Recently, the World Health Organization (WHO) has expressed concern over the lack of new antibiotics to counter drug-resistant infections.
Antimicrobial resistant infections are a major threat to global health, as access to effective antibiotics underpins basic and modern medicine. Cancer chemotherapy, invasive surgeries, organ transplantations and complicated deliveries can only be performed without the risk of serious infections because of access to effective
Mortality and morbidity from resistant infections is on the rise globally, and all countries are affected. In the United States alone, each year more than 2.8 million people get an antibiotic-resistant infection, resulting in more than 35,000 deaths.
In Europe, antibiotic resistance is responsible for an estimated
33,000 deaths annually. Globally, children and neonates are disproportionately affected by antibiotic resistant infections, particularly in low and middle-income countries.
Pneumonia and bloodstream infections causing sepsis are among the major causes of childhood mortality under the age of 5. Approximately 30% of newborns with sepsis die due to bacterial infections resistant to first-line antibiotics.
Infection prevention and control as well as the conservation of existing antibiotics through antimicrobial stewardship programmes is key to the prevention and control of antimicrobial resistance. In addition, to ensure continued effective treatment of bacterial resistant infections, there is also an urgent need for the development of new antibacterial agents.
WHO priority pathogens:
The clinical pipeline remains insufficient to tackle the challenge of increasing emergence and spread of antimicrobial resistance.
It is primarily driven by small- or medium-sized enterprises (SMEs), with large pharmaceutical companies continuing to exit the field.
Half of the new agents target carbapenem resistant Enterobacteriaceae (CRE); however, only one is of a new class. New approved antibiotics to treat carbapenem-resistant Acinetobacter baumannii and Pseudomonas aeruginosa are absent. Thus, there is a visible mismatch between the few newly approved antibiotics and the WHO priority pathogens list.
Of the two new β-lactam/BLI combinations that have been approved, vaborbactam is a first-in-class BLI that contains a cyclic boronate pharmacophore and relebactam, a diazabicyclooctane (DBO) analogue. Both are active against many CRE isolates, but not against CRE where resistance is due to MBLs such as the New Delhi metallo-β-lactamase (NDM) enzyme. Pretomanid, which was approved by the US Food and Drug Administration (FDA) in August 2019 for use within a set drug-combination treatment for MDR TB, is the first new TB drug to be developed and registered by a not-for-profit organization, the Global Alliance for TB Drug Development (TB Alliance).
Eight new antibacterial agents have been approved since 1 July 2017, but overall, they have limited clinical benefits.
One new anti-tuberculosis (anti-TB) agent, pretomanid, developed by a not-for-profit
organization, has been approved for use within a set drug-combination treatment for MDR TB.
The current clinical pipeline contains 50 antibiotics and combinations (with a new therapeutic entity) and 10 biologicals, of which 32 antibiotics are active against the WHO priority pathogens:
- Six of these agents fulfil at least one of the innovation criteria; only two of these are active against the critical MDR Gram-negative bacteria.
More than 40% of the pipeline targeting WHO priority pathogens consists of additional β-lactam and β-lactamase inhibitor (BLI) combinations, with a major gap in activity against metallo-βlactamase (MBL) producers.
The anti-TB and C. difficile antibacterial pipeline is more innovative than the WHO priority pathogens pipeline, with more than half of the antibiotics fulfilling all of the innovation criteria.
Gram-negative bacteria, such as Klebsiella pneumoniae and Escherichia coli, can cause severe and often deadly infections that pose a particular threat for people with weak or not yet fully developed immune systems, including newborns, ageing populations, people undergoing surgery and cancer treatment.
The report highlights a worrying gap in activity against the highly resistant NDM-1 (New Delhi metallo-beta-lactamase 1), with only three antibiotics in the pipeline. NDM-1 makes bacteria resistant to a broad range of antibiotics, including those from the carbapenem family, which today are the last line of defence against antibiotic-resistant bacterial infections.
On a more positive note, the pipeline for antibacterial agents to treat tuberculosis and Clostridium difficile (which causes diarrhea) is more promising, with more than half of the treatments fulfilling all the innovation criteria defined by WHO.
Overall, the newly approved products have limited clinical benefit over existing treatments. The lack of differentiation against existing treatments, their non-inclusion in clinical guidelines and their higher prices in comparison to existing generic treatments make it difficult to predict their place in the treatment landscape.
As six of the eight are from existing classes where multiple resistance mechanisms are well established, the possibility of fast emergence of resistance to these new agents is foreseen.
Preclinical development review
The pre-clinical pipeline shows more innovation and diversity, with 252 agents being developed to treat WHO priority pathogens.
However, these products are in the very early stages of development and still need to be proven effective and safe. The optimistic scenario, the report indicates, is for the first two to five products to become available in about 10 years.
Note: The WHO news release is based on two reports- one on antibacterial agents in clinical development; the other on pre-clinical drug development. The first review is limited to new therapeutic entities that are in Phase 1–3 clinical trials and do not have market authorization for human use anywhere in the world. It is restricted to agents that could potentially be used to treat bacterial infections caused by the WHO priority pathogens, TB or C. difficile and that have a specific antibacterial effect. The analysis does not include:
- preventive interventions, such as vaccines or topical decolonizing agents;
- immunomodulating or microbiome modulating agents;
- nonspecific inorganic substances;
- biodefence agents;
- agents not developed for systemic use (injectable or oral formulations) but only for
- topical application (e.g. creams or eye drops);
- new formulations of existing treatments; or
- analysis of clinical effectiveness.
Link to the related WHO news release:
Links to the two new reports mentioned in the news release: