The World Health Organisation has released a list of 12 bacteria it says pose the greatest threat to human health as a way of urging governments and the drug development industry to incentivize and launch an R&D response against the increasing global issue of antibiotic resistance.
WHO lists pathogens that are the greatest threats to humanity
The World Health Organisation has highlighted 12 families of bacteria, the majority of which have become resistant to available antibiotic treatments, on a newly established watch list of critical threats – similar concerns as those raised by the US Centers for Disease Control and Prevention (CDC) in a 2013 report on the top 18 drug-resistant threats.
The WHO's list highlights in particular the threat of gram-negative bacteria that are resistant to multiple antibiotics. "This list is a new tool to ensure R&D responds to urgent public health needs," Dr Marie-Paule Kieny, the WHO's assistant director-general for health systems and innovation, said in statement. "Antibiotic resistance is growing and we are fast running out of treatment options. If we leave it to market forces alone, the new antibiotics we most urgently need are not going to be developed in time," she added.
The WHO's list of bacteria families – developed in collaboration with the division of infectious diseases at the University of Tübingen, Germany – is split into three priority categories: critical, high and medium.
Priority 1: CRITICAL
- Acinetobacter baumannii, carbapenem-resistant
- Pseudomonas aeruginosa, carbapenem-resistant
- Enterobacteriaceae, carbapenem-resistant,ESBL-producing
Priority 2: HIGH
- Enterococcus faecium, vancomycin-resistant
- Staphylococcus aureus, methicillin-resistant, vancomycin-intermediate and resistant
- Helicobacter pylori, clarithromycin-resistant
- Campylobacter spp., fluoroquinolone-resistant
- Neisseria gonorrhoeae, cephalosporin-resistant, fluoroquinolone-resistant
Priority 3: MEDIUM
- Streptococcus pneumoniae, penicillin-non-susceptible
- Haemophilus influenzae, ampicillin-resistant
- Shigella spp., fluoroquinolone-resistant
Criteria for selecting the pathogens on this list included how many treatment options remain and whether new antibiotics to treat them are already in the pipeline; as well as measures like how deadly the infections caused are and whether hospitals stays are required for those infected.
Dr Sue Hill, director of the department of essential medicines and health products at the WHO, told Scrip, "Even though there has been a lot of investment in the last couple of years from both private and public funding aimed at stimulating R&D for antibiotics, what we still see is a relatively limited number of products in the pipeline." Hill noted that one of the WHO's next steps this year is to carry out a thorough pipeline analysis for treatments targeting the pathogens highlighted on its watch list. The WHO is also considering a global stewardship framework for monitoring and guiding the best use of antibiotics worldwide, looking for at the development of new drugs and how to repurpose available anti-infectives. Futhermore, the organization has an ongoing partnership with the non-profit group Drugs for Neglected Diseases Initiative (DNDI), focused on stimulating new R&D methods for antibiotics.
"The purpose of this list was to define more precisely the bugs we need antibiotics for most, to direct research efforts to the areas with the most need," Hill said. She compared the list to some of the WHO's previous projects, such as the 2013 Priority Medicines for Europe and the World report and the R&D Blueprint for Action to Prevent Epidemics that was released in May last year.
The list has received more than 124,000 downloads since its release on the WHO's website on Monday Feb. 27. Hill noted that one query raised about the list so far is the fact tuberculosis was not included as a threat. She clarified that while new drugs for TB is a major priority for the WHO, it is an initiative that has been defined for some years. "The idea of this list was to go beyond the pathogens where we already have priority measures in place," she added. "We know TB, malaria and HIV, for example, need new drugs – these have been R&D priorities for some time."
Hill highlighted that current antibiotic developers or those looking to expand into antibiotic research should not only focus on pathogens highlighted as critical risks. "Drugs targeting the pathogens in the medium threat category might be easier or cheaper to developer. One of the reasons the critical group has that heading is because we have more problems with resistance there and see fewer product coming through the pipeline."
Hill realizes that the economic setup for developers of new antibiotics is still unfit for purpose. "It is clear the standard market models are not working and are inappropriate," she said, "the last thing we want are new antibiotics developed and sold to millions of people. We want a new drug developed and locked up for future use."
Hill noted that this requires different thinking around incentives because companies are asked to invest in developing products but at the same time told not to sell them. "We have to think about whether buying out patents is an option, offering prizes – for example, like the FDA's priority review voucher system. We are having these discussions now to see what will be the appropriate mechanisms for incentivizing companies," she said.
As well as industry's response to the list, Hill hopes to spur academic groups and basic science researchers to act on the call to arms against antimicrobial resistance.
What's In the Pipeline?
Pipeline activity for the three pathogens highlighted by the WHO as critical threats – acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacteriaceae– is limited, concentrated mainly in the early-stages of development.
According to data held by Informa Pharma Intelligence's Biomedtracker, there are only three compounds in development targeting acinetobacter baumannii gram-negative bacteria, of these only one has entered the clinic. Entasis Therapeutics has a Phase I program (active in Australia) for EXT2541, a broad and potent inhibitor of class A, C, and D beta-lactamases. The company is developing the combination of sulbactam and ETX2514 for the treatment of severe Acinetobacter baumannii infections. The Phase I study is slated for completion by June this year.
Antibiotic treatments against Pseudomonas aeruginosa are more advanced than A.baumannii. Biomedtracker has two Phase II programs listed: MEDI3902 from AstraZeneca PLC and panobacumab from Aridis Pharmaceuticals LLC. AstraZeneca's drug has been granted Fast Track status in the US and topline data from the Phase II EVADE trial in mechanically ventilated patients for the prevention of nosocomial pneumonia caused by pseudomonas aeruginosa are expected in 2018.
Targeting Enterobacteriaceae, Achaogen Inc., in partnership with Ionis Pharmaceuticals Inc., has three Phase III trials ongoing for antibiotic candidate plazomicin. The drug is being tested as a treatment for urinary tract infections, septicemia and hospital acquired pneumonia.
Comparison To CDC Analysis
In 2013 the CDC published a report outlining the top 18 drug-resistant threats, also categorized by level of concern: urgent, serious and concerning.
The pathogens at the top of both these lists remain similar four years apart, highlighting the slow progress in uptake of antibiotic research programs. The WHO's number one concern, resistant Acinetobacter baumannii, also topped the CDC's serious threats list in 2013. However, Neisseria gonorrhoeae was labelled an urgent threat in the US in 2013, but this pathogen has only been categorized as a high priority in 2017 by the WHO.
Drug resistant Pseudomonas aeruginosa, a critical threat on the WHO's list, was also considered a serious threat by the CDC four years earlier.