PLEASE NOTE: The Viewpoints on our website are to be read and freely shared by all. If they are republished, the following text should be used: “This Viewpoint was originally published on the REVIVE website revive.gardp.org, an activity of the Global Antibiotic Research & Development Partnership (GARDP).”

The views and opinions expressed in this article are solely those of the original author(s) and do not necessarily represent those of GARDP, their donors and partners, or other collaborators and contributors. GARDP is not responsible for the content of external sites.

In 2017, the World Health Organization (WHO) introduced the AWaRe (Access, Watch, Reserve) framework for classifying antibiotics based on their impact on antimicrobial resistance (AMR) and activity against multidrug-resistant organisms (MDRO).¹

Access, Watch and Reserve antibiotics

Access group antibiotics, e.g. amoxicillin, are often the first or second choice empiric treatment options for common infections with a lower impact on AMR than Watch and Reserve antibiotics.² Watch group antibiotics, e.g. ciprofloxacin, have higher resistance potential and should be a focus of antibiotic stewardship efforts. Reserve group antibiotics, e.g. cefiderocol, are characterized by their activity against MDRO, and their use should be restricted for the treatment of confirmed or suspected infections due to these organisms. The 2023 WHO Model List of Essential Medicines (EML) contains 20 Access antibiotics, 12 Watch antibiotics and 9 Reserve antibiotics (the overall 2023 AWaRe list, including antibiotics not on the EML, classifies 87 Access, 141 Watch, 29 Reserve antibiotics and 103 not-recommended fixed-dose combinations).^3,4

Most Access and Watch antibiotics (on and off the EML) are “old”, generic and inexpensive. In contrast, many Reserve antibiotics have been recently approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA), are under patent protection and are often costly. Current treatment options for MDRO infections may have toxicity concerns (e.g. colistin), or the choice of options may be extremely limited for specific pathogens (e.g. metallo-beta-lactamase (MBL) producing Enterobacterales, the predominant carbapenem-resistant pathogen in many low-and middle-income countries (LMICs)). Ideally, new Reserve antibiotics would have higher clinical efficacy than older antibiotics (e.g. reduced mortality), acceptable toxicity, and a low propensity to select for resistance. They should be priced so that they are accessible and affordable for all patients and healthcare systems who need them. Essential new Reserve antibiotics should also be registered and approved by regulatory authorities worldwide. Furthermore, new Reserve antibiotics should include molecules active against the priority pathogens with the highest global burden. Unfortunately, this is more difficult than expected: “new” does not necessarily mean “better” or “more innovative” since almost all newly approved agents belong to existing classes of antibiotics, with very few being active against MBL-producing strains.⁵

“While we acknowledge that PK/PD data are crucial, these data may not translate to dependable evidence that favourable clinical outcomes will be achieved in patients.”

Evaluation of Reserve antibiotics for the WHO EML

Before a medicine is added to the WHO EML, it undergoes a rigorous evaluation of the evidence for efficacy and safety by an independent panel of experts. Applications for adding new Reserve antibiotics to the EML have been evaluated for recent EML updates. Unfortunately, the evidence generated by the industry-sponsored pivotal trials for regulatory approval has been insufficient to judge whether these new antibiotics offer clear advantages over older alternatives in terms of clinical efficacy. Furthermore, when developing the WHO AWaRe antibiotic book, which provides guidance on the appropriate use of all antibiotics included in the WHO EML, the evidence base to inform best practices for Reserve antibiotics was insufficient to adequately inform the formal development of any guidance on their optimal use.^6,7

For none of the new Reserve antibiotics recently reviewed by the WHO EML were the pivotal studies in MDRO (predominantly carbapenem-resistant organisms (CRO)) adequately powered to demonstrate the clinical superiority of the new treatment of infections caused by these organisms. These new agents have been licensed following non-inferiority trials mainly conducted in complicated urinary tract infections and intraabdominal infections, as required by the regulatory authorities, but recruited very few patients with MDRO pathogens. The design (uncontrolled) and sample size (small) of subsequent pathogen-based studies in high-risk populations have been insufficient to inform “real-life” optimal use of these new antibiotics. Post-approval non-randomized studies that specifically look at treatment in patients with infections caused by MDRO are prone to multiple biases and cannot adequately substitute large pragmatic prospective randomized trials. Furthermore, the Infectious Diseases Society of America (IDSA) noted that the evidence was inadequate to produce formal guidelines for treating MDRO infections and hence issued guidance based predominantly on expert opinion.⁸ Pharmacokinetics-pharmacodynamics (PK/PD) data are not a substitute for adequately powered clinical studies.

While we acknowledge that PK/PD data are crucial, these data may not translate to dependable evidence that favourable clinical outcomes will be achieved in patients. We acknowledge that trials in high-risk populations infected by CRO are challenging as evidenced by the trial comparing plazomicin to colistin as part of a combination-therapy regimen for serious infections caused by carbapenem-resistant Enterobacterales; this terminated prematurely because after two years of recruitment only 39 patients could be randomized.⁹ Reserve antibiotics are specifically intended to be used in patients that invariably fulfil this criterion. Antibiotic stewardship principles mandate that these agents should not be widely used indiscriminately in patients at low risk of MDRO infections to limit the emergence of resistance to these agents and keep them effective as long as possible. The lack of representativeness of the trial population does not only apply to target MDRO and antibiotic resistance but also concerns an underrepresentation of important populations (e.g. people living in LMICs, immunosuppressed individuals, pregnant women, children, neonates) for whom these antibiotics are frequently indicated. Proposals for addressing these information gaps through innovative trial designs have been made in the literature.^10,11

“Innovations in the post-licensing downstream area of obtaining adequate clinical and health-economic evidence to inform country-level implementation and patient-level access to newly approved antibiotics are just as important as innovation in the upstream search for new antibiotics.”

The need for high-quality evidence on new antibiotics is an urgent problem

The WHO EML aims to provide evidence-based guidance to countries on selecting the most effective and safe medicines for priority health conditions of the population. Some countries are now conducting Health Technology Assessments to inform whether a new Reserve antibiotic should be added to their national EML. This requires data on comparative clinical efficacy, toxicity, health economic outcomes and longevity (selection of resistance). Ideally, these data would be obtained through adequately powered public-health-focused trials with broad inclusion criteria that represent “real-life” patient populations at high risk of MDRO, including patients in low-resource settings and neglected patient populations (e.g. premature babies). The scientific, academic and public health communities and other stakeholders need to advocate for the need for these trials with funders.

Given the urgency of the problem and the lack of alternatives, several new Reserve antibiotics have been added to the WHO EML despite the very low-quality evidence. The lack of high-quality evidence on new antibiotics is a neglected but urgent problem. The current strong global focus on enhancing innovation in early drug development is necessary, but the emphasis on the other parts of the pipeline is wholly insufficient. Innovations in the post-licensing downstream area of obtaining adequate clinical and health-economic evidence to inform country-level implementation and patient-level access to newly approved antibiotics are just as important as innovation in the upstream search for new antibiotics. Both ends of the antibiotic R&D pipeline are dry.

References

1. Sharland M, Gandra S, Huttner B, Moja L, Pulcini C et al. (2019) Encouraging AWaRe-ness and discouraging inappropriate antibiotic use-the new 2019 Essential Medicines List becomes a global antibiotic stewardship tool. Lancet Infect Dis. 19(12):1278-80.
2. Sulis G, Sayood S, Katukoori S, Bollam N, George I et al. (2022) Exposure to World Health Organization’s AWaRe antibiotics and isolation of multidrug resistant bacteria: a systematic review and meta-analysis. Clin Microbiol Infect. 28(9):1193-202.
3. World Health Organization (2023) WHO Model List of Essential Medicines – 23rd list. [Accessed 07/12/2023]
4. World Health Organization (2023) AWaRe classification of antibiotics for evaluation and monitoring of use. [Accessed 07/12/2023]
5. World Health Organization (2022) 2021 Antibacterial agents in clinical and preclinical development: an overview and analysis. [Accessed 07/12/2023]
6. World Health Organization (2022) The WHO AWaRe (Access, Watch, Reserve) antibiotic book2022. [Accessed 07/12/2023]
7. Zanichelli V, Sharland M, Cappello B, Moja L, Getahun H et al. (2023). The WHO AWaRe (Access, Watch, Reserve) antibiotic book and prevention of antimicrobial resistance. Bull World Health Organ. 101(4):290-6.
8. Tamma PD, Aitken SL, Bonomo RA, Mathers AJ, van Duin D et al. (2023) Infectious Diseases Society of America 2023 Guidance on the treatment of antimicrobial resistant Gram-negative infections. Clin Infect Dis. ciad428
9. McKinnell JA, Dwyer JP, Talbot GH, Connolly LE, Friedland I et al. (2019) Plazomicin for infections caused by carbapenem-resistant Enterobacteriaceae. N Engl J Med. 380(8):791-3.
10. de Kraker MEA, Sommer H, de Velde F, Gravestock I, Weiss E et al. (2018) Optimizing the design and analysis of clinical trials for antibacterials against multidrug-resistant organisms: A white paper from COMBACTE’s STAT-Net. Clin Infect Dis. 67(12):1922-31.
11. Lanini S, Ioannidis JPA, Vairo F, Pletschette M, Portella G et al. (2019) Non-inferiority versus superiority trial design for new antibiotics in an era of high antimicrobial resistance: the case for post-marketing, adaptive randomised controlled trials. Lancet Infect Dis. (12):e444-e51.