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There is no doubt that the world needs new antibiotics, especially truly innovative ones with new modes of actions to attack drug-resistant bacteria and counter the silent surge of antimicrobial resistance (AMR). The challenges and barriers in achieving these kinds of innovations and the consequences of failing to resolve this complex issue are well known in both academic and policy circles^1,2. However, there is also another challenge related to antibiotics which has received less attention, namely the growing lack of availability of old, common antibiotics such as penicillin, either because they are not registered in less commercially attractive countries or because of supply shortages. In particular, antibiotic shortages afflict countries of all levels of income and produce far-reaching negative consequences, ranging from patient suffering because of lack of treatments to increased healthcare costs and, eventually, also to a rise in the number of drug-resistant infections.

I have been working on the issue of antibiotic shortages for the last three years through the Swedish multi-sectorial platform PLATINEA, which involves academia, healthcare, public authorities and industry. Together we have identified about 60 causes of antibiotics shortages and singled out ten possible solutions to address this problem, starting from about 30 alternatives. Here I discuss the nature and impact of antibiotic shortages. I also discuss the causes behind them, and finally, present a set of possible solutions to address this.

The shortage of antibiotics: A growing problem

The shortage of antibiotics is not a new issue but has been slowly increasing in the last 10 years across the world^3,4,5,6. An example of a global shortage is ceftibuten, a third-generation cephalosporin, which was withdrawn from most countries in 2016. Others include piperacillin-tazobactam where repeated accidents in an active pharmaceutical ingredient (API) factory since 2017 impacted the production and benzathine penicillin which was unavailable in 2015 in around 40 countries due to insufficient production capacity⁷.

Identifying the causes of shortages of antibiotics and proposing solutions to address them is just the first step in a long and complex process of change that will need to involve the whole antibiotics field, including industry, healthcare, public authorities and transnational bodies.

An antibiotic shortage may cost up to $20-30 million per event⁸ including costs for more expensive substitutes, longer hospitalization, increased morbidity and even mortality if alternative therapies are not available. This is, unfortunately, the typical situation of low-income countries. As shortages result in patients receiving suboptimal or broad-spectrum antibiotics, it can lead to increased drug resistance, or necessitate the use of reserve antibiotics to treat common infections⁹.

The causes of antibiotics shortages

There are many complex reasons behind shortages. Single events can be caused by an unexpected demand increase such as the current COVID-19 pandemic, production disruptions (e.g. accidents) or quality problems^3,4. However, the root cause is the low profitability afflicting the whole antibiotic field^10,11. Most antibiotics are ‘generics’, with the positive effect of several competitors producing them and their prices falling, but they have now fallen to a point where fewer and fewer suppliers want to provide them. From the buyer’s side, procurement procedures unleash price races ‘to the bottom’^4,8 and avoid volume commitments which would reduce uncertainty for antibiotics suppliers.

On the production side, other causes of shortages are rigid manufacturing systems unable to cope with uncertain demand and the hard-to-motivate investments required to expand and upgrade facilities if margins on antibiotics are so low. The risk of shortages is further aggravated by the fact that providers have offshored API production to a few geographically concentrated locations in China and India⁸, with increased natural disaster and geopolitical risks. Moreover, antibiotic supply chains stretch globally and are today more fragile^4,12, because the large geographic and cultural distances make it more difficult to communicate between the various actors in the chain and to coordinate physical flows of goods moving between various locations. The lack of transparency of supply chains also makes it difficult for buyers to assess the true risk of shortages^4,8. This in turn reflects a general problem of weak collaboration between the various stakeholders in the antibiotic field, especially industry, public authorities and healthcare providers.

Possible solutions

There are many possible solutions to address, and more importantly prevent, antibiotic shortages. In the short-term, actors operating at various steps of the supply chain can introduce warning systems, increased level of stocks and better demand forecasts^8,10. Long-term changes, however, will require new economic models to give more incentives to improve availability. These include fixed yearly payments for a guaranteed supply of selected antibiotics (as currently piloted by Sweden and the UK)^13,14,15, rewards for suppliers achieving high delivery precision⁴, and procurement models allocating tendered amounts to several suppliers⁸. This will reduce dependence on a single supplier and keep alternative ones in the marketplace.

Further, more transparency across supply chains would allow to identify and assess the risk of shortages associated with a particular plant^4,5. Another solution for smaller customers or for customers considered unattractive is jointly procuring antibiotics to achieve a critical mass towards suppliers³, or the more extreme solution of stimulating local production of critical antibiotics⁸. While all these individual solutions are important, it is also necessary to improve coordination in the antibiotic field through task-oriented collaboration platforms. These are increasingly needed at an international level as antibiotic shortages are a common problem among several countries and many of its causes relate to the global structure of the industry. Moreover, these collaboration platforms need to include all relevant sectors and stakeholders involved in the issue, from academia to healthcare providers as well as those from public authorities, industry and NGOs.

An antibiotic shortage may cost up to $20-30 million per event including costs for more expensive substitutes, longer hospitalization, increased morbidity and even mortality if alternative therapies are not available.

PLATINEA is an example of such a platform. It operates in Sweden and has organized an international workshop which was held on March 17, 2021, at the Uppsala Health Summit. This workshop focused on three solutions against antibiotics shortages, namely: (1) increased transparency in supply chains and (2) improved profitability for antibiotics providers, which would, in turn, enable (3) investments in new and upgraded factory. For details about this workshop, see here.

Identifying the causes of shortages of antibiotics and proposing solutions to address them is just the first step in a long and complex process of change that will need to involve the whole antibiotics field, including industry, healthcare, public authorities and transnational bodies. Implementing these solutions will require investment as well as changes in routines and regulations, which might create substantial barriers. Therefore, engagement and collaboration between stakeholders will be essential to improve the supply of antibiotics globally.

References

1. AMR Review (2015) Securing new drugs for future generations: the pipeline of antibiotics. 
2. DRIVE-AB (2018) Revitalizing the antibiotic pipeline: Stimulating innovation while driving sustainable use and global access. 
3. The Organisation for Economic Co-operation and Development (OECD) (2020) Shortage of medicines in OECD countries, Directorate for Employment, Labour and Social Affairs. Health Committee.
4. US Food and Drug Administration (FDA) (2019) Drug shortages: root causes and potential solutions. 
5. Tängden, T., Pulcini, C., Aagaard, H., Balasegaram, M., Levy Hara, G., Nathwani, D., Sharland, M., Theuretzbacher, U., & Cars, O. (2018).Unavailability of old antibiotics threatens effective treatment for common bacterial infections, Lancet Infectious Diseases, 2018;18:242-244.
6. Pulcini, C, Beovic, B, Béraud, G, Carlet, J, Cars, O, Howard, P, Levy-Hara G, Li G, Nathwani D, Roblot F & Sharland, M, (2017) Ensuring universal access to old antibiotics: a critical but neglected priority. Clinical Microbiology and Infection, 23(9), 590-592.
7. Nurse-Findlay, S., Taylor, M.M., Savage, M., Mello, M.B., Saliyou, S., Lavayen, M., et al. (2017). Shortages of benzathine penicillin for prevention of mother-to-child transmission of syphilis: An evaluation from multi-country surveys and stakeholder interviews. PLoS Med 14(12): e1002473.
8. World Health Organization (WHO) (2019) Meeting Report Antibiotic Shortages: Magnitude, Causes and Possible Solutions. Norwegian Directorate of Health, Oslo, Norway 10-11 December 2018. 
9. React (2020) Shortages and AMR – why should we care? 4 consequences of antibiotic shortages. 
10. Cogan D, Karrar K, & Iyer J., (2018). Shortages, stockouts and scarcity: the issues facing the security of antibiotic supply and the role for pharmaceutical companies. Access to Medicine Foundation. 
11. Cirz R, Krause KM. (2020) The antibiotics marketplace collapse: It’s just math, and it’s a solvable equation. 
12. Bradford PA (2020) Why are new antibacterials failing as commercial products? 
13. Gotham D, Moja L, Van der Heijden, Paulin S, Smith I, Beyer P (2020) Reimbursement models to tackle market failures for antimicrobials: Approaches taken in France, Germany, Sweden, the United Kingdom, and the United States, Health Policy. 
14. The Public Health Agency of Sweden (2021) Questions and Answers on Procurement in pilot study for new reimbursement model. 
15. U.K National Institute for Health and Care Excellence (2021) Models for the evaluation and purchase of antimicrobials.