0% and 96.7%, of the ITpA index 42.6% and 90.0%, of the modified ITpA indices 51.8% and 68.3% (first modification) and 53.7% and 63.3% (second modification). The AVGA/TPHA index yielded a specificity of 91.7% (11/12). The CSF VDRL test was positive in 55/60 (91.7%) of samples from patients with neurosyphilis and in none of the controls (0/54). A CSF-TPHA titre greater than 1:320 was observed in 59/60 (98.3%) of the neurosyphilis specimens and in none of the controls (0/54). A TPHA index above an outcome of 70, a positive CSF-TPHA test at a titre greater than 1:320 and, with lower sensitivity, the criteria of the Centers for Disease Control (CDC) guidelines yield the most reliable results for laboratory support to a diagnosis of neurosyphilis. The modified TPHA index, the ITpA index, and its 2 modifications produce results of minor sensitivity and poor specificity. Observations on the AVGA/THPA index are too limited yet for judgement. The diagnostic significance of a CSF-TPHA titre above 320 needs further confirmation on a greater number of observations made by different laboratories.
Alfredo Franco, Lucia Aprea, Chiara Dell'Isola, Francesco Saverio Faella, Francesca Maria Felaco, Elio Manzillo, Fiorella Martucci, Teresa Pizzella, Matilde Sansone, Francesco Simioli, Stefania Simioli, Crescenzo Maria Izzo
Clinical case of seroconversion for syphilis following a needlestick injury: why not take a prophylaxis?
Infez Med. 2007 Sep;15(3):187-90.
Abstract/Text
A 47-year-old woman was pricked accidentally with a needle previously used for a neurosyphilitic man. At day 0 she had no positive laboratory results for the infection, while the source, at day 1, had TPHA positive, but no post-exposure prophylaxis (PEP) against syphilis was prescribed. The subject missed the day 30 follow-up, and underwent our visit at day 90, when she showed no clinical signs, but she seroconverted (VDRL = positive 1/2; TPHA = positive 1/320; FTA-Abs IgG and IgM = present). She started antibiotic therapy, and currently her serological status is VDRL = positive 1/2, TPHA = positive 1/160, FTA-Abs IgM = negative.
