The World Health Organization (WHO) has described antimicrobial resistance (AMR) as one of the top global public health and development threats, reporting that ‘bacterial AMR was directly responsible for 1.27 million global deaths in 2019 and contributed to 4.95 million deaths’ (WHO, 2023).
Given the ongoing nature of this worldwide threat, attention has been turning towards a natural antibacterial phenomenon that could influence the treatment of bacterial infections.
Bacteriophages, or phages, are naturally occurring obligate intracellular parasites of bacteria and were discovered independently in 1915 by British pathologist Frederick Twort, and in 1917 by French-Canadian microbiologist Félix d’Hérelle, with Twort describing a ‘glassy transformation’ of micrococci colonies, and d’Hérelle isolating what he termed an ‘anti-microbe’ of Shigella (Salmond and Fineran, 2015). In his first paper, d’Hérelle reported that the presence of phages correlated with disease clearance in patients with dysentery, and in a rabbit study he showed that phages conferred protection from infection with Shigella (Salmond and Fineran, 2015).
The first use of phages in 1919 to treat a bacterial infection ushered in a so-called ‘golden age’ of phage therapy, before the antibiotic era saw a decline in this novel treatment in what Jones et al (2023) call the geopolitical West, although ‘phage therapy remained in widespread use in the geopolitical East, where it remains a valuable antimicrobial tool.’ However, ‘the geopolitical West’ has recognised the importance of this approach. For example, 2018 saw the launch of the Center for Innovative Phage Applications and Therapeutics at the University of California, San Diego, and in May 2019 a team of researchers and clinicians ‘successfully treated a seriously ill teenager with cystic fibrosis who had disseminated infection by Mycobacterium abscessus using a cocktail of genetically engineered phages’ (Schmidt, 2019).
However, phage therapy is not without its challenges, one of which, as Leptihn and Loh (2022) point out, is their extreme host specificity. For example, ‘[d]epending on the host bacteria, some phages are highly selective, infecting less than 1% of tested strains, while others kill around 5–15% of bacterial isolates’ (Leptihn and Loh, 2022).
In terms of the clinical application of phage therapy, in a worst-case scenario in which a single phage infects only 1% of clinical isolates, a hypothetical phage therapy centre would need to have ‘at least 300 phages at hand, ready for each and every pathogenic species when a patient comes in for treatment’ (Leptihn and Loh, 2022).
And there are ethical dimensions to be explored. For example, Anomaly (2020) asserts that ‘[t]he moral reason for governments – apart from private firms – to support phage research is that individual companies have not been willing to invest much in research and development, in part because they are uncertain how they might profit from phage therapy.’
More specifically, Suleman et al (2024) make an ethical case ‘for why it is crucially important for the UK to invest in Good Manufacturing Practice (GMP) for both ongoing unlicensed and future licensed phage therapy.’ The authors point out that at present there are no licensed medical phage products in the UK, although phages may be used on an ad hoc basis in accordance with Medicine and Healthcare products Regulatory Agency guidance on a named patient basis when licensed alternatives like antibiotics do not meet a patient's clinical needs.
Further, using phages as an unlicensed medicine presents a challenge mainly ‘because of pharmacologistics and the National Health Service's unfamiliarity around handling and using phages’ (Suleman et al, 2024). Access to phages produced to GMP, argue Suleman et al (2024), will not only help achieve effective patient care and better outcomes, but ‘[t]he UK also has the potential to become a global leader in the timely and cost-efficient manufacturing and supply of a therapy that meets internationally recognised standards.’
Schmidt (2019), however, cites a view that GMP production costs pose a major hurdle, and quotes a commentator who says scientists still have a long way to go in terms of characterising basic phage biology and its interactions with pathogenic bacteria. As one researcher observes: ‘Phages are viruses and they will do what they want to do and not necessarily what we want them to … So ultimately when phages are widely used – and I think they will be – it has to be on firm scientific footing’ (Schmidt, 2019).