Introduction

Despite growing discussions about antibiotics and antibiotic resistance and their impact on global public health in the last two decades, strategies to specifically address antibiotic shortages remain under-explored. Last year, the European Union opted against designating antibiotic shortages as a “major event” as that labeling would empower the European Medicines Agency to orchestrate a unified response at the pan-European level (EMA, 2023a; Grover, 2023). Instead of seeking a pan-European solution for medicine shortages, the EU’s pharmaceutical reform aims to primarily concentrate on stockpiling (EMA, 2023b). However, this tactic might introduce challenges in other countries, for instance, the United Kingdom (U.K.), exacerbating the strains within the supply chain and, yet again, neglecting the need for a more systematic solution addressing the antibiotic supply chain on the global level (Campbell, 2024).

Over recent years, reports and discussions about antibiotic shortages of commonly prescribed antibiotics have gained much attention, especially in high-income countries, such as the United States (U.S.) and European countries. Those debates surfaced as surprising yet growing issues in the countries that once dominated antibiotic production and have well-established economic and health systems. Antibiotic shortages can significantly undermine the management of infectious diseases and compromise the quality of patient care, as healthcare providers might have to resort to less optimal or more expensive alternative treatments (Ellner et al., 1993; Osterholm, 2000; Strausbaugh et al., 2001). These alternatives may be less effective, entail a higher risk of adverse side effects, or contribute to the accelerated emergence of antibiotic-resistant bacteria (Gundlapalli et al., 2013; Quadri et al., 2015).

In 2018, the U.S. Food and Drug Administration (FDA) formed a Drug Shortages Task Force to look into the country’s persistent drug shortages, including antibiotics, to find long-term solutions (Nedelman, 2018). Despite the FDA’s long-term effort to mitigate isolated incidents of drug shortages in the last few decades, there has not been a firm impact on the underlying structural concerns that give rise to these recurring challenges (FDA, 2018). In addition, in 2018, the World Health Organization (WHO) meeting in Oslo, Norway, specifically discussed antibiotic shortages, focusing on the magnitude, causes, and possible solutions (WHO, 2018). Some countries that completely depend on antibiotic imports, such as Norway, carried out pilot studies to evaluate the feasibility of local production of commonly prescribed antibiotics, emphasizing awareness and growing concern about the issue (Helsedirektoratet, 2022).

The root causes of recent episodes of antibiotic shortages in high-income countries are multifaceted, reflecting a complex interplay of economic, logistical, and regulatory factors in the pharmaceutical industry, which has undergone significant and systematic changes in the past decades. Market incentives have had a significant influence on what pharmaceuticals are being researched and developed (R&D), but financialization also has had a strong influence on how pharmaceuticals are valued and where they are produced (Craddock, 2007; Londeix & Martin, 2022; Roy, 2023; Sell, 2019). Some scholars have offered insights into how capitalism has reshaped the pharmaceutical industry and the “pharmaceutical geographies” in the past few decades (Greene, 2016). For instance, during the 1990s, a growing number of pharmaceutical firms outsourced their activities to local firms and institutes in emerging economies (Chaudhuri, 2005; Haakonsson et al., 2013; Horner, 2022). As a result, new geographies of the global pharmaceutical industry were created, increasing dependency on Chinese- and Indian-manufactured pharmaceuticals (Baxerres & Cassier, 2022; Baxter et al., 2013; Horner, 2022). A critical vulnerability within the antibiotic supply chain is the global dependence on a limited number of manufacturers for the mass production of antibiotic pharmaceutical ingredients (APIs) (Fischer et al., 2023; Meiser et al., 2020). This dependence introduces significant risks, including the potential for production interruptions, leading to global supply chain disruptions. The COVID-19 pandemic starkly highlighted these vulnerabilities, showcasing how shifts in pharmaceutical production priorities and export limitations can drastically impact antibiotic availability worldwide (Bjerke, 2022; Cohen, 2022; Zhang, 2023). The situation is further exacerbated by a growing stringent regulatory landscape in the U.S. and European countries, which indirectly increased the cost of manufacturing and impeded the supply of existing antibiotics, thereby limiting access to essential medications (Smith, 1980; Sparling, 2001). Later, with the growing challenge of antibiotic resistance, examples of stricter antibiotic restrictions included setting quotas for generic substitutions. These high-level control measures were aimed at encouraging appropriate prescribing, but, in turn, they directly influence the availability of antibiotics in some countries (Power, 2006).

However, antibiotic shortages are far from a new phenomenon in the 21st century. In this commentary, we explore how antibiotic supply shortages have evolved from a few isolated incidents to a global concern. Based on historical analysis of antibiotic shortages, our goal is to offer a more nuanced understanding of the complex array of factors contributing to these shortages, which have evolved from localized issues to global urgencies.

Our analysis primarily uses examples from high-income Western countries, the U.S. and Europe, that dominated the development, manufacturing, and market of antibiotics (Bud, 2008; Daemmrich, 2009; NEUSHUL, 1993). However, later, we also employ examples of other countries as the issue grew over time. In the following sections, we will first explore early instances of antibiotic shortages before 2000, focusing primarily on cases from the U.S. This analysis highlights the characteristics of these shortages, which were mainly associated with technical and regulatory issues. However, during the 1990s, economic and geographic factors began to play a more explicit and significant role in antibiotic shortages. As such, the further analysis emphasizes cases from the past two decades, illustrating how the issue has evolved from local supply chain glitches to a systematic global challenge with a growing number of incidents. The cases selected for our analysis are from historical archives, government research documents, and media reports, all accessible online. We acknowledge that the selection of the cases is limited to what we could document, especially for early instances. Nonetheless, this commentary highlights how the phenomena of antibiotic shortages have a long history and have posed a significant challenge to well-established pharmaceutical industries, thriving economies, and robust health systems, although pharmaceutical shortages are often mistakenly associated with lower- and middle-income countries. Such misconception can potentially undermine the severity of antibiotic shortages worldwide. As a result, there is a need for a global reassessment of the supply chain resilience and regulatory effectiveness of antibiotics to prevent further worsening and neglect of the issues (Choe et al., 2020; Greene, 2016; Tängdén et al., 2018).

Early cases of antibiotic shortages

In the 1970s and 1980s, unexpected shortages of essential antibiotics like penicillin G highlighted the vulnerabilities within the pharmaceutical supply chain within the U.S. For example, Johns Hopkins Hospital experienced a temporary scarcity of intravenous penicillin G in 1976, a situation mirrored across the U.S. The company Squibb, a major supplier, faced production hiccups as it moved facilities from New Jersey to Maryland, contributing to the shortage (Culliton, 1976). The incident revealed the complexities and vulnerabilities within the U.S. domestic pharmaceutical supply chains. Concurrently, the industry faced an innovation decline, with a significant drop in the number of new drugs entering the market. For example, in the U.K., the number decreased from over 250 annually in the 1960s to about 100 by the late 1970s and early 1980s. It was suggested that the decline was due to several factors, including increased development cost and time due to stricter regulatory requirements, which have stifled innovation and led to fewer, larger companies dominating the industry (Smith, 1980). Manufacturing issues have occasionally slowed down production or led to sudden unavailability of products. For instance, in the 1990s, streptomycin became unavailable when the sole U.S. manufacturer ceased production rather than modify its process to address problems with the drug substance manufacturer, a European firm that could no longer ensure the drug was free of microbial contamination (Ellner et al., 1993). Thus, in the 1970s and the 1980s, much discussion was focused on the practical implications of regulatory changes and manufacturing challenges for drug availability on the local level. However, later discussions delved into a broader analysis of the industry’s struggle with innovation, increasing regulatory pressures, and market dynamics.

During the 1990s, the U.S. experienced a significant resurgence of tuberculosis (TB) accompanied by an increase in drug-resistant strains of the disease. This period also faced a critical shortage of effective antibiotics, posing a challenge to public health. During this time, TB cases saw a significant jump from 22,201 in 1985 to 26,673 in 1992. Streptomycin was used in the standard TB treatment regimen aimed to address the growing issue of drug-resistant strains. However, there was a supply shortage of streptomycin that had begun in mid-1991 (FDA, 1993). The main supplier, Pfizer, Inc., could not keep up with the supply of TB treatments in the face of escalating cases, as emphasized by FDA Commissioner David A. Kessler. Eventually, the FDA team collaborated with global pharmaceutical companies to find a supplier willing to provide the U.S. market with necessary medications (Ellner et al., 1993; FDA, 1993).

This crisis highlighted the vulnerabilities in the supply chain for essential medicines and dependencies in the supply of licensed drugs. In 1990, the production of TB drugs, except for isoniazid, was monopolized by single companies, both for the drug product and the active ingredient. The lack of a structured mechanism to monitor the supply of TB drugs (and other pharmaceuticals) further complicated the situation. Although the Federal Food, Drug, and Cosmetic Act mandated manufacturers to report issues to the FDA and submit annual production reports, it was the market that primarily governed the management of inventories at various stages of distribution (Ellner et al., 1993). Moreover, shortages of cycloserine, ethionamide, and capreomycin were due to temporary manufacturing glitches at the sole U.S. producers of these pharmaceuticals (ibid). Paraaminosalicylic acid faced similar issues due to internal manufacturing problems at its sole U.S. producer. The shortage of isoniazid was more complex, involving multiple factors. German company Bayer, one of the two global producers of the drug substance, stopped manufacturing it at the end of 1988 (Ellner et al., 1993). Additionally, other U.S. manufacturers ceased operations around that time following heightened scrutiny of the generic drug industry in 1989 (CBO, 1998). This reduction in manufacturers disrupted the distribution chain for the finished pharmaceutical, making isoniazid harder to locate in spite of its availability (Ellner et al., 1993). As we can see from these cases, there is a long history of the U.S. depending on a single or few manufacturers of antibiotics and such dependence has been one key cause of antibiotic supply shortages long before the COVID-19 pandemic.

Another significant example of antibiotic shortage is detailed in the context of Tularemia treatment in the U.S. Tularemia, a rare and challenging-to-diagnose disease, has traditionally been treated with streptomycin. However, due to shortages of this antibiotic, healthcare providers have been forced to resort to alternative treatments, such as gentamicin and doxycycline, which have had varying degrees of success (CDC, 2002; Cross, 1997; Strausbaugh et al., 2001). This situation underscored the difficulties in managing infectious diseases when first-line antibiotics are unavailable, necessitating flexibility in treatment approaches and reliance on less preferred, potentially less effective options. Furthermore, the penicillin G shortage in 1999 exemplifies the serious impact of antibiotic shortages. The recall of penicillin products by Marsam Pharmaceuticals, a major manufacturer, due to regulatory concerns at its manufacturing site, resulted in a significant shortage of these types of penicillin across the country. It highlighted the vulnerability of antibiotic supply chains to manufacturing issues and the importance of having robust systems in place to ensure the continuous supply of essential medications (CDC, 1999; Harbarth, 2000).

By the 2000s, reports of antibiotic shortages became more alarming, affecting a wide range of agents and prompting concerns over patient care, resistance development, and the ability to respond to public health emergencies. The turn of the century brought attention to broader and more severe shortages of antibacterials, as reported by the Infectious Diseases Society of America’s (IDSA) Emerging Infections Network (EIN) (Strausbaugh et al., 2001). A survey conducted among IDSA members revealed that nearly 90% had experienced shortages of vital drugs, including meropenem, penicillin G, ticarcillin/clavulanate, cefazolin, and gentamicin. These shortages compelled 81% of the respondents to modify treatment plans, impacting roughly 10,000 patients across the nation (ibid). The situation was described as a potential “wake-up call,” suggesting that the reliability of antibiotic supply chains was at risk. The survey not only underscored the penicillin G shortages but also highlighted significant shortages of other antibiotics too (Sparling, 2001; Strausbaugh et al., 2001). The shortage of piperacillin-tazobactam in 2002 and its potential association with increased rates of Clostridium difficile-associated diarrhea in hospitals illustrated the impact of shortages on antibiotic utilization and infection control, again, affecting treatment regimens and patient care (Bosso & Kokko, 2004). These examples of shortages exemplified the larger issues at play, including the discontinuation of production by major manufacturers and the reliance on market mechanisms to control drug inventories.

From local to global concern

After 2000, the global pharmaceutical manufacturing geographies experienced significant changes, which created more complications in the intricate pharmaceutical supply chains. Antibiotic shortages have gradually grown from a local to a global concern over the past three decades, as antibiotic shortages have developed from mostly temporary local incidents to a more persistent and global-wide phenomenon. In 2011, the U.S. Senate hearing on “Prescription Drug Shortage: Examining a Public Health Concern and Potential Solutions” again showed the growing and serious issue of pharmaceutical shortages, including antibiotics, in the U.S. (Aitken, 2011). It was highlighted that the number of prescription drug shortages had tripled over the past five years, severely impacting patient care and putting lives at risk. Of the 127 drug shortages tracked by the FDA during the period from January 1, 2010, to August 26, 2011, oncology drugs accounted for 28 percent of shortages, followed by antibiotics at 13 percent. The hearing shed light on various aspects contributing to the shortages, including regulatory challenges, manufacturing issues, market dynamics, and the role of the FDA in responding to these crises (ibid). The FDA’s efforts to address the issue were discussed, including strengthening the agency’s ability to respond by improving its shortage notification system and working collaboratively with manufacturers to mitigate shortages when they occur (Aitken, 2011). The hearing highlighted the urgent need for concerted efforts from all stakeholders, including government agencies, manufacturers, healthcare providers, and legislators, to develop sustainable solutions to ensure the availability of essential medications for all patients.

In 2015, a study showed the trends and implications of antibacterial drug shortages in the U.S. over a thirteen-year period from 2001 to 2013 (Quadri et al., 2015). Utilizing data from the University of Utah Drug Information Service database, the study identified 148 antibacterial drugs that experienced shortages, with a notable increase in the frequency of shortages after 2007. The study highlighted the significant impact of these shortages on clinical practice, particularly the challenges in treating multidrug-resistant infections due to the limited availability of effective antibiotics. The majority of the shortages involved broad-spectrum agents and injectable drugs, with a substantial proportion having no available alternatives. This situation forced healthcare providers to modify antibacterial selection, often leading to the use of less effective, more toxic, or more expensive alternatives. The reasons for drug shortages varied but included similar reasoning as before, such as manufacturing problems, supply-demand imbalances, and discontinuation by manufacturers (ibid).

In addition to the U.S., many other countries in the West have been experiencing antibiotic shortages. In 2006, the European Society of Clinical Microbiology and Infectious Diseases Study Group for Antibiotic Policies conducted a survey throughout Europe, which showed that a substantial number of hospital pharmacies in Europe have experienced antibacterial drug shortages (Harbarth et al., 2007). Moreover, in 2010, another survey was performed in 38 countries among experts in Europe, the U.S., Canada, and Australia, again showcasing antibiotic shortages in these countries. The major finding was that many potentially useful antibiotics, usually low cost and marketed as generics with a long history of tolerability and safety data, are not available in many countries (Pulcini et al., 2012). Further investigation into antibiotic shortages within European hospitals, as captured through a series of surveys conducted by the European Association of Hospital Pharmacists from 2013 to 2020, offered a detailed analysis of the evolving fluctuation in the incidence of antibiotic availability (Miljković et al., 2022).

A particular case of antibiotic shortages in Europe was linked to a factory explosion in China, which reveals the growing dependency on the global supply chain of pharmaceuticals. In 2017, Swedish public health officials reported and managed a shortage of piperacillin/tazobactam, a kind of “last resort” antibiotic that is given to hospitalized patients with severe infections, including sepsis. An explosion at a Chinese manufacturing facility allegedly caused the shortage. It was one of the very few manufacturers in the world that were producing the pharmaceutical ingredients for the antibiotic. Swedish academics and officials worried about the situation and argued that “a system in which there are only a few producers of essential drugs is not sustainable” and that the antibiotic shortage issue should be high on the international agenda (Bactiguard, 2017). The explosion not only affected Sweden but also had a sweeping effect in Europe. According to one report, in the aftermath of the accident, the German Federal Institute for Drugs and Medical Devices announced that there was a supply shortage of mono-preparations containing piperacillin and fixed-dose combination products (piperacillin with the beta-lactamase inhibitor). The report concluded that Germany depended on one single facility in China that produced a vital medical product and that German legislators should have an obligation to guarantee that dependency on a few facilities in China or India does not hinder the security of the supply chain and the safety of patients (ECA, 2017).

Also in 2017, Aljazeera reported that there had been a penicillin and ampicillin shortage in South Africa in the past two years that affected many locals who relied on the drugs, such as patients with rheumatic heart disease (Guimaraes, 2017; Guimaraes & Asrar, 2017). The author writes that similar shortages could be found in at least 18 countries, including the U.S., Canada, Portugal, France, and Brazil, where penicillin G had been hard to obtain due to the low profit margin of traditional antibiotics and the fragmented supply chain. As a temporary solution, many countries facing shortages had to turn to Chinese manufacturers as the remaining producers of penicillin APIs are predominantly located in China. In 2018, Forbes published a report titled “Fragile antibiotic supply chain causes shortages and is a national security threat.” (Stone, 2018). As a practicing infectious disease physician themselves, the author argues that shortages of antibiotics should be elevated as a matter of national security, as American patients rely on few manufacturers and sources of pharmaceutical raw materials, among which many are located in China and India (Shafiq et al., 2021). The author further argues that although the U.S. retains some pharmaceutical manufacturing facilities in Puerto Rico, a potential trade war with China, India, Europe, and Canada might have a devastating impact on the U.S. as the country is heavily reliant on imports of essential medicines.

The shortage problem became even more highlighted after the disruption of the COVID-19 pandemic. According to a report compiled by the Center for Infectious Disease Research and Policy (CIDRAP), the COVID-19 pandemic has jolted the global pharmaceutical market at all levels and production points. Many drugs essential for treating COVID-19 patients, including azithromycin and vancomycin, were in shortage as the need increased dramatically (CIDRAP, 2020). Furthermore, stay-at-home orders, factory lockdowns, and shipping slowdowns in China directly affected the global pharmaceutical supply chain as Hubei Province in China, where the first COVID-19 outbreak was reported alone, had 37 manufacturers of APIs for U.S. drug products. Drugs produced in Hubei include ibuprofen, hydromorphone, metoprolol, metformin, zidovudine, azithromycin, clindamycin, and levofloxacin. The export freeze in China, India, and the U.K. also affected the drug supply in the U.S. during this period (Bookwalter, 2021). However, although disruptions of COVID-19 were gradually mitigated, drug shortages in the U.S. persisted. As we have previously argued, there are multifaceted and systematic reasons behind drug shortages rather than a single cause. In November 2022, Boston Global published a short comment about the antibiotic shortage in the U.S. It briefly reported that amoxicillin, an antibiotic commonly used to treat conditions like ear infections and strep throat in children, was in short supply in the U.S. The FDA informed that the four drug makers that were selling nearly all the amoxicillin in the country had limited supply, especially in liquid form used for kids. The report ended by saying that it was unclear whether the shortage was caused by increasing demand or whether certain companies were having trouble producing the drug and, therefore, putting strain on other suppliers (BCG, 2022).

As we can see from these cases, although antibiotic shortages have gradually become a persistent and global phenomenon, this concern has long been neglected in the broader discussions of antibiotic resistance. We can only wait and see whether the upcoming United Nations General Assembly, scheduled for September 2024 in New York with antibiotics on the agenda, will include discussions and solutions for antibiotic shortages.

Conclusion

The escalation of antibiotic shortages from isolated incidents to a global public health concern encapsulates the complexity and critical nature of addressing this issue holistically. By examining specific instances of antibiotic shortages in high-income countries, particularly in the U.S. and Europe, pioneers in antibiotic production, we aim to illustrate how these shortages have evolved from isolated events into widespread global phenomena, highlighting the interconnected vulnerabilities within economic, regulatory, and supply chain systems. We showcase how countries that once dominated the field of antibiotics, with robust economies and health systems, have become vulnerable to antibiotic shortages. Through historical analysis, we reveal how the problem has developed from localized and isolated incidents to a global and systematic issue, resulting in a dependency on a limited number of manufacturers for the bulk production of APIs. This reliance has introduced significant risks, as starkly illustrated by the COVID-19 pandemic, which exposed the fragility of global supply chains and underscored the imperative for more diversified and robust manufacturing capacities, elevating the issue to a global health security concern that warrants high-level political attention.

In particular, early antibiotic shortages in the U.S. have already revealed critical issues within its domestic pharmaceutical supply chains, regulatory environments, and market mechanisms. The economic environment and geographies of antibiotic API production in China and India highlighted the broader systemic flaws of the global pharmaceutical manufacturing landscape. Incidents of antibiotic shortages worldwide reveal the vulnerabilities and dependencies in a global pharmaceutical supply chain. This commentary puts forward how the issue has developed from isolated incidents and manufacturing glitches to a universal challenge impacting nations across various income or health system levels. As such, it calls for a global reassessment of the supply chain resilience and regulatory effectiveness of traditional antibiotics. Addressing this crisis urgently is pivotal not just for infectious disease management but also for advancing the broader goals of global health security and equity.