10th August 2021

To celebrate our 50th anniversary, we’re inviting a select number of experts to share what they see as being the 21st-century solutions to one of the biggest and most complex challenges of our generation: antimicrobial resistance. In this post, Laura Piddock explores the challenges involved in re-stimulating the antimicrobial drug development market…

The discovery of antibiotics heralded the start of a new medical era. Millions of lives have been saved and previously fatal infections such as bacterial pneumonia and blood stream infections were treated. Yet today, antimicrobial resistance (AMR) is outpacing research and development of new drugs at an alarming rate. In April 2021, WHO warned in its latest ‘Antibacterial Pipeline Report’ 1 that the pipeline was insufficient to counter rising drug-resistance in bacteria for which there is a high or critical priority for new treatments.2

The warning comes at a moment when unprecedented cooperation, resources, and political will have led to scientific success to address COVID-19, with new vaccines obtaining emergency authorization less than a year after WHO declared a pandemic. While recognizing that we must find different antibiotic development, political and economic models, there is hope from these early successes for COVID-19 that the world can address the global public health crisis of AMR. These models are essential if we are to defeat drug-resistant infections in the coming decades and ensure that efforts to develop new antibiotics meet the needs of all people, especially addressing drug-resistant infections that have a disproportionate impact on vulnerable populations, such as neonates and children and those in low- and middle-income countries.

What do I mean by a different political model? 

One in which diverse countries, whether ‘high-income’, ‘middle-income’, or ‘low-income’, are all able to contribute equally as partners in setting priorities for antibiotic research and development and contribute resources. Drug development today is managed by a small number of countries and organisations that set priorities and make most major decisions.  While this has produced some successes, it has also left many people behind and some drug-resistant infections ignored. We need to build a model of drug development that makes space for all countries to participate in priority setting and contribute on equal terms, with contributions coming in different shapes and sizes.

Working in partnership across sectors

Infectious diseases, including pneumonia and sepsis, are a leading cause of death and disability in children under the age of five. Children, and especially new-born babies, are also among the most vulnerable to drug-resistant infections. The lack of research and development for this population is putting their lives at risk.

One example of working across sectors is the Global Antibiotic Research and Development Partnership (GARDP)3 funded by and working with governments in many different parts of the world, including for governance, scientific collaboration, and to gather evidence to support the use of antibiotics for vulnerable populations. GARDP’s priorities are based upon WHO priority pathogens and under-served populations, therefore they are working with governments, research institutes, and universities3 to address the need for new antibiotics for babies and children. This includes developing new antibiotics and providing evidence to support the use of existing antibiotics (used in adults) for babies and children. In collaboration with KEMRI-Wellcome Trust Research Programme in Kenya and the Centre for Tropical Medicine and Global Health at the University of Oxford, GARDP completed a study to assess the blood levels (pharmacokinetics) of the antibiotic fosfomycin.4 This research will help to establish a safe dose of fosfomycin that can be used in combination with other antibiotics to treat new-born babies with sepsis.

We also need a new economic model.

What do I mean and why another model when recent mechanisms have recently been launched by the UK government5 and the pharmaceutical industry (AMR Action Fund)? 6

The current model of drug development is not working to develop new antibiotics and the new mechanisms will not solve all the problems. Developing a new antibiotic is difficult, in part because of the scientific complexity of targeting infections by WHO priority pathogens and because it requires significant time and money to produce the clinical and pharmaceutical development data required to support regulatory approval and guidance on how best to use new antibiotics.   Since new antibiotics should be used sparingly, and should be offered affordably, companies find the market potential of antibiotics unattractive compared to the possibilities from other therapeutics. Even when there is commercial investment in a new antibiotic, there may be insufficient incentive to register the product for adult use in more than a few countries or to develop formulations appropriate for children.

A public-private model: A different way of working

By working in partnership with both the public and private sector, the tremendous research and development expertise and knowledge of the private sector, and the basic science skills, resources, and capacities of the public sector, can be pooled, into a partnership that develops new antibiotics on a not-for-profit basis. By doing so, not only can drugs be developed outside of the normal commercial pressures of the pharmaceutical market but can ensure that all relevant indications and formulations are developed.

GARDP is already putting such a public-private model into practice. For example, GARDP is partnering with Entasis Therapeutics to develop a novel antibiotic called zoliflodacin, the only drug being developed specifically to treat gonorrhea and active against Neisseria gonorrheae resistant to all currently used antibiotics. N. gonorrheae, the cause of gonorrhea is particularly prone to drug resistance, hence it is a WHO priority pathogen. The scale of gonorrhea is staggering. Every year there are 87 million infections. These have a huge impact on wellbeing, fertility, and productivity in the workplace.

Following positive phase 2 clinical trial results, zoliflodacin is being evaluated in a global phase 3 trial. If successful and the drug is approved, GARDP will be responsible for introducing the drug in up to 148 countries around the world (and Entasis 44; another three are negotiable). Helping to get this important new drug registered and used responsibly to meet the needs of people, will avoid many of the life-altering consequences of untreated gonorrhea.

The Future?

After three decades of underinvestment in developing new antibiotics, we know a new way forward is needed for the next three decades and beyond. Unlike with COVID-19, we already have advance warning of the consequences of failing to act against the global health crisis of AMR.  We can act differently and make drug development of new antibiotics not only a success against drug-resistant infections, but a model of cooperation across public and private sectors that can inspire progress against the many health challenges to come. To succeed, political will and courage to take the bold decision to act differently is needed, now.

 

References/suggested reading

(1) 2020 Antibacterial Agents in Clinical and Preclinical Development: an overview and analysis.  World Health Organization. https://www.who.int/publications/i/item/9789240021303

(2) Global Priority List of Antibiotic-Resistant Bacteria to Guide Research, Discovery, and Development of New Antibiotics.  World Health Organization. https://www.who.int/medicines/publications/WHO-PPL-Short_Summary_25Feb-ET_NM_WHO.pdf?ua=1

(3) Global Antibiotic Research and Development Partnership: About GARDP.  https://gardp.org/who-we-are/about-gardp/

(4) Zoe Kane, Silke Gastine, Christina Obiero, Phoebe Williams, Sheila Murunga, Johnstone Thitiri, Sally Ellis, Erika Correia, Borna Nyaoke, Karin Kipper, John van den Anker, Mike Sharland, James A Berkley, Joseph F Standing. 2021. IV and oral fosfomycin pharmacokinetics in neonates with suspected clinical sepsis. Journal of Antimicrobial Chemotherapy, April 21. dkab083, https://doi.org/10.1093/jac/dkab083

(5) Global AMR Innovation Fund.  https://www.gov.uk/government/groups/the-global-amr-innovation-fund

(6) AMR Action Fund. https://amractionfund.com/

 

Laura Piddock joined the Global Antibiotic Research and Development Partnership (GARDP) in January 2018. As GARDP’s Scientific Director, Laura leads the Discovery and Exploratory Research and Scientific Affairs programmes. She also contributes to GARDP’s Policy and Advocacy activities.

GARDP’s Discovery and Exploratory research activities currently focus on two Gram-negative bacterial species (Klebsiella pneumoniae and Acinetobacter baumannii) on WHO’s critical priority list – these often cause difficult-to-treat hospital-acquired infections, including bloodstream infections. Scientific Affairs encompasses a range of activities including webinars, co-organising the annual Antimicrobial Chemotherapy conference with BSAC, Viewpoint articles and an Antimicrobial Encyclopaedia. Many of the Scientific Affairs’ activities are delivered via the REVIVE project (revive.gardp.org) that was created to ensure that expertise and knowledge is made available, and the antimicrobial R&D community is supported online to connect, share, and acquire information.

Laura is also Professor of Microbiology at the University of Birmingham, UK. Since she started her PhD in 1982, she has been at the forefront of antimicrobial research. Laura began her career in a clinical environment and successfully integrated this background with academic research. Her current University research focuses on understanding regulation (switching on and off) of bacterial multidrug resistance (MDR) efflux pumps that export antibiotics out of bacteria. She has published over 250 articles in international peer reviewed journals and given over 200 presentations at international conferences.

Laura has advised organisations such as the World Health Organization, and scientific data from her team has been used by national governmental agencies when deciding whether to withdraw the licences of some antibiotics from veterinary medicine. In 2001, Prof. Piddock was made a Fellow of the American Academy of Microbiology. In 2017, she was appointed as a founding Fellow of the European Society of Clinical Microbiology and Infectious Diseases. Until 30 September 2017, Prof. Piddock was the British Society for Antimicrobial Chemotherapy Chair in Public Engagement. Furthermore, until December 2018 she was the Chair of the EU Joint Programming Initiative on Antimicrobial Resistance Scientific Advisory Committee.

Laura is an enthusiastic communicator about antibiotic resistance and the lack of new antibacterial treatments. She has given talks to various groups at local, national, and international level. Laura frequently contributes to both the local, national, and international media (print, radio, television and digital) and has been interviewed, advised on, and appeared in, several documentaries for numerous global networks including BBC (One, Two, Four, Radio 2, Radio 4, Radio 5 Live), Al Jazeera, CNN, Channel 4 and Sky News.

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Initial response from BSAC

Laura’s blog is very timely as we enter the third wave of the COVID-19 pandemic in the UK. She draws parallels between the achievements of the past 18 months in the response to the pandemic (a relevant example being the rapid development, licencing, manufacture and distribution of vaccines), and what is required to re-stimulate the antimicrobial drug development market. Surely we can learn from that experience?

At very least, it demonstrates that, given sufficient political will, antimicrobial resistance could be managed. In 2016, the O’Neill AMR Review proposed that investment of 1.6 billion US$ worldwide each year as market entry rewards would make a material difference to drug development. This is a tiny fraction of the money that Governments have been able to find for the pandemic response.

Laura also outlines the valuable contribution that organisations such as GARDP are able to make in facilitating the development of new compounds and shepherding them through the complex and financially high-risk regulatory pathway. However, she also emphasises the vulnerability that results from antimicrobial drug development and production being led by a relatively few countries and organisations. Antimicrobial agents are fundamental to modern healthcare and all countries have an important stake in their development

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