Garrod lecture: achieving the UNGA AMR mortality reduction goals

The world into which antibiotics were introduced in 1942 was very different from the one we live in. In many countries, improved water, sanitation, public health, hygiene and use of vaccines have reduced the burden of infectious diseases in general and bacterial infections in particular. Rising incomes are driving appropriate and inappropriate access to antibiotics but are also enabling higher rates of hospitalization in settings where sicker and more immune-compromised patients have greater exposure to high concentrations of resistant bacteria. Public funding for antibiotics increased briefly but is now on the decline with global cuts in both national and global funding for health. Without continued support, it is unclear whether we can successfully treat patients with bacterial infections in the future.

In 2024, the United Nations General Assembly (UNGA) adopted the goal of reducing mortality from antibiotic resistance-related infections by 10%. To achieve this goal, we need to rethink our current approach to how antibiotics are innovated and used. There are major blindspots and areas of wishful thinking as to how we are approaching the problem of access to effective antibiotics. This paper reviews recent trends and opportunities to enable long-term sustainable access to effective antibiotics.

Antibiotics: the four box problem

Each year, an estimated 7.7 million deaths are associated with bacterial infection of which close to 5 million are associated with some degree of antibiotic resistance. In other words, the 5 million people died with a drug-resistant infection but not necessarily of an untreatable infection. There are three elements of the challenge of appropriate access to effective antibiotics captured in Figure 1. The second row is a subset of the first row, and the burden in each box may overlap with another box: for instance, if disease burden were averted with expanded coverage of vaccines and infection prevention and control (IPC) (dark blue), the burden avertable with expanded access to existing antibiotics (orange) would be lower. Overall, this figure provides a framework to understand the opportunities for reaching the UN target using four approaches: prevent infections, use current antibiotics better, expand access to antibiotics that are already available and find new antibiotics while ensuring those that are accessible to patients in need are also available.

Figure 1.

Avertable burden of disease from bacterial infections.

Two of these areas—improvements in diagnosis and health system capacity to deliver on interventions to improve appropriate access—cut across all four boxes and are discussed at the end.

Prevent infections (blue box)

Work published in the 2024 Lancet series on ‘Sustainable Access to Effective Antibiotics’ shows that expanding access to water, sanitation and hygiene (WASH) infrastructure and paediatric vaccination could together avert a major share of deaths linked to antibiotic resistance in communities. Specifically, universal WASH coverage could prevent an estimated 247 800 deaths (95% CI: 160 000–337 800), while paediatric vaccines could prevent ∼181 500 deaths (95% CI: 153 400–206 800) associated with community-acquired resistant infections.¹

In addition, strengthening IPC within healthcare settings could save another 337 000 lives (95% CI: 250 200–465 200) each year. Taken together, these three intervention categories—WASH, vaccination and IPC—could collectively prevent ∼18% of all antimicrobial resistance (AMR) related deaths in low- and middle-income countries (LMICs) annually. Implementing them at scale would bring these countries’ mortality rates from AMR close to those seen in high-income nations.¹

But new tools could further reduce this burden. For example, maternal vaccination against Klebsiella pneumoniae could avert 80 258 [CrI: 18 084 to 189 040] neonatal deaths and 399 015 [CrI: 334 523 to 485 442] neonatal sepsis cases yearly worldwide, accounting for >3.40% [CrI: 0.75 to 8.01] of all neonatal deaths. The largest relative benefits are in Africa (Sierra Leone, Mali, Niger) and South-East Asia (Bangladesh) where vaccination could avert >6% of all neonatal deaths.² New vaccines against E. coli, Shigella and Staphylococcus aureus could have a significant effect on burden but development has been slow.

Improve appropriate antibiotic use and stewardship (green box)

AMR is a compelling framing of the problem in high-income countries where these infections constitute a larger proportion of infection related deaths than in LMICs where a significant number of deaths are caused by infections that are preventable with water and sanitation, vaccines and hospital infection control, or are easily treatable. This divergence between the needs of countries depending on their level of development is poorly reflected in priorities both of funders as well as of the World Health Organization in how countries should tackle AMR.³ The Global Action Plan is intended to be a template that can be adapted by countries but in practice, there has been little by way of adaptation, resource mobilization or follow up action on many national action plans. Many national action plans have been largely government focused efforts and have left out professional organization, private sector and civil society, all of which play a significant role in how antibiotics are used.

The concept of appropriate antibiotic use is widely misunderstood and is conflated with having access to a prescription. Antibiotics are overused and misused even in settings where there are clinicians. An average of ∼30% (∼13 000 tons) of global consumption of antibiotics—roughly equal to the annual antibiotic consumption in China—is inappropriate.⁴ Inappropriate antibiotic use is ∼6% higher in LMICs than in high-income countries, but this difference is absent once we adjust for physicians per capita, which is a proxy of access to care. In other words, it is simply not the case that antibiotics are misused to a greater extent in LMICs.

There is significant scope to improve how existing patients are being treated with antibiotics. Often, the challenge is not access but the appropriate selection of antibiotics. With poorly targeted antibiotics, patients incur the costs and unnecessary side effects of treatment with none of the benefits. Displacing broad-spectrum antibiotic use with narrow spectrum drugs can help but only if they are supported by diagnostics and can be easily integrated into clinical algorithms, which would then need to be adhered to.

The idea of stewardship itself needs be re-examined. Existing antimicrobial stewardship programmes have generally been designed for high-income settings, and without adaptation, they may hinder, rather than help, access to effective antibiotics in countries with limited resources.⁵ A new model of antibiotic availability and usage in LMICs that prioritizes evidence-based rapid guidance for clinical decision making. New stewardship metrics are needed that will maximize lives saved and disease burden averted for each course of antibiotics administered.

Expand access to existing antibiotics (orange box)

Although failing antibiotics are a problem everywhere, the greater challenge in many low-income countries is lack of access to the agents that could treat antibiotic-resistant infections. Figure 2(a) and (b) shows the mortality rates in countries broken down by low, lower-middle, upper-middle and high-income countries. The lower rates of mortality due to AMR in high-income countries probably reflects both lower rates of resistance as well as greater access to newer antibiotics.

Figure 2.

(a) Death rates from bacterial infections by income group, 2019. Comparing AMR and all bacterial infection death rates across country income levels, age standardized. (b) Death count from bacterial infections by income group, 2019. Comparing AMR and all bacterial infection death counts across country income levels.

Lack of access in low- and lower-middle-income countries reflects of combination of reasons including lack of commercial viability for the product within the country to justify product registration, poor regulatory capacity that delays product registration, high prices, and lack of clinician capacity to prescribe the antibiotic. The framing of the problem as one solely related to AMR is not helpful. The challenge at hand is one of appropriate access to effective antibiotics, which encompasses both AMR, which needs to be tackled with newer antibiotics that can address infections that no longer respond to first line drugs, as well as routine antibiotics that are simply not reaching patients in need. A study found that of the 25 new drugs developed between 1999 and 2014 only 12 were sold in >10 countries. The most widely distributed new chemical entities reached >70 countries within 10 years and 30 within 3 years, spanning five regions and three income groups. Just over half (52%) targeted antibiotic-resistant infections, with limited diversity in pathogens or indications.⁶ Antibiotics developed or marketed by US or European firms had far broader reach than those from Japan, which rarely expanded beyond Asia. Even when drugs are registered, pricing and other barriers prevent patient access.

A more recent study counted 1.5 million carbapenem-resistant Gram-negative infections in eight countries in 2019, but observed that only 103 647 received appropriate treatment, reflecting a treatment gap of nearly 1.4 million cases.⁷ These are huge lost opportunities to reduce AMR related morbidity and mortality simply by expanding access to drugs we already have.

The work that lies ahead is in quantifying the avertable burden associated with expanding access to existing antibiotics to treat all bacterial infections, and in identifying and tackling barriers to expand appropriate access. This work needs to focus on high-burden populations, children and the elderly, who may need more nuanced and focused approaches.

We need to explicitly address barriers that companies face in registering their product outside of the high-income world, as well as find ways to lower access barriers within countries once the drug is available. This needs to be accompanied by changes in diagnostics and other approaches discussed earlier to facilitate appropriate use.

Develop new antibiotics with a focus on access (purple box)

Because antibiotics will lose efficacy over time regardless of whether they are used appropriately, finding new antibiotics is critical. While drugs to treat bacterial infections have received far less funding than other disease areas, they have attracted a larger allocation of funding and more attention compared with the other three boxes. Without improving diagnostics and access to existing antibiotics, it is unclear how new antibiotics will make much of a difference to the global burden of disease from bacterial infections. Interventions to improve appropriate existing antibiotics will also enhance the public health impact of new antibiotics.

The antibiotic supply pipeline was robust by the end of the 1980s when there was a significantly large demand in high-income countries to support new drugs. There may be three explanations for this. First, the cost of drug development was much lower in the 30 years before 1980 than in the 30 years since.⁸ This secular increase in the cost of development is not specific to anti-infectives and covers all drug categories and reflects more stringent regulatory requirements, greater difficulty in patient recruitment and increased clinical trial costs, all of which are amplified by the fact that the opportunity cost of capital is the single largest component of drug development costs.

Second, the market for drugs for bacterial infections in high-income countries where these drugs were marketed was bigger in the earlier period, before the introduction of vaccines against pneumococcal pneumonia, Hib and rotavirus. Before 2000, children under the age of five were the single largest population receiving antibiotics, making blockbuster antibiotics such as Augmentin (amoxicillin-clavulanate) possible. That is no longer the case because of vaccines, but this is not a bad thing.

Third, while there are certainly multi-drug-resistant infections at present, the fact remains that bacterial infections and also untreatable bacterial infections are far less common in high-income countries that are the main target market for pharmaceutical companies. By contrast, markets in LMICs have not received much attention from companies because of smaller revenues and margins, even though most patients live in these countries. The current product development pipeline is a poor fit for the needs of the market. The failure of an antibiotic to be commercially successful does not automatically mean that the economics are poor, and could reflect a poor product-market fit, a problem not unique to antibiotics or even the pharmaceutical industry.

Although yet to be validated, the Indian stock market is betting that cefepime-zidebactam will have a large market both in India and the rest of the world indicating that there is support for antibiotics that address LMIC markets. However, many antibiotics have failed commercially. Some were me-too drugs without a clear therapeutic advantage over existing options: for example, ceftobiprole and telavancin, which offered only modest benefits compared with older β-lactams or glycopeptides. Others targeted extremely small markets in high-income countries, making them prohibitively expensive and further depressing demand and revenues: for instance, cefiderocol and delafloxacin, both approved for niche indications but priced too high for broad uptake. And some had not focused enough on simple things such as bringing down cost of production through medicinal chemistry that limited the numbers of markets they could sell into while breaking even (such as plazomicin, eravacycline or ceftolozane–tazobactam). It simply cannot be the case that there is a huge unmet need for antibiotics and yet no commercially viable way of meeting that need: in essence the definition of market failure used by many in the AMR world. A more likely diagnosis is that the burden in high-income countries of truly untreatable infections remains relatively small and not sufficient to support the high costs of developing a new antibiotic. And the pharmaceutical industry has not yet pivoted a model of serving patients in LMICs as a primary market.

A related issue that most new antibiotics are not suited for patients in LMICs either in terms of target product profile or price, or both. A related issue is that new narrow spectrum niche drugs that require complex diagnostics even in HICs may face access challenges in LMICs where diagnostic access is far more limited. Figure 3(a) shows the number of countries in which newer chemical entities were sold in 2023, reflecting a lack of product registration in many countries. Only 11 molecules were registered in >10 countries. Figure 3(b) shows that only six drugs accounted for other 95% of the total volume of sales in these countries potentially reflecting other barriers to access including lack of diagnostics and high price.

Figure 3.

(a) Number of countries that sold each molecule, 2023. (b) Volume of drugs sold since the date of introduction.

This is because, traditionally, antibiotics have been developed for high-income markets before seeping down to lower resource populations. That model is no longer working since small and medium enterprises (SMEs) that constitute nearly four-fifths of companies in the new antibiotics space simply do not have the expertise or bandwidth to consider innovation for LMICs where most patients in need of new antibiotics live. Without access to those markets, the SMEs are unable to generate sufficient revenues in high-country patients alone and die a rapid death. In the past decade, nearly 90% of SMEs have gone bankrupt with a few managing to sell themselves to larger pharmaceutical companies, an increasingly difficult proposition given the shrinking number of large companies in the antibiotics business. There is mismatch here. Large companies, which thrive on marketing drugs to a large number of customers, increasingly find antibiotics incompatible with this model both because of pressures to reduce inappropriate use and the lack of willingness of third-party payers to cover the high costs of new antibiotics, a course of which can run to several thousand dollars in comparison to the cheaper drugs, which work, albeit unreliably.

Meanwhile, patients in LMICs could both benefit from new antibiotics and would constitute a large market to provide revenues for antibiotic manufacturers. However, to achieve that, drug development should be planned with these markets in mind. The notion of first registering with the European Medicines Agency and the US Food and Drug Administration before entering countries such as India, Brazil or South Africa makes little sense, given both the high cost of European Medicines Agency and US Food and Drug administration registration and the fact that the main markets do not lie in the US or Europe. A more feasible approach would be to register first in the Global South, something that some companies are already considering.

Incentive mechanisms including pull incentives are gaining currency in some countries, but are still not large enough to meaningfully influence the flagging momentum for new drug development. They are unlikely to scale much further for two reasons. First, the fiscal space for spending is shrinking because of increased government debt. Second, the pitch for PASTEUR and DISARM in the USA, in which the subscription model has been made on the basis of how to save the pharmaceutical industry. Lawmakers are more interested in saving patients than in saving companies and, as a consequence, it is an uphill battle to get support for these legislations. Therefore, any pitch for support for new drug development needs to focus on patients. Third, pull incentives alone are unlikely to be large enough to be able to protect companies from bankruptcy, or to attract risk capital. Far more effective would be the availability of a clear market demand composed of paying customers rather than of government financing whose long-term future may be uncertain.

Cross-cutting issues

Diagnostics lie at the heart of the challenge of how to best use antibiotics. In LMICs they are not widely available. In a recent study, we found that only 1.3% of laboratories in 15 countries in Africa had the capacity for bacteriological testing.⁹ A small subset were able to do susceptibility testing, but even this capacity was underused. This is not just a problem in resource-poor settings. Meanwhile in high-income countries, diagnostics are widely ignored. A retrospective study in six of the best institutions in the USA found that clinicians simply do not use information to de-escalate antibiotics. Two-thirds of patients on antibiotics in that study had no discernible indication such as a fever, abnormal white blood count or a radiology report that would justify being on antibiotics.

The traditional sequence going from symptoms to culture to pathogen identification and susceptibility to appropriate choice of antibiotic are feasible for diseases such as HIV/AIDS or TB when there is sufficient time to determine the right course of treatment, and where laboratory facilities, even if not available close to the patient, are accessible within a few days. But they may not make sense for acute non-TB bacterial infections in resource-limited settings. Even when laboratories return critical results, they do not always reach decision makers efficiently.¹⁰ When response time is critical, as it often is for acute bacterial infections, healthcare providers start with the broadest-spectrum empirical treatments that are then rarely modified by diagnostic results.^11,12 These broad-spectrum empirical antibiotics are often continued despite culture results suggesting resistance or alternative diagnoses.^13,14

The diagnostics pathway needs to be redesigned to proceed more quickly from patient examination to appropriate choice of antibiotic therapy. Where possible, point of care rapid diagnostic tests can be helpful but may be too expensive for some settings. Here artificial intelligence/machine learning-based (AI/ML) can help. AI/ML has been proposed for pathogen identification, prediction of bacterial resistance,¹⁵ and for new antibiotic development. However, a key use of AI/ML may be in mapping physiological parameters to optimize treatment protocols. The effectiveness of an antibiotic in real-world settings depends on both pathogen attributes but also host parameters including immune status, organ function (especially renal and hepatic), age, body composition and genetic differences in drug metabolism. Conditions such as immunosuppression, obesity or liver disease can alter how antibiotics are absorbed, distributed or cleared. The site and severity of infection, presence of biofilms and barriers such as the blood–brain barrier also affect drug delivery. In addition, gastrointestinal health, drug interactions and comorbidities can affect treatment outcomes. These factors necessitate individualized antibiotic selection and dosing to ensure optimal efficacy and minimize toxicity or resistance.

Health system capacity is second area of transversality. The strength of health systems, whether in terms of availability and adherence to clinical treatment guidelines, training and capacity building for appropriate use of antibiotics, or addressing the issue of incentives for disease prevention and use of antibiotics, is central to the issue of appropriate antibiotic access. The health system barriers to improved appropriate access tend to be varied across countries and need to be prioritized and addressed at that level rather than on the basis of global or regional observations. Insufficient funding underlies health system capacity: much of the gains made in tackling HIV/AIDS, tuberculosis and malaria were made possible by both domestic resources and overseas development assistance by high-income countries. Shrinking fiscal space due to public debt worldwide and changes in the political landscape have made it unlikely that similar resources will be easily available to tackle bacterial infections unless there is a concerted effort to make the case for this investment.

Wrapping up

In summary, there are significant opportunities to seriously rethink how we propose to meet the UNGA target of a 10% reduction in AMR mortality. Focusing on expanding existing prevention tools and investing in new vaccines, improving appropriate use of antibiotics where they are currently available and access is not a problem, expanding appropriate access to antibiotics in places where newer drugs have not reached, and finally rethinking drug development to place an LMIC market as the focus both for choice of drugs to invest in and in terms of prioritizing product registration could all help meet the UNGA target. We have placed too much emphasis on new drugs alone solving the problem in terms of allocation of resources and, while R&D is important, it is unlikely to make much of a difference to the likelihood of meeting the UNGA target unless challenges with appropriate use and access are solved. Also, too much attention has been paid to national action plans that are far too generic and poorly adapted from the Global Action Plan to be of much help in most countries and remain an unfunded mandate. The NAPs give countries the impression that they are doing something to tackle AMR while the reality is that precious little is really being achieved. Instead, focusing sharply on a few areas where progress and outcomes are measurable would do more to help reach the UNGA’s global mortality goal by 2030.

Transparency declarations

None to declare.

Funding

R.L.'s time was supported by a grant (083527) from the Gates Foundation to the One Health Trust.