Developed resistances to certain antibiotics have occurred since their creation in the 1940s. Scientists found the first case of resistance just four years after antibiotics entered mass production. Only recently, however, has the issue taken a critical turn. Resistant strains of Methicillin-resistant Staphylococcus aureus (MRSA) and other bacteria are present in hospitals globally. These present severe risks to patients. With the crisis growing, the pressure is on pharmaceutical firms foremost to present a solution. But considering the World Health Organisation (WHO) recently announced serious failures to invest in the area, the question arises of whether enough is being done by those in the best place to resolve the problem.

What is Antimicrobial Resistance?

Antimicrobial, or antibiotic, resistance is the ability of micro-organisms such as bacteria to resist the effects of antibiotic medication. It generally evolves through natural selection or selective pressure, and can be transferred between bacteria by plasmid exchange. 

This evolution can come about in a number of different ways. These include overuse of later-generation antibiotics; wrong diagnoses and treatments; improper use of antibiotics by patients; or the use of antibiotic medication in livestock as a growth promoter, prevalent particularly in China.

One of the most well-known examples of antibiotic-resistant bacteria is MRSA, a “superbug” (i.e. carrying several resistant genes). It is endemic in hospitals as well as a number of urban regions around the world. The illness causes fast-acting and deadly diseases such as necrotizing pneumonia, severe sepsis and necrotizing fasciitis. Other resistant bacteria, such as Streptococcus pneumoniae and Enterococcus faecium, are becoming more resistant to antibiotics 

The fallout of such resistance is considerable. Beyond the threat of illnesses such as pneumonia, gonorrhoea and tuberculosis becoming conventionally untreatable, antibiotic resistance will in turn lead to longer stays in hospitals for patients, increased strain on medical services and a rising mortality rate.. 

Current Actions

Since coming to the fore of global consciousness in 2014, the response to antimicrobial resistance has risen significantly. In 2015 the WHO created a global plan to improve awareness and reduce incidents of resistant infections. The plan would also optimise use of antibiotic medicines and encouraging sustainable investment in new drugs to kill resistant bacteria. 

The following year, the UN General Assembly signed a declaration to support a co-ordinated approach, looking particularly at human and animal health and agriculture. Global national action plans have been made, and several initiatives are being led to address the concern. These include: 

• The World Antibiotic Awareness Week, held each November
• The Global Antimicrobial Resistance Surveillance System, a standardised approach to collecting, analysing and sharing data on resistance to improve decision-making and government action
• The Global Antibiotic Research and Development Partnership between WHO and the Drugs for Neglected Diseases initiative to encourage R&D through partnerships, hoping by 2023 to deliver four new treatments

Beyond the UN and WHO, the US Centers for Disease Control and Prevention (CDC) have launched their own Antibiotic Resistance Solutions Initiative. This contributes to national action plans and enhances lab capacity to report resistance.

Individual companies and charities have created other projects, like the Pew Charitable Trusts’ Shared Platform for Antibiotic Research and Knowledge (SPARK). This is a Cloud-based virtual lab to encourage sharing of data and insights into antimicrobial bacteria. SPARK also analyses and integrates biological and chemical data from studies. 

What is Pharma Doing?

The U.K’s Association of the British Pharmaceutical Industry (ABPI) argued that pharma is “fighting a war on five fronts.” These are:

• Reducing unnecessary use of antibiotics – including by training healthcare professionals on antibiotics use and removing volume-based incentives for sales teams
• Ensuring bacteria are not overly exposed to antimicrobials on site. MSD committed $100 million to infrastructure upgrades, ensuring factory discharges contain no harmful residuals
• Developing new antibiotics – including an NHS-partnered ‘subscription-style’ payment model to incentivise new antibiotics R&D
• Slowing infection spread by maximising uptake of vaccines and ensuring hospitals accord with prevention controls 
• Fighting global antibiotic resistance – Pfizer, for instance, noted its launch of the Antimicrobial Testing Leadership and Surveillance website, one of the largest such surveillance programs in the world. 

Despite these efforts, according to WHO the sector that can make the biggest difference is not doing enough. Pharmaceutical companies are creating “insufficient [development efforts] to tackle the challenge of increasing emergence and spread of antimicrobial resistance.”

It said those drugs being developed by big pharma only offer limited improvements on drugs already in the market. According to its report, the majority of innovations are instead being made by small or medium-sized pharma companies, though these have only eight new antibacterial drugs have been created since 2017 – with “limited clinical benefits.”

This is compounded by the pressures placed on smaller pharma organisations, which are often insurmountable: antibiotic frontrunner Achaogen made news last year after filing for bankruptcy, losing dozens of pipeline drugs and its FDA-approved antibiotic plazomicin, effective in treating infections caused by superbug Enterobacteriaceae. 

The WHO cited sector concerns around the current lack of treatment for gram-negative bacteria, which can cause pneumonia, bloodstream infections and meningitis. 

Is Pharma Doing Enough?

Assessing the pipeline alone, it would seem that the pharma community really is pushing for action against these concerns: 32 of the 50 antibiotics currently in pipelines will address pathogens described as ‘global priorities’. Of these, three target New Delhi metallo-beta-lactamase 1, a dangerous enzyme which makes bacteria resistant to a wide range of antibiotics, including one commonly seen as the ‘last line of defence’ against antimicrobial-resistant infections. 

This is not the whole truth, however. A number of companies, such as Novartis in July 2018, are actively leaving the field, two years after it set out to combat the problem. Merck, Roche, GSK and Pfizer are some of the few remaining pharma giants still involved in the sector. 

A second WHO report, looking at preclinical drugs in development, was more promising than the first: it found that 252 of those currently under investigation could potentially target ‘global priority’ bacteria, though scientists have yet to make safety and efficacy tests on many of these. Most will also require a decade to bring to market.

Despite the limited attention focused on the area, some benefits have been seen. The drug pretomanid, developed by the not-for-profit TB Alliance, has been approved for patients with drug-resistant tuberculosis. 

The WHO’s director, Hanan Balkhy, certainly thought more could be done. While he noted that a number of initiatives were under way, pharma companies must contribute “with…innovative new medicines.” 

Discussion from the sector almost unanimously agrees however that the issue is more complex than “not trying hard enough”. It comes down to profit, and the lack of it in the antibiotics field. Sales of new antibiotics are a fraction of the return from other drug classes. Efforts to increase profit, such as extended patent lifetimes and proposals to guarantee minimum sales, have largely failed to reverse the trend. 

Possible Answers to the Problem

Following Achaogen’s collapse, a number of groups including the Pew Charitable Trusts and Infectious Diseases Society of America wrote to Congress in February 2019, proposing a series of measures to push forward development of new antibiotics. These measures included tax incentives for pharma companies, ‘pull’ incentives that increase new antibiotics’ value and changes in pharmaceutical reimbursement – for example a $1 billion market entry reward over five years for companies that receive regulatory approval for an antibiotic that addresses a specified public health need. 

Last year saw the Developing an Innovative Strategy for Antimicrobial Resistant Microorganisms (DISARM) Act of 2019 introduced in the U.S. This would alter Medicare to reimburse hospitals who treat patients with anti-microbial infections by removing disincentives for using new antibiotics. 

Experts have discussed changing the payment model for antibiotics. Antibiotics don’t fit into the current model due to the short duration of patient use, limiting the drugs sold. The need to limit antibiotics prescribed or sold also reduces pharma sales. 

This model change is doubly necessary due to the pressure antibiotics will face from competitors. Most classes of antibiotic have lost exclusivity. This means that companies can produce generic alternatives to undercut the hard work of big pharma. 

Any significant research into the area of antimicrobial resistance makes two things abundantly clear. The first is the necessity of big pharma stepping up their efforts in antibiotic R&D and pipeline activities. The second is the fact that unless major changes are made to the way such drugs are priced in the market, this will never happen. Beyond charitable organisations, big pharma is first and foremost a money-making enterprise, one that needs a constant stream of financial remuneration to operate. Unless new antibiotics become a viable, successful business decision, the dream of a new wave of antibiotics to fight resistance is simply impractical. 

Joshua Neil, Editor
Proventa International