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Antibiotic therapy for adults with neurosyphilis

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Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

To assess the effectiveness and safety of antibiotics for the management of neurosyphilis in adults.

Background

Description of the condition

Neurosyphilis is an infection of the central nervous system (CNS) caused by Treponema pallidum, a spirochete capable of infecting almost any organ or tissue in the body causing protean clinical manifestations (Conde‐Sendín 2002; Philip 2014). Neurosyphilis is a tertiary manifestation of syphilis. In many cases it goes unnoticed although approximately one‐third of people infected with T. pallidum display cerebrospinal fluid (CSF) abnormalities, such as pleocytosis, elevated protein concentration, or reactivity of serological test, suggestive of invasion of the CNS by T. pallidum. Between 1% to 5% of patients with neurosyphilis develop neurological symptoms (Berger 2014; Marra 2009; O'Donnell 2005).

The epidemiology of neurosyphilis has largely paralleled that of syphilis in general (Berger 2014). By the early 1950s, a dramatic decline occurred as a consequence of the widespread use of antibiotics (Berger 2014). However, incidence has increased due to the onset of the acquired immunodeficiency syndrome pandemic (van der Bij 2005). Currently, early neurosyphilis is more common than late neurosyphilis, and is most frequently seen in patients with human immunodeficiency virus (HIV) infection (van der Bij 2005). Worldwide, it was estimated that by 1999, 11.6 million new cases of syphilitic infection occurred per year (Berger 2014). In 1999, there were approximately 107,000 new cases in North America, 136,000 new cases in Western Europe, 3.8 million new cases in Sub‐Saharan Africa, 4 million cases in South Asia, and 2.9 million cases in Latin America (Berger 2014). A study conducted in The Netherlands showed an incidence of neurosyphilis of 0.47 per 10,000 adults, about 60 new cases per year, and suggests that given the frequency of atypical manifestations of the disease, reintroduction of screening of neurosyphilis has to be considered (Daey 2014).

Clinical manifestations of CNS invasion can occur during any stage of the infection, and include asymptomatic neurosyphilis, acute meningeal syphilis, meningovascular syphilis, paretic neurosyphilis, and tabetic neurosyphilis (Cohen 2013). Acute meningeal syphilis can occur early in syphilis infection and is a well‐described feature of secondary syphilis. Late neurologic complications of syphilis, which present after long periods of latency, are caused by meningovascular, or parenchymal damage, or both. Vascular involvement leading to focal ischemia can present with neurologic deficits including hemiparesis, aphasia, and focal or generalized seizures (Cohen 2013). General paresis is a chronic meningoencephalitis with direct invasion of the cerebrum by T. pallidum, that usually manifests after 15 to 20 years and includes manifestations of progressive dementia with changes in personality, affect, sensorium, intellect, and speech (Cohen 2013). The characteristics of neurosyphilis may be modified by the concomitant presence of immunosuppressive agents or conditions such as HIV/AIDS (Zetola 2007). HIV infection may be associated with an increased risk of development of early neurological complications, likely due to the inability to control the CNS infection after invasion (Zetola 2007). See Appendix 1 for medical terms.

Diagnosis of neurosyphilis is based on serological tests, such as fluorescent treponemal antibody absorption test (FTA ABS), serum microhemagglutination–T. pallidum (MHA‐TP), non‐treponemal test like rapid plasma reagin (RPR), or Venereal Disease Research Laboratory (VDRL) (Berger 2014). See Appendix 2 for details of the operative performance of each test.

Also, the diagnosis of neurosyphilis uses CSF findings and other criteria related to the patient with clinical manifestations of neurosyphilis such as, positive VDRL or positive CSF FTA‐ABS, and white blood cells count (polymorphonuclear leucocytes and/or lymphocytes) > 5/mL or CSF protein > 0.45 g/L or IgG Index > 0.6 (Timmermans 2004). On the other hand, the CSF should be examined of any patient with syphilis and any neurological or ophthalmic symptoms or signs (cognitive dysfunction, motor or sensory defects, visual or auditory symptoms, cranial nerve palsies, meningismus). A CSF examination should also be considered in patients who fail to respond to therapy with an appropriate decline in nontreponemal antibody titer (Katz 2012). See Appendix 3 for details of the criteria for neurosyphilis diagnosis.

Description of the intervention

Three antibiotic groups are prescribed in adult patients with neurosyphilis: β‐lactam antibiotics, tetracyclines, macrolides. Aditionally, chloramphenicol is used for the disease`s treatment (Berger 2014; Conde‐Sendín 2002).

β‐lactam antibiotics

Intramuscular penicillin G is the first line option drug for treating people with any stage of syphilis. The preparation used (i.e. benzathine, aqueous procaine, or aqueous crystalline), the dosage, and the length of treatment depend on the stage and clinical manifestations of the disease (Berger 2014). According to international guidelines for treating neurosyphilis, crystalline penicillin should be administered in doses of 24 million units intravenous over 10 to 14 days (CDC 2010; French 2009). Procaine penicillin should be administered in doses of 2.4 million units intramuscular once daily plus probenecid 500 mg orally four times a day, both for 10 to 14 days. Some specialists administer benzathine penicillin but studies revealed that the drug levels in the cerebrospinal fluid are too low to eliminate T. pallidum (Musher 2008).

This antimicrobial group is the most frequent elicitor of drug hypersensitivity reactions (Chambers 2001; Torres 2010). However, β‐lactams are generally safe drugs and serious adverse events are rare and allergy is over‐diagnosed (Lagacé‐Wiens 2012; Pietri 2001). There is a particular reaction in patients with syphilis when they receive antibiotic, namely the Jarisch‐Herxheimer reaction. It is a transient immunological reaction characterized by symptoms such as fever, chills, headache, myalgias, and exacerbation of existing cutaneous lesions. These clinical findings are manifested over a short‐term period, i.e. 24 hours after starting treatment (Belum 2013).

Ceftriaxone, a third‐generation cephalosporin, is another β‐lactam antibiotic used for treating neurosyphilis patients. It is active in vitro against T. pallidum with a good blood–brain barrier penetration. Ceftriaxone taken daily for 10 to 14 days is considered an alternative for neurosyphilis patients with penicillin allergy, when penicillin anaphylaxis is considered an absolute contraindication (Pietri 2001).

Tetracyclines

The tetracyclines are active against T. pallidum (Deck 2012). Doxycycline is considered an alternative regime for neurosyphilis treatment and can be used at 200 mg orally twice a day for 28 days. This drug is a second generation tetracycline with increased oral bioavailability and tissue penetration. Doxycycline is absorbed in the duodenum and effective concentrations may be achieved in the CSF in patients with neurological infections. Patients should receive a dose of 200 mg for seven days. The most common side effects are pill esophagitis, photosensitivity, and staining of teeth and bone (Eisen 2010).

Macrolides

Erythromycin is active against T. pallidum (Deck 2012). The regime recommended of erythromycin for people with neurosyphilis is 500 mg orally four times a day for 30 days (Berger 2014). The most frequent adverse events associated with this drug are anorexia, nausea, vomiting, diarrhea, and gastrointestinal intolerance which are due to a direct stimulation of intestinal motility and is a common reason for discontinuing erythromycin and substituting with another antibiotic. Erythromycins can produce acute cholestatic hepatitis (fever, jaundice, impaired liver function), probably as a hypersensitivity reaction. Other allergic reactions include fever, eosinophilia, and rashes (Deck 2012).

Chloramphenicol

As other treatment options, chloramphenicol has been used to treat neurosyphilis (1 g endovenously for 14 days; Conde‐Sendín 2002). However, it can cause disturbances in red cell maturation and irreversible aplastic anemia (Guglielmo 2014).

How the intervention might work

The aim of the neurosyphilis treatment is to obtain sufficiently high antibiotic levels in the CNS during the long and irregular time frame where the bacteria is reproducing. Therefore, the treatment should be long and antibiotic dose high (Conde‐Sendín 2002).

The β‐lactam antibiotics share a common structure and mechanism of action: inhibition of synthesis of the bacterial peptidoglycan cell wall, which is essential for their normal growth and development (Pietri 2001). They inhibit the growth of sensitive bacteria by inactivating enzymes located in the bacterial cell membrane, called penicillin binding proteins (PBPs). Therapeutic concentrations of penicillins are achieved readily in tissues and in secretions such as joint fluid, pleural fluid, pericardial fluid, and bile. CSF penetration is poor except in the presence of inflammation. Penicillin concentration in the CSF is variable but is < 1% plasma when the meninges are normal (Pietri 2001). When there is inflammation, concentrations in CSF may increase to as high as 5% of the plasma value. Penicillins are eliminated rapidly, particularly by glomerular filtration and renal tubular secretion, such that their half‐lives in the body are short, typically 30 to 90 minutes, and require frequent administration when given parenterally. Probenecid blocks the renal tubular secretion of penicillin. Therefore, the concurrent administration of probenecid prolongs the elimination of penicillin G and, consequently, increases the serum concentrations. As a consequence, concentrations of these drugs in urine are high (Macdougall 2011).

Among tetracyclines, the experience for the treatment of CNS infections is greatest with doxycycline. The lipophilic drug doxycycline is readily absorbed after oral application (> 80%) (Nau 2010). Macrolides penetrate well into tissue, but because of their relatively high molecular mass and probably also because of their affinity for P‐glycoprotein, they do not reach sufficient CSF concentrations in the absence of meningeal inflammation (Nau 2010). Also, chloramphenicol binds reversibly to the 50S portion of the bacterial ribosome at a site close to, but not identical to, the binding sites for the macrolides (Archer 2011). These group of antibiotics inhibit the protein synthesis of T. pallidum and interfere with protein synthesis in protein human cells (Levinson 2012).

Why it is important to do this review

Since 2000 incidence of early‐stage syphilis in the United States of America and Europe has increased (Marra 2004). Adequate treatment of people with neurosyphilis is fundamental to prevention of neurological sequelae. The dose, mode of administration and duration of the antibiotic treatment against T. pallidum are paramount to achievement of this objective. According to international guidelines, aqueous crystalline penicillin is the first‐line treatment for neurosyphilis, while procaine penicillin plus probenecid, amoxicillin, ceftriaxone, and doxycycline could be used as alternative regimes when the parenteral administration is not feasible (CDC 2010; French 2009). Current recommendations are based on what is known about the pharmacokinetics of the available drugs, the effect on T. pallidum in vitro, laboratory considerations, biological plausibility, expert opinion, case studies, and clinical experience (CDC 2010). However, T. pallidum is highly sensitive to penicillin, and T. pallidum is capable of acquiring plasmids that produce the enzyme penicillinase. Clinical data are lacking on the optimal dose and duration of treatment and the long term efficacy of antimicrobials other than penicillin (CDC 2010; Kingston 2008). There are many potential complications due to treatment for neurosyphilis. Jarsich‐Herxheimer is one, but other adverse reactions are also associated with antibiotic administration (Ali 2002). In this scenario it is important to demonstrate what potential complications are associated with the treatment for neurosyphilis.

Several studies suggest that patients with neurosyphilis could be immunocompromised i.e., patients with human immunodeficiency virus (HIV) infection, they have a higher likelihood of developing neurosyphilis (Berger 2014). The first choice treatment for neurosyphilis intravenous therapy is aqueous penicillin. However, due to known allergic reaction and therapeutic failures, especially in HIV patients, it is necessary to know if there is a different therapy option and there is need to conduct a critical appraisal of the randomized clinical trials in this subgroup of patients (Lasso 2009).

Objectives

To assess the effectiveness and safety of antibiotics for the management of neurosyphilis in adults.

Methods

Criteria for considering studies for this review

Types of studies

We will only include randomized clinical trials with parallel design. We will not apply any restrictions regarding treatment follow‐up, setting, or publication status.

Types of participants

Men and women, regardless of age. We will only include patients with definitive diagnosis of neurosyphilis, including HIV‐seropositive patients. Due to absence of consensus on diagnostic criteria for neurosyphilis and HIV, we will adopt the recommendations for HIV infection detailed by Berger 2014 (see Appendix 3 for details).

Types of interventions

We will consider the control group as the group that is receiving the β‐lactam antibiotic regime and intervention group as the group receiving other antibiotic schemes in the management of adult patients with neurosyphilis.

  • Penicillin: aqueous crystalline penicillin G, procaine penicillin plus probenecid, amoxicillin probenecid, in any dosage and regimen;

  • Third‐cephalosporin generation: ceftriaxone, in any dosage and regimen;

  • Tetracyclines: doxycycline, in any dosage and regimen;

  • Macrolides: erythromycin, in any dosage and regimen;

  • Other antibiotic schemes for neurosyphilis in any dosage or regimen.

We will compare these different antibiotic classes used as single agents or in combination or different duration of treatment. Likewise, we will include any antibiotic regimen combined with probenecid (Kent 2008).

Types of outcome measures

Primary outcomes

  1. Microbiological cure: defined as a decrease in the CSF Venereal Disease Research Laboratory test (VDRL) titer by two dilutions or revert to non‐reactive within two years after completion of therapy for patients with definitive diagnosis of syphilis (Ali 2002; Nayak 2012). The CSF should be examined at the end of treatment to document a fall in cell count, and it should then be examined at six‐month intervals for two to three years. The leukocyte count should return to normal within one year of treatment (usually six months), and the protein level should return to normal within two years (Berger 2014);

  2. Clinical cure: defined as continued absence of signs or symptoms, or the serum RPR decreasing by four‐fold within two years of treatment (Bilgrami 2014);

  3. Adverse events: in general defined by the International Conference on Harmonisation (ICH) Guidelines for Good Clinical Practice (ICH‐GCP 1997) as any untoward medical occurrence that at any dose results in death, is life‐threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability or incapacity, or is a congenital anomaly or birth defect. We will consider all other adverse events as non‐serious (ICH‐GCP 1997). Within adverse events, we will describe reported outcomes, such as the Jarisch‐Herxheimer reaction, a common manifestation that is a transient immunological reaction characterized by and constitutional symptoms such as fever, chills, headache, myalgias, and exacerbation of existing cutaneous lesion after the administration of β‐lactam antibiotics (Belum 2013). Also, we will describe other adverse events related to other antibiotic regimes administered such as pill esophagitis, photosensitivity, staining of teeth and bone in tetracycline administration or fever, eosinophilia, and rashes in macrolides. When chloramphenicol is administered, we will describe events of disturbances in red cell maturation and irreversible aplastic anemia (Deck 2012; Eisen 2010; Guglielmo 2014).

Secondary outcomes

  1. Recurrence of neurosyphilis;

  2. Time to recovery: defined as the time to achieve clinical or microbiological cure;

  3. Quality of life, according to de definition of the concept adopted in each study and using any validated scale;

  4. All causes of withdrawals.

Search methods for identification of studies

We will use both electronic searching in bibliographic databases and handsearching, as described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We will download and managed the search results using Endnote bibliographic software. Also, we will remove duplicate records of the same study.

Electronic searches

We will contact with the Trials Search Coordinator (TSC) of the Sexually Transmitted Infections Cochrane Review Group in order to implement a comprehensive search strategy to capture as many relevant RCTs as possible in electronic databases. For this purpose, we will use a combination of exploded controlled vocabulary (MeSH, Emtree, DeCS) and free‐text terms (considering spelling variants, plurals, synonyms, acronyms, and abbreviations) for "neurosyphilis" and "antibiotic therapy", with field labels, truncation, proximity operators, and Boolean operators. We will improve the sensitivity of the search strategies by including keywords from relevant RCTs detected by earlier searches. We have listed the search strategies in Appendix 4.

Specifically, we will search in the following electronic databases:

  • MEDLINE, Ovid platform: inception to present;

  • MEDLINE In‐Process & Other Non‐Indexed Citations, Ovid platform: inception to present;

  • MEDLINE Daily Update, Ovid platform: inception to present;

  • EMBASE.com: inception to present;

  • The Cochrane Central Register of Controlled Trials (CENTRAL), Ovid platform: inception to present;

  • LILACS, iAHx interface: inception to present.

We will update these searches within six months before publication of this Cochrane Review.

Searching other resources

We will attempt to identify additional relevant trials by:

1. Searching in the Sexually Transmitted Infections Cochrane Review Group's Specialized Register, which includes randomized controlled trials (RCTs) and controlled clinical trials, from 1944 to 2012, located through:

  • Electronic searching in MEDLINE, EMBASE, CENTRAL, and LILACS;

  • Online handsearching in journals not indexed in MEDLINE or EMBASE, according to the journals' master list of the Sexually Transmitted Infections Cochrane Review Group.

2. Searching in trials registers:

3. Searching for grey literature in the System for Information on Grey Literature in Europe "OpenGrey" (http://www.opengrey.eu/)

4. Contacting authors of all RCTs identified by others methods. We will send a comprehensive list of RCTs included in the review along with the criteria for considering studies to the first author of each included trial, asking for any additional studies published or unpublished that might be relevant.

5. Handsearching conference proceeding abstracts of the following events:

  • The International Society for Sexually Transmitted Diseases Research ‐ ISSTDR (http://www.isstdr.org/): 2007, 2009, and 2011;

  • The British Association for Sexual Health and HIV ‐ BASHH (http://www.bashh.org/): 2004, 2006, 2007, and 2009;

  • International Congress on Infectious Diseases ‐ ICID (http://www.isid.org/): 2010 and 2012;

  • The International Union against Sexually Transmitted Infections ‐ IUSTI (http://www.iusti.org/): 2011 and 2012;

  • International Society for Infectious Diseases ‐ ISID (http://www.isid.org/): 2011;

  • International Meeting on Emerging Diseases and Surveillance ‐ IMED (http://www.isid.org/): 2007, 2009, and 2011;

  • Interscience Conference on Antimicrobial Agents and Chemotherapy ‐ ICAAC (http://www.icaac.org/): 2011 and 2012;

  • The International Federation of Gynecology and Obstetrics ‐ FIGO (http://www.figo2012.org/home/): 2012.

6. Handsearching within previous systematic reviews and other relevant publications on the same topic.

7. Handsearching within reference lists of all relevant RCTs identified by others methods.

Data collection and analysis

Selection of studies

We will follow the methods for study selection by using the steps delineated by theCochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). Two review authors (DB, LC) will independently screen the titles and abstracts obtained to identify potential trials for inclusion eligibility, using Early Review Organizing Software (EROS) (Ciapponi 2011 ; Glujovsky 2011; McQuay 1998). If we cannot complete screening satisfactorily based on the title and abstract, we will obtain the full text article for assessment. We will present the results of the study selection as a flowchart according to the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) statement (Moher 2009). We will resolve any disagreements through discussion and consensus. A third author (AMC) will act as referee if necessary. We will also contact the trial authors to resolve any doubts about available information or in case of disagreements.

Data extraction and management

Two review authors (DB, LC) will independently extract data by collecting the following information using pre‐designed data collection forms: review, reviewer and study information, eligibility criteria, characteristics of participants (age, gender, country), trial design and funding, intervention duration and dosages, and outcomes. We will test this format prior to extended use. We will resolve discrepancies through discussion or, if required, we will consult a third author (AMC). One author (DB) will enter data into RevMan 2014 and two review authors (AJ, AMC) will independently check it for accuracy. If necessary, we will also contact the corresponding trial authors for further details.

Data extraction format

We will develop and pilot standardized forms to extract data mainly related to the following aspects:

  1. Study location and setting;

  2. Trial design and power calculation;

  3. Ethical approval;

  4. Inclusion and exclusion criteria;

  5. Baseline characteristics of trial participants including sex, age, sexual orientation, pregnancy status for women, diagnostic test used to detect T. pallidum;

  6. Types of intervention: opportunistic or systematic invitation for screening; number of screening rounds, screening interval;

  7. Types of comparison group: usual care, alternative screening method;

  8. Types of outcome: primary, secondary;

  9. Report of methodological characteristics (see Assessment of risk of bias in included studies for details).

Numerical data extraction

We will extract the following numerical data:

  1. Number of people assessed for eligibility;

  2. Numbers randomized to intervention and comparison groups;

  3. Numbers receiving screening in intervention and comparison groups (at each screening round if multiple rounds);

  4. Numbers included in analyses in intervention and comparison groups;

  5. Numbers with outcomes in intervention and comparison groups.

Assessment of risk of bias in included studies

Two review authors (DB, LC) will independently assess the risk of bias of each trial using a simple form, following the domain‐based evaluation as described in Higgins 2011. We will resolve any discrepancies through discussion with AMC. We will use the 'Risk of bias' tool and generate 'Risk of bias' tables. We will assess the risk of bias for each of the following criteria:

Random sequence generation (checking for possible selection bias)

For each included trial, we will describe the method used to generate the allocation sequence in sufficient detail to allow an assessment of whether it should produce comparable groups. We will assess the method as at:

  • Low risk of bias (any truly random process, e.g. random number table; computer random number generator);

  • High risk of bias (any non‐random process, e.g. odd or even date of birth; hospital or clinic record number); or

  • Unclear risk of bias.

Allocation concealment (checking for possible selection bias)

We will describe for each included trial the method used to conceal allocation to interventions prior to assignment and will assess whether intervention allocation could have been foreseen in advance of, or during recruitment, or changed after assignment. We will assess the method as at:

  • Low risk of bias (e.g. telephone or central randomization; consecutively numbered sealed opaque envelopes);

  • High risk of bias (open random allocation; unsealed or non opaque envelopes, alternation; date of birth);

  • Unclear risk of bias.

Blinding of participants and personnel (checking for possible performance bias)

For each included trial we will describe the methods used, if any, to blind study participants and personnel from knowledge of which intervention a participant received. We will consider that trials are at low risk of bias if they were blinded, or if we judge that the lack of blinding would be unlikely to affect results. We will assess blinding separately for different outcomes or classes of outcomes.

We will assess the methods as:

  • Low, high or unclear risk of bias for participants;

  • Low, high or unclear risk of bias for personnel.

Blinding of outcome assessment (checking for possible detection bias)

We will describe for each included trial the methods used, if any, to blind outcome assessors from knowledge of which intervention a participant received. We will assess blinding separately for different outcomes or classes of outcomes.We will assess methods used to blind outcome assessment as:

  • Low, high or unclear risk of bias.

Incomplete outcome data (checking for possible attrition bias due to the amount, nature and handling of incomplete outcome data)

For each included trial and for each outcome or class of outcomes we will describe the completeness of data including attrition and exclusions from the analysis. We will state whether attrition and exclusions were reported and the numbers included in the analysis at each stage (compared with the total number of randomized participants), reasons for attrition or exclusion where reported, and whether missing data were balanced across groups or were related to outcomes. Where sufficient information is reported, or can be supplied by the trial authors, we will re‐include missing data in the analyses which we undertake.

We will assess methods as at:

  • Low risk of bias (e.g. no missing outcome data; missing outcome data balanced across groups);

  • High risk of bias (e.g. numbers or reasons for missing data imbalanced across groups; 'as treated' analysis done with substantial departure of intervention received from that assigned at randomization);

  • Unclear risk of bias.

We will use a cut‐off point of 20% to consider that a trial is at low or high risk of bias according to the level of missing data.

Selective reporting (checking for reporting bias)

We will describe for each included trial how we investigated the possibility of selective outcome reporting bias and what we found. We will assess the methods as at:

  • Low risk of bias (where it is clear that all of the study’s prespecified outcomes and all expected outcomes of interest to the review have been reported);

  • High risk of bias (where not all the study’s pre‐specified outcomes have been reported; one or more reported primary outcomes were not pre‐specified; outcomes of interest are reported incompletely and so cannot be used; study fails to include results of a key outcome that would have been expected to have been reported);

  • Unclear risk of bias.

Other biases

For each included trial we will describe any important concerns we have about other possible sources of bias. We will assess whether each trial was free of other problems that could put it at risk of bias:

  • Low risk of other bias;

  • High risk of other bias;

  • Unclear whether there is risk of other bias.

Overall risk of bias

We will make explicit judgements about whether studies are at high risk of bias, according to the criteria given in Higgins 2011. We will assess the likely magnitude and direction of the bias and whether we consider it is likely to impact on the findings. We will explore the impact of the level of bias by undertaking sensitivity analyses ‐ see Sensitivity analysis. We will use the GRADE approach in order to produce a 'Summary of Findings' table (GRADEpro 2014; Higgins 2011).

We will downgrade the quality of evidence depending on the presence of the following factors:

  1. Study limitations;

  2. Inconsistency of results;

  3. Indirectness of evidence;

  4. Imprecision;

  5. Publication bias.

Measures of treatment effect

For dichotomous data (clinical cure, adverse events, microbiological cure, recurrence of neurosyphilis, withdrawals) we will present results as summary risk ratios (RR) with 95% confidence intervals (CIs). The RR as a relative effect measure has consistency, works well with a low or high rate of events, and is easy to interpret and use in clinical practice.

For continuous data (i.e. quality of life) we will use the mean difference if outcomes are measured in the same way between trials. We will use the standardized mean difference to combine trials that measure the same outcome but use different methods. Finally, we will use hazard ratio (HR) with 95% CIs to summarize the time to recovery data in survival analysis.

Unit of analysis issues

Where we identify a clinical trial as having randomly assigned participants into several intervention groups, we will consider the control group as the group that is receiving β‐lactam antibiotic regime and intervention group as the group that is receiving other antibiotic schemes in the management of adult patients with neurosyphilis. To avoid confusion for the reader, we will include all intervention groups of the trial in the notes cell of the 'Characteristics of included studies' table, providing a detailed description only of the intervention groups relevant to the review, and only these groups will be used in our analyses. Finally, in order to overcome a unit‐of‐analysis error for a trial that could contribute multiple, correlated comparisons, we will combine all relevant experimental intervention groups of the included trials into a single group and also combine all relevant control intervention groups into a single control group, in order to create a single pair‐wise comparison (Higgins 2011).

Dealing with missing data

In the case of missing data on participants or missing statistics (such as standard deviations) we will contact the trial authors. If unsuccessful, our main analysis will be based on complete data but we will perform sensitivity analyses for worse and best case scenarios. Regarding the primary outcomes, we will include patients with incomplete or missing data in sensitivity analyses by imputing them according to the following scenarios (Hollis 1999):

  • Poor outcome analysis: assuming that drop‐outs or participants lost from both the experimental and the control arms experienced the outcome, including all randomized participants in the denominator;

  • Good outcome analysis: assuming that none of the drop‐outs or participants lost from the experimental and the control arms experienced the outcome, including all randomized participants in the denominator;

  • Extreme case analysis favoring the experimental intervention ('best‐worst' case scenario): none of the drop‐outs or participants lost from the experimental arm, but all of the drop‐outs or participants lost from the control arm experienced the outcome, including all randomized participants in the denominator;

  • Extreme case analysis favoring the control ('worst‐best' case scenario): all drop‐outs or participants lost from the experimental arm, but none from the control arm experienced the outcome, including all randomized participants in the denominator.

Assessment of heterogeneity

We will assess statistical heterogeneity by graphical interpretation and with an I2 statistic and Chi2 test . We will judge heterogeneity as considerable if I2 is greater than 50% or if the P value in the Chi2 test is less than 0.10 (Higgins 2011).

Assessment of reporting biases

We will attempt to assess publication bias by using a funnel plot, which is usually used to illustrate variability between trials in a graphical way. We will need at least 10 trials in order to be able to make judgements about asymmetry and, if asymmetry is present, we will attempt to explore other causes for it (Sterne 2011).

Data synthesis

We will carry out statistical analyses using RevMan 2014. We will use fixed‐effect meta‐analysis for combining data where it is reasonable to assume that trials are estimating the same underlying treatment effect: i.e. where trials are examining the same intervention, and the trials' populations and methods are judged sufficiently similar. If there is clinical heterogeneity sufficient to expect that the underlying treatment effects differ between trials, or if we detect substantial statistical heterogeneity, we will use random‐effects meta‐analysis to produce an overall summary if an average treatment effect across trials is considered clinically meaningful. The random‐effects summary will be treated as the average range of possible treatment effects and we will discuss the clinical implications of treatment effects differing between trials. If the average treatment effect is not clinically meaningful we will not combine trials. If we use random‐effects analyses, we will present the results as the average treatment effect with 95% CIs, and the estimates of T² and I² statistics.

Trial sequential analysis

We will apply trial sequential analysis as cumulative meta‐analyses are at risk of producing random errors due to sparse data and repetitive testing of the accumulating data (Brok 2009; Wetterslev 2008). To minimize random errors, we will calculate the required information size (i.e. the number of participants needed in a meta‐analysis to detect or reject a certain intervention effect) (Wetterslev 2008). The required information size calculation should also account for the heterogeneity or diversity present in the meta‐analysis (Wetterslev 2008). In our meta‐analysis, we will base the diversity‐adjusted required information size on the event proportion in the control group; assumption of a plausible RR reduction of 20% on the RR reduction observed in the included trials with low risk of bias; a risk of type I error of 5%; a risk of type II error of 20%; and the assumed diversity of the meta‐analysis. We will add the trials according to the year of publication, and if more than one trial has been published in a year, we will add trials alphabetically according to the last name of the first trial author. On the basis of the required information size, we will construct trial sequential monitoring boundaries (Lan 1983; Thorlund 2009; Wetterslev 2008). These boundaries will determine the statistical inference one may draw regarding the cumulative meta‐analysis that has not reached the required information size; if the trial sequential monitoring boundary is crossed before the required information size is reached, firm evidence may perhaps be established and further trials may turn out to be superfluous. On the other hand, if the boundary is not surpassed, it is most probably necessary to continue doing trials in order to detect or reject a certain intervention effect. That can be determined by assessing if the cumulative Z‐curve crosses the trial sequential boundaries. Furthermore, trial sequential analysis can test the futility before the required information size has been reached, i.e. trial sequential analysis provides an area of futility. If futility boundaries are crossed, then further trials may be unnecessary (CTU 2011). We will conduct TSA using software from the Copenhagen Trial Unit (CTU 2011).

Subgroup analysis and investigation of heterogeneity

We anticipate clinical heterogeneity in the effects of the intervention and we propose to conduct the following subgroup analyses if data are available:

  1. By type of antibiotic regimen;

  2. HIV‐seronegative versus HIV‐seropositive patients;

  3. Patients with symptomatic versus asymptomatic neurosyphilis;

  4. Baseline serum RPR titer (i.e. two dilution decrease for baseline);

  5. Trials with industry bias versus trials without industry bias.

We will only perform subgroup analysis for primary outcomes. If it is necessary, we will do post hoc subgroup analyses. We will specify the reason sufficiently and will interpret the results with caution.

Sensitivity analysis

If sufficient trials are identified, we plan to conduct sensitivity analyses as follows:

  1. Including only randomized clinical trials at low risk of bias (Higgins 2011). As it is unlikely that we will find many trials at low risk of bias in all items, we plan to choose three core domains instead of all, namely: generation of allocation sequence, allocation concealment, and blinding or masking.

  2. Repeating the analysis taking attrition bias into consideration.