Conclusions
In 2012, the World Health Organization estimated that 930,000 cases of maternal syphilis resulted in cases of 350,000 congenital syphilis.[1] In Japan, the National Institute of Infectious Diseases reported that the number of patients with syphilis is increasing.[5] As the incidence of women with syphilis increases in Japan, incidence of congenital syphilis also increases.[6] The efficacy of penicillin for treatment of syphilis is well established by clinical experience and is the only treatment option with documented efficacy.[3]
Both case-patients described in this report were given amoxicillin and probenecid. A pharmacokinetic study reported that oral amoxicillin and probenecid could attain treponemicidal concentrations in cerebrospinal fluid; therefore, these drugs were considered alternative agents for treatment of neurosyphilis.[7] Tanizaki et al.[8] reported that treatment with oral amoxicillin (3 g) and probenecid (750 mg) was highly effective in and well tolerated by syphilis patients with HIV infection. However, in their report, all patients were men.
For case-patient 2, we changed treatment to ceftriaxone, which is active against T. pallidum and has an effective concentration in cerebrospinal fluid. Marra et al.[9] reported that ceftriaxone is an alternative to penicillin for treatment of neurosyphilis or early syphilis among HIV-infected patients. US Centers for Disease Control and Prevention guidelines recommend ceftriaxone as an alternative treatment of syphilis in nonpregnant women.[3] However, data regarding the use of ceftriaxone for treatment of maternal infections and prevention of congenital syphilis are insufficient.[3]
Because RPR titers for both case-patients became nonreactive, treatment with amoxicillin plus probenecid and ceftriaxone successfully prevented syphilis in both fetuses. Amoxicillin and probenecid are not routinely prescribed for pregnant women because of little evidence of their efficacy in preventing congenital syphilis. Because benzathine penicillin G is not available in Japan, intravenous penicillin G is used to treat maternal syphilis. However, this treatment option requires hospitalization for frequent administration; admission of all maternal syphilis patients is not feasible.
Although ceftriaxone can be administered once a day, it requires daily hospital visits. Azithromycin is not recommended for use during pregnancy,[3] and treatment failures for fetuses have been reported.[10] Tetracyclines are contraindicated during pregnancy.[3] Therefore, we used amoxicillin in accordance with guidelines for Japan.[4]
One study reported the effect of probenecid during pregnancy on fetal outcomes.[11] Because probenecid can cross the placental barrier, its use in pregnancy must follow careful consideration of anticipated benefits and possible hazards.[12] Probenecid was prescribed to increase serum levels of penicillin. Amoxicillin monotherapy might be considered for treatment maternal syphilis if an appropriate dose is given.
The World Health Organization estimates that 5.6 million doses of 2.4 million units of benzathine penicillin are needed annually to treat all syphilis cases, and 930,000 doses are needed to prevent all cases of congenital syphilis.[13] In May 2016, the 69th World Health Assembly reported that benzathine penicillin had been in short supply for several years.[14] Therefore, during shortages of penicillin, it is prudent to consider alternative treatment regimens.
In conclusion, amoxicillin and ceftriaxone should be considered as alternatives to penicillin for treatment of maternal syphilis. Further studies evaluating the efficacy of amoxicillin and ceftriaxone are warranted.
Emerging Infectious Diseases. 2017;23(5):827-829. © 2017 Centers for Disease Control and Prevention (CDC)
