Articles

Ceftriaxone compared with benzylpenicillin in the treatment

of neurosyphilis in France: a retrospective multicentre study
Thomas Bettuzzi*, Aurélie Jourdes*, Olivier Robineau, Isabelle Alcaraz, Victoria Manda, Jean Michel Molina, Maxime Mehlen, Charles Cazanave,
Pierre Tattevin, Sami Mensi, Benjamin Terrier, Alexis Régent, Jade Ghosn, Caroline Charlier, Guillaume Martin-Blondel†, Nicolas Dupin†

Summary
Background Intravenous benzylpenicillin is the gold-standard treatment for neurosyphilis, but it requires prolonged Lancet Infect Dis 2021
hospitalisation. Ceftriaxone is a possible alternative treatment, the effectiveness of which remains unclear. We aimed Published Online
to assess the effectiveness of ceftriaxone compared with benzylpenicillin in the treatment of neurosyphilis. May 26, 2021
https://doi.org/10.1016/
S1473-3099(20)30857-4
Methods We did a retrospective multicentre study including patients with neurosyphilis who were treated at one of
This online publication has
eight tertiary care centres in France, from Jan 1, 1997, to Dec 31, 2017. We defined neurosyphilis as positive treponemal been corrected. The corrected
and non-treponemal tests and at least one of otic syphilis, ocular syphilis, either neurological symptom with a positive version first appeared at
result on cerebrospinal fluid (CSF)-VDRL or CSF-PCR tests, or more than five leukocytes in a CSF cell count. Patients thelancet.com/infection on
August 5, 2021
with neurosyphilis were identified from the medical information department database of each centre and assigned to
one of two groups on the basis of the initial treatment received (ie, benzylpenicillin group or ceftriaxone group). The *Joint first authors

primary outcome was the overall clinical response (ie, proportion of patients with a complete or partial response) †Joint last authors

1 month after treatment initiation. The secondary endpoints were proportions of patients with a complete response at Service de Dermatologie
(T Bettuzzi MD,
1 month and serological response at 6 months, and length of hospital stay.
Prof N Dupin MD) and Service
de Médecine Interne
Findings Of 365 patients with a coded diagnosis of neurosyphilis in one of the eight care centres during 1997–2017, (Prof B Terrier PhD,
208 were included in this study (42 in the ceftriaxone group and 166 in the benzylpenicillin group). The mean age of A Régent PhD), Hôpital Cochin,
Assistance Publique—Hôpitaux
patients was 44·4 years (SD 13·4), and 193 (93%) were men. We observed 41 instances of overall clinical response (98%) de Paris (AP-HP), Paris, France;
in the ceftriaxone group versus 125 (76%) in the benzylpenicillin group (crude odds ratio [OR] 13·02 [95% CI EpiDermE, University Paris Est
1·73–97·66], p=0·017). After propensity score weighting, overall clinical response rates remained different between Créteil, Créteil, France
the groups (OR 1·22 [95% CI 1·12–1·33], p<0·0001). 22 (52%) patients in the ceftriaxone group and 55 (33%) in the (T Bettuzzi); Service des
Maladies Infectieuses et
benzylpenicillin group had a complete response (crude OR 2·26 [95% CI 1·12–4·41], p=0·031), with no significant Tropicales, Centre Hospitalier
difference after propensity score weighting (OR 1·08 [95% CI 0·94–1·24], p=0·269). Serological response at 6 months Universitaire de Toulouse,
did not differ between the groups (21 [88%] of 24 in the ceftriaxone group vs 76 [82%] of 93 in the benzylpenicillin Toulouse, France (A Jourdes MD,
group; crude OR 1·56 [95% CI 0·42–5·86], p=0·50), whereas hospital stay was shorter for patients in the ceftriaxone Prof G Martin-Blondel PhD);
Service Universitaire des
group than for those in the benzylpenicillin group (mean 13·8 days [95% CI 12·8–14·8] vs 8·9 days [5·7–12·0], Maladies Infectieuses et du
p<0·0001). No major adverse effects were reported in either group. Voyageur, Hôpital Dron,
Tourcoing, France
Interpretation Our results suggest that ceftriaxone is similarly effective to benzylpenicillin for the treatment of (O Robineau MD, I Alcaraz MD);
Département des Maladies
neurosyphilis, potentially decreasing the length of hospital stay. Randomised, controlled trials should be done to Infectieuses, Hôpital Saint
confirm these results. Louis et Lariboisière, AP-HP,
Paris, France (V Manda MD,
Funding None. Prof J M Molina PhD); Université
de Paris, Paris, France (V Manda,
Prof J M Molina, C Charlier PhD);
Copyright © 2021 Elsevier Ltd. All rights reserved. Service de Maladies
Infectieuses, Hôpital Pellegrin,
Introduction Early-stage neurosyphilis usually presents as meningitis, Centre Hospitalier Universitaire
de Bordeaux, Bordeaux,
Syphilis is a sexually transmitted disease caused by cranial nerve palsies, or ocular and otic syphilis, whereas France (M Mehlen MD,
Treponema pallidum. A resurgence of syphilis has been late-stage neurosyphilis encompasses general paresis Prof C Cazanave PhD); Service de
reported since the turn of the century worldwide, as has and tabes dorsalis. Neuro­vascular syphilis can occur at Maladies Infectieuses, Centre
Hospitalier Universitaire de
been observed for other sexually transmitted diseases, both stages.3,5
Rennes, Rennes, France
particularly among men who have sex with men. A large According to European, US, and UK guidelines, the (Prof P Tattevin PhD,
proportion of those affected are people living with gold-standard treatment for neurosyphilis is intravenous S Mensi MD); Service de
HIV/AIDS. The incidence of syphilis was 9·5 cases benzylpenicillin (24 million international units per day Maladies Infectieuses, Hôpital
Bichat, AP-HP, Paris, France
per 100 000 inhabitants in the USA in 2017,1 and 7·1 cases for 10–14 days).6–8 However, this treatment requires four
(Prof J Ghosn PhD); Service de
per 100 000 inhabitants in Europe in 2017, an increase of injections per day, resulting in a long hospital stay. Few Maladies Infectieuses, Hôpital
more than 70% since 2010.2 Neurosyphilis accounts data are available concerning the safety and efficacy of Necker, AP-HP, Paris, France
for 1·8–3·5% of syphilis cases.3 Its diagnosis is often alternative treatments for neurosyphilis that could lessen (C Charlier); INSERM UMR 1291
- CNRS UMR 5051, Toulouse
challenging because of polymorphic clinical manifes­ the burden of patient care and be used in patients allergic
Institute for Infectious and
tations, and it is strongly associated with HIV infection.3,4 to penicillin. Ceftriaxone is active against T pallidum in

www.thelancet.com/infection Published online May 26, 2021 https://doi.org/10.1016/S1473-3099(20)30857-4 1

 Articles
Inflammatory Diseases,
Université Toulouse III,
Toulouse, France
(Prof G Martin-Blondel); Centre
National de Référence de la
Syphilis, Institut Cochin, Unité
Inserm U1016, Université de
Paris, Paris, France
(Prof N Dupin)
Correspondence to:
Prof Nicolas Dupin, Centre
National de Référence de la
Syphilis, Institut Cochin, Unité
Inserm U1016, Université de
Paris, Paris 75014, France
nicolas.dupin@aphp.fr
See Online for appendix
2 www.thelancet.com/infection Published online May 26, 2021 https://doi.org/10.1016/S1473-3099(20)30857-4
Research in context
Evidence before this study
Neurosyphilis is a disease that, although rare, can have very
serious consequences. According to European, US, and UK
guidelines, the gold-standard treatment is intravenous
benzylpenicillin for 10–14 days. Nonetheless, because of
insufficient evidence, the same guidelines do not agree on
the use of ceftriaxone, a treatment that could allow outpatient
parenteral antimicrobial therapy and thus reduce the duration
of hospitalisation. To assess the evidence on ceftriaxone
effectiveness in treating neurosyphilis, we searched PubMed
from inception to June 1, 2020, entering the terms
“neurosyphilis” AND “treatment” with language restrictions of
English and French. Scarce evidence exists on the effectiveness
of ceftriaxone, as only case reports and small studies have been
published. Some studies were restricted to patients living with
HIV, reporting an 80% response rate, or patients with syphilitic
uveitis, reporting a 67% response rate. Clinical trials on
neurosyphilis are practically difficult because of the rareness of
the disease. To better assess the effectiveness of ceftriaxone in
patients with neurosyphilis, we did this multicentre,
retrospective, observational study.
Added value of this study
The aim of our study was to ascertain whether ceftriaxone
could achieve the same clinical outcomes as benzylpenicillin in
the treatment of neurosyphilis. Two groups of patients were
experimental models,9 has intermediate diffusion rates
in CSF,10 and can be administered once daily. Several
studies have suggested that it is an effective treatment for
neurosyphilis, but most of the clinical data obtained to
date originate from case reports and small studies.11
Previous studies were mostly limited to syphilitic uveitis12
or people living with HIV/AIDS,13–15 used unclear
outcome definitions,13,15 and some studies included
combination treatments.12
If ceftriaxone proves to be as effective as benzylpenicillin,
it could be used as outpatient parenteral antimicrobial
therapy (OPAT). This approach would decrease the length
of hospital stay, which would be beneficial both eco­
nomically and in terms of the patients’ quality of life. In
this study, we compared the effectiveness of ceftriaxone
with that of the recommended regimen of benzylpenicillin
for the treatment of neurosyphilis.
Methods
Study design and participants
We did a retrospective multicentre cohort study in
patients with neurosyphilis at eight tertiary care centres
in France from Jan 1, 1997, to Dec 31, 2017 (appendix p 2).
Patients were selected from the medical information
department database of each centre for the 1997–2017
period (International Classification of Diseases, version
10 codes A504, A521, and A523). To be included, patients
defined on the basis of initial treatment used: intravenous
ceftriaxone (2 g once daily) or intravenous benzylpenicillin
(3–4 million units every 4 h). We used inverse probability
treatment weighting to address indication bias. We found that,
compared with benzylpenicillin, ceftriaxone exhibited a
weighted odds ratio of 1·22 (95% CI 1·12–1·33) for proportions
of patients with an overall clinical response (complete response
and partial response) and 1·08 (0·94–1·24) for proportions of
patients with a clinical complete response. The two groups did
not differ according to serological response, but hospital stay
was shorter for the ceftriaxone group than for the
benzylpenicillin group. To our knowledge, this is the first
large-scale multicentre study assessing the effectiveness of
ceftriaxone in neurosyphilis.
Implications of all the available evidence
Our results suggest that ceftriaxone could represent a reliable
alternative to benzylpenicillin to treat neurosyphilis. Ceftriaxone
could be used as the first-line treatment for neurosyphilis in
patients allergic to penicillin. In addition, for selected patients
ready for home discharges, ceftriaxone used as outpatient
parenteral antimicrobial therapy would reduce the duration of
hospitalisation, with potential cost-savings and improvements
to patients’ quality of life. Randomised, controlled trials are
needed to confirm that ceftriaxone is as efficacious as
benzylpenicillin for the treatment of neurosyphilis.
had to be older than 18 years with a confirmed diagnosis
of neurosyphilis. Neurosyphilis was defined as ocular
syphilis, otic syphilis, the presence of neurological
symptoms associated with more than five leukocytes
on CSF cell counts, a positive result on the CSF-VDRL
test, or a positive CSF T pallidum PCR test; at least one
positive treponemal test on serum, such as ELISA, the
fluorescent treponemal antibody test, or the T pallidum
haemagglutination assay; and one positive non-trep­
onemal test, such as a serological VDRL test or rapid
plasma reagin test. All diagnoses were made by an
infectious diseases or ophthalmology specialist and
retrospectively reviewed by AJ and TB; in case of
disagreement, diagnoses were further reviewed by
GM-B or ND to reach a decision. Patients with late-
stage neurosyphilis (defined as tabes dorsalis, general
paresis, dementia, parenchymatous syphilis, or negative
serological VDRL tests), asymptomatic neurosyphilis, or
an alternative diagnosis were excluded. Two groups of
patients were defined on the basis of initial treatment:
intravenous ceftriaxone (2 g once daily) or intravenous
benzylpenicillin (3–4 million units every 4 h). Patients
had to be treated for at least 10 days to be eligible for
inclusion.
The study was done in accordance with Good Clinical
Practice and the Declaration of Helsinki, and was approved
by the Toulouse University Hospital ethics committee

(RnIPH 2020-16) and covered by the MR-004 reference
methodology (National Commission on Informatics and
Liberty [CNIL] number: 2206723 version 0). In accordance
with French law on ethics, patients were informed that
their codified data would be used for the study. The study
was also declared to the Institut National des Données de
Santé, under number MR2914170420.
Covariates of interest
We extracted clinical data from medical charts, including
age, sex, HIV and immunosuppression status, and
history of syphilis and other sexually transmitted
diseases. Data on systemic glucocorticoid treatment
were also collected. Neurosyphilis was separated
into five different subtypes according to clinical
characteristics: meningitis, facial palsy, otic syphilis,
neurovascular syphilis, and ocular syphilis (which
encompasses over­ lapping forms, including anterior,
intermediate, and posterior uveitis, and optic neuritis).
A single patient could present with several subtypes of
neurosyphilis (eg, ocular syphilis and meningitis).
Extraneurological and ophthalmological symptoms,
such as skin rash, lymphadenopathy, and alopecia, were
also assessed. The biological variables of interest that we
collected included serum VDRL or rapid plasma reagin
titres at diagnosis and 6 months after treatment, CSF
VDRL titres at diagnosis and 6 months after treatment,
CSF cell counts, and CSF protein concentrations. Data
were collected retrospectively by TB, AJ, MM, and SM,
and verified by TB, AJ, ND, and GM-B. Available reports
of adverse events were collected from the medical files
of patients.
Outcomes
Clinical response 1 month after treatment initiation was
retrospectively assessed by the investigators using data
obtained from the medical charts. Clinical complete
response was defined as the total disappearance of
neurological or ophthalmological symptoms; clinical
partial response was defined as a clinically relevant
improvement in symptoms without a return to baseline.
For uveitis, complete response was defined as total
recovery of previous vision and partial response as a
recovery of vision without reaching a complete response.
For otic syphilis, complete response was defined as total
recovery of previous hearing and partial response as
recovery without reaching a complete response. For
meningitis, complete response was defined as total
recovery from meningeal symptoms and partial response
as recovery with sequelae, such as epilepsy or cognitive
impairment. For facial palsies, complete response was
defined as total recovery from the palsy and partial
response as incomplete recovery. For neurovascular
syphilis, complete response was defined as recovery
from neurological symptoms and partial response as
recovery with sequelae, such as aphasia or motor deficit.
In the case of overlapping forms, recovery in both
www.thelancet.com/infection Published online May 26, 2021 https://doi.org/10.1016/S1473-3099(20)30857-4 3
Articles
categories was required for patients to be considered to
display a complete or partial response.
The primary outcome was overall response (proportion
of patients with a complete response or partial response)
at 1 month after treatment initiation. Secondary outcomes
were proportions of patients with a complete response at
1 month and a serological response (decrease to a quarter
of the original level in serum VDRL titres) 6 months after
treatment, and length of hospital stay. An evaluation of
CSF control via lumbar puncture after 6 months was not
possible due to the small sample size.
Statistical analysis
Because of the retrospective nature of the study, a sample
size calculation was not done. Quantitative variables are
reported as median (IQR) or mean (SD), and categorical
variables are reported as n (%). The ceftriaxone and
benzylpenicillin groups were compared using χ² or
Fisher’s exact tests, as appropriate, for categorical
variables and Student’s t test or Wilcoxon-Mann-Whitney
test for quantitative variables. We initially estimated the
association between treatment and clinical response
with an unadjusted logistic regression model. Given the
variation between groups in the baseline characteristics,
we then did a weighted logistic regression analysis,
using the inverse probability of treatment weighting for
overall response and complete response. We estimated a
propensity score, defined as the probability of treatment
allocation conditional on measured baseline covariates.
Each patient’s weight was equal to the inverse of the
probability of receiving the treatment that the patient
received. This method is used to reduce the indication
bias of treatment allocation. A non-parsimonious multi­
variable logistic regression analysis was done to estimate
the probability of each patient receiving ceftriaxone
365 patients hospitalised with a coded diagnosis of
neurosyphilis between 1997 and 2017 (ICD-10
code A521, A523, or A504)
157 excluded
59 other diagnosis
41 no data
37 asymptomatic
11 no cerebrospinal fluid
pleiocytosis
6 general paresis or
tabes dorsalis
3 other treatment
208 patients included
166 initially treated with 42 initially treated with ceftriaxone
benzylpenicillin
Figure 1: Flow chart of patients
CSF=cerebrospinal fluid.
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negative outcomes, and was unlinked to treatment

Ceftriaxone (n=42) Benzylpenicillin (n=166) p value*
allocation. Standardised differences were used for
Age (years) 44·4 (13·4) 47·1 (12·2) 0·23 quanti­tative comparisons of the baseline covariates
Sex ·· ·· 0·74 measured between the benzylpenicillin and ceftriaxone
Female 2 (5%) 13 (8%) ·· groups in the sample weighted by the inverse probability
Male 40 (95%) 153 (92%) ·· of treatment. A threshold of 10% was used to assess
People who live with HIV/AIDS 23 (55%) 79 (48%) 0·49 imbalance.16 The C statistic was also computed.
History of syphilis 1 (2%) 18 (11%) 0·13 Patients who changed treatment regimen remained in
Neurosyphilis subtype ·· .. 0·0064 their initial treatment group for the intention-to-treat
Uveitis 14 (33%) 90 (54%) ·· analysis. Two sensitivity analyses were done. The first
Anterior uveitis 9 (21%) 50 (30%) ·· included CSF-VDRL in the model, and the second was a
Intermediate uveitis 8 (19%) 45 (27%) ·· per-protocol analysis. Moreover, for the assessment of
Posterior uveitis 11 (26%) 77 (46%) ·· response homogeneity, several subgroup analyses were
with retinitis 7 (17%) 53 (32%) ·· done according to HIV status, neurosyphilis subtype,
with papillitis 8 (19%) 42 (25%) ·· and CSF leukocytosis of more than five cells per μL.
Optic neuritis 6 (14%) 3 (2%) ·· All statistical analyses were done with R software
Meningitis 8 (19%) 33 (20%) ·· (Comprehensive R Archive Network Project 3.6.3). All
Facial palsy 1 (2%) 9 (5%) ·· tests were two-tailed, and p-values less than 0·05 were
Neurovascular 4 (10%) 7 (4%) ·· considered significant.
Otic syphilis 8 (19%) 41 (25%) ··
Other neurological signs ·· ·· 0·46 Role of the funding source
Confusion 2 (5%) 9 (5%) ·· There was no funding source for this study.
Peripheral neuropathy 3 (7%) 6 (4%) ··
Ataxia 1 (2%) 3 (2%) ·· Results
Myelitis 1 (2%) 0 (0) ·· Of 365 patients with a coded diagnosis of neurosyphilis
Epilepsy 0 (0%) 3 (2%) ··
during the study period, we included 208 in this study
Other clinical signs ·· ·· 0·36
(figure 1). Patients had a median age of 47 years
Eruption 11 (26%) 49 (30%) ··
(IQR 36–56), 193 (93%) were men, and 102 (49%) were
people living with HIV/AIDS (including 99 [97%] men;
Lymphadenopathy 2 (5%) 5 (3%) ··
table 1, appendix p 3). The treatment used was
Eruption and lymphadenopathy 1 (2%) 13 (8%) ··
decided by the clinicians caring for the patients. 42 (20%)
Alopecia 1 (2%) 2 (1%) ··
of 208 patients were initially treated with ceftriaxone and
Serum VDRL titre 32 (16–128) 64 (32–128) 0·49
166 (80%) were initially treated with benzylpenicillin.
CSF leukocytosis (elements per mm³)† 42 (101; n=38) 53 (115; n=128) 0·57
67 (40%) patients from the benzylpenicillin group and
CSF proteins (mg/L)† 0·68 (0·40; n=34) 0·82 (0·68; n=120) 0·25
14 (33%) from the ceftriaxone group presented with signs
Positive CSF-VDRL‡ 8/29 (28%) 55/115 (48%) 0·054
of secondary syphilis, such as eruptions, affected
Treatment with systemic corticoids 5 (12%) 48 (29%) 0·029
lymph nodes, or both. The two groups differed in terms
Data are mean (SD), n (%), or median (IQR), unless otherwise stated. CSF=cerebrospinal fluid. *All tests were two-tailed of the clinical type of neurosyphilis (p=0·0064), with
and considered significant if p<0·05. Fisher’s exact tests or Student’s t tests were done, as appropriate. †Data are mean
(SD; number of participants with data available). ‡Data are n/N (%).
uveitis more frequent in the benzylpenicillin group
(54% [90 of 166 patients]) than in the ceftriaxone group
Table 1: Characteristics of patients according to treatment regimen (33% [14 of 42 patients]; table 1). Similarly, a higher
proportion of the patients in the benzylpenicillin group
than in the ceftriaxone group had positive CSF-VDRL
given their baseline covariates (ie, the propensity score results (48% [55 of 114 patients] vs 28% [eight of 29 patients],
of each patient). The variables included in the propensity p=0·054), which might have influenced the choice of
score were prespecified before the outcome analysis and treatment. CSF T pallidum PCR was done on 32 patients
included centre, age at diagnosis, HIV status, previous and was positive for seven (22%; one [25%] of four in the
episodes of syphilis, and clinical form of neurosyphilis ceftriaxone group and six [21%] of 28 in the penicillin
(ie, uveitis, optic neuritis, otic syphilis, meningitis, group). During the study, 38 patients (23%) initially
neurovascular syphilis, or facial palsy). We did not treated with benzylpenicillin were switched onto
include CSF-VDRL in the primary analysis because 30% ceftriaxone after a median of 7 days (IQR 5–12), but these
of patients had missing data for this variable, a gap that patients remained in the benzylpenicillin group for the
we concluded was too large to render the analysis intention-to-treat analysis. This group consisted of
meaningful. Moreover, to avoid bias, we did not include 16 patients with uveitis, 14 with otic syphilis, six with
systemic glucocorticoid use in the model because this meningitis, and two with facial palsies, but no patient
treatment was always initiated several days after the with neurovascular syphilis. Conversely, no patient
introduction of antibiotic treatment, mostly in cases of initially treated with ceftriaxone was switched onto

4 www.thelancet.com/infection Published online May 26, 2021 https://doi.org/10.1016/S1473-3099(20)30857-4

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benzylpenicillin. The median duration of treatment was

Ceftriaxone Benzylpenicillin p value
14 days (IQR 14–14; range 10–21) for each group.
The median propensity score was 0·10 (IQR 0·00–0·18) Intention-to-treat analysis
in the benzylpenicillin group and 0·54 (0·25–0·58) in Complete response, propensity score-weighted OR* 1·08 (0·94–1·24) 1 (ref) 0·27
the ceftriaxone group (p<0·0001; appendix p 5). The Overall response, propensity score-weighted OR* 1·22 (1·12–1·33) 1 (ref) <0·0001
C statistic of the model was 0·88 (95% CI 0·82–0·92). Length of hospital stay, days (95% CI) 8·9 (5·7–12·0) 13·8 (12·8–14·8) <0·0001
After application of the inverse probability of treatment Serological response, crude OR (n=117) 1·56 (0·42–5·86) 1 (ref) 0·50
weighting method, 16 of the 17 variables included had a Per-protocol analysis
standardised mean difference below 10% (appendix p 6). Complete response, propensity score-weighted OR* 1·22 (1·06–1·42) 1 (ref) 0·0079
The threshold was exceeded slightly for optic neuritis Overall response, propensity score-weighted OR 1·22 (1·11–1·34) 1 (ref) <0·0001
(10·3%) due to its higher prevalence in the ceftriaxone Including CSF-VDRL (n=144)
group than in the benzylpenicillin group (table 1; Complete response, propensity score-weighted OR* 1·18 (1·01–1·38) 1 (ref) 0·037
appendix p 6). We nevertheless retained this variable in Overall response, propensity score-weighted OR 1·27 (1·13–1·42) 1 (ref) <0·0001
the model because we considered it to be a subvariable of OR=odds ratio. CSF=cerebrospinal fluid. *The variables included in the propensity score were age, sex, centre, HIV status,
the clinical form of neurosyphilis. neurosyphilis subtype, and history of syphilis.
41 overall clinical responses (98%) were observed in
Table 2: Endpoints according to treatment regimen
the ceftriaxone group compared with 126 (76%) in the
benzylpenicillin group (crude odds ratio [OR] 13·02
[95% CI 1·73–97·66]; p=0·017). This difference persisted
Ceftriaxone Benzylpenicillin Odds ratio
after propensity score weighting (OR 1·22 [95% CI (95% CI)
1·12–1·33]; p<0·0001; table 2). 22 complete responses
HIV-positive 14/23 32/79 2·28 (0·89–6·09)
(52%) were observed in the ceftriaxone group compared
HIV-negative 8/19 23/87 2·02 (0·71–5·64)
with 55 (33%) in the benzylpenicillin group (crude
Uveitis 8/14 28/90 2·95 (0·94–9·74)
OR 2·26 [95% CI 1·12–4·41]; p=0·031). This difference
Otic syphilis 5/8 9/41 5·92 (1·18–29·67)
was not significant after propensity score weighting 21/46
Neurosyphilis* 8/13 1·90 (0·54–6·70)
(OR 1·08 [95% CI 0·94–1·24]; p=0·269; table 2). At least 5 cells per μL in CSF 14/23 38/102 2·14 (0·89–5·20)
Consistent results were obtained for the sensitivity Fewer than 5 cells per μL in CSF 6/13 2/27 10·71 (1·75–65·23)
analyses, although the difference was significant after Overall 22/42 54/166 2·26 (1·12–4·41)
propensity score weighting (table 2). Of 38 patients who
0·50 1·0 2·0 4·0 8·0 16·0 32·0 64·0
switched from benzylpenicillin to ceftriaxone, 32 (84%)
had an overall clinical response and 17 (45%) had a Favours benzylpenicillin Favours ceftriaxone
complete response. Serological responses at 6 months
Figure 2: Complete response rates in patients treated with ceftriaxone or benzylpenicillin, by HIV status,
did not differ between the groups (88% [21 of 24 patients] subtype of neurosyphilis, and CSF cellularity
in the ceftriaxone group vs 82% [76 of 93 patients] in the Odds ratios and their 95% CIs are presented with a log-linear scale. Vasculitis and facial palsy were grouped with
benzylpenicillin group), but patients were hospitalised meningitis because there were too few events. *Includes neurovascular syphilis, facial palsy, and meningitis.
for less time in the ceftriaxone group than in the
benzylpenicillin group (table 2). Subgroup analyses A prospective study considering all forms of syphilis
according to HIV status, neurosyphilis subtype, and has already reported a better serological response to
CSF leukocytosis revealed no differences in complete ceftriaxone, at a dose of 1 g daily intravenously for 10 days,
response rates between the groups (figure 2). Given the than to two weekly injections of benzathine benzyl­
small size of the groups, neurovascular syphilis and penicillin,17 but a meta-analysis reported no difference
facial palsies were grouped with meningitis. It was not between ceftriaxone and penicillin.18 T pallidum probably
possible to calculate the OR for overall response in most invades the CNS early on, as T pallidum is isolated in the
of the different subgroups, because the rate of response CSF of 30% of patients with primary and secondary
was 100% in the ceftriaxone group. Absolute values and syphilis.19 Relapses of neurosyphilis have been shown to
percentages of overall response in the different occur after benzathine benzylpenicillin treatment,
subgroups are provided in the appendix (p 4). No major particularly among people living with HIV/AIDS,4,20
adverse effects were reported in either group. but the risk of developing symptomatic neurosyphilis
is unknown, and there is no evidence available to
Discussion establish whether asymptomatic neuro­syphilis is predic­
In this study, ceftriaxone was similarly effective as the tive of treatment failure.21 Ceftriaxone has intermediate
gold-standard, benzylpenicillin, for the treatment of CSF diffusion features, similar to benzylpenicillin in
neurosyphilis, according to proportions of patients with uninflamed and inflamed meninges,10 and might therefore
overall and complete clinical responses at 1 month and be considered a good alternative to benzylpenicillin.20 A
serological response at 6 months. Moreover, the use of few studies have reported ceftriaxone to be effective for
ceftriaxone was associated with a shorter length of stay in treating neurosyphilis in people living with HIV/AIDS,14
hospital. with a response rate of 80%, and in patients with uveitis,12

www.thelancet.com/infection Published online May 26, 2021 https://doi.org/10.1016/S1473-3099(20)30857-4 5

 Articles
with a response rate of 67%, but US and UK guidelines
are not in line with European guidelines, which
recommend the use of ceftriaxone in these cases.6–8 Our
subgroup analyses were consistent with these previous
findings. However, as the number of patients in each
subgroup was small, the results must be interpreted
with caution, without extrapolation beyond a general
homogeneity of the results.
Our results support the use of ceftriaxone as an
alternative to benzylpenicillin for the treatment of
neurosyphilis, with several potential benefits. First, for
patients allergic to penicillin, a penicillin desensitisation
treatment regimen is often recommended, but this
regimen delays syphilis treatment, which might
conceivably have negative consequences. For patients
with no contraindication to cephalosporins, particularly
in the absence of cross-allergy to penicillin, ceftriaxone
might be an appropriate first-line treatment. Second,
once-daily ceftriaxone is already widely and safely used
in OPAT programmes.22 Patients with neurosyphilis who
are ready for hospital discharge are therefore potential
candidates for the completion of OPAT with ceftriaxone,
which might decrease costs and improve patients’
quality of life.23 However, these advantages must be
weighed against the broader antimicrobial spectrum
of ceftriaxone than of benzylpenicillin, resulting in a
higher ecological burden on microbiota and a higher
risk of the emergence of antibiotic resistance and
Clostridioides difficile infection.24
There is still no consensus definition of neurosyphilis,
and its diagnosis remains challenging. In this study, we
chose to exclude cases of asymptomatic neurosyphilis,
because there is no consensus on treatment, clinical
outcome is difficult to assess, and CSF abnormalities are
likely to resolve with usual treatment for secondary
syphilis.3,5 The sensitivity of CSF-VDRL for the diagnosis
of neurosyphilis has been estimated at 30–70%,25 and
that of CSF-PCR as 6–77%.26 Moreover, although CSF
pleocytosis is a marker of meningitis,3 CSF examination
could be normal in up to 30% of ocular syphilis27 and
90% of otic syphilis cases.28 A diagnosis of neurosyphilis
cannot, therefore, be ruled out on the basis of a normal
CSF examination. However, positive findings on clinical
examination associated with positive treponemal and
non-treponemal tests remain strongly suggestive of
neurosyphilis. In this study, more than a third of patients
presented with clinical signs of secondary syphilis.
Therefore, given the challenging nature of neurosyphilis
diagnosis, careful screening for extraneurological signs
is warranted.
The strengths of this study are its sample size, with the
inclusion of patients from eight referral centres in
France, and the use of a propensity score. However, this
study is also subject to several limitations, particularly
its retrospective design and the indication bias of
treatment allocation. The sample size, although
reasonably large for this rare condition, might not be
6 www.thelancet.com/infection Published online May 26, 2021 https://doi.org/10.1016/S1473-3099(20)30857-4
enough to draw any definitive conclusions. The use of a
weighted propensity score partly corrects this bias but
cannot replace randomisation. Our results suggest that
the use of ceftriaxone is associated with shorter hospital
stay than the use of benzylpenicillin, but we cannot
exclude the possibility that patients in the benzylpenicillin
group experienced more severe disease, necessitating a
longer stay in hospital regardless of treatment. Moreover,
almost all patients in our study were men and 49% were
people living with HIV/AIDS, consistent with findings
for the current European endemic,29 but very different
from Asian or African reports,30,31 making our results
less generalisable to other countries. Finally, the
retrospective design of this study precluded an in-depth
analysis of the adverse effects associated with the use of
ceftriaxone.
In the context of the current rapid re-emergence of
syphilis, this study suggests that ceftriaxone might be
considered as a reliable alternative to benzylpenicillin for
the treatment of neurosyphilis. In selected patients,
OPAT with ceftriaxone might make it possible to decrease
the length of hospital stay, potentially reducing costs
and improving quality of life for patients. However,
randomised, controlled trials are warranted to identify
the best treatment options for neurosyphilis.
Contributors
ND and GM-B designed the study. TB, AJ, MM, and SM collected the
data. TB analysed the data and designed the figures. ND and GM-B
interpreted the data. TB and AJ wrote the first version of the manuscript,
with contributions from CC, OR, IA, VM, JMM, CC, PT, BT, AR, and JG.
TB, AJ, GMB, and ND verified the data. All authors had full access to all
the data in the study and had final responsibility for the decision to
submit for publication.
Declaration of interests
JMM reports grants from Gilead, Merck, and Viiv Healthcare, outside
the submitted work. JG reports grants from Gilead and ViiV Healthcare
and personal fees from Gilead, ViiV Healthcare, Janssen, and Merck
Sharp & Dohme, outside the submitted work. OR reports personal fees
and non-financial support from ViiV, Merck Sharp & Dohme, and
Gilead, and grants from Merck Sharp & Dohme, outside the submitted
work. All other authors declare no competing interests.
Acknowledgments
We thank Emilie Sbidian and Agnès Sommet for their assistance with
the analysis and interpretation of the statistics for this study. We thank
Veronique Baclet, Thomas Huleux, Alexa Debard, Lucie Lelièvre,
Muriel Alvarez, Lydie Porte, Pauline Lansalot-Matras, Camille Garnier,
Caroline Protin, Morgane Mourguet, Gaspard Grouteau, Sarah Pellerin,
and Pierre Delobel for their contributions to patient care.
Data sharing
De-identified participant data and a data dictionary are available upon
reasonable request to Prof Nicolas Dupin (nicolas.dupin@aphp.fr) and
Prof Guillaume Martin-Blondel (martin-blondel.g@chu-toulouse.fr).
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