who guidelines for the treatment of treponema pallidum ......t. pallidum, no β-lactam-antibiotics...

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WHO guidelines for the treatment of Treponema pallidum (syphilis)

Web annex E: Systematic reviews for syphilis guidelines July 2016 * The full guidelines are available at: www.who.int/reproductivehealth/publications/rtis/syphilis-treatment-guidelines/en/

http://www.who.int/reproductivehealth/publications/rtis/syphilis-treatment-guidelines/en/

http://www.who.int/reproductivehealth/publications/rtis/syphilis-treatment-guidelines/en/

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Contents

Recommendations 1 and 2 ..................................................................................................................................... 5

Question 1: Should benzathine penicillin G 2.4 million units (MU) × 1 compared with other treatments be used for treating adults and adolescents, including HIV-positive patients, with early syphilis? ............................................................................................................................................................. 5

Question 2: Should benzathine penicillin G 2.4 MU 1 compared with other treatments be used for treating adults and adolescents, including HIV-positive patients, with early syphilis with penicillin allergy? ...................................................................................................................................................... 5 Criteria............................................................................................................................................................................... 5

Subgroup: early syphilis (primary, secondary or latent < 2 years) in penicillin allergy patients ................................... 5 Search ................................................................................................................................................................................ 5

For systematic reviews .................................................................................................................................................. 5 For randomized and non-randomized studies .............................................................................................................. 6

Screening of studies and data extraction ......................................................................................................................... 6 Methods of analysis .......................................................................................................................................................... 7 Results ............................................................................................................................................................................... 7 PRISMA .............................................................................................................................................................................. 8 Characteristics of included studies ................................................................................................................................... 9 Effects of interventions ................................................................................................................................................... 13 Risk of bias ...................................................................................................................................................................... 18 References ...................................................................................................................................................................... 19 Acceptability.................................................................................................................................................................... 20 Search .............................................................................................................................................................................. 20 Results ............................................................................................................................................................................. 20 Characteristics of included studies ................................................................................................................................. 20 Findings ........................................................................................................................................................................... 21 References ...................................................................................................................................................................... 21

Recommendations 3 and 4 ................................................................................................................................... 22

Question 3: Should benzathine penicillin G 2.4 MU × 1 compared with other treatments be used for treating pregnant women with early syphilis? ...................................................................................... 22

Question 4: Should benzathine penicillin G 2.4 MU x 1 compared with other treatments be used for treating pregnant women with early syphilis with penicillin allergy? ......................................... 22 Criteria............................................................................................................................................................................. 22

Subgroup: early syphilis (primary, secondary or latent < 2 years) in pregnant women with penicillin allergy .......... 22 Search .............................................................................................................................................................................. 22

For systematic reviews ................................................................................................................................................ 22 For randomized and non-randomized studies ............................................................................................................ 22

Screening of studies and data extraction ....................................................................................................................... 23 Methods of analysis ........................................................................................................................................................ 23 Results ............................................................................................................................................................................. 23 PRISMA ............................................................................................................................................................................ 23 Characteristics of included studies ................................................................................................................................. 24 Effects of interventions ................................................................................................................................................... 25

Subgroup of pregnant women with penicillin allergy ................................................................................................. 27 Risk of bias ...................................................................................................................................................................... 29 References ...................................................................................................................................................................... 30 Acceptability.................................................................................................................................................................... 30


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Question 5: Should benzathine penicillin G 2.4 MU × 1 dose weekly × 3 weeks compared with other treatments be used in adults and adolescents, including HIV-positive patients, with late syphilis? ...................................................................................................................................................................... 32 Criteria............................................................................................................................................................................. 32 Search .............................................................................................................................................................................. 32


Screening of studies and data extraction ....................................................................................................................... 32 Methods of analysis ........................................................................................................................................................ 32 Results ............................................................................................................................................................................. 33 PRISMA ............................................................................................................................................................................ 33 Characteristics of included studies ................................................................................................................................. 33 Effects of interventions ................................................................................................................................................... 33 Risk of bias ...................................................................................................................................................................... 34 References ...................................................................................................................................................................... 34 Acceptability.................................................................................................................................................................... 34


Question 6: Should benzathine penicillin G 2.4 MU × 1 weekly × 3 weeks compared with other treatments be used for treating pregnant women with late syphilis? ................................................. 35 Criteria............................................................................................................................................................................. 35 Search .............................................................................................................................................................................. 35


Screening of studies and data extraction ....................................................................................................................... 35 Methods of analysis ........................................................................................................................................................ 35 Results ............................................................................................................................................................................. 36 PRISMA ............................................................................................................................................................................ 36 Characteristics of included studies ................................................................................................................................. 36 Effects of interventions ................................................................................................................................................... 36 Risk of bias ...................................................................................................................................................................... 37 References ...................................................................................................................................................................... 37 Acceptability.................................................................................................................................................................... 37

Recommendation 9 ................................................................................................................................................. 39

Question 7: In infants with congenital syphilis, or in infants whose mothers had untreated syphilis, inadequately treated syphilis or adequately treated syphilis, what are the treatment options? ...................................................................................................................................................................... 39

Question 8: In infants who are clinically normal but whose mothers had untreated syphilis, inadequately treated syphilis or syphilis that was treated with non-penicillin regimens, what are the treatment options? .................................................................................................................................. 39 Criteria............................................................................................................................................................................. 39

Congenital syphilis: multiple scenarios of proven or possible infection ...................................................................... 39

Recommendation 10 .............................................................................................................................................. 40

Question 9: In infants who are clinically normal and whose mothers had syphilis that was adequately treated with no signs of reinfection, what is the recommended course of action? .. 40 Search .............................................................................................................................................................................. 40


Screening of studies and data extraction ....................................................................................................................... 40 Methods of analysis ........................................................................................................................................................ 40 PRISMA ............................................................................................................................................................................ 40 Results ............................................................................................................................................................................. 41

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Effects of interventions ................................................................................................................................................... 42 Risk of bias ...................................................................................................................................................................... 42 References ...................................................................................................................................................................... 43

Additional information for syphilis used in recommendations ............................................................. 44

In patients who would need penicillin treatment for syphilis, what are the effects of skin testing vs verbal history for penicillin allergy? ............................................................................................ 44 Criteria............................................................................................................................................................................. 44 Search .............................................................................................................................................................................. 44 References ...................................................................................................................................................................... 45

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Recommendations 1 and 2

Question 1: Should benzathine penicillin G 2.4 million units (MU) × 1 compared with other treatments be used for treating adults and adolescents, including HIV-positive patients, with early syphilis?

Question 2: Should benzathine penicillin G 2.4 MU 1 compared with other treatments be used for treating adults and adolescents, including HIV-positive patients, with early syphilis with penicillin allergy?

Criteria

Population Intervention Comparator Outcome Adults and adolescents, HIV-positive patients with early syphilis (primary, secondary or latent < 2 years)

Benzathine PCN 2.4 MU × 1

Ceftriaxone 1 g IM qd × 10–14 days Azithromycin 2 g × 1 Benzathine PCN 2.4 MU × 3 Benzathine PCN 2.4 MU × 2 Doxycycline 100 mg po bid × 14 days Erythromycin 500 mg po qid × 14 days

Critical: Serological response, clinical cure Important: Transmission to partner, antimicrobial resistance, compliance, side-effects (including allergy, toxicity), HIV transmission or acquisition, STI complications

bid: twice daily; IM: intramuscular; MU: million units; PCN: penicillin; po: by mouth (orally); qid: four times daily; STI: sexually transmitted infection

Subgroup: early syphilis (primary, secondary or latent < 2 years) in penicillin allergy patients Population Intervention Comparator Outcome

Penicillin allergy patients with early syphilis (primary, secondary or latent < 2 years)

PCN desensitization and PCN

Ceftriaxone 1 g IM qd × 10–14 days Azithromycin 2 g × 1 Doxycycline 100 mg po bid × 14 days Erythromycin 500 mg po qid × 14 days

Critical: Serological response, clinical cure, allergic reaction/anaphylactic shock Important: Transmission to partner, antimicrobial resistance, compliance, side-effects (including allergy, toxicity), HIV transmission or acquisition, STI complications

bid: twice daily; IM: intramuscular; PCN: penicillin; po: by mouth (orally); qd: once daily; qid: four times daily

Search

For systematic reviews We searched the Trip database (January 2011 to January 2015) and databases for systematic reviews (Cochrane Database of Systematic Reviews [CDSR], Economic Evaluation Database [EED], Database of Abstracts of Reviews of Effects (DARE), Health Technology Assessment [HTA] up to January 2014). The search strategy included keywords and text words for syphilis. We did not restrict by language. We found 11 systematic reviews, five of which were used as a second verification of included studies.

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For randomized and non-randomized studies We used one search of the databases to find articles for all five questions. We searched MEDLINE, Embase (up to 26 February 2015), CENTRAL (up to March 2015) and LILACS (up to 19 April 2015). The search strategy included keywords and text words for syphilis and the above-mentioned drugs. We excluded editorials, case reports, news, book chapters, meta-analyses and systematic reviews. We did not restrict by language. We also reviewed reference lists of relevant studies, guidelines and systematic reviews. Search strategy 1 syphilis.mp. 2 treponema pallidum.mp. 3 chancre*.mp. 4 or/1-3 5 azithromycin.mp. 6 ceftriaxone.mp. 7 benzathine.mp. 8 doxycycline.mp. 9 erythromycin.mp. 10 penicillin.mp. 11 procaine.mp. 12 benzyl.mp. 13 macrolide*.mp. 14 cephalosporin*.mp. 15 tetracycline*.mp. 16 or/5-15 17 (co or cn or dr or dt or rh or si or th).fs. 18 (th or tu).xs. 19 17 or 18 20 4 and 16 and 19 21 limit 20 to (book or book series or editorial or letter or note or "review" or case reports or meta-analysis or news or systematic reviews) 22 case report/ 23 20 not (21 or 22) 24 remove duplicates from 23 The electronic database search for primary studies found 2799 non-duplicate records for all PICO questions (population, intervention, comparator, outcome). After title and abstract screening for early and late syphilis, we retrieved 178 articles in full text (see Figure 1 for the PRISMA Study Flow diagram).

Screening of studies and data extraction

One investigator screened titles and abstracts for relevant studies, and the results were compared with studies cited by relevant guidelines and systematic reviews. The full texts of potentially relevant studies were retrieved and the full text was screened by two investigators. A third investigator resolved disagreements. Screening forms were developed and piloted by at least two investigators. Non-randomized studies that compared at least two groups receiving different interventions or different doses of the same intervention, or evaluated one group (of at least 40 people) receiving an intervention, were also included. Data were abstracted by one investigator and verified by another. A third investigator resolved disagreements. We collected data for studies on adults, adolescents, HIV-positive or -negative patients, pregnant women, patients with penicillin allergy, patients with congenital syphilis, where there were more than 40 patients in the study, or that reported any of these outcome(s): clinical cure, serological response, transmission to partner, antimicrobial resistance, compliance, side-effects, HIV transmission or acquisition, STI complications, allergic reactions, mother-to-child transmission, adverse pregnancy outcomes, congenital deformities, congenital syphilis manifestation and randomized controlled trials (RCTs) or non-RCTs (see table of characteristics of included studies). Most studies did not provide details about the number of people randomized to each group or the losses to follow-up in each group, and

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did not include people who did not comply with protocol. We collected data for a per-protocol analysis. The data extraction form was developed and piloted by at least two investigators.

Methods of analysis

We present the synthesized results by outcome in the Results section. We analysed the data using Review Manager (RevMan) [Computer program], version 5.2 (Copenhagen: The Nordic Cochrane Center, The Cochrane Collaboration, 2012) and, when available, we include the forest plots of the statistical analyses. For dichotomous outcomes, we pooled the relative risks (e.g. risk ratios and odds ratios) from randomized studies and pooled relative risks from non-randomized studies with two comparison groups. When a study included only one group, we calculated the risk of an event or proportion of an outcome and then pooled the proportions from each study weighted by the generic inverse variance. When results could not be pooled we summarized the results from the individual studies narratively. When available, we pooled and report data for subgroups by HIV status. The heterogeneity of pooled results is reported using the I2 statistic.

Results

We found five reviews: Bai et al., 2012; Blank et al., 2011; Blencowe et al., 2011; Clement et al., 2014; and Galvao et al., 2013 (see References). The reviews did not cover all of the interventions and populations, but we used the search results from these reviews to confirm the studies to include. From our comprehensive search of electronic databases, we included 7 randomized and 18 non-randomized studies with two groups or one group.

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PRISMA

Figure 1. PRISMA Study Flow diagram

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Characteristics of included studies

Most studies do not stratify by HIV status and only report serological cure as an outcome. No two-arm studies report on the use of erythromycin. Most studies do not use the exact doses identified by the Guideline Development Group (GDG). Studies were included when over 90% of patients were defined as “early”.

STUDY (design)

POPULATION STUDY CHARACTERISTICS OUTCOME

TREATMENT Population Number (N) Age Inclusion criteria Exclusion criteria Country

Randomized controlled trials

Hook 2002 Adults/ adolescents

74 30 (18–56) Positive for early syphilis, > 18 years, willingness to participate

Pregnancy, breastfeeding, allergy to β-lactam antibiotics, history of IV drug abuse, history of anti-treponemal drug 30 days prior, advanced HIV, severe liver/renal disease, unreliability (determined by investigators)

USA Serological response, side-effects, HIV transmission or acquisition, clinical cure

Benzathine PCN 2.4 MU IM × 1 Azithromycin 2 g po × 1 Azithromycin 2 g po × 2 (1/week)

Hook 2010 Adults/ adolescents

568 27 18-55years, early syphilis, reactive serology, not pregnant, no antibiotics active against T. pallidum, no β-lactam-antibiotics allergies

Pregnancy, allergy to β-lactam antibiotics, treatment with anti-treponemal drugs

USA, Madagascar

Clinical cure, serological response, side-effects

Benzathine PCN 2.4 MU IM × 1 Azithromycin 2 g po × 1

Katsambas 1987

Adults/ adolescents

36 – Patients suffering from primary or secondary syphilis

Not reported Greece Serological response, clinical cure, side-effects

Ceftriaxone 1 g IM qd × 3 days Benzathine PCN 2.4 MU IM × 1 initially then 2.4 MU IM once weekly × 4 weeks

Kiddugavu 2005

Adults/ adolescents

952, but 619 received both azithromycin and penicillin

37 Positive serology Not reported Uganda Serological response

Benzathine PCN 2.4 MU IM × 1 Azithromycin 1 g po

Moorthy 1987

Adults/ adolescents

20 28 (18–44) Male, 18–60, clinical signs of syphilis, positive lab test, early/primary syphilis

Antibiotics in the past 7 days Singapore Serological response

Ceftriaxone 3 g IM × 1 Ceftriaxone 2 g IM × 2 Benzathine PCN 2.4 MU IM × 1 Ceftriaxone 2 g IM × 5

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Riedner 2005

Adults/ adolescents; HIV+ve –52.1%

628 at first (clinical and serological), then 300 excluded for non-confirmatory serology

27 (15–60) Serologically positive for early syphilis, > 18 years, residence in city study was conducted

Pregnancy, allergy to β-lactam antibiotics, treatment with anti-treponemal drugs last 24 months

Tanzania Serological response, side-effects, clinical cure

Benzathine PCN 2.4 MU IM × 1 Azithromycin 2 g po × 1

Sena 2011 Adults/ adolescents

465 27.1 HIV-negative participants aged >18 years with early syphilis. All participants were required to have reactive syphilis serological tests

Not mentioned North America, Madagascar

Serological response

Benzathine PCN 2.4 MU IM × 1 Azithromycin 1 g po x1 Doxycycline 100 mg po bid × 14 days

Non-randomized trials

Ghanem 2006

Adults/ adolescents

287 34 Early syphilis Negative serology pretreatment, treatment not documented

USA Serological response

Benzathine PCN 2.4 MU IM × 1 Doxycycline 100 mg po bid × 14 days

González-López

2009

Adults/ adolescents including HIV+ve and HIV–ve

347 39.37 Patients with syphilis Not mentioned Madrid Serological response

Penicillin Doxycycline

Jinno 2013 Adults/ adolescents including HIV+ve

560 40 Serological follow-up available at 9–12 months, positive serology at diagnosis, early syphilis

Late syphilis/syphilis of unknown duration, no documentation of treatment, serology at diagnosis not positive


Benzathine PCN 2.4 MU IM × 1 Benzathine PCN 2.4 MU IM weekly × 3 weeks Doxycycline 100 mg po bid × 14 days

Li 2014 Adults/ adolescents

606 (not allergic to penicillin) + 35 (allergic to penicillin)

35 Patients were diagnosed with syphilis

Patients lost to follow-up within 6 months were excluded)

China Serological response

Benzathine PCN 2.4 MU IM × 1 Doxycycline 100 mg po bid × 14 days or tetracycline 500 mg po, qid × 14 days

Long 2006 Adults/ adolescents

96 (not reported how many initially in

Not reported

18–40 years old, live in neighbourhood, frequent microvenues at which study was conducted, 1 in 3 of eligible

Peru Serological response

Benzathine PCN 2.4 MU IM × 1 Doxycycline 100 mg po bid × 14 days

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each group) persons was asked to participate

Petersen 1984

Adults/ adolescents

667 (not all treatments relevant for our analysis)

Not reported

Early syphilis, follow up at 12 months

Denmark, Greenland

Serological response

Benzathine PCN 2.4 MU IM × 1 Benzathine PCN 2.4 MU IM weekly × 2 weeks Benzathine PCN 2.4 MU IM weekly × 3 weeks Doxycycline 100 mg bid po × 14 days

Psomas 2012

Adults/ adolescents

116 (93 HIV-positive but not reported separately)

42 (23–79) Early syphilis, > 18 years, positive lab test, outcome available at 12 months

France Serological response

Benzathine penicillin G different doses Ceftriaxone different doses Doxycycline different doses

Talwar 1992

Adults/ adolescents

1532 Not reported

Early syphilis Previous episode of syphilis India Serological response

Benzathine PCN 2.4 MU IM × 1 Benzathine PCN 2.4 MU IM weekly × 2 weeks

Tittes 2013 Adults/ adolescents including HIV+ve

249 36 Early syphilis, at least one follow-up visit at 90 days, positive serology pretreatment

Reinfection, other treatment Austria Serological response

Benzathine PCN 2.4 MU × 1 Benzathine PCN 2.4 MU IM weekly × 3 weeks

Wong 2008 445 27.9 All patients with a first-time diagnosis of primary syphilis who had at least 2 serological titres within 12 months (1 titre at or around the date of treatment [i.e. baseline titre] and at least 1 follow-up post-treatment test)

HIV patients, non-reactive RPR test, inadequate follow-up, 6 months

Canada Serological response

Benzathine PCN 2.4 MU × 1 Benzathine PCN 2.4 MU IM weekly × 3 weeks

Yang 2014 Adults/ adolescents including HIV+ve

573 33.1 HIV-infected patients were eligible for this observational study if they were 20 years or older, had early syphilis (i.e. primary, secondary or early latent), and had reactive RPR

Patients with a prior history of syphilis who received treatment within 12 months before enrolment were excluded. In addition, patients

Taiwan Serological response

Benzathine PCN 2.4 MU IM × 1 Benzathine PCN 2.4 MU IM weekly × 3 weeks

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titres of 1 : 4 or greater and a reactive result of TPPA test (titre 1 : 320), for which 1 or 3 weekly doses of BPG (2.4 MU, 1170 IU/mg) were administered IM

were excluded if they were pregnant, received antibiotics such as penicillin, ceftriaxone, doxycycline or macrolides for syphilis or other infections within the preceding 12 months or during follow-up, were lost to follow-up immediately after treatment, had a history of penicillin allergy, or were receiving immunosuppressants, immunomodulators or chemotherapy

Non-randomized studies – 1 group study

Agmon-Levin 2010

Adults/ adolescents including HIV+ve

71 42 Syphilis patients Not reported Israel Serological response

Benzathine PCN 2.4 MU IM × 1

Fiumara 1986

Adults/ adolescents

588 34 Patients with primary syphilis Patients who had a recorded history of previous treatment for syphilis or signs of previous infection, such as stigmas of congenital syphilis. Patients with reinfection syphilis are known to have a slower serological response to treatment


Benzathine PCN 2.4 MU IM weekly × 2 weeks

Rolfs 1997 Adults/ adolescents

137 – Patients with primary syphilis If they were pregnant, under 18 years of age, or unable to receive penicillin; if they had received antibiotics effective against T. pallidum within the preceding 2 weeks; and if such therapy was required at enrolment in addition to treatment for syphilis


Benzathine PCN 2.4 MU IM × 1

bid: twice daily; BPG: benzathine penicillin G; IM: intramuscular; HIV +ve: HIV positive; HIV –ve: HIV negative: MU: million units; PCN: penicillin; po: by mouth (orally); qid: four times daily; RPR: rapid plasma regain; TPPA: T. pallidum particle agglutination

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Effects of interventions

Other treatments vs benzathine penicillin G (BPG) 2.4 MU × 1 dose Serological cure Randomized controlled trials and non-randomized studies with two groups

Serological cure Early syphilis one-arm

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Clinical cure Randomized controlled trials and non-randomized studies with two groups Hook (2002), Hook (2010) and Riedner (2005) compared with azithromycin 2 g × 1 dose. Hook (2002 and 2010) report that all patients in both groups were clinically cured; Riedner reports that in the azithromycin group 24 out of 25 patients were cured. Katsambas (1987) compared BPG 2.4 MU × 1 dose initially and 2.2 MU every 7 days repeated 4 times with ceftriaxone 1 g IM 1 daily for 3 days repeated 4 times, and all were cured.

Serological cure in HIV-positive adults Randomized controlled trials and non-randomized studies with two groups

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Psomas (2012) reports that there were no differences in outcomes between patients with or without HIV. González-López (2009) report that among 187 HIV-positive persons [hazard ratio (95% confidence interval) 0.61 (0.39–0.96) P = 0.035)] demonstrated a slower serological response to treatment. Yinnon (1996) reported among 128 participants (n = 28 in each group) with early or late syphilis (HIV+ve or HIV–ve) and treated with 1 dose BPG 2.4 MU IM or 3 doses BPG 2.4 MU IM or other – doxycycline, intravenous (IV) penicillin, amoxicillin, overall 56% (29 of 52) of HIV-positive patients (early or late) did not experience a fourfold decrease in rapid plasma reagin (RPR) titres compared with 38% (20 of 52) of HIV-negative patients after 6 months (P = 0.06). After 12 months this deceased to 44% and 29%, respectively (P = 0.07). Blank et al. (2011) assessed studies published between 1980 and June 2008 on treatment of syphilis in HIV-infected subjects. Serological outcomes of people treated with BPG (2.4 MU IM for early syphilis and 7.2 MU IM for late latent syphilis) could be assessed in a total of 197 people with early, and 245 people with late, latent syphilis. There are even fewer data available on the use of doxycycline (100 mg orally twice a day) to treat early syphilis in HIV-infected subjects: 20 total cases. The range of probabilities for serological failure with BPG 2.4 MU IM was 6.9% (95% CI, 2.6–14.4%) to 22.4% (11.7–36.6%); that of BPG 7.2 MU in late latent syphilis was 19.4% (11.9–28.9%) to 31.1% (22.3–40.9%). They also mentioned that the probability of failure among HIV-negative subjects was lower (for early syphilis [Riedner 2005] BPG × 1: 3.8 [0.8–10.8]) than for HIV-infected subjects (BPG × 1: 6.9 [2.6–14.4]), although most comparisons were not statistically significant owing to small numbers. Blank et al. (2011) assessed studies published between 1980 and June 2008 on treatment of syphilis in HIV-infected subjects. Table 1 below shows the studies published after 2009 and not covered by Blank et al. (2011). Table 1: Syphilis studies published in 2009 not included in the review by Blank et al. (2011)

Study Number of participants

Treatments Serological cure at month 12

Knaute 2012

264 including 90 primary, 133 secondary, 33 latent and 8 tertiary syphilis HIV+ve = 112, HIV–ve = 152

1 dose BPG, 2.4 MU IM

3 doses BPG, 2.4 MU IM, 1-week intervals

Aqueous crystalline penicillin G, daily 6 × 3–4 MU IV for 10–14 days

Serological response to treatment was influenced by syphilis stage but not by HIV infection and reinfection.

Tong 2013

HIV–ve = 1327 Benzathine penicillin 2.4 MU IM for early syphilis

7.2 MU total (2.4 MU IM each at 1-week intervals × 3 weeks) for late syphilis

Doxycycline (100 mg po bid × 14 days)

Azithromycin (2.0 g either IM or IV qd × 10–14 days

870 patients achieved a serological cure, and 457 patients (34.4%) remained in the serofast state. The results indicated that patients with early syphilis had a higher likelihood of a serological cure at 12 months than patients with late syphilis, and the odds ratio was 2.391.

Dionne-Odom 2013

1321 individuals Nearly all received a single dose of

benzathine penicillin, but 44 individuals with prevalent disease were treated with 2 weekly doses and 24 individuals received 3 weekly doses of benzathine penicillin

Overall, 51% of individuals had a successful response to therapy within 180 days and 67% had responded by 400 days. Serological response at 400 days showed no differences between HIV-positive and HIV-negative cases. Although a positive RPR was more common in the HIV-infected partners, HIV infection did not impact the likelihood of serological response to therapy (odds ratio 1.001; P = 0.995).

bid: twice daily; BPG: benzathine penicillin G; HIV+ve: HIV-positive; HIV–ve: HIV-negative IM: intramuscular; IV: intravenous;

MU: million units; po: by mouth (orally); qd: once daily

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HIV transmission or acquisition Randomized controlled trials and non-randomized studies with two groups. Hook 2002 reports that there were no HIV seroconversions. Adverse events Randomized controlled trials with two groups – azithromycin 2 g po × 1 dose vs BPG 4 MU IM × 1

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Randomized controlled trials with two groups – ceftriaxone 1 g im or IV × 10–14 days vs BPG 4 MU × 1

The following outcomes were not measured in the studies: transmission to partner, antimicrobial resistance, compliance, HIV transmission, allergic reaction or acquisition, STI complications.

Risk of bias

Randomized studies – see forest plots. Non-randomized studies with two comparison arms (LOW, MOD, HIGH indicate risk of bias; NI, no information)

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Agmon-Levin 2010 HIGH MOD LOW NI MOD LOW LOW HIGH

Dionne-Odom 2013 HIGH MOD LOW NI MOD LOW LOW HIGH

Fiumara 1986 HIGH MOD LOW NI LOW LOW LOW HIGH

Ghanem 2006 LOW LOW LOW LOW LOW LOW LOW LOW

González-López 2009 HIGH MOD LOW NI LOW LOW LOW HIGH

Jinno 2013 LOW LOW LOW NI LOW LOW LOW MOD Knaute 2012 HIGH MOD LOW NI MOD LOW LOW HIGH

Li 2014 MOD LOW LOW NI LOW LOW LOW MOD

Long 2006 MOD LOW LOW NI LOW LOW LOW MOD

Petersen 1984 MOD LOW LOW NI HIGH LOW LOW MOD

Psomas 2012 MOD LOW LOW NI LOW LOW LOW MOD

Rolfs 1997 MOD LOW LOW NI LOW LOW LOW MOD

Talwar 1992 MOD LOW LOW NI LOW LOW LOW MOD

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Tittes 2013 MOD LOW LOW NI LOW LOW LOW MOD

Tong 2013 HIGH MOD LOW NI LOW LOW LOW HIGH

Wong 2008 MOD LOW LOW NI LOW LOW LOW MOD

Yinnon 1996 MOD MOD LOW NI LOW LOW LOW MOD

Yang 2014 MOD LOW LOW NI LOW LOW LOW MOD

References

Systematic reviews 1. Bai ZG, Wang B, Yang K, Tian JH, Ma B, Liu Y, Jiang L, Gai QY, He X, Li Y. Azithromycin versus penicillin G

benzathine for early syphilis. Cochrane Database Syst Rev. 2012;(6):CD007270. 2. Blank LJ, Rompalo AM, Erbelding EJ, Zenilman JM, Ghanem KG. Treatment of syphilis in HIV-infected subjects: a

systematic review of the literature. Sex Transm Infect. 2011;87:9e16. 3. Blencowe H, Cousens S, Kamb M, Berman S, Lawn JE. Lives Saved Tool supplement detection and treatment of

syphilis in pregnancy to reduce syphilis related stillbirths and neonatal mortality. BMC Public Health. 2011;11(Suppl 3):S9.

4. Clement ME, Lance NO, Hicks CB. Treatment of syphilis: a systematic review. JAMA. 2014;312(18):1905-17. 5. Galvao TF, Silva MT, Serruya SJ, Newman LM, Klausner JD, Pereira MG, Fescina R. Safety of benzathine penicillin

for preventing congenital syphilis: a systematic review. PLoS One. 2013;8(2):e56463. doi:10.1371/journal.pone.0056463.

Included studies 1. Agmon-Levin N, Elbirt D, Asher I, Gradestein S, Werner B, Sthoeger Z. Syphilis and HIV co-infection in an Israeli

HIV clinic: incidence and outcome. Int J STD AIDS. 2010;21(4):249-52. 2. Dionne-Odom J, Karita E, Kilembe W, Henderson F, Vwalika B, Bayingana R et al. Syphilis treatment response

among HIV-discordant couples in Zambia and Rwanda. Clin Infect Dis. 2013;56(12):1829-37. 3. Fiumara NJ. Treatment of primary and secondary syphilis: serologic response. J Am Acad Dermatol.

1986;14(3):487-91. 4. Ghanem KG, Erbelding EJ, Cheng WW, Rompalo AM. Doxycycline compared with benzathine penicillin for the

treatment of early syphilis. Clinical Infect Dis. 2006;42(6):e45-9. doi:10.1086/500406. 5. González-López JJ, Fernández Guerrero ML, Luján R, Fernandez Tostado S, de Górgolas M, Requena L. Factors

determining serologic response to treatment in patients with syphilis. Clin Infect Dis. 2009;49(10):1505–11. doi:10.1086/644618.

6. Hook IEW, Martin DH, Stephens J, Smith BS, Smith K. A randomized, comparative pilot study of azithromycin versus benzathine penicillin G for treatment of early syphilis. Sex Transm Dis. 2002;29(8):486-90.

7. Hook IEW, Behets F, Van Damme K, Ravelomanana N, Leone P, Sena AC et al. A Phase III equivalence trial of azithromycin versus benzathine penicillin for treatment of early syphilis. J Infect Dis. 2010;201(11):1729-35.

8. Jinno S, Anker B, Kaur P, Bristow CC, Klausner JD. Predictors of serological failure after treatment in HIV-infected patients with early syphilis in the emerging era of universal antiretroviral therapy use. BMC Infect Dis. 2013;13:605.

9. Katsambas A, Adoniou C, Katsarou A, Kerkidou A, Stratigos J. Comparative study of ceftriaxone and benzathine penicillin G in the treatment of primary and secondary syphilis. Chemioterapia. 1987;6(2 Suppl): 549-50.

10. Knaute DF, Graf N, Lautenschlager S, Weber R, Bosshard PP. Serological response to treatment of syphilis according to disease stage and HIV status. Clin Infect Dis. 2012;55(12):1615-22. doi:10.1093/cid/cis757.

11. Kiddugavu Mg, Kiwanuka N, Wawer MJ, Serwadda D, Sewankambo NK, Wabwire-Mangen F, et al.; Rakai Study Group. Effectiveness of syphilis treatment using azithromycin and/or benzathine penicillin in Rakai, Uganda. Sex Transm Dis. 2005;32(1):1-6.

12. Li J, Zheng HY. Early syphilis: serological treatment response to doxycycline/tetracycline versus benzathine penicillin. J Infect Dev Ctries. 2014;8(2):228-32. doi:10.3855/jidc.3013.

13. Long CM, Klausner JD, Leon S, Jones FR, Giron M, Cuadros J et al. Syphilis treatment and HIV infection in a population-based study of persons at high risk for sexually transmitted disease/HIV infection in Lima, Peru. Sex Transm Dis. 2006;33(3):151-5.

14. Moorthy TT, Lee CT, Lim KB, Tan T. Ceftriaxone for treatment of primary syphilis in men: a preliminary study. Sex Transm Dis. 1987;14(2):116-8.

http://www.ncbi.nlm.nih.gov/pubmed/?term=Pereira%20MG%5BAuthor%5D&cauthor=true&cauthor_uid=23437138

http://www.ncbi.nlm.nih.gov/pubmed/?term=Fescina%20R%5BAuthor%5D&cauthor=true&cauthor_uid=23437138

http://www.ncbi.nlm.nih.gov/pubmed/?term=Elbirt%20D%5BAuthor%5D&cauthor=true&cauthor_uid=20378895

http://www.ncbi.nlm.nih.gov/pubmed/?term=Asher%20I%5BAuthor%5D&cauthor=true&cauthor_uid=20378895

http://www.ncbi.nlm.nih.gov/pubmed/?term=Gradestein%20S%5BAuthor%5D&cauthor=true&cauthor_uid=20378895

http://www.ncbi.nlm.nih.gov/pubmed/?term=Werner%20B%5BAuthor%5D&cauthor=true&cauthor_uid=20378895

http://www.ncbi.nlm.nih.gov/pubmed/?term=Sthoeger%20Z%5BAuthor%5D&cauthor=true&cauthor_uid=20378895

http://www.ncbi.nlm.nih.gov/pubmed/?term=Karita%20E%5BAuthor%5D&cauthor=true&cauthor_uid=23487377

http://www.ncbi.nlm.nih.gov/pubmed/?term=Kilembe%20W%5BAuthor%5D&cauthor=true&cauthor_uid=23487377

http://www.ncbi.nlm.nih.gov/pubmed/?term=Henderson%20F%5BAuthor%5D&cauthor=true&cauthor_uid=23487377

http://www.ncbi.nlm.nih.gov/pubmed/?term=Vwalika%20B%5BAuthor%5D&cauthor=true&cauthor_uid=23487377

http://www.ncbi.nlm.nih.gov/pubmed/?term=Bayingana%20R%5BAuthor%5D&cauthor=true&cauthor_uid=23487377

http://www.ncbi.nlm.nih.gov/pubmed/?term=Knaute%20DF%5BAuthor%5D&cauthor=true&cauthor_uid=22955437

http://www.ncbi.nlm.nih.gov/pubmed/?term=Bosshard%20PP%5BAuthor%5D&cauthor=true&cauthor_uid=22955437

20

15. Petersen CS, Jorgensen BB, Pedersen NS. Treatment of early infectious syphilis in Denmark. A retrospective serological study. Dan Med Bull. 1984;31(1):70-2.

16. Psomas KC, Brun M, Causse A, Atoui N, Reynes J, Le Moing V. Efficacy of ceftriaxone and doxycycline in the treatment of early syphilis. Med Mal Infect. 2012;42(1):15-9. doi:10.1016/j.medmal.2011.10.003.

17. Riedner G, Rusizoka M, Todd J, Maboko L, Hoelscher M, Mmbando D et al. Single-dose azithromycin versus penicillin G benzathine for the treatment of early syphilis. N Engl J Med. 2005;353(12):1236-44.

18. Rolfs RT, Joesoef MR, Hendershot EF, Rompalo AM, Augenbraun MH, Chiu M et al. A randomized trial of enhanced therapy for early syphilis in patients with and without human immunodeficiency virus infection. N Engl J Med. 1997;337(5):307-14.

19. Sena AC, Wolff M, Martin DH, Behets F, Van Damme K, Leone P, et al. Predictors of serological cure and serofast state after treatment in HIV-negative persons with early syphilis. Clin Infect Dis. 2011;53(11):1092-9.

20. Talwar S, Tutakne MA, Tiwari VD. VDRL titres in early syphilis before and after treatment. Genitourin Med. 1992;68(2):120-2.

21. Tittes J, Aichelburg MC, Antoniewicz L, Geusau A. Enhanced therapy for primary and secondary syphilis: a longitudinal retrospective analysis of cure rates and associated factors. Int J STD AIDS. 2013;24(9):703-11.

22. Tong ML, Lin LR, Liu GL, Zhang HL, Zeng YL, Zheng WH et al. Factors associated with serological cure and the serofast state of HIV-negative patients with primary, secondary, latent, and tertiary syphilis. PLoS One. 2013;8(7):e70102.

23. Wong T, Singh AE, De P. Primary syphilis: serological treatment response to doxycycline/tetracycline versus benzathine penicillin. Am J Med. 2008;121(10):903-8.

24. Yinnon AM, Coury-Doniger P, Polito R, Reichman RC. Serologic response to treatment of syphilis in patients with HIV infection. Arch Int Med. 1996;156(3):321-5.

25. Yang CJ, Lee NY, Chen TC, Lin YH, Liang SH, Lu PL. One dose versus three weekly doses of benzathine penicillin G

for patients co-infected with HIV and early syphilis: a multicenter, prospective observational study. PLoS One.

2012;9(10).

Acceptability

Search

We searched for reviews and studies specific to syphilis treatment acceptability. For systematic reviews we searched the Trip database (January 2011 to January 2015) and databases for systematic reviews (CDSR, EED, DARE, HTA up to January 2014). The search strategy included keywords and text words for syphilis. We did not restrict by language. We used one search of the databases to find articles for all five questions. We searched MEDLINE, Embase (up to 26 February 2015), CENTRAL (up to March 2015) and LILACS (up to 19 April 2015). The search strategy included keywords and text words for syphilis and the above-mentioned drugs. We excluded editorials, case reports, news, book chapters, meta-analyses and systematic reviews. We did not restrict by language. We also reviewed reference lists of relevant studies, guidelines and systematic reviews.

Results

The electronic database search for primary studies found 2799 non-duplicate records for all PICO questions. After title and abstract screening for syphilis, we retrieved 229 articles in full text and included four studies on treatment acceptability specific to syphilis.


Study

Number of participants

Country Treatments and number of participants

Chauhan 2006

31 men UK Benzathine penicillin two injections of benzathine penicillin 1 week apart: 28 men (70%) Benzathine penicillin weekly injections for 3 weeks co-infected with HIV:3 (7.5%) Doxycycline: 2

Crowe 1997 210 UK Procaine penicillin: 90 (high regimen: 1.8 g daily + oral probenecid 500 mg every 6 h for 17 days) + 57 (low regimen: 0.6 g daily for 10–17 days) + 21 mixed regimen: 0.5–2.4 g Doxycycline or amoxicillin: 42

Kingston 72 UK Procaine penicillin IM: 56

http://www.ncbi.nlm.nih.gov/pubmed/?term=Joesoef%20MR%5BAuthor%5D&cauthor=true&cauthor_uid=9235493

http://www.ncbi.nlm.nih.gov/pubmed/?term=Hendershot%20EF%5BAuthor%5D&cauthor=true&cauthor_uid=9235493

http://www.ncbi.nlm.nih.gov/pubmed/?term=Rompalo%20AM%5BAuthor%5D&cauthor=true&cauthor_uid=9235493

http://www.ncbi.nlm.nih.gov/pubmed/?term=Augenbraun%20MH%5BAuthor%5D&cauthor=true&cauthor_uid=9235493

http://www.ncbi.nlm.nih.gov/pubmed/?term=Behets%20F%5BAuthor%5D&cauthor=true&cauthor_uid=21998287

http://www.ncbi.nlm.nih.gov/pubmed/?term=Van%20Damme%20K%5BAuthor%5D&cauthor=true&cauthor_uid=21998287

http://www.ncbi.nlm.nih.gov/pubmed/?term=Liu%20GL%5BAuthor%5D&cauthor=true&cauthor_uid=23894598

http://www.ncbi.nlm.nih.gov/pubmed/?term=Zeng%20YL%5BAuthor%5D&cauthor=true&cauthor_uid=23894598

http://www.ncbi.nlm.nih.gov/pubmed/?term=Zheng%20WH%5BAuthor%5D&cauthor=true&cauthor_uid=23894598

http://www.ncbi.nlm.nih.gov/pubmed/?term=Wong%20T%5BAuthor%5D&cauthor=true&cauthor_uid=18823862

http://www.ncbi.nlm.nih.gov/pubmed/?term=Singh%20AE%5BAuthor%5D&cauthor=true&cauthor_uid=18823862

http://www.ncbi.nlm.nih.gov/pubmed/?term=De%20P%5BAuthor%5D&cauthor=true&cauthor_uid=18823862

http://www.ncbi.nlm.nih.gov/pubmed/?term=Yinnon%20AM%5BAuthor%5D&cauthor=true&cauthor_uid=8572843

http://www.ncbi.nlm.nih.gov/pubmed/?term=Coury-Doniger%20P%5BAuthor%5D&cauthor=true&cauthor_uid=8572843

http://www.ncbi.nlm.nih.gov/pubmed/?term=Polito%20R%5BAuthor%5D&cauthor=true&cauthor_uid=8572843

http://www.ncbi.nlm.nih.gov/pubmed/?term=Reichman%20RC%5BAuthor%5D&cauthor=true&cauthor_uid=8572843

http://www.ncbi.nlm.nih.gov/pubmed/?term=Yang%20CJ%5BAuthor%5D&cauthor=true&cauthor_uid=25286091

http://www.ncbi.nlm.nih.gov/pubmed/?term=Lee%20NY%5BAuthor%5D&cauthor=true&cauthor_uid=25286091

http://www.ncbi.nlm.nih.gov/pubmed/?term=Chen%20TC%5BAuthor%5D&cauthor=true&cauthor_uid=25286091

http://www.ncbi.nlm.nih.gov/pubmed/?term=Lin%20YH%5BAuthor%5D&cauthor=true&cauthor_uid=25286091

http://www.ncbi.nlm.nih.gov/pubmed/?term=Liang%20SH%5BAuthor%5D&cauthor=true&cauthor_uid=25286091

http://www.ncbi.nlm.nih.gov/pubmed/?term=Lu%20PL%5BAuthor%5D&cauthor=true&cauthor_uid=25286091

21

2004 Doxycycline: 15 Amoxicillin: 1

Tayal 2009 80 UK Benzathine penicillin 2.4 MU two doses (1 week apart) IM: 75 Doxycycline 100 mg twice daily 2 weeks: 4 Amoxicillin 500 mg 2-week course plus probenecid 500 mg four times daily: 1

Findings

Chauhan (2006) noted that procaine penicillin G is the recommended first line of treatment in the UK. However, this entails daily injections and all patients rejected this option. He also found that the overall percentage of patients who finished syphilis treatment was 90% and only 10% of the patients refused injections, underlining the fact that compliance may be better with weekly rather than daily injections. Kingston (2004) and Crowe et al. (1997) have suggested excellent compliance to procaine penicillin G (86% and 88%, respectively). Crowe et al. (1997) in their study found 22% of the patients initially declined the daily injections and were then commenced on doxycycline. The reasons for declining therapy were refusal to have injections (25 cases), inability to attend daily (6 cases), penicillin allergy (10 cases) and bleeding disorder (1 case). Tayal (2009) stated that all patients were offered two injections of benzathine penicillin (2.4 MU IM) 1 week apart and the treatment rate of the population was 100%. The acceptability and compliance with Dual Path Platform (DPP®) Syphilis Screen & Confirm test were not varied in relation to gender, ethnic origin and stage of syphilis/treponemal infection.

References

1. Chauhan M, Serisha B, Sankar KN, Pattman RS, Schmid ML. Audit of the use of benzathine penicillin, post-

treatment syphilis serology and partner notification of patients with early infectious syphilis. Int J STD AIDS. 2006;17(3):200-2

2. Crowe G, Theodore C, Forster GE, Goh BT. Acceptability and compliance with daily injections of procaine penicillin in the outpatient treatment of syphilis-treponemal infection. Sex Transm Dis. 1997;24(3):127-30.

3. Kingston MA, Higgins SP. Audit of the management of early syphilis at North Manchester General Hospital. Int J STD AIDS. 2004;15(5):352-4.

4. Owusu-Edusei K, Gift TL, Ballard RC. Cost-effectiveness of a dual non-treponemal/treponemal syphilis point-of-care test to prevent adverse pregnancy outcomes in sub-Saharan Africa (Provisional abstract). Sex Transm Dis. 2011;38:997-1003.

5. Tayal S, Ahmed MS, Hanif U. Audit of early syphilis: Teesside experience 2005–2007. Int J STD AIDS. 2009;20(9):647-9.

http://www.ncbi.nlm.nih.gov/pubmed/?term=Chauhan%20M%5BAuthor%5D&cauthor=true&cauthor_uid=16510011

http://www.ncbi.nlm.nih.gov/pubmed/?term=Serisha%20B%5BAuthor%5D&cauthor=true&cauthor_uid=16510011

http://www.ncbi.nlm.nih.gov/pubmed/?term=Sankar%20KN%5BAuthor%5D&cauthor=true&cauthor_uid=16510011

http://www.ncbi.nlm.nih.gov/pubmed/?term=Pattman%20RS%5BAuthor%5D&cauthor=true&cauthor_uid=16510011

http://www.ncbi.nlm.nih.gov/pubmed/?term=Schmid%20ML%5BAuthor%5D&cauthor=true&cauthor_uid=16510011

http://www.ncbi.nlm.nih.gov/pubmed/?term=Crowe%20G%5BAuthor%5D&cauthor=true&cauthor_uid=9132978

http://www.ncbi.nlm.nih.gov/pubmed/?term=Theodore%20C%5BAuthor%5D&cauthor=true&cauthor_uid=9132978

http://www.ncbi.nlm.nih.gov/pubmed/?term=Forster%20GE%5BAuthor%5D&cauthor=true&cauthor_uid=9132978

http://www.ncbi.nlm.nih.gov/pubmed/?term=Goh%20BT%5BAuthor%5D&cauthor=true&cauthor_uid=9132978

http://www.ncbi.nlm.nih.gov/pubmed/?term=Tayal%20S%5BAuthor%5D&cauthor=true&cauthor_uid=19710341

http://www.ncbi.nlm.nih.gov/pubmed/?term=Ahmed%20MS%5BAuthor%5D&cauthor=true&cauthor_uid=19710341

http://www.ncbi.nlm.nih.gov/pubmed/?term=Hanif%20U%5BAuthor%5D&cauthor=true&cauthor_uid=19710341

22


Question 3: Should benzathine penicillin G 2.4 MU × 1 compared with other treatments be used for treating pregnant women with early syphilis?

Question 4: Should benzathine penicillin G 2.4 MU x 1 compared with other treatments be used for treating pregnant women with early syphilis with penicillin allergy?

Criteria

Population Intervention Comparator Outcome

Pregnant women with early syphilis (primary, secondary or latent < 2 years)


Ceftriaxone 1 g IM qd × 10–14 days Azithromycin 2 g × 1 Benzathine PCN 2.4 MU × 3 doses Benzathine PCN 2.4 MU × 2 doses Erythromycin 500 mg po qid × 14 days

Critical: Mother-to-child transmission, serological response, low birth weight/pre-term, stillbirth/neonatal death, clinical cure, congenital deformities, side-effects (including allergy, toxicity) Important: Compliance, antimicrobial resistance, STI complications, transmission to partner, HIV transmission or acquisition

IM: intramuscular; MU: million units; PCN: pencillin; po: by mouth (orally); qd: daily; qid: four times daily

Subgroup: early syphilis (primary, secondary or latent < 2 years) in pregnant women with penicillin allergy Population Intervention Comparator Outcome

Pregnant women with penicillin allergy with early syphilis (primary, secondary or latent < 2 years)

PCN desensitization and PCN

Ceftriaxone 1 g IM qd × 10–14 days Azithromycin 2 g × 1 Erythromycin 500 mg po qid × 14 days

Critical: Mother-to-child transmission, serological response, low birth weight/pre-term, stillbirth/neonatal death, clinical cure, congenital deformities, side-effects (including allergy, toxicity), anaphylaxis Important: Compliance, antimicrobial resistance, STI complications, transmission to partner, HIV transmission or acquisition

IM: intramuscular; PCN: pencillin; po: by mouth (orally); qid: four times daily

Search

For systematic reviews We searched the Trip database (January 2011 to January 2015) and databases for systematic reviews (CDSR, EED, DARE, HTA up to January 2014). The search strategy included keywords and text words for syphilis. We did not restrict by language. We found 11 systematic reviews and included five systematic reviews as a second verification of included studies.

For randomized and non-randomized studies We used one search of the databases to find articles for all five questions. We searched MEDLINE, Embase (up to 26 February 2015) CENTRAL (up to March 2015) and LILACS (up to 19 April 2015). The search strategy included

23

keywords and text words for syphilis and the above-mentioned drugs. We excluded editorials, case reports, news, book chapters, meta-analyses and systematic reviews. We did not restrict by language. We also reviewed reference lists of relevant studies, guidelines and systematic reviews. See recommendation 1 for “Search strategy” and “PRISMA”. The electronic database search for primary studies found 2799 non-duplicate records for all PICO questions. After title and abstract screening for early and late syphilis, we retrieved 178 articles as relevant. After title and abstract screening for syphilis in pregnancy, we retrieved 22 articles in full text (see PRISMA).


See this section under Recommendations 1 and 2.

Methods of analysis

See this section under Recommendations 1 and 2.

Results

We found one review related to syphilis in pregnancy: Blencowe et al. (2011, see below). The review did not cover all of the interventions, but we used the search results from this review to confirm the studies to include. We included 13 studies (8 as “early” and 5 as “not identified as early and/or late” syphilis on treatment pregnant women) from our search. 1. Blencowe H, Cousens S, Kamb M, Berman S, Lawn JE. Lives Saved Tool supplement detection and treatment of


PRISMA

See Figure 1, Recommendations 1 and 2.

24


Most studies do not stratify by HIV status. No two-arm studies report on the use of erythromycin. Most studies do not use the exact doses mentioned in the PICO questions. There are no randomized controlled trials. We included studies with fewer than 40 participants for allergy patients. Study information Population Study characteristics Outcome Intervention 1

First author and year

Population Number (N) Age (mean/median, range)

Inclusion criteria Exclusion criteria

Country Outcome Treatment

Alexander 1999 Pregnant women 340 24 Positive serology, untreated syphilis

USA Mother-to-child transmission, serological response, stillbirth/neonatal death


Chang 1995 Pregnant women 51 women, 53 newborns

Not reported Positive serology South Korea

Mother-to-child transmission Benzathine PCN 2.4 MU × 3

Donders 1997 Pregnant women 180 23 Positive serology, delivery at study hospital, adverse pregnancy outcomes not caused by other condition

South Africa

Low birth weight/pre-term delivery, stillbirth/neonatal death

No treatment Benzathine PCN 2.4 MU × 1 Benzathine PCN 2.4 MU × 2 Benzathine PCN 2.4 MU × 3

Mullick 2005 Pregnant women 186 Not reported Positive serology South Africa

Compliance Benzathine PCN 2.4 MU × 3

Myer 2004 Pregnant women 1043 26 (13–48) Positive serology Penicillin < 1 week before delivery

South Africa

Stillbirth/neonatal death No treatment Benzathine PCN 2.4 MU × 1 Benzathine PCN 2.4 MU × 2 Benzathine PCN 2.4 MU × 3

Phaosavasdi 1989 Pregnant women 197 Positive serology Thailand Compliance, stillbirth/neonatal death, low birth weight/pre-term delivery, side-effects, mother-to-child transmission, serological response


Wendel 1985 Pregnant women including penicillin allergy

13 Not reported Early syphilis, positive skin test for penicillin allergy

USA Serological response, mother-to-child transmission, allergic reaction/anaphylactic shock, side-effects

PCN desensitization

Zhou 2005 Pregnant women including penicillin allergy

11 25 (22–34) HIV-negative, early syphilis, positive skin test for penicillin allergy, prior safe usage of cephalosporins

China Serological response, clinical cure, mother-to-child transmission, side-effects, compliance

Ceftriaxone 250 mg IM

× 10–14 days, repeated at

28 weeks gestational age

IM: intramuscular; MU: million units; PCN: penicillin

25


Other treatments vs benzathine penicillin G (BPG) 2.4 MU × 1 dose Serological cure Non-randomized studies with one group

Prevention of mother-to-child transmission Non-randomized studies with one group

Compliance Non-randomized studies with one group

26

Stillbirth/neonatal death Non-randomized studies with two groups

Non-randomized studies with one group

Pre-term delivery/low birth weight Non-randomized studies with two groups

Non-randomized studies with one group Low birth weight

27

Pre-term delivery

Subgroup of pregnant women with penicillin allergy Other treatments vs benzathine penicillin G 2.4 MU × 1 dose Serological cure Non-randomized studies with one group

Clinical cure Non-randomized studies with one group

28

Prevention of mother-to-child transmission Non-randomized studies with one group

Compliance Non-randomized studies with one group

Stillbirth/neonatal death Non-randomized studies with one group

Adverse events Non-randomized studies with one group Jarisch–Herxheimer reaction

29

Allergic reaction (urticaria, pruritus) Adverse effects – pregnant early syphilis

Fever

Table 2 provides details of a few more studies not classified as early and/or late syphilis on treatment pregnant women Table 2: Studies on treatment of pregnant women for syphilis without identifying the stage of syphilis Study Number of

participants – pregnant women

Treatments Outcomes

Watson-Jones 2002

n = 1688 Single-dose benzathine penicillin (2.4 MU IM) There was no increased risk for adverse pregnancy outcome for women treated for high-titre active syphilis (odds ratio 0.76; 95% CI, 0.4–1.4) or low-titre active syphilis (odds ratio 0.95; 95% CI, 0.6–1.5), compared with sero-negative women. Single-dose treatment is effective in preventing adverse pregnancy outcomes attributable to maternal syphilis

Zhang 2004

Treatment and no treatment = 93 (50 + 30 + 13) + 99

Penicillin, dibenzyl penicillin, erythromycin Premature birth and fetal intrauterine death were 1/93 and 1/93, respectively, in treatment group compared with 28/99 and 32/99 in no-treatment group.

Klein 1990 n = 33 Single-dose benzathine penicillin (2.4 MU IM) or two additional doses for late syphilis

The Jarisch–Herxheimer reaction occurred in 15 (45%) of the 33 subjects

Myles 1998

n = 31 Single-dose benzathine penicillin (2.4 MU IM) Found 20 cases of probable Jarisch–Herxheimer reaction (40%). Thirteen of 31 patients (41.9%) developed regular uterine contractions, median onset, 10 h. All resolved within 24 h of treatment.

Lu 2001 n = 64 Single-dose benzathine penicillin (2.4 MU IM) for 3 weeks

Occurrences of premature birth, fetal intrauterine death and stillbirth were 0; in the untreated group 4, 11 and 3, respectively.

Risk of bias

Non-randomized studies (LOW, MOD, HIGH indicate risk of bias; NI, no information)

30

First author, Year C

on

fou

nd

ing

Sele

ctio

n o

f p

arti

cip

ants

Mea

sure

men

t o

f

inte

rve

nti

on

s

Inte

nd

ed

inte

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nti

on

s

Mis

sin

g d

ata

Mea

sure

men

t o

f

ou

tco

mes

Rep

ort

ing

Ove

rall

Alexander 1999 MOD Low LOW NI LOW LOW LOW MOD

Chang 1995 MOD LOW LOW NI LOW LOW LOW MOD

Donders 1997 MOD LOW LOW NI LOW LOW LOW MOD

Klein 1990 MOD LOW LOW NI MOD LOW LOW MOD

Lu 2001 HIGH MOD LOW NI LOW LOW LOW HIGH

Mullick 2005 MOD LOW LOW NI MOD LOW LOW MOD

Myer 2004 LOW LOW LOW NI LOW LOW LOW LOW

Myles 1998 MOD LOW LOW NI LOW LOW LOW MOD

Phaosavasdi 1989 MOD LOW LOW NI LOW LOW LOW MOD

Watson-Jones 2002 HIGH MOD LOW NI MOD LOW LOW HIGH

Wendel 1985 MOD LOW LOW NI LOW LOW LOW MOD

Zhang 2004 HIGH MOD LOW NI LOW LOW LOW HIGH

Zhou 2005 MOD LOW LOW NI LOW LOW LOW MOD

References

1. Alexander JM, Sheffield JS, Sanchez PJ, Mayfield J, Wendel Jr GD. Efficacy of treatment for syphilis in pregnancy.

Obstet Gynecol. 1999;93(1):5-8. 2. Chang SN, Chung KY, Lee MG, Lee JB. Seroreversion of the serological tests for syphilis in the newborns born to

treated syphilitic mothers. Genitourin Med. 1995;71(2):68-70. 3. Donders GGG, Desmyter J, Hooft P, Dewet GH. Apparent failure of one injection of benzathine penicillin G for

syphilis during pregnancy in human immunodeficiency virus-seronegative African women. Sex Transm Dis. 1997;24(2):94-101.

4. Klein VR, Cox SM, Mitchell MD, Wendel GD Jr. The Jarisch-Herxheimer reaction complicating syphilotherapy in pregnancy. Obstet Gynecol. 1990;75(3 Pt I):375-80.

5. Lu J, Huang C, Zeng Y. Syphilis in pregnancy women. Zhonghua fu chan ke za zhi 2001;36(8):456-9 (in Chinese). 6. Mullick S, Beksinksa M, Msomi S. Treatment for syphilis in antenatal care: compliance with the three dose

standard treatment regimen. Sex Transm Infect. 2005;81(3):220-2. 7. Myer L, Karim SSA, Lombard C, Wilkinson D. Treatment of maternal syphilis in rural South Africa: effect of

multiple doses of benzathine penicillin on pregnancy loss. Trop Med Int Health. 2004;9(11):1216-21. 8. Myles TD, Elam G, Park-Hwang E, Nguyen T. The Jarisch-Herxheimer reaction and fetal monitoring changes in

pregnant women. Obstet Gynecol. 1998;92(5):859-64. 9. Phaosavasdi S, Snidvongs W, Thasanapradit P, Ungthavorn P, Bhongsvej S, Jongpiputvanich S et al. Effectiveness

of benzathine penicillin regimen in the treatment of syphilis in pregnancy. J Med Assoc Thai. 1989;72(2):101-8. 10. Watson-Jones D, Gumodoka B, Weiss H, Changalucha J, Todd J, Mugeye K et al. Syphilis in pregnancy in

Tanzania. II. The effectiveness of antenatal syphilis screening and single-dose benzathine penicillin treatment for the prevention of adverse pregnancy outcomes. J Infect Dis. 2002;186(7):948-57.

11. Wendel GD Jr., Stark BJ, Jamison RB, Molina RD, Sullivan TJ. Penicillin allergy and desensitization in serious infections during pregnancy. N Engl J Med. 1985;312(19):1229-32.

12. Zhang XM, Zhang RN, Lin SQ, Chen SX, Zheng LY. Clinical analysis of 192 pregnant women infected by syphilis. Zhonghua fu chan ke za zhi. 2004;39(10):682-6.

13. Zhou P, Gu Z, Xu J, Wang X, Liao K. A study evaluating ceftriaxone as a treatment agent for primary and secondary syphilis in pregnancy. Sex Transm Dis. 2005;32(8):495-8.

Acceptability

Patient values and preferences, acceptability and cost: specific to syphilis infections

http://www.ncbi.nlm.nih.gov/pubmed/?term=Watson-Jones%20D%5BAuthor%5D&cauthor=true&cauthor_uid=12232835

http://www.ncbi.nlm.nih.gov/pubmed/?term=Gumodoka%20B%5BAuthor%5D&cauthor=true&cauthor_uid=12232835

http://www.ncbi.nlm.nih.gov/pubmed/?term=Weiss%20H%5BAuthor%5D&cauthor=true&cauthor_uid=12232835

http://www.ncbi.nlm.nih.gov/pubmed/?term=Changalucha%20J%5BAuthor%5D&cauthor=true&cauthor_uid=12232835

http://www.ncbi.nlm.nih.gov/pubmed/?term=Todd%20J%5BAuthor%5D&cauthor=true&cauthor_uid=12232835

http://www.ncbi.nlm.nih.gov/pubmed/?term=Mugeye%20K%5BAuthor%5D&cauthor=true&cauthor_uid=12232835

31

1. Chauhan M, Serisha B, Sankar KN, Pattman RS, Schmid ML. Audit of the use of benzathine penicillin, post-treatment syphilis serology and partner notification of patients with early infectious syphilis. Int J STD AIDS. 2006;17(3):200-2.





Additional references

1. Global Burden of Disease Study 2013 Collaborators. Global, regional, and national incidence, prevalence, and

years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990–2013: a

systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2015;386(9995):743-800.

doi:10.1016/S0140-6736(15)60692-4.

2. Newman L, Rowley J, Vander Hoorn S, Wijesooriya NS, Unemo M, Low N et al. Global estimates of the

prevalence and incidence of four curable sexually transmitted infections in 2012 based on systematic review and

global reporting. PLoS One. 2015;10(12):e0143304. doi:10.1371/journal.pone.0143304.










32


Question 5: Should benzathine penicillin G 2.4 MU × 1 dose weekly × 3 weeks compared with other treatments be used in adults and adolescents, including HIV-positive patients, with late syphilis?

Criteria


Adults and adolescents, HIV positive patients with latent syphilis > 2 years or syphilis of unknown duration

Benzathine PCN 2.4 MU IM once weekly × 3 weeks

Azithromycin Ceftriaxone 1 g IM or IV qd × 10 days Benzathine PCN 2.4 MU × 1, once weekly × 2 weeks Doxycycline 100 mg po bid × 30 days Erythromycin 500 mg po qid × 30 days

Critical: Serological response, compliance Important: Transmission to partner, antimicrobial resistance, side-effects (including allergy, toxicity), HIV transmission or acquisition, STI complications

bid: twice daily; IM: intramuscular; IV: intravenous; MU: million units; PCN: penicillin; qd: once daily; qid: four times daily

Search


For randomized and non-randomized studies We used one search of the databases to find articles for all five questions. We searched MEDLINE, Embase (up to 26 February 2015) CENTRAL (up to March 2015) and LILACS (up to 19 April 2015). The search strategy included keywords and text words for syphilis and the above-mentioned drugs. We excluded editorials, case reports, news, book chapters, meta-analyses and systematic reviews. We did not restrict by language. We also reviewed reference lists of relevant studies, guidelines and systematic reviews. See recommendation 1 for “Search strategy” and “PRISMA”. The electronic database search for primary studies found 2799 non-duplicate records for all PICO questions. After title and abstract screening for early and late syphilis, we retrieved 178 articles in full text as relevant (see PRISMA). We included only one study with two groups. We reported only on the randomized controlled trials here, since the non-randomized studies reported early and late syphilis together.


See this section under recommendation 1.

Methods of analysis


33

Results

We found five reviews: Bai et al., 2012; Blank et al., 2011; Blencowe et al., 2011; Clement et al., 2014 and Galvao et al., 2013 (see below). The reviews did not cover all of the interventions and populations, but we used the search results from these reviews to confirm the studies to include. From our comprehensive search of electronic databases, we included one non-randomized study with two groups. 1. Bai ZG, Wang B, Yang K, Tian JH, Ma B, Liu Y, Jiang L, Gai QY, He X, Li Y. Azithromycin versus penicillin G






PRISMA

See Figure 1 under Recommendations 1 and 2.


There is very limited evidence on the treatment of late syphilis in two-arm studies. Most studies do not stratify by HIV status and report only serological cure as an outcome. No two-arm studies report on the use of erythromycin. Most studies do not use the exact doses mentioned in the PICO questions.

Study Population Study characteristics

First name Year

Population Type of syphilis

N Age

(mean SD)

Inclusion criteria

Exclusion criteria

Country Outcome Treatment: dose

Kiddugavu 2005

Adult, HIV-positive and HIV-negative

Primary, early latent and late latent syphilis

952, but 619 of them received both azithromycin and penicillin

35.5 10.7 Participants with serological syphilis (TRUST with TPHA confirmation)

Not reported

Uganda Serological cure

Benzathine penicillin G 2.4 MU

× 1

Azithromycin 2 g × 1

MU: million units; TPHA: Treponema pallidum haemagglutination assay; TRUST: Toluidine Red Unheated Serum Test


Other treatments vs benzathine penicillin G 2.4 MU × 1 dose Serological cure Randomized controlled trials with two groups.



34

Clinical cure, allergic reaction, transmission to partner, antimicrobial resistance, compliance, side-effects, HIV transmission or acquisition, STI complications These outcomes were not measured in the studies.

Risk of bias

Randomized studies – see forest plots.

References

1. Kiddugavu Mg, Kiwanuka N, Wawer MJ, Serwadda D, Sewankambo NK, Wabwire-Mangen F et al.; Rakai Study Group. Effectiveness of syphilis treatment using azithromycin and/or benzathine penicillin in Rakai, Uganda. Sex Transm Dis. 2005;32(1):1-6.

Acceptability


1. Chauhan M, Serisha B, Sankar KN, Pattman RS, Schmid ML. Audit of the use of benzathine penicillin, post-treatment syphilis serology and partner notification of patients with early infectious syphilis. Int J STD AIDS. 2006;17(3):200-2


3. Kingston MA, Higgins SP. Audit of the management of early syphilis at North Manchester General Hospital. Int J STD AIDS. 2004; 15(5):352-4.

4. Owusu-Edusei K, Gift TL, Ballard RC: Cost-effectiveness of a dual non-treponemal/treponemal syphilis point-of-care test to prevent adverse pregnancy outcomes in sub-Saharan Africa (Provisional abstract). Sex Transm Dis. 2011;38:997-1003.






doi:10.1016/S0140-6736(15)60692-4.

2. Newman L, Rowley J, Vander Hoorn S, Wijesooriya NS, Unemo M, Low N et al. Global estimates of the prevalence and incidence of four curable sexually transmitted infections in 2012 based on systematic review and global reporting. PLoS One. 2015;10(12):e0143304. doi:10.1371/journal.pone.0143304.




http://www.ncbi.nlm.nih.gov/pubmed/?term=Global+Estimates+of+the+Prevalence+and+Incidence+of+Four+Curable+Sexually+Transmitted+Infections+in+2012+Based+on

35


Question 6: Should benzathine penicillin G 2.4 MU × 1 weekly × 3 weeks compared with other treatments be used for treating pregnant women with late syphilis?

Criteria


Pregnant women with latent syphilis > 2 years or syphilis of unknown duration

Benzathine PCN 2.4 MU IM 3 doses (1/week × 3 weeks)

Azithromycin Ceftriaxone 1 g IM or IV qd × 10 days Benzathine PCN 2.4 MU once weekly × 2 weeks Erythromycin 500 mg po qid × 30 days

Critical: Mother-to-child transmission, serological response, low birth weight/pre-term, stillbirth/neonatal death, congenital deformities, compliance Important: Antimicrobial resistance, STI complications, transmission to partner, HIV transmission or acquisition, side-effects (including allergy, toxicity)

IM: intramuscular; IV: intravenous; MU: million units; PCN: penicillin; po: by mouth (orally); qd: once daily; qid: four times daily

Search


For randomized and non-randomized studies We used one search of the databases to find articles for all five questions. We searched MEDLINE, Embase (up to 26 February 2015) CENTRAL (up to March 2015) and LILACS (up to 19 April 2015). The search strategy included keywords and text words for syphilis and the above-mentioned drugs. We excluded editorials, case reports, news, book chapters, meta-analyses and systematic reviews. We did not restrict by language. We also reviewed reference lists of relevant studies, guidelines and systematic reviews. See recommendation 1 for “Search strategy” and “PRISMA”. The electronic database search for primary studies found 2799 non-duplicate records for all PICO questions. After title and abstract screening for early and late syphilis, we retrieved 178 articles in full text and excluded 106 as not relevant. After title and abstract screening, for syphilis in pregnancy, we retrieved 22 articles in full text as relevant (see PRISMA).



Methods of analysis


36

Results

We found five reviews: Bai et al. (2012), Blank et al. (2011), Blencowe et al. (2011), Clement et al. (2014) and Galvao et al. (2013) (see below). The reviews did not cover all of the interventions and populations, but we used the search results from these reviews to confirm the studies to include. From our comprehensive search of electronic databases, we included one non-randomized study. 1. Bai ZG, Wang B, Yang K, Tian JH, Ma B, Liu Y, Jiang L, Gai QY, He X, Li Y. Azithromycin versus penicillin G






PRISMA

See Figure 1 under Recommendations 1 and 2.


There are few studies on late syphilis in pregnancy. Most studies do not stratify by HIV status. No two-arm studies report on the use of erythromycin. Most studies do not use the exact doses mentioned in the PICO questions. There are very few studies. There are no randomized controlled trials. We included studies with > 40 participants for allergy patients.

Study information Population Study characteristics Outcome Intervention 1

First author Year

Population N Age (value, mean/median, range)

Inclusion criteria

Exclusion criteria

Country Outcome Treatment

Alexander 1999 pregnant women

340 24 positive serology, untreated syphilis

Not mentioned

USA Mother-to-child transmission, serological response, stillbirth/neonatal death

Benzathine PCN 2.4 MU × 1 dose

MU: million units; PCN: penicillin


Other treatments vs benzathine penicillin G 2.4 MU × 1 Serological cure Non-randomized studies with one group. In Alexander (1999), 134 of the 136 patients treated with BPG 2.4 MU × 3 were serologically cured.



37

Prevention of mother-to-child transmission Non-randomized studies with one group. In Alexander (1999), mother-to child transmission could be prevented in all 136 cases with mothers treated with BPG 2.4 MU × 3 were serologically cured.

Stillbirth/neonatal death Non-randomized studies with one group. Alexander (1999) reports that there were no stillbirths in a group of 136 women treated with BPG 2.4 MU × 3.

Risk of bias

Non-randomized studies (LOW, MOD, HIGH indicate risk of bias; NI, no information).

First Author, Year C

on

fou

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ing

Sele

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f

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Mea

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f

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nti

on

s

Inte

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ed

inte

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nti

on

s

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sin

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ata

Mea

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Alexander 1999 MOD LOW LOW NI LOW LOW LOW MOD

References

1. Alexander JM, Sheffield JS, Sanchez PJ, Mayfield J, Wendel Jr GD. Efficacy of treatment for syphilis in pregnancy. Obstet Gynecol. 1999;93(1):5-8.

Acceptability














38




1. Bateman DA, Phibbs CS, Joyce T, Heagarty MC. The hospital cost of congenital syphilis. J Pediatr. 1997;130(5):752-8.




doi:10.1016/S0140-6736(15)60692-4.




39

Recommendation 9

Question 7: In infants with congenital syphilis, or in infants whose mothers had untreated syphilis, inadequately treated syphilis or adequately treated syphilis, what are the treatment options?

Question 8: In infants who are clinically normal but whose mothers had untreated syphilis, inadequately treated syphilis or syphilis that was treated with non-penicillin regimens, what are the treatment options?

Criteria

Congenital syphilis: multiple scenarios of proven or possible infection Scenario 1: Infants with congenital syphilis


Infants with congenital syphilis

Benzyl penicillin 100 000–150 000 U/kg/day × 10–15 days Procaine penicillin 50 000 U/kg/day × 10–15 days

Ceftriaxone:

Infants < 30 days: Ceftriaxone 75 mg/kg BW IM/IV qd × 10–14 days

Infants ≥ 30 days: Ceftriaxone 100 mg/kg BW IM/IV qd × 10–14 days

Critical: Clinical cure, serological response, congenital syphilis manifestation

BW: body weight; IM: intramuscular; IV: intravenous; qd: once daily Scenario 2: Infants clinically normal, but mother with syphilis not treated, inadequately treated or treated with non-penicillin


Infants clinically normal, but mother with syphilis not treated, inadequately treated or treated with non-penicillin

Benzyl penicillin 100 000–150 000 U/kg/day × 10–15 days Procaine penicillin 50 000 U/kg/day × 10–15 days

Benzathine penicillin 50 000 U/kg IM single dose Ceftriaxone:

Infants < 30 days: Ceftriaxone 75 mg/kg BW IM/IV qd × 10–14 days

Infants ≥ 30 days: Ceftriaxone 100 mg/kg BW IM/IV qd × 10–14 days

No treatment

Critical: Clinical cure, serological response, congenital syphilis manifestation

BW: body weight; IM: intramuscular; IV: intravenous; qd: once daily

40

Recommendation 10

Question 9: In infants who are clinically normal and whose mothers had syphilis that was adequately treated with no signs of reinfection, what is the recommended course of action?

Scenario 3: Infants clinically normal but mother treated, no signs of reinfection


Infants clinically normal but mother treated, no signs of reinfection

Benzathine penicillin 50 000 U/kg IM single dose

No treatment Ceftriaxone:

Infants < 30 days: Ceftriaxone 75 mg/kg BW IM/IV single dose × 1 day

Infants ≥ 30 days: Ceftriaxone 100 mg/kg BW IM/IV single dose × 1 day

Critical: Clinical cure, Serologic response, congenital syphilis manifestation

BW: body weight; IM: intramuscular; IV: intravenous

Search


For randomized and non-randomized studies We used one search of the databases to find articles for all five questions. We searched MEDLINE, Embase (up to 26 February 2015) CENTRAL (up to March 2015) and LILACS (up to 19 April 2015). The search strategy included keywords and text words for syphilis and the above-mentioned drugs. We excluded editorials, case reports, news, book chapters, meta-analyses and systematic reviews. We did not restrict by language. We also reviewed reference lists of relevant studies, guidelines and systematic reviews. See recommendation 1 for “Search Strategy” and “PRISMA”. The electronic database search for primary studies found 2799 non-duplicate records for all PICO questions. After title and abstract screening, for syphilis treatment, we retrieved 229 articles in full text as relevant. After title and abstract screening for congenital syphilis, we retrieved 29 articles in full text (see PRISMA).



Methods of analysis


PRISMA


41

Results

We included nine studies from our search. Risks of infant/fetus with congenital syphilis in pregnant women Mother with syphilis not treated: Newman review showed that 217 678 live births with syphilis/1 360 485 women with syphilis not treated resulted to 16 live births with syphilis/100 women with syphilis not treated in addition, others would have died stillbirth or neonatal death or premature (160/1000). 1. Gomez GB, Kamb ML, Newman LM, Mark J, Broutet N, Hawkes SJ. Untreated maternal syphilis and adverse

outcomes of pregnancy: a systematic review and meta-analysis. Bull World Health Organ. 2013;91(3):217-26. doi:10.2471/BLT.12.107623.

2. Newman L, Kamb M, Hawkes S, Gomez G, Say L, Seuc A, Broutet N. Global estimates of syphilis in pregnancy and associated adverse outcomes: analysis of multinational antenatal surveillance data. PLoS Med. 2013;10(2):e1001396.

Mother treated with medication other than penicillin: A systematic review found that when mothers are treated, the risk of congenital syphilis is 0.03 times the risk in infants born to untreated mothers; from this it can be roughly estimated that there would be 4.8 births with congenital syphilis per 1000 treated mothers. Only half of these infants (2.4 per 1000) would be expected to show signs or symptoms of congenital syphilis. Therefore in 1000 treated mothers there would be a risk of 2–3 infants born with congenital syphilis who are clinically normal. But if the mother is not treated, the risk of congenital syphilis is 16% (16 live births with syphilis/100 women). If azithromycin is given, there is a decrease risk to 1.05 thus 0.03/1.05 resulting to 0.029 risk of congenital syphilis with azithromycin translating to 4.6 live babies with congenital syphilis. With doxycycline and ceftriaxone approximately there is a decrease risk to 1.14 thus resulting to 0.03/1.14 translating to 0.042 risk of congenital syphilis translating to 2.5 live babies with congenital syphilis. 1. Blencowe H, Cousens S, Kamb M, Berman S, Lawn JE. Lives Saved Tool supplement detection and treatment of


2. Gomez GB, Kamb ML, Newman LM, Mark J, Broutet N, Hawkes SJ. Untreated maternal syphilis and adverse outcomes of pregnancy: a systematic review and meta-analysis. Bull World Health Organ. 2013;91(3):217-26. doi:10.2471/BLT.12.107623.

3. Newman L, Kamb M, Hawkes S, Gomez G, Say L, Seuc A, Broutet N. Global estimates of syphilis in pregnancy and associated adverse outcomes: analysis of multinational antenatal surveillance data. PLoS Med. 2013;10(2):e1001396.

Mother treated with penicillin: A random effects meta-analysis produced an estimated risk ratio for congenital syphilis of 0.03 (95% CI 0.02–0.07) in those pregnant women with syphilis treated with penicillin, compared to those untreated. These results are consistent with a small prospective uncontrolled series examining 11 Venereal Disease Research Laboratory (VDRL) positive women identified between 14 and 19 weeks gestation. Amniocentesis confirmed foetal infection in four out of 11 cases. All four mothers were treated with 2 doses of 2.4 MU penicillin G 1 week apart. No infant had serological evidence of congenital infection. Another larger case series of penicillin-treated antenatal attendees with active syphilis reported that 98.2% (95% CI 96.2–99.3%) of pregnancies resulted in an uninfected infant. Timing of treatment is very important in subsequent risk of congenital syphilis. In a large prospective cohort study in China, women commencing treatment before 20 weeks’ gestation had a lower rate of congenital syphilis risk ratio (RR) = 0.50 (95% CI 0.38–0.64) than women treated after 20 weeks.

http://www.ncbi.nlm.nih.gov/pubmed/?term=Gomez%20GB%5BAuthor%5D&cauthor=true&cauthor_uid=23476094

http://www.ncbi.nlm.nih.gov/pubmed/?term=Kamb%20ML%5BAuthor%5D&cauthor=true&cauthor_uid=23476094

http://www.ncbi.nlm.nih.gov/pubmed/?term=Newman%20LM%5BAuthor%5D&cauthor=true&cauthor_uid=23476094

http://www.ncbi.nlm.nih.gov/pubmed/?term=Mark%20J%5BAuthor%5D&cauthor=true&cauthor_uid=23476094

http://www.ncbi.nlm.nih.gov/pubmed/?term=Broutet%20N%5BAuthor%5D&cauthor=true&cauthor_uid=23476094

http://www.ncbi.nlm.nih.gov/pubmed/?term=Hawkes%20SJ%5BAuthor%5D&cauthor=true&cauthor_uid=23476094

http://www.ncbi.nlm.nih.gov/pubmed/23476094

42

1. Blencowe H, Cousens S, Kamb M, Berman S, Lawn JE. Lives Saved Tool supplement detection and treatment of syphilis in pregnancy to reduce syphilis related stillbirths and neonatal mortality. BMC Public Health. 2011;11(Suppl 3):S9.

We assume similar effects for live births, stillbirths, etc. Therefore if 160/1000 pregnant women were not treated, then 0.03 risk if treated with penicillin results to 4.8/1000 live births with congenital syphilis.


See Evidence profile for recommendations 9 and 10 (see Web annex D).

Risk of bias

Randomized controlled trials:

Ran

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Non-randomized studies (LOW, MOD, HIGH indicate risk of bias; NI, no information) First Author, Year

Co

nfo

un

din

g

Sele

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n o

f

par

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ts

Mea

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Fujii 1988 MOD MOD LOW NI LOW LOW LOW MOD

Lago 2013 MOD LOW LOW NI LOW LOW LOW MOD

Paryani 1994 MOD LOW LOW NI LOW LOW LOW MOD

Sangtawesin 2005 MOD LOW LOW NI LOW LOW LOW MOD

Valentini 2004 MOD LOW LOW NI LOW LOW LOW MOD

43

References

1. Fujii R, Hashira S, Sakata H, Inyaku F, Fujita K, Maruyama S et al. [Pharmacokinetics and clinical evaluation of

ceftriaxone in neonates]. Jpn J Antibiot. 1988;41(9):1237-50. 2. Lago EG, Vaccari A, Fiori RM. Clinical features and follow-up of congenital syphilis. Sex Transm Dis.

2013;40(2):85-94. 3. Paryani SG, Vaughn AJ, Crosby M, Lawrence S. Treatment of asymptomatic congenital syphilis: Benzathine versus

procaine penicillin G therapy. J Pediatr. 1994;125(3):471-5. 4. Product monograph PrBICILLIN® L-A (penicillin G benzathine) sterile injection (for deep intramuscular injection

only) antibiotic. Quebec: Pfizer Canada Inc. 2011. 5. Radcliffe M. Single-dose benzathine penicillin in infants at risk of congenital syphilis – results of a randomised

study. South African Med J. 1997;87(1):62-5. 6. Roerig. Buffered PFIZERPEN (penicillin G potassium) for injection. New York (NY): Pfizer Inc.; 2005

(https://www.pfizer.com/files/products/uspi_pfizerpen.pdf, accessed 8 July 2016). 7. Sangtawesin V, Lertsutthiwong W, Kanjanapattanakul W, Khorana M, Horpaopan S. Outcome of maternal

syphilis at Rajavithi Hospital on offsprings. J Med Assoc Thai. 2005;88(11):1519-25. 8. Valentini P, Speziale D, Grillo RL, D'Apolito A, Angelone DF, Ngalikpima CJ et al. Congenital syphilis: still an open

question. Ital J Pediatr. 2004;30(5):312-9. 9. WHO ceftriaxone safety. Second Meeting of the Subcommittee of the Expert Committee on the Selection and

Use of Essential Medicines. Geneva: World Health Organization; 29 September to 3 October 2008. Acceptability





4. Owusu-Edusei K, Gift TL, Ballard RC: Cost-effectiveness of a dual non-treponemal/treponemal syphilis point-of-care test to prevent adverse pregnancy outcomes in sub-Saharan Africa (Provisional abstract). Sex Transm Dis. 2011;38:997-1003.


6. International drug price indicator guide, 2014 edition (updated annually). Medford (MA): Management

Science for Health; 2015 (http://erc.msh.org/dmpguide/pdf/DrugPriceGuide_2014.pdf, accessed 6 June

2016).


1. Bateman DA, Phibbs CS, Joyce T, Heagarty MC. The hospital cost of congenital syphilis. J Pediatr. 1997;130(5):752-8.




doi:10.1016/S0140-6736(15)60692-4.


https://www.pfizer.com/files/products/uspi_pfizerpen.pdf














44

Additional information for syphilis used in recommendations

In patients who would need penicillin treatment for syphilis, what are the effects of skin testing vs verbal history for penicillin allergy?

Criteria

(Note: will based on risks and benefits of treating patients with non-penicillins vs penicillins)


Adults and adolescents for penicillin treatment

Skin testing

Verbal history of severe allergic reaction

Critical: Allergic reaction, anaphylactic shock, death

Search

We conducted a separate search for randomized and non-randomized studies for skin testing in people with syphilis updated up to June 2015. The search strategy is below. Cochrane Central Register of Controlled Trials (April 2015), Embase (1980 to 2015 Week 21), Ovid MEDLINE® In-Process & Other Non-Indexed Citations and Ovid MEDLINE® (1946 to present). -------------------------------------------------------------------------------- 1 syphilis.mp. 2 treponema pallidum.mp. 3 chancre*.mp. 4 or/1-3 5 penicillin*.mp. 6 exp penicillins/ 7 5 or 6 8 skin.mp. 9 test*.mp. 10 8 and 9 11 allerg*.mp. 12 7 and 10 13 7 and 11 14 12 or 13 15 4 and 14 16 remove duplicates from 15 We found 592 unique citations. One investigator screened title and abstract and 15 were potentially relevant. Another investigator screened studies in full text and no studies were specifically in people with syphilis. We conducted a scoping review of the literature for systematic reviews using the Clinical Query feature in Pubmed for reviews of skin testing for penicillin allergy with no restriction of condition/disease. We found one systematic review published in 2001 (search date up to October 2000) reporting the diagnostic test accuracy of skin testing: 1. Salkind AR, Cuddy PG, Foxworth JW. The rational clinical examination. Is this patient allergic to penicillin? An

evidence-based analysis of the likelihood of penicillin allergy. JAMA. 2001;285(19):2498-505.

45

References

1. You might be allergic to penicillin. Then again, you might not. In: ACAAI.org [website]. Arlington Heights (IL):

American College of Allergy, Asthma and Immunology (ACAAI); 2014 (http://acaai.org/news/you-might-be-allergic-penicillin-then-again-you-might-not, accessed 30 June 2016).

2. Co Minh HB, Bousquet PJ, Fontaine C, Kvedariene V, Demoly P. Systemic reactions during skin tests with beta-lactams: a risk factor analysis. J Allergy Clin Immunol. 2006;117:466–8.

3. Lockey RF, Benedict LM, Turkeltaub PC, Bukantz SC. Fatalities from immunotherapy (IT) and skin testing (ST). J Allergy Clin Immunol. 1987;79:660–77.

4. Nolan RC, Puy R, Deckert K, O’Hehir RE, Douglass JA. Experience with a new commercial skin testing kit to identify IgE-mediated penicillin allergy. Intern Med J. 2008;38:357–61.

5. Riezzo I, Bello S, Neri M, Turillazzi E, Fineschi V. Ceftriaxone intradermal test-related fatal anaphylactic shock: a medico-legal nightmare. Allergy. 2010;65:130–1.

6. Sogn DD, Evans R 3rd, Shepherd GM, Casale TB, Condemi J, Greenberger PA et al. Results of the National Institute of Allergy and Infectious Diseases Collaborative Clinical Trial to test the predictive value of skin testing with major and minor penicillin derivatives in hospitalized adults. Arch Intern Med. 1992;152(5):1025-32.

7. Van Dellen RG. Skin testing for penicillin allergy. J Allergy Clin Immunol. 1981;68:169-70.

http://acaai.org/news/you-might-be-allergic-penicillin-then-again-you-might-not

http://acaai.org/news/you-might-be-allergic-penicillin-then-again-you-might-not

who guidelines for the treatment of treponema pallidum ......t. pallidum, no β-lactam-antibiotics...

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