Combination of Amoxicillin 3000 mg and Probenecid Versus 1500 mg Amoxicillin Monotherapy for Treating Syphilis in Patients With Human Immunodeficiency Virus: An Open-Label, Randomized, Controlled, Non-Inferiority Trial

Abstract

Background Amoxicillin plus probenecid is an alternative to intramuscular benzathine penicillin G for treating syphilis in the United Kingdom. Low-dose amoxicillin is an alternative treatment option used in Japan. Methods We conducted an open-label, randomized, controlled, non-inferiority trial between August 31, 2018, and February 3, 2022, to compare 1,500 mg low-dose amoxicillin monotherapy with the combination of 3,000 mg amoxicillin and probenecid (non-inferiority margin 10%). Patients with human immunodeficiency virus (HIV) infection and syphilis were eligible. The primary outcome was the cumulative serological cure rate within 12 months post-treatment, measured using the manual rapid plasma reagin card test. Secondary outcomes included safety assessment. Results A total of 112 participants were randomized into two groups. Serological cure rates within 12 months were 90.6% and 94.4% with the low-dose amoxicillin and combination regimens, respectively. Serological cure rates for early syphilis within 12 months were 93.5% and 97.9% with the low-dose amoxicillin and combination regimens, respectively. Non-inferiority of low-dose amoxicillin compared with amoxicillin plus probenecid overall and for early syphilis was not confirmed. No significant side effects were detected. Conclusion This is the first randomized controlled trial to demonstrate a high efficacy of amoxicillin-based regimens for treating syphilis in patients with HIV infection, and the non-inferiority of low-dose amoxicillin compared with amoxicillin plus probenecid was not seen. Therefore, amoxicillin monotherapy could be a good alternative to intramuscular benzathine penicillin G with fewer side effects. However, further studies comparing with benzathine penicillin G in different populations and with larger sample sizes are needed. Clinical trials registration University Hospital Medical Information Network (UMIN000033986)

Syphilis Treatment: Systematic Review and Meta-Analysis Investigating Nonpenicillin Therapeutic Strategies

“…Of 38 articles reviewed in further detail, 27 met the inclusion criteria for this systematic literature review [ 11–37 ] ( Figure 1 ). Ten were randomized clinical trials [ 11 , 13 , 16 , 18 , 19 , 22 , 23 , 25 , 26 , 29 ], 16 were retrospective cohort studies [ 12 , 14 , 15 , 17 , 20 , 21 , 24 , 27 , 28 , 30–34 , 36 , 37 ], and 1 was a prospective cohort study [ 35 ].…”

“…Of 38 articles reviewed in further detail, 27 met the inclusion criteria for this systematic literature review [ 11–37 ] ( Figure 1 ). Ten were randomized clinical trials [ 11 , 13 , 16 , 18 , 19 , 22 , 23 , 25 , 26 , 29 ], 16 were retrospective cohort studies [ 12 , 14 , 15 , 17 , 20 , 21 , 24 , 27 , 28 , 30–34 , 36 , 37 ], and 1 was a prospective cohort study [ 35 ]. Twelve were conducted in East Asia [ 11 , 13 , 14 , 21–23 , 28 , 31 , 33–36 ], 7 in North America [ 15 , 17–19 , 26 , 29 , 32 ], 5 in Europe [ 16 , 24 , 27 , 30 , 37 ], 2 in Africa [ 20 , 25 ] and 1 in South America [ 12 ].…”

“…Ten were randomized clinical trials [ 11 , 13 , 16 , 18 , 19 , 22 , 23 , 25 , 26 , 29 ], 16 were retrospective cohort studies [ 12 , 14 , 15 , 17 , 20 , 21 , 24 , 27 , 28 , 30–34 , 36 , 37 ], and 1 was a prospective cohort study [ 35 ]. Twelve were conducted in East Asia [ 11 , 13 , 14 , 21–23 , 28 , 31 , 33–36 ], 7 in North America [ 15 , 17–19 , 26 , 29 , 32 ], 5 in Europe [ 16 , 24 , 27 , 30 , 37 ], 2 in Africa [ 20 , 25 ] and 1 in South America [ 12 ]. Five compared benzathine penicillin G (BPG) or penicillin derivative (amoxicillin) monotherapy with a combined therapy [ 11 , 14 , 16 , 26 , 36 ], and 21 compared penicillin with a different drug monotherapy [ 12 , 13 , 15 , 17–19 , 21–25 , 27–35 , 37 ].…”

“…Twelve were conducted in East Asia [ 11 , 13 , 14 , 21–23 , 28 , 31 , 33–36 ], 7 in North America [ 15 , 17–19 , 26 , 29 , 32 ], 5 in Europe [ 16 , 24 , 27 , 30 , 37 ], 2 in Africa [ 20 , 25 ] and 1 in South America [ 12 ]. Five compared benzathine penicillin G (BPG) or penicillin derivative (amoxicillin) monotherapy with a combined therapy [ 11 , 14 , 16 , 26 , 36 ], and 21 compared penicillin with a different drug monotherapy [ 12 , 13 , 15 , 17–19 , 21–25 , 27–35 , 37 ]. As for the control group, only 1 study did not use penicillin, using amoxicillin instead [ 11 ].…”

“…Five compared benzathine penicillin G (BPG) or penicillin derivative (amoxicillin) monotherapy with a combined therapy [ 11 , 14 , 16 , 26 , 36 ], and 21 compared penicillin with a different drug monotherapy [ 12 , 13 , 15 , 17–19 , 21–25 , 27–35 , 37 ]. As for the control group, only 1 study did not use penicillin, using amoxicillin instead [ 11 ]. Kiddugavu et al [ 20 ] had the only study to include 3 arms (penicillin monotherapy, azithromycin monotherapy, and combined penicillin plus azithromycin).…”