16 June 2022 - - Japan-based pharmaceutical company Shionogi and Co., Ltd's European subsidiary, Shionogi B.V. has signed an agreement with NHS England to begin a subscription payment model reimbursement of Cefiderocol in England, the company said.

In this model, companies are paid a fixed sum for antimicrobials based on a health technology assessment of their value to the NHS, rather than the volumes used.

Shionogi welcomes the introduction of pull incentives to help bring urgently needed new antibiotics to market.

The deal follows draft guidance from NICE issued in April, which recommended Cefiderocol within its marketing authorisation as an option to treat severe multidrug resistant aerobic Gram-negative bacterial infections.

It also states that the drug should be reserved for difficult to treat resistant infections, where there are few alternative options, and can only be used either in the microbiology-directed treatment setting, or as risk-based empiric treatment.

NICE's evaluation of Cefiderocol considered long-term population benefits, including the 'insurance/diversity' value of having additional antimicrobial treatment options available for the future, and the 'enablement' value associated with the continued ability to provide other healthcare (such as chemotherapy and surgical procedures), that might otherwise be jeopardised by increasing antimicrobial resistance.

Cefiderocol is one of two antimicrobial products selected and made available as part of the scheme by NICE and NHS England6 because they address key disease areas of unmet need in the UK and internationally, treating serious infections including blood stream infection, sepsis and hospital or ventilator acquired pneumonia (HAP and VAP).

Shionogi has entered into an initial three-year contract, with the option to extend, by agreement, for up to another seven years, receiving an annual, value-based payment.

While developing antibiotics is a long, costly and uncertain process, commercialisation can also be challenging.

Once launched, there is often a low frequency of use driven by the need for stewardship to prevent resistance development.

Low use leads to limited revenues, which in turn restricts continued commercialisation and new product research.

As a result of these economic challenges, many large pharmaceutical companies are no longer active in the development and commercialisation of antibiotics, and several smaller biotech companies have filed for bankruptcy.

Antimicrobial resistance is a major health burden which urgently needs to be addressed. There are 700,000 deaths globally, ~25,000 deaths per year in the EU7 and 5,000 deaths in England from infections with multidrug-resistant bacteria.

Infections caused by carbapenem-resistant Gram-negative bacteria are often associated with a high mortality rate.

If no action is taken, antibiotic resistance is predicted to result in 10m deaths every year globally by 2050, at a cumulative cost to global economic output of 100 trillion.

The increasing resistance of many infections caused by Gram-negative bacteria to existing therapies, including carbapenem-resistant Enterobacterales and non-fermenting species such as P. aeruginosa, A. baumannii, and S. maltophilia, makes them difficult to treat and results in high mortality rates.

The World Health Organization have identified carbapenem-resistant strains of Enterobacterales, P. aeruginosa and A. baumannii as the top priority in the research and development of new antibiotics.

Cefiderocol is the first antibiotic to address all three major mechanisms of carbapenem-resistance and is an important treatment option to address this urgent unmet need.

Cefiderocol is the world's first siderophore cephalosporin antibiotic with a novel mechanism of entry through the outer membrane of Gram-negative pathogens by using the bacteria's own iron uptake system to gain cell entry, acting like a Trojan horse.

In addition to entering cells by passive diffusion through porin channels, Cefiderocol binds to ferric iron and is actively transported into bacterial cells through the outer membrane via the bacterial iron transporters, which function to incorporate this essential nutrient for bacteria.

These mechanisms allow Cefiderocol to achieve high concentrations in the periplasmic space where it can bind to penicillin-binding proteins and inhibit cell wall synthesis in the bacterial cells.