Volumne 15

Bacteriophage therapy: a viable alternative to antibiotics?

Samuel Nellany BSc (Hons), Medical student, University of Glasgow

Published on 01/08/2026
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BGTHA Journal Edition 17

Outline

Figures

Figure 1 – This shows the key structural components of a bacteriophage

Abstract

The increasing prevalence of antimicrobial resistance has promoted renewed interest in bacteriophage therapy as an alternative to antibiotics. This paper briefly summarises the history and mechanism of bacteriophage therapy. The effectiveness of bacteriophage therapy is discussed and phage therapy is compared to antibiotics regarding specificity and potential resistance development.
It looks at the potential of combining these two treatments. The barriers that currently limit widespread use are explored; these include regulatory challenges and production issues. While bacteriophage therapy appears promising, further research and development will be required before widespread use can be seriously considered.

Introduction

Since the discovery of penicillin in 1928 by Alexander Fleming, antibiotics have become fundamental to everyday medical practice and have saved millions.1,2 First used widely during World War 2, penicillin significantly decreased mortality from bacterial infections among allied soldiers.3 Post war, antibiotics were developed further and became more widely available. They have allowed dramatic advances in surgery and chemotherapy.1,4 Despite this, their effectiveness is increasingly threatened by the spread of multidrug-resistant (MDR) bacteria, thought to have been primarily driven by the inappropriate use and over-prescription of antibiotics.5 

MDR bacteria are responsible for increases in morbidity and mortality globally.6 Lower and middle-income countries are disproportionally affected. This is due to higher rates of communicable disease as well as inadequate sanitation and healthcare systems.7 Antimicrobial resistance (AMR) is thought to be one of the most serious threats to public health in the 21st century.8 It is predicted to potentially cause around 50 million deaths by 2050.9
Increasing resistance has led to a need to limit antibiotic use and pursue antibiotic alternatives. One of these alternatives is bacteriophage therapy.

Bacteriophages (or phages) are viruses that infect and replicate in solely bacteria. These are found in multiple different environments including soil, oceans and even the human gut.10 While it is debated whether bacteriophages were discovered by Frederick Twort in 1915 or Félix d’Hérelle in 1917, d’Hérelle was the first to trial the use of bacteriophages as a treatment for bacterial infections.11

Early research by d’Hérelle using bacteriophages to treat cholera and dysentery were successful and attracted the interest of several governments.11 Phage production facilities and research institutes were established in the Soviet Union in the 1930s and research has continued in Eastern Europe to the modern day.12,13 Bacteriophage therapy research was largely abandoned following the widespread adoption of penicillin in the 1940s. Penicillin was easier to produce and acted against a wide range of bacteria.14 However, the increasing rise of antibiotic 2 resistance has renewed interest in bacteriophage therapy globally with particular interest in their potential as a treatment for MDR infections.15

Bacteriophage structure

Bacteriophage structure varies however most consist of a capsid (this contains the bacteriophage genome which can be DNA or RNA) and a tail.16,17 A baseplate and fibres located at the end of the tail allow the phage to recognise and bind to specific receptors on the bacterial surface and initiate infection (Figure 1).18 As a result, each bacteriophage shows a high degree of host specificity. Typically, they are only able to infect one bacterial species or specific strains of that species.17 A mixture of phages can be used in “cocktails” in order to target a wide range of infective bacterial species.19

Figure 1 – This shows the key structural components of a bacteriophage
Figure 1 – This shows the key structural components of a bacteriophage

The mechanism of bacteriophage therapy

Bacteriophages replicate either by the lytic cycle or the lysogenic cycle. Attachment is the first stage of the lytic cycle. The bacteriophage will recognise and bind to receptor sites on the surface of the bacterial cell. Next, the bacteriophage penetrates and injects its genetic material leaving an empty capsid outside. The injected phage material then degrades the bacterial chromosome and hijacks the host cell machinery. This allows the synthesis of new phage components such as DNA (or RNA), tails and capsids. These newly synthesised components
are assembled into complete bacteriophages. The final stage is lysis. Phage proteins and enzymes rupture the bacterial cell wall, killing the bacterium and releasing the newly assembled phages. These phages can then go on to infect and kill more bacteria.20,21 As long as their host bacteria are present they will continue to replicate.22 The lysogenic cycle follows a similar process of attachment and penetration. However, instead of replicating and lysing the host cell immediately, the phage integrates its DNA with the host genome. 

This integrated form is known as a prophage and can give the bacterium new characteristics. This integrated DNA is replicated alongside the bacterial genome during cell division so bacteriophage genetic material is passed on to daughter cells. If the bacterial cell is exposed to stress the prophage DNA can remove itself and enter the lytic cycle, taking some of the bacterial host DNA when they do this.21,23 Phages that undergo the lytic cycle are preferred for bacteriophage therapy as they cause the bacteria to undergo lysis immediately. They do not carry the risk of transferring genes between cells that could potentially cause drug resistance.24 The effectiveness of bacteriophage therapy Studies show that bacteriophages are capable of significantly reducing bacterial populations in biofilms.25 Biofilms grow on medical devices such as catheters and prostheses. 26,27 These are extremely resistant to antibiotics because the biofilm matrix limits penetration of antibiotics and protects bacteria against immune responses by the host.28 One study showed how a mixture of phages could dramatically reduce the density of planktonic biofilms caused by Staphylococcus aureus.29 Targeting these with bacteriophages may be a viable option for removing them from medical devices in future.

Mice treated with phages have shown increased survival rates and reduced bacterial count compared to controls. One study identified a novel phage (MSP15), that had broad spectrum activity against Methicillin-resistant S. aureus (MRSA). There was a 100% survival rate in all mice given a high dose of MSP15.30 Similarly, another study demonstrated that two newly developed bacteriophages were able to treat and clear MDR Acinetobacter baumannii infections in mice models.31 A review of 32 animal model studies found that bacteriophage therapy significantly improved survival and reduced bacterial load.32
The majority of human evidence currently available comes from compassionate use case studies where phages were used after all conventional treatments had failed. One report describes how bacteriophage nebulisation reduced the bacterial load of carbapenem-resistant Pseudomonas aeruginosa and reduced inflammation markers in a patient.33 A review of case studies of prosthetic joint infections
treated with bacteriophages suggested that phage treatment was largely very effective.34 While case study evidence appears promising, these lack comparative treatments and the results cannot be generalised to a larger, more diverse population.
Some small randomised controlled trials (RCT) have been performed. An RCT of 60 people found that phage therapy was generally effective in sterilising chronic wounds.35 However larger RCTs and long-term data collection are needed to better determine the effectiveness of bacteriophage therapy in humans.

Specificity of phage therapy

Conventional antibiotics are known to act against a wide range of bacterial species. However, this lack of specificity results in the disruption and eradication of beneficial protective bacterial communities. This can cause further issues or infections. Antibiotic use is linked to Clostridium difficile or Candida albicans infections in humans due to the loss of protective microbiota.36,37 In contrast, bacteriophages have a much narrower specificity as they target particular bacterial species through recognition of receptors. Sequencing has been used to demonstrate that the antibiotic azithromycin significantly reduced gut microbiota whereas with phage therapy it was largely intact.38
Phages may therefore have a role in travel medicine in the treatment of bacterial gastrointestinal infections such as traveller’s diarrhoea. Phage therapy could eliminate disease-causing bacteria while reducing unnecessary antibiotic exposure and minimising disruption to the intestinal microbiota. However, it can be difficult to know which phage to administer without first identifying the bacteria causing the infection. This limits the usefulness of bacteriophage therapy as a first line treatment. It also requires genetic sequencing technology which may not be widely accessible in all hospitals, especially in lower-income countries.

The potential to resensitise bacteria to antibiotics

Bacteria have developed various methods for becoming resistant to antibiotics. Some include: enzymatic inactivation of the antibiotic, increased efflux and reduced penetration of the antibiotic into the cell.39 While bacteria can develop resistance to bacteriophages, phages have demonstrated the ability to co-evolve with the host to develop new targets.40 Phages have been induced to target new bacterial strains: In one study phages were experimentally evolved over 30 days to kill a wider range of bacteria including MDR species.41 Studies have also investigated the potential of inducing resistance to bacteriophages in bacteria in order to restore sensitivity to existing antibiotics.42 It was demonstrated that the OMKO1 bacteriophage induced a selection pressure on MDR P. aeruginosa. Cells that became resistant to the bacteriophage showed reduced efflux pump activity. This resulted in them becoming re-sensitised to several antibiotics.43

Phage-antibiotic synergyantibiotics

There is increasing interest in the possibility of using both antibiotics and phages in combination. Some combinations result in greater bacterial clearance than either treatment alone; this effect is known as phage-antibiotic synergy. However, others appear to act antagonistically.44-46 Understanding of the mechanisms behind this is limited and they appear to differ for each combination. For example, one study found that a combination of ciprofloxacin and phages resulted in greater clearance of P. aeruginosa in mice models than
either treatment alone.47 As antibiotics are relatively cheap and widely accessible, combination therapy may be a practical and effective option for treatment in future.

Safety of phage therapy

Current research suggests that bacteriophage therapy is well tolerated and safe. There were no adverse reactions reported when Myoviridae bacteriophages were used in treatment of severe S. aureus infections.48 A review of preclinical and clinical data found that they have a favourable safety profile with minimal adverse side effects.49 Despite this there are some concerns. It is thought that phage therapy could cause sepsis due to release of endotoxins following lysis of bacteria.10,49 There are also concerns regarding the immune response generated
in response to bacteriophages. Phages may cause an inflammatory response but whether this is harmful or beneficial is not yet fully
understood.50 While only minor side effects have been reported, long term safety data is lacking and further research is required.

Production issues

Phage production is expensive. Facilities are required for the production, identification and purification of suitable bacteriophages.Improvement in technology and culturing methods are reducing the costs but initial setup costs are still high.51 No facility currently exists in the UK; it is estimated that setting up one for the NHS could cost 20 – 30 million pounds.52 Phages are also extremely susceptible to changes in temperature and exposure to UV light. Slight changes can severely impact their effectiveness and stability.53 There are also concerns about contamination during production. If the final product is not pure it could contain toxins, proteins or even lysogenic species.54

Regulatory challenges

Current regulatory guidelines limit the widespread clinical use of bacteriophage therapy. As it is a live, often personalised therapy it is not regulated for clinical use in many countries and there is uncertainty on how to classify this type of medication.55,56 This is why it has largely been restricted to compassionate, experimental use where regulations are often more relaxed.57 A further barrier to development is patenting. Currently patent protection for bacteriophages isolated from the natural environment, as most are, is limited.55 Companies are unlikely to consider researching and producing phages if they cannot gain market exclusivity for them.

Conclusion

Bacteriophage therapy shows promise as an alternative to antibiotics. They are able to selectively target bacteria and cause minimal disruption to the human microbiome which is a clear advantage over antibiotics. While studies in various models have shown effectiveness, the evidence-base is still limited. Further randomised controlled trials in humans are needed. Safety of phage therapy generally appears good but there are some minor concerns. There are also several hurdles relating to the production of phages and the regulations around
phage therapy which need to overcome for it to be a viable clinical option. Bacteriophage therapy is unlikely to completely replace antibiotics in the near future however could form part of additional treatment options or even be used in combination with antibiotics. Use of bacteriophages in clinical practice could support global antimicrobial stewardship efforts by reducing dependence on broadspectrum antibiotics and helping to limit the spread of antimicrobial resistance.

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