Is ceftriaxone similarly effective to benzylpenicillin in neurosyphilis?

Thomas Bettuzzi and colleagues1Bettuzzi T Jourdes A Robineau O et al.Ceftriaxone compared with benzylpenicillin in the treatment of neurosyphilis in France: a retrospective multicentre study.Lancet Infect Dis. 2021; (published online May 26.)https://doi.org/10.1016/S1473-3099(20)30857-4Summary Full Text Full Text PDF PubMed Scopus (3) Google Scholar report the results of a large-scale, retrospective, multicentre study assessing the effectiveness of ceftriaxone for the treatment of neurosyphilis compared with benzylpenicillin in France. This pioneering study provides evidence that ceftriaxone represents a reliable alternative to benzylpenicillin in the treatment of neurosyphilis and potentially decreases the length of hospital stay. However, a full understanding of the Article by Bettuzzi and colleagues1Bettuzzi T Jourdes A Robineau O et al.Ceftriaxone compared with benzylpenicillin in the treatment of neurosyphilis in France: a retrospective multicentre study.Lancet Infect Dis. 2021; (published online May 26.)https://doi.org/10.1016/S1473-3099(20)30857-4Summary Full Text Full Text PDF PubMed Scopus (3) Google Scholar requires further discussion of several issues. First, patients with late-stage neurosyphilis (defined as tabes dorsalis, general paresis, dementia, parenchymatous syphilis, or negative serological VDRL tests) and asymptomatic neurosyphilis were excluded. Therefore, the authors should rigorously highlight the specific conclusion that ceftriaxone is only as effective as benzylpenicillin for patients with five different subtypes of neurosyphilis (meningitis, facial palsy, otic syphilis, neurovascular syphilis, and ocular syphilis). Second, the authors mainly analysed clinical responses at 1 month and serological responses at 6 months after treatment initiation, as well as length of hospital stay. They did not follow the European syphilis treatment guidelines2Janier M Unemo M Dupin N et al.2020 European guideline on the management of syphilis.J Eur Acad Dermatol Venereol. 2021; 35: 574-588Crossref PubMed Scopus (27) Google Scholar to evaluate cerebrospinal fluid (CSF) at 6 weeks to 6 months after treatment of neurosyphilis. The authors attributed the absence of evaluation of CSF control via lumbar puncture after 6 months to the small sample size. Although one study3Marra CM Maxwell CL Tantalo LC et al.Normalization of serum rapid plasma reagin titer predicts normalization of cerebrospinal fluid and clinical abnormalities after treatment of neurosyphilis.Clin Infect Dis. 2008; 47: 893-899Crossref PubMed Scopus (94) Google Scholar has suggested that normalisation of serum rapid plasma reagin titres correctly predicts success of treatment of neurosyphilis, and a follow-up lumbar puncture can be avoided, CSF examination remains the cornerstone for the diagnosis and monitoring of neurosyphilis.4Gonzalez H Koralnik IJ Marra CM Neurosyphilis.Semin Neurol. 2019; 39: 448-455Crossref PubMed Scopus (15) Google Scholar Successful neurosyphilis treatment not only results in resolution of clinical abnormalities, but also of CSF abnormalities.4Gonzalez H Koralnik IJ Marra CM Neurosyphilis.Semin Neurol. 2019; 39: 448-455Crossref PubMed Scopus (15) Google Scholar Third, the proportion of patients presenting with more than one subtype of neurosyphilis (p=0·0064), receiving systemic corticoid treatment (p=0·029), and having positive CSF-VDRL results (p=0·054) was higher in the benzylpenicillin group than in the ceftriaxone group.1Bettuzzi T Jourdes A Robineau O et al.Ceftriaxone compared with benzylpenicillin in the treatment of neurosyphilis in France: a retrospective multicentre study.Lancet Infect Dis. 2021; (published online May 26.)https://doi.org/10.1016/S1473-3099(20)30857-4Summary Full Text Full Text PDF PubMed Scopus (3) Google Scholar Given that syphilitic uveitis, posterior uveitis, and panuveitis are more likely to lead to permanent vision loss than anterior or intermediate uveitis,5Amaratunge 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: 68-74Crossref PubMed Scopus (99) Google Scholar the significant difference in the proportion of patients with posterior uveitis in the benzylpenicillin group versus the ceftriaxone group (77 [46%] of 166 vs 11 [26%] of 42) could lead to a biased conclusion. These results suggest that the condition of the patients in the benzylpenicillin group was more serious than the condition of those in the ceftriaxone group, which could result in patients in the benzylpenicillin group having a worse clinical response to the treatment and a longer hospital stay. Finally, there are a few minor errors in the text. First, in the Research in context panel, the authors suggest that “ceftriaxone could be used as the first-line treatment for neurosyphilis in patients allergic to penicillin”.1Bettuzzi T Jourdes A Robineau O et al.Ceftriaxone compared with benzylpenicillin in the treatment of neurosyphilis in France: a retrospective multicentre study.Lancet Infect Dis. 2021; (published online May 26.)https://doi.org/10.1016/S1473-3099(20)30857-4Summary Full Text Full Text PDF PubMed Scopus (3) Google Scholar However, in patients allergic to penicillin, using ceftriaxone could be a dangerous option, even though cross-allergies are rare.2Janier M Unemo M Dupin N et al.2020 European guideline on the management of syphilis.J Eur Acad Dermatol Venereol. 2021; 35: 574-588Crossref PubMed Scopus (27) Google Scholar Therefore, we consider that “particularly in the absence of crossallergy to penicillin” should be added to the end of this sentence. Second, according to table 1, the number of patients with positive CSF-VDRL results in table 2 should be 143. Finally, we consider that the results for length of hospital stay and serological response in the per-protocol analysis population should be included in table 2. We declare no competing interests. We thank Qianglin Fang, Chongguang Yang, Yawen Jiang, Siyang Liu, Huicui Meng, Jinqiu Yuan, and Yiqiang Zhan for their comments during the preparation of this Correspondence. Ceftriaxone compared with benzylpenicillin in the treatment of neurosyphilis in France: a retrospective multicentre studyOur results suggest that ceftriaxone is similarly effective to benzylpenicillin for the treatment of neurosyphilis, potentially decreasing the length of hospital stay. Randomised, controlled trials should be done to confirm these results. Full-Text PDF