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Antibiotic therapy for adults with neurosyphilis (Review)

Buitrago-Garcia D, Martí-Carvajal AJ, Jimenez A, Conterno LO, Pardo R

Buitrago-Garcia D, Martí-Carvajal AJ, Jimenez A, Conterno LO, Pardo R.

Antibiotic therapy for adults with neurosyphilis.
Cochrane Database of Systematic Reviews 2019, Issue 5. Art. No.: CD011399.
DOI: 10.1002/14651858.CD011399.pub2.

www.cochranelibrary.com

Antibiotic therapy for adults with neurosyphilis (Review)

Copyright © 2019 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
 Cochrane Trusted evidence.
Informed decisions.
Library Better health. Cochrane Database of Systematic Reviews

[Intervention Review]

Antibiotic therapy for adults with neurosyphilis

Diana Buitrago-Garcia1,2, Arturo J Martí-Carvajal3, Adriana Jimenez4, Lucieni O Conterno5, Rodrigo Pardo6

1Cochrane Ecuador. Centro de Investigación en Salud Pública y Epidemiología Clínica (CISPEC). Facultad de Ciencias de la Salud Eugenio
Espejo, Universidad Tecnológica Equinoccial, Quito, Ecuador. 2Clinical Epidemiology, Fundación Universitaria de Ciencias de la Salud-
FUCS, Bogotá, Colombia. 3Iberoamerican Cochrane Network, Valencia, Venezuela. 4Microbiology-Infectious Diseases, Fundación
Universitaria de Ciencias de la Salud-Hospital de San José, Bogota, Colombia. 5Division of Infectious Diseases, Department of Internal
Medicine,School of Medicine,, University of Campinas, Distrito de Barão Geraldo, Brazil. 6Clinical Research Institute, Faculty of Medicine,
Universidad Nacional de Colombia, Bogota, Colombia

Contact address: Diana Buitrago-Garcia, Clinical Epidemiology, Fundación Universitaria de Ciencias de la Salud-FUCS, Cra 49 95-79,
Bogotá, Colombia. [email protected].

Editorial group: Cochrane STI Group.

Publication status and date: New, published in Issue 5, 2019.

Citation: Buitrago-Garcia D, Martí-Carvajal AJ, Jimenez A, Conterno LO, Pardo R. Antibiotic therapy for adults with neurosyphilis.
Cochrane Database of Systematic Reviews 2019, Issue 5. Art. No.: CD011399. DOI: 10.1002/14651858.CD011399.pub2.

Copyright © 2019 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

ABSTRACT

Background
Neurosyphilis is an infection of the central nervous system, caused by Treponema pallidum, a spirochete capable of infecting almost any
organ or tissue in the body causing neurological complications due to the infection. This disease is a tertiary manifestation of syphilis.
The first-line treatment for neurosyphilis is aqueous crystalline penicillin. However, in cases such as penicillin allergy, other regimes of
antibiotic therapy can be used.

Objectives
To assess the clinical effectiveness and safety of antibiotic therapy for adults with neurosyphilis.

Search methods
We searched the Cochrane Library, CENTRAL, MEDLINE, Embase, LILACS, World Health Organization International Clinical Trials Registry
Platform and Opengrey up to April 2019. We also searched proceedings of eight congresses to a maximum of 10 years, and we contacted
trial authors for additional information.

Selection criteria
We included randomised clinical trials that included men and women, regardless of age, with definitive diagnoses of neurosyphilis,
including HIV-seropositive patients. We compared any antibiotic regime (concentration, dose, frequency, duration), compared to any other
antibiotic regime for the treatment for neurosyphilis in adults.

Data collection and analysis

Two review authors independently selected eligible trials, extracted data, and evaluated risk of bias. We resolved disagreements by
involving a third review author. For dichotomous data (serological cure, clinical cure, adverse events), we presented results as summary
risk ratios (RR) with 95% confidence intervals (CI). We assessed the quality of evidence using the GRADE approach.

Main results
We identified one trial, with 36 participants diagnosed with syphilis and HIV. The participants were mainly men, with a median age of 34
years. This trial, funded by a pharmaceutical company, compared ceftriaxone in 18 participants (2 g daily for 10 days), with penicillin G, also

Antibiotic therapy for adults with neurosyphilis (Review) 1

Copyright © 2019 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
 Cochrane Trusted evidence.
Informed decisions.
Library Better health. Cochrane Database of Systematic Reviews

in 18 participants (4 million/Units (MU)/intravenous (IV) every 4 hours for 10 days). The trial reported incomplete and inconclusive results.
Three of 18 (16%) participants receiving ceftriaxone versus 2 of 18 (11%) receiving penicillin G achieved serological cure (RR 1.50; 95% CI:
0.28 to 7.93; 1 trial, 36 participants very low-quality evidence); and 8 of 18 (44%) participants receiving ceftriaxone versus 2 of 18 (18%)
participants receiving penicillin G achieved clinical cure (RR 4.00; 95% CI: 0.98 to 16.30; 1 trial, 36 participants very low-quality evidence).
Although more participants who received ceftriaxone achieved serological and clinical cure compared to those who received penicillin G,
the evidence from this trial was insufficient to determine whether there was a difference between treatment with ceftriaxone or penicillin G.

In this trial, the authors reported what would usually be adverse events as symptoms and signs in the follow-up of participants.
Furthermore, this trial did not evaluate recurrence of neurosyphilis, time to recovery nor quality of life. We judged risk of bias in this
clinical trial to be unclear for random sequence generation, allocation, and blinding of participants, and high for incomplete outcome data,
potential conflicts of interest (funding bias), and other bias, due to the lack of a sample size calculation. We rated the quality of evidence
as very low.

Authors' conclusions
Due to low quality and insufficient evidence, it was not possible to determine whether there was a difference between treatment
with ceftriaxone or Penicillin G. Also, the benefits to people without HIV and neurosyphilis are unknown, as is the ceftriaxone safety
profile.Therefore, these results should be interpreted with caution. This conclusion does not mean that antibiotics should not be used
for treating this clinical entity. This Cochrane Review has identified the need of adequately powered trials, which should be planned
according to Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) recommendations, conducted and reported
as recommended by the CONSORT statement. Furthermore, the outcomes should be based on patients' perspectives taking into account
Patient-Centered Outcomes Research Institute (PCORI) recommendations.

PLAIN LANGUAGE SUMMARY

Antibiotic therapy for adults with neurosyphilis

Review Question

We reviewed the clinical effectiveness and safety of antibiotic therapy for adults with neurosyphilis.

Background

Syphilis is a condition caused by a micro-organism called Treponema pallidum. At any stage of syphilis an individual can acquire
neurosyphilis, which is an infection of the central nervous system (brain and spinal cord). The infection can be spread throughout the
central nervous system, causing complications in the brain and spine. It may occur during early or late syphilis and it can have severe
consequences for patients. Research has shown that people who are also infected with HIV are more likely to get neurosyphilis. Antibiotics
are used to treat neurosyphilis. The first option is aqueous crystalline penicillin. However, in some cases, such as penicillin allergy, other
antibiotics can be used.

Study characteristics

We searched the medical literature up to April 2019 for trials that evaluated the effectiveness and safety of drugs proposed for the
management of neurosyphilis in adults. We found only one randomised clinical trial that met our criteria (patients are randomly put into
groups to receive different treatments). This trial involved 36 adults with both syphilis and HIV, who were mainly men, with a median age
of 34 years. The trial compared two drugs: ceftriaxone (2 g once daily), and penicillin G (4 million units every 4 hours for 10 days). It was
funded by a pharmaceutical company.

Key findings

The trial reported serological cure, which is a decrease in the levels of the infection shown by laboratory analysis of fluids in the brain and
spinal cord (known as cerebrospinal fluids), and clinical cure, which is the absence of signs or symptoms of neurosyphilis. Only three of 18
participants receiving ceftriaxone and two of 18 participants receiving penicillin G achieved serological cure; and eight of 18 participants
receiving ceftriaxone and two of 18 participants receiving penicillin G achieved clinical cure.

There was not enough evidence to allow us to state if there is a difference between treatment with ceftriaxone or Penicillin G for
neurosyphilis in adults. The outcomes evaluated could change when trials with a better design become available. Additionally, we did not
identify any evidence related to the effectiveness and safety of other drugs proposed to manage this condition.

Quality of evidence

The quality of the evidence was very low for the outcomes serological cure and clinical cure due to problems with the trial's design and
methods, and because there was only a small number of participants.

Antibiotic therapy for adults with neurosyphilis (Review) 2

Copyright © 2019 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.