A WHO review of the number of new antibiotics currently in the pipeline shows that only 12 new antibiotics entered the market in the five years from 2017-21. And there are very few (only 27) in development in clinical trials against pathogens considered critical* by the WHO, such as Acinetobacter baumannii and Pseudomonas aeruginosa. Of these 27, only six are considered “innovative” enough to be able to overcome antibiotic resistance using WHO criteria* and only two of those six target highly drug-resistant forms of these microbes.
The market faces a catalog of problems and no miracle drugs are being developed to address growing antibiotic resistance.
This update on the state of the antibiotic landscape is presented in a special online session of the European Congress of Clinical Microbiology and Infectious Diseases (ECCMID 2023, Copenhagen, April 15-18) and is presented by Dr. Valeria Gigante , WHO Team Leader, Antimicrobial Resistance Division, Geneva, Switzerland. “In the five years covered by this report, we have only approved 12 antibiotics , and only one of them, Cefiderocol , can attack all the pathogens considered critical by the WHO,” explains Dr. Gigante. “And there are only 27 more currently in development in phase 1 to 3 clinical trials, with little innovation. Only four of the 27 have new mechanisms of action, and most are not new classes of drugs, but the evolution of existing classes.”
Currently, one antibiotic, Solithroymcin , which will be used to treat community-acquired pneumonia and other infections, is in the ’new drug application’ stage (it has gone through clinical trials and is awaiting marketing authorization) and seven other products They are in phase 3 trials with their effectiveness evaluated. Dr. Gigante explains that since failures are possible even in Phase 3 trials, it is difficult to predict if and when a marketing authorization will be granted for these drugs.
According to recent estimates, almost 5 million deaths are already associated each year due to antimicrobial resistance (AMR). However, the true burden of resistance could be even greater. Additionally, AMR disproportionately affects poor people who have little access to more expensive second-line antibiotics that might work when first-line medications fail.
The last new class of antibiotics was discovered in the 1980s
Antimicrobials are not as lucrative a prospect as other treatments for pharmaceutical companies, because they are mostly short-term treatments and antibiotic stewardship programs aim to preserve or "save" any new drugs until they are desperately needed. And they are just as likely to fail during the research and development process as any other drug for other conditions, yet they offer a fraction of the revenue returns compared to, say, cancer and cardiology drugs. As a result of these and other factors, the research and development process for new antibiotics is challenging and poorly funded. The last new class of antibiotics was discovered in the 1980s and the first antibiotic in this class, daptomycin , came to market in 2003.
Antimicrobial resistance develops due to overuse and inappropriate use, such as people not completing their full course of antibiotics or because they were prescribed the wrong antibiotic or, in some countries, antibiotics that are widely used without a prescription medical. The global trend of inappropriate antibiotic use is demonstrated by the time it takes to develop resistance to new antibiotics: for antibiotics released between 1930 and 1950, the average time to develop resistance was 11 years; for antibiotics launched between 1970 and 2000 it was only 2 to 3 years.
This silent pandemic of antibiotic resistance continues to grow around the world. Experts repeatedly warn of a "doomsday scenario" in which routine medical procedures, for example antibiotic prophylaxis in the treatment of cancer or other diseases, would no longer be effective and untold numbers of people could die. due to infections that were previously simple and treatable.
An example of a drug resistance mechanism that worries experts is New Delhi metallo-beta-lactamase 1 (NDM-1). Bacteria that contain the gene to produce this enzyme can break down (and are therefore resistant to) a wide range of carbapenem antibiotics , considered part of the last line of defense in antibiotic treatments where other antimicrobials have failed. The most common bacteria that produce this enzyme are Escherichia coli and Klebsiella pneumoniae , but the NDM-1 gene can spread from one strain of bacteria to another. The prevalence of NDM-1-containing bacteria continues to grow worldwide.
Dr. Gigante says, “There is a significant gap regarding products that address multidrug resistant (MDR) pathogens such as Acinetobacter baumannii and Pseudomonas aeruginosa (only one licensed agent against all critical pathogens and few in development). Very few agents target metallo-β-lactamases, the prevalence of which continues to increase. Few new and innovative antibiotics are expected in the coming years. We have no silver bullets .”
She adds: “The rapid increase in multidrug-resistant infections around the world is worrying. We are running out of time to bring new antibiotics to market to combat this urgent threat to public health. Without immediate action, we risk returning to a pre-antibiotic era in which common infections become deadly.”
She concludes: "While we face significant challenges in the fight against antimicrobial resistance, research and development efforts are underway to discover and develop new and hopefully innovative antimicrobial agents, and we have seen promising results in recent years. "With greater investment and collaboration across sectors, we can make progress in the fight against antimicrobial resistance and ensure that patients have equitable and global access to effective treatments for drug-resistant bacterial infections."
In the second presentation of this session, Professor Venkatasubramanian Ramasubramanian, President, Society of Clinical Infectious Diseases of India and Consultant, Infectious Diseases and Tropical Medicine, Apollo Hospitals, based in Chennai, India, asks if the current antibiotic portfolio is sufficient to address the needs of countries with a high burden of drug-resistant infections.
He says: “We have reached the post-antibiotic era . “The current arsenal of antibacterials is woefully insufficient to make a difference in the fight against the ongoing threat of antibiotic resistance.”
He highlighted innovation challenges, including the withdrawal of large companies from the antibacterial research space, commercial failures of smaller biotech companies, lack of effective policy and regulatory solutions, poor return on investments, cheap generics and fluctuations in waves of infectivity.
He says: “We lack a sustainable economic model for antibacterial innovation. “To exacerbate the problem, current products being evaluated primarily cater to the requirements of developed nations, resulting in a mismatch, especially in developing countries with a high resistance burden.”
Professor Ramasubramanian will highlight the discrepancy in the list of priority pathogens between the WHO and the US Centers for Disease Control and Prevention. He says: "This inconsistency is magnified in the list of certain countries like India, which have a high burden of disease organisms Another twist in the story is when new molecules are developed for resistant organisms, which have shown promise during the development stage, do not work when strains exclusive to certain countries are tested. This is due to the new mechanisms of resistance that appear to continually evolve in high-burden countries.
Some possible solutions to address the current crisis, including streamlining and fast-tracking clinical trials evaluating new antimicrobials; public-private partnerships in the short, medium and long term, more investment in basic scientific research that underpins the development of antibiotics and other financial incentives including tax exemptions and better reimbursement models from national health agencies.
