Global shortages of penicillin

Treatment of syphilis prevents transmission, reduces the risk of long-term sequelae, and reduces the risk of HIV transmission and acquisition for both men and women. Worldwide, an estimated 6.3 million cases of syphilis occur each year, with approximately 1 million of these diagnosed in pregnant women. Benzathine penicillin G (BPG) is the only WHO-recommended treatment for pregnant women with syphilis. It is the only known drug able to cross the placenta barrier and treat the unborn baby in the womb.

WHO estimates that approximately 661 000 cases of congenital syphilis occur globally each year. Tragically, syphilis is the second leading infectious cause of stillbirths worldwide. Yet syphilis-associated perinatal deaths can easily be prevented with a single dose of low-cost BPG. In addition to syphilis, BPG is used to treat several other diseases including rheumatic fever, yaws and Lyme disease, among others.

Treatment with penicillin has been hampered by periodic and prolonged shortages of benzathine penicillin in numerous countries, including high-, low- and middle-income countries. A survey conducted in 2015–2016 by WHO and partners showed that 41% of respondent countries reported penicillin shortages or stock-outs during those years. In 2019, 5% reported BPG stock-outs.

Those shortages signify an urgent need to ensure stable and quality-assured supplies of benzathine penicillin, while evaluating alternative treatment options, including for pregnant women. During the period of shortages, some countries reported that pregnant women with syphilis were untreated or treated with alternative medications – contributing to more than half a million estimated congenital syphilis cases (based on WHO case definition).

Although shortages have reduced significantly in the past few years, the underlying market failures that led to the shortages persist. 

Treating Syphilis with Penicillin injection: a solution not used enough

The global market size for penicillin ranged between 55 million and 85 million vials per year in 2015, according to a market estimation conducted by the Clinton Health Access Initiative. As an off-patent medication, BPG is sold at a very low price. Furthermore, some countries set a cap at which BPG can be purchased by governments, helping to keep the price low. On the other hand, as a sterile injectable, it is also expensive to manufacture, requiring significant financial investment in specialized infrastructure. The low selling price limits the enthusiasm for commercial manufacturers to enter or even continue in the BPG market.

In addition, there are concerns about the quality of the active pharmaceutical ingredient (API) manufacturing. None of the current API manufacturers of BPG have market authorization from a global regulatory authority, such as WHO, and some have recently experienced quality issues, which have disrupted supply.

While current manufacturers have the capacity to meet global demand for BPG, some enforce minimum purchase order quantities. This can be challenging, particularly for smaller countries, where demand for BPG is often not high. The BPG supply chain is also challenging, with a chain of “sole sourcing” from countries wholesalers, formulators and manufacturers. This makes the alternative supply difficult when changes occur in the production, quality, regulation or specification of the product.

There are also factors at the country level that aggravate the BPG market dynamics. These include inaccurate forecasts of needs, weak procurement systems, and clinical misconceptions of adverse effects and other knowledge gaps about syphilis treatment, which all contribute to global shortages.

One of the targets of the Global health sector strategy for sexually transmitted infections 2022-2030 is the elimination of congenital syphilis as a public health problem. To achieve this, the strategy recommends countries increase the coverage levels of antenatal care to 95%, of pregnant women tested for syphilis to 95%, and of those diagnosed receiving adequate treatment with BPG to 95%. These targets are only achievable if the availability of BPG can be ensured.

Steps to harmonize product quality and specification standards among manufacturers are needed to help ease issues around manufacturing. A common product specification accepted by all major stakeholders would lower costs and allow for product substitution should any single supplier discontinue manufacturing. WHO is inviting manufacturers and supporting the prequalification of BPG to assure quality.

On the demand side, WHO and partners are collaborating with countries to accelerate the response towards elimination of congenital syphilis. This includes strengthening national supply-chain infrastructure to improve BPG forecasting and procurement needs, as well as steps to mitigate future stock-outs and shortages.

WHO is also developing a range of tools for health-care providers to address a number of misconceptions about BPG – notably unfounded fears about an elevated risk of adverse events following its use.