The development of antimicrobial agents has saved many lives worldwide since the discovery of penicillin in 1928. [1] However, the spread of antimicrobial resistance (AMR), which occurs when bacteria, viruses, fungi or parasites no longer respond to existing treatments, has limited their use. According to the World Health Organization (WHO), there are 4.95 million deaths every year attributed to AMR. The organization regards AMR as one of the top ten global threats to public life. [2, 3] This piece will focus on antimicrobial resistance in bacterial infections.
AMR in bacteria is a natural survival mechanism. Its spread has been accelerated by the misuse and overuse of antibiotics and antimicrobials in hospitals, the community, particularly in countries where antibiotics are available without prescriptions, and in farming. Beating AMR will need a variety of different approaches, including the development of new antibiotics, the use of monoclonal antibodies, greater use of diagnostics to allow precision prescribing, and vaccinations to prevent the incidence and spread of bacterial infections. [3]
Using diagnostic tools to reduce AMR
According to a review in 2017, up to half of antibiotics used in Western countries are unnecessary. Using patient-centred, cost-effective diagnostics could reduce this figure drastically; the challenge, however, is ensuring that the diagnostics are rapid enough to make a difference, and that they can be integrated into the clinical pathway. [4] Diagnostics also can be used to monitor the epidemiology of AMR, improving treatment guidelines and patient management. [5]
The impact of new antibiotics and antimicrobials
Antibiotics can be classified under the WHO AWaRe framework into three groups - Access, Watch and Reserve - based on their impact on AMR and their activity against multidrug-resistant organisms (MDRO). The Access group are the first or second choice for common infections, and the Watch group contains antibiotics that have a greater resistance potential, so should be stewarded carefully. Reserve antibiotics are restricted for use against MDRO infections. [6]
Many companies have moved out of antibiotic and antimicrobial development because of the challenges of the science, the rapid development of resistance, the clinical and regulatory hurdles, and the low return on investment. [3] The latter is two-pronged; it is as a result of generic competition diving antibiotic prices down to very low levels, and the need to keep new antibiotics as a treatment of last resort (Reserve group), meaning that prescribing levels are low. Because of this, the R&D pipeline for new antibiotics isn't as robust as it needs to be.
There are a variety of programs designed to boost R&D in AMR around the world, including the AMR Accelerator (Europe), INCATE (Incubator for Antibacterial Therapies in Europe), CARB-X (Combating Antibiotic-Resistant Bacteria Biopharmaceutical Accelerator; global), Joint Programming Initiative on Antimicrobial Resistance (JPIAMR; global) and the AMR National Action Plan (UK), amongst others.
According to a 2023 review, the number of candidates in early-stage clinical development is increasing, and includes antibiotics and antimicrobials with new mechanisms of action and new targets. However, the late-stage pipeline is still sparse, with a decline in Phase III candidates. [7] Recent antibiotic approvals have been rare and include Zevtera (ceftobiprole medocaril) for Staphylococcus aureus bloodstream infections, acute bacterial skin and skin structure infections and community-acquired bacterial pneumonia. [8] No new antibiotics for gram-negative infections have been approved in 50 years.
Antimicrobials and antibiotics in development include:
● Roche's zosurabalpin, a tethered macrocyclic peptide in Phase I development against Carbapenem-resistant Acinetobacter baumanni (CRAB) [9, 10]
● Glox Therapeutics' bacteriocins, engineered proteins in preclinical development against drug-resistant pathogenic gram-negative bacteria such as Pseudomonas aeruginosa and Klebsiella pneumoniae [9]Read More
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