“Time is running out”: WHO review warns there are not enough antibiotics in the pipeline to combat urgent health threat
Drugs in development mostly cater to the needs of high-income countries, rather than lower income countries where the burden of drug-resistant infections is typically higher.
- 17 March 2023
- 5 min read
- by Linda Geddes
A World Health Organization (WHO) review has warned that there are too few antibiotics in the pipeline to tackle critical pathogens, and no 'silver bullet' drugs that will combat the growing threat posed by antimicrobial resistance (AMR), which the UN estimates could kill 10 million people a year by 2050.
"Time is running out for us to bring new antibiotics to market and combat this urgent threat to public health. Without immediate action, we risk returning to a pre-antibiotic era where common infections become deadly."
– Dr Valeria Gigante, Team Lead in WHO’s Antimicrobial Resistance Division
Just 12 new antibiotics entered the market in the five years from 2017-21, while only six of 27 antibiotics currently being tested against WHO's 'critical list' of bacteria for which new antibiotics are urgently needed, are considered innovative enough to overcome antibiotic resistance. Just two of them are capable of targeting highly-drug resistant forms of these microbes.
This update on the state of the antibiotic landscape was delivered at a special online session of the European Congress of Clinical Microbiology and Infectious Diseases in Copenhagen on 15 March, and was based on a WHO report evaluating the pipelines of antibacterial candidates published last year.
Delivering the update, Dr Valeria Gigante, Team Lead in WHO's Antimicrobial Resistance Division, said: "The rapid increase of multidrug-resistant infections worldwide is concerning. Time is running out for us to bring new antibiotics to market and combat this urgent threat to public health. Without immediate action, we risk returning to a pre-antibiotic era where common infections become deadly.
"In the five years covered by this report, we have had just 12 antibiotics approved, with only one of these – Cefiderocol– able to target all the pathogens deemed critical by WHO.
"There are only 27 more currently under 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 drug classes, but evolution of existing classes."
Silent pandemic
Experts have repeatedly warned of a 'doomsday scenario' in which routine medical procedures become all but impossible because of the risk of picking up a resistant infection, and countless people die from what were previously simple, treatable conditions. Already, some five million deaths each year are attributed to AMR, with those living in poorer countries disproportionately affected, because they have less access to more expensive antibiotics that could work when first-line drugs fail.
New antibiotics are coming. One of them, Solithroymcin – which could be used to treat community acquired pneumonia and other infections – has passed through clinical trials and is currently awaiting market authorisation, and a further seven products are in phase 3 trials having their efficacy assessed. Since failures are possible even in phase 3 trials, it is difficult to predict if and when market authorisation for these drugs would be granted, Gigante said.
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One drug-resistance mechanism that experts are concerned about is New Delhi metallo-beta-lactamase 1 (NDM-1). Bacteria containing the gene to produce this enzyme can break down a wide-range of carbapenem antibiotics – considered part of the last line of defence for treating antibiotic resistant infections. The most common bacteria that make this enzyme are Escherichia coli and Klebsiella pneumoniae, but the gene for NDM-1 can spread from one strain of bacteria to another, and its prevalence is growing worldwide.
Dr Gigante said: "There is a major gap regarding products addressing multi-drug resistant (MDR) pathogens such as Acinetobacter baumannii and Pseudomonas aeruginosa. Very few agents target metallo-beta-lactamases, which continue to grow in prevalence. Few new innovative antibiotics are expected in the coming years. We have no silver bullets."
Mismatched priorities
In a separate presentation, Prof Venkatasubramanian Ramasubramanian, president of the Clinical Infectious Diseases Society of India, flagged challenges such as the withdrawal of large companies from the antibacterial research space, commercial failures of smaller biotechnology companies, lack of effective policy and regulatory solutions for antimicrobial resistance.
He also highlighted differences in the priority pathogen lists and the (CDC), with some species ranked as "high" and "medium" threats by the WHO, not making it onto the CDC's list, and others ranked as "critical" by the WHO classified as "serious" by the CDC – meaning they require prompt and sustained action, rather than urgent and aggressive action.
"This incongruity is magnified in the list of certain countries like India, who have a high burden of drug resistant organisms," he said. "We lack a sustainable economic model for anti-bacterial innovation. To exacerbate the issue, the current products under evaluation mainly cater to the requirements of the developed nations, resulting in a mismatch, especially in developing countries with a high burden of resistance.
A further twist to the story is when new molecules are developed for resistant organisms that have shown promise during the developmental stage, [they] fail to perform when strains unique to certain countries are tested. This is due to newer mechanisms of resistance that seem to be continually evolving in high burden countries."
Possible solutions include the streamlining and fast-tracking of clinical trials assessing new antimicrobials; public-private partnerships across the short, medium and long term, more investment in basic science research that underpins antibiotic development, and other financial incentives including tax breaks and better reimbursement models from national health agencies, Ramasubramanian said.
