Shortages of benzathine penicillin for prevention of mother-to-child transmission of syphilis: An evaluation from multi-country surveys and stakeholder interviews

Abstract

Background

Benzathine penicillin G (BPG) is the only recommended treatment to prevent mother-to-child transmission of syphilis. Due to recent reports of country-level shortages of BPG, an evaluation was undertaken to quantify countries that have experienced shortages in the past 2 years and to describe factors contributing to these shortages.

Methods and findings

Country-level data about BPG shortages were collected using 3 survey approaches. First, a survey designed by the WHO Department of Reproductive Health and Research was distributed to 41 countries and territories in the Americas and 41 more in Africa. Second, WHO conducted an email survey of 28 US Centers for Disease Control and Prevention country directors. An additional 13 countries were in contact with WHO for related congenital syphilis prevention activities and also reported on BPG shortages. Third, the Clinton Health Access Initiative (CHAI) collected data from 14 countries (where it has active operations) to understand the extent of stock-outs, in-country purchasing, usage behavior, and breadth of available purchasing options to identify stock-outs worldwide. CHAI also conducted in-person interviews in the same 14 countries to understand the extent of stock-outs, in-country purchasing and usage behavior, and available purchasing options. CHAI also completed a desk review of 10 additional high-income countries, which were also included. BPG shortages were attributable to shortfalls in supply, demand, and procurement in the countries assessed. This assessment should not be considered globally representative as countries not surveyed may also have experienced BPG shortages. Country contacts may not have been aware of BPG shortages when surveyed or may have underreported medication substitutions due to desirability bias. Funding for the purchase of BPG by countries was not evaluated. In all, 114 countries and territories were approached to provide information on BPG shortages occurring during 2014–2016. Of unique countries and territories, 95 (83%) responded or had information evaluable from public records. Of these 95 countries and territories, 39 (41%) reported a BPG shortage, and 56 (59%) reported no BPG shortage; 10 (12%) countries with and without BPG shortages reported use of antibiotic alternatives to BPG for treatment of maternal syphilis. Market exits, inflexible production cycles, and minimum order quantities affect BPG supply. On the demand side, inaccurate forecasts and sole sourcing lead to under-procurement. Clinicians may also incorrectly prescribe BPG substitutes due to misperceptions of quality or of the likelihood of adverse outcomes.

Conclusions

Targets for improvement include drug forecasting and procurement, and addressing provider reluctance to use BPG. Opportunities to improve global supply, demand, and use of BPG should be prioritized alongside congenital syphilis elimination efforts.

Abstract

Using country-level surveys and stakeholder interviews, Stephen Nurse-Findlay and colleagues investigate the global frequency of benzathine penicillin shortages and uncover commonly noted causes.

Author summary

Why was this study done?

• A single dose of low-cost benzathine penicillin G (BPG) ends syphilis infectivity in adults with no documented risk of antibiotic resistance. In spite of this, syphilis continues to infect millions globally.

• Pregnant women with syphilis are particularly vulnerable, as fetal transmission of the infection can cause stillbirth. The only recommended treatment for syphilis in pregnant women is BPG.

• Congenital syphilis remains a significant contributor to early infant mortality, particularly in low- and middle-income countries.

• There are several reasons for this, but one of the most important is a global shortage of BPG.

• In 2015, WHO began to receive anecdotal country reports of BPG stock-outs.

• WHO decided to assess these shortages, describe global supply and demand drivers, and propose viable policy solutions.

What did the researchers do and find?

• The team completed 3 surveys to assess global BPG shortages occurring during 2014–2016.

• The first was distributed to 41 countries and territories in the Americas and 41 African countries.

• The second was emailed to 28 US Centers for Disease Control and Prevention country directors.

• The third was used in in-person interviews in 14 countries by the Clinton Health Access Initiative.

• In all, 95 of 114 unique countries and territories responded to the surveys. Of these, 39 reported a BPG shortage and 56 reported no BPG shortage.

• The team discovered 3 major issues. First, countries often obtain their product from a single wholesaler, which often obtains its products from a single final dose formulator, which often obtains its active ingredient from a single manufacturer. This “sole sourcing,” combined with a highly consolidated market, makes alternative supply difficult if there are production, quality, regulatory, or specification changes within a country’s supply chain.

• Second, as an off-patent medication, BPG commands a market price of pennies per dose. However, as a sterile injectable, it is also expensive to manufacture. These economics have led manufacturers to either abandon BPG production or implement stringent ordering protocols that compromise supply for low- and middle-income countries.

• Third, inaccurate country forecasts, weak procurement systems, and clinical knowledge gaps about syphilis treatment have compromised demand for and procurement of BPG.

What do these findings mean?

• Widespread BPG shortages compromise treatment of adult syphilis, prevention of congenital syphilis, and treatment of other BPG-indicated conditions (including rheumatic heart disease).

• An uninterrupted supply of quality-assured active pharmaceutical ingredient and final formulated product will simplify BPG procurement for high-burden countries.

• Countries must strengthen their supply chain, purchasing, forecasting, and procurement infrastructure to mitigate shortage risk and reduce demand-side stock-outs.

• Countries must also strengthen testing for and treatment of maternal syphilis (and prevention of congenital syphilis) with BPG.