Given the average progression rates and the development duration associated with traditional research and development (R&D) models, the current pipeline will generate few new antibiotics in the coming years.
According to the 2021 report by the World Health Organization only 2 of the 12 newly approved antibacterials represent a new class. Lack of innovation means that the emergence of resistance to these newly approved antibacterials is probable. The majority (7 out of 12) of the newly approved antibiotics are classified as “Reserve” according to the WHO 2021 AWaRe classification, while three are in the “Watch” group. This means that most new agents presently in development, if approved, will likely be in the Reserve group and thus considered last-resort antibiotics to be used only where previous treatment lines have failed.
Innovation remains a challenge for Gram-negative bacterial species
Antibacterial agents in clinical development do not address the problem of extensively or pan-drug-resistant Gram-negative bacteria. Novel antibiotics targeting the critical WHO priority pathogens are still lacking; in particular, carbapenem-resistant A. baumannii and P. aeruginosa, continue to be insufficiently addressed. The antibacterial agents in clinical development that target WHO priority pathogens are mainly β-lactam / β-lactam inhibitor combinations.
The anti-tuberculosis clinical antibacterial pipeline is more innovative, with half of the antibacterials meeting at least one innovation criteria for belonging to a new chemical class. Regarding C. difficile infections, there are five products in the pipeline and four of them are innovative agents.
The clinical direct-acting small molecule (“traditional”) pipeline remains dominated by improvements in existing classes. To overcome existing cross-resistance, more new classes of antibacterials are needed, including antibacterials addressing new targets and using new modes of action. The innovation criteria should be designed in each new product under development including a low propensity for resistance development, at least by mutation, and characteristics that promote cell permeation and/or efflux avoidance.
Diversity in non-traditional approaches
Innovative approaches that could be used as an alternative to, or complementary and synergistic with, traditional antibacterial agents that are being pursued hold the potential to curb AMR. In the present scenario, where traditional products have a limited lifespan before resistance emerges and their value is preserved by stewardship measures, non-conventional approaches seem to offer opportunities to tackle AMR from different angles.
Most of the non-traditional agents are in early clinical stages, and many of these will likely face development hurdles as/if they progress through the pipeline. In addition, over 90% of the non-traditional agents are pathogen-specific strategies, a majority of which target Staphylococcus aureus and C. difficile. This selectivity confirms a trend observed also in the preclinical space and requires significant diagnostic availability for optimal use, which is often not available outside of specialised health-care facilities and poses a challenge in low-resource settings.
Gaps and constraints in the current clinical research and development landscape
The traditional antibacterial agents under development remain insufficient to adequately address the enormous threat posed by AMR. There is a gap in the development of products addressing pathogens with a broad spectrum of resistance to authorized antibacterial agents.
Only one among the authorised products and few among the antibacterial agents under development address the critical pathogens. In addition, most of them are combinations of β-lactams with β-lactam inhibitors but very few agents target metallo-β-lactamases which continue to grow in prevalence. Thus, in terms of therapeutic targets, the pipeline remains largely unequipped against multidrug resistant A. baumannii and P. aeruginosa.
Regarding innovation and indirectly the potential for cross-resistance, we are missing antibacterial agents meeting at least one of the WHO innovation criteria and at the same time targeting the critical Gram-negative bacteria.
In addition, appropriate oral formulations for outpatient treatment along with optimised paediatric formulations are generally lacking across the entire clinical pipeline