In CDC’s 2021 Sexually Transmitted Infections Treatment Guidelines on syphilis, the preferred therapy for late latent syphilis or syphilis of unknown duration is benzathine penicillin G, 2.4 million units intramuscularly, once a week for three weeks, allowing for an interval of seven to nine days between doses even in cases of pregnancy, and up to 14 days in nonpregnant patients. However, the ongoing manufacturer’s delay since April 2023 has created a supply shortage of this preferred anti-infective drug with estimated recovery expected in December 2027. This has prompted the search for alternative therapies like doxycycline or lentocilin, or an exploration of ways to use the existing supply of BPG more efficiently.
A CDC-led retrospective study published in Clinical Infectious Diseases used CDC National Notifiable Diseases Surveillance System data from 2016 to 2021 to extract information on patients with late or unknown duration of syphilis who were diagnosed in Florida, Louisiana, Arizona, Michigan, North Carolina and Virginia.
The study compared cases who received treatment with 1, 2, 3 or > 3 doses of BPG, and cases who received doxycycline for < 28 days and ≥ 28 days. The study’s primary outcome was adequate serologic response as defined as fourfold decrease in titers between pre- and post-treatment within a 24-month period.
In the study, 18,028 cases met inclusion criteria for analysis, with 80% of cases (14,461) receiving BPG, 18% (3,255) receiving doxycycline, and 2% (312) receiving a combination of BPG and doxycycline; 75% of all cases met the primary outcome. Overall, the likelihood of a fourfold titer decrease did not differ across treatment regimens of 1, 2, 3 or > 3 doses of BPG, or cases who received doxycycline for ≥ 28 days.
Only 1% of the cases received doxycycline for < 28 days, and the study did not report the probability of a fourfold decline in titers by 24 months in this subset.
About 26% of cases received the recommended 3 injections of BPG within CDC guideline intervals, and about 37% of cases received 3 injections of BPG at unknown intervals. Around 11% of cases received only 1 injection; 3% received 2 injections of BPG; and 2% received ≥ 4 injections of BPG.
This study highlights the difficulties in treating late syphilis or syphilis of unknown duration with BPG injections as only 26% of cases received the therapy within the time-sensitive guideline parameters.
However, given this study found no statistically significant difference in treatment effectiveness as measured by a fourfold decrease in nontreponemal titers for cases treated with 1, 2 or 3 doses of weekly BPG injections or with 28 days of doxycycline, perhaps giving a single dose of BPG will improve compliance without sacrificing treatment failures.
Study limitations include using data based on local health department investigations in six U.S. states, which may not have uniform reporting practices, leading to data that may misclassify syphilis stages. Other limitations are discussed thoroughly in the accompanying commentary, but the study provides good evidence to consider using single-dose BPG or 28-day doxycycline as alternatives to 3 weekly doses of BPG, especially with the ongoing shortages of BPG.
(Pugsley et al. Clin Infect Dis. Published online: Feb. 23, 2026.)
