Conventional antibiotic therapies may be insufficient for a small and diverse group of patients with difficult to treat bacterial infections. This population is characterised by one or more of the following:
• antibiotic resistance
• antibiotic sensitivity but clinical recalcitrance
• high risk of death or significant complications if surgical intervention is used to manage their infection
• patient specific factors that preclude the use of conventional antibiotics.
Bacteriophage therapy may, at the discretion of the responsible clinician, be appropriate management for patients with difficult to treat bacterial infections. A bacteriophage laboratory is being trialled within NHS Tayside. Bacteriophage therapy is not currently licensed by the Medicines and Healthcare Products Regulatory Agency and use must comply with their guidance on the supply of unlicensed medicinal products, available here.
Published evidence on bacteriophage therapy primarily consists of a heterogeneous collection of small single arm cohort studies, small case series and individual case studies. The majority of patients in these studies received bacteriophage therapy in combination with conventional antibiotic therapies. This means that there is a limited evidence base regarding the clinical effectiveness and safety of bacteriophage therapy.
The use of bacteriophage therapy is supported by a small number of randomised controlled trials suggesting that bacteriophage therapy may be effective for patients with difficult to treat bacterial infections.
Exploratory SHTG economic modelling and analysis suggest that the addition of bacteriophage therapy to standard of care is likely to be a cost effective use of resources within a subpopulation of patients with treatment-refractory diabetic foot infection at high risk of lower extremity amputation.
Use of bacteriophage in Scotland must be accompanied by the collection of data to monitor the clinical effectiveness and safety of bacteriophage therapy for specific clinical indications, in order to inform ongoing decision making on the provision of bacteriophage therapy in Scotland.
NHSScotland is required to consider Scottish Health Technologies Group (SHTG) advice.
1. In reaching their recommendations, the Council took into account the range of information and evidence that was gathered as part of the health technology assessment (HTA) process,
including the published literature, the SHTG economic evaluation, and public and patient experiences gathered through engagement with Antibiotic Research UK.
2. The Council acknowledged that antimicrobial resistance is a global public health challenge and that bacteriophage therapy offers a promising alternative or adjunct to conventional
antibiotics.
3. The Council recognised the significant impact that difficult to treat bacterial infections have on patients’ quality of life and that of their family members.
4. Clinical experts outlined the burden of difficult to treat bacterial infections for patients across NHSScotland and highlighted the potential value of bacteriophage therapy as an adjunctive treatment for these patients.
5. The Council agreed that the focus of the research question was on patients with difficult to treat bacterial infections, and that bacteriophage therapy would not be considered for use in
a general patient population until sufficient clinical evidence exists. An overview of the current use of bacteriophage therapy across Western Europe and North America on a compassionate use basis was provided, and recent guidelines for the use of bacteriophage
therapy in clinical practice produced by the Antimicrobial Resistance Leadership Group in the United States of America were highlighted.
6. The Council noted the differences in the reported efficacy of bacteriophage therapy between observational evidence and RCTs. Clinical experts outlined the complexity of conducting
clinical trials with a biological medicine such as bacteriophage therapy versus chemical medicines such as conventional antibiotics. They explained that for efficacy to be observed, a therapeutic amount of the correct bacteriophages must be delivered to the correct area to treat infections containing a sufficient number of susceptible bacterial cells. It was noted that trials that have not demonstrated efficacy are unlikely to have fulfilled one or more of these requirements.
7. The Council discussed the history of bacteriophage from their discovery in the early 20th century to their subsequent manipulation and therapeutic use. It was noted that as naturally occurring organisms, bacteriophage are non-patentable and it was suggested that this may have hindered their use in modern medical settings.
8. The Council asked about the availability of guidance for the clinical use of bacteriophage in patients with different types of infection. Clinical experts explained that further research is required to establish a recommended dose and duration of treatment in specific clinical indications. Experts went on to say that dose and duration is currently guided by the published literature as well as being based on each individual patient’s response to treatment.
9. The Council discussed the potential for long-term adverse events associated with bacteriophage therapy, and stated the importance of gathering this safety data. Clinical experts were not aware of any long-term adverse events, but noted that antibodies to a
particular bacteriophage can develop during prolonged treatment. The Medicines and Healthcare Products Regulatory Agency’s Yellow Card System facilitates the collection of adverse event data.
10. The Council acknowledged the value of the SHTG economic evaluation in informing its decision making, while noting that it was an exploratory analysis within a specific subpopulation of patients within the overall population of the recommendation.
11. The Council debated the practicalities of accessing bacteriophage products and expertise from the bacteriophage laboratory hosted within NHS Tayside. It was explained that the bacteriophage laboratory is grant funded for one-year. It was suggested that, if NHSScotland was to manufacture its own bacteriophage products, this should be consolidated within a single specialist centre for financial reasons and to aid the development of expertise.
12. The Council highlighted potential equality issues regarding access to treatment between urban and rural health boards. It was explained that patients could be treated with bacteriophage therapy at their local hospital regardless of their geographical location which may mitigate equality of access
1. The secondary literature regarding the clinical effectiveness and safety of bacteriophage therapy for patients with difficult to treat bacterial infections consists of seven systematic reviews based primarily on single-arm observational studies and case series.3-9 Three of these systematic reviews were excluded from the evidence synthesis due to the degree of overlap in included studies.
2. Evidence on the clinical effectiveness and safety of bacteriophage therapy should be interpreted with caution owing to a high risk of bias and indirectness (caused by studies including healthy volunteers or patients with acute infections) in primary studies.
Clinical effectiveness
3. The most recent systematic review (53 studies; two comparative; n=2,218) compared patients receiving bacteriophage therapy with a control group receiving standard of care or placebo across several medical and surgical specialties.
3 Based on a pooled analysis of randomised controlled trials (RCTs), patients in the control group were more likely to show clinical improvement than patients who received bacteriophage therapy (50% vs 43.8%; two RCTs). Conversely, patients treated with bacteriophage therapy were more likely to achieve bacterial eradication than those in the control group (16.6% vs 0.0%; 1 RCT).
4. A second systematic review (20 studies; 0 comparative; n=51) outlined the effect of bacteriophage therapy, with or without conventional antibiotic therapy, on patients with bone and joint infections.4 Criteria for success following treatment were satisfied in 71% of treatment episodes; success by indication was 57% for patients with periprosthetic joint infections and 88% for patients with osteomyelitis.
5. A third systematic review (27 studies; two comparative; n=1,579) reported results for the
effectiveness of bacteriophage therapy, with or without conventional antibiotic therapy, in
patients with three different infection types:
a. burn wound infections: 49.6% of patients achieved clinical resolution, 27.9% showed
improvement, and 22.5% showed no improvement. Excluding three studies that did
not clearly report on clinical resolution, or where the bacteriophage therapy dropped
below the therapeutic dose, resulted in 89.2% of patients achieving clinical resolution.
b. chronic wound or ulcer infections: 65.8% achieved clinical resolution, 20.3% showed
improvement, and 13.9% showed no improvement.
c. dermatological infections: 87.3% achieved clinical resolution, 6.8% showed
improvement, and 5.9% showed no improvement.
6. The fourth systematic review (30 studies; three comparative; n>1,152, one study did not report patient numbers) reported results for bacteriophage therapy in patients with multidrug resistant infections.6 Twenty-six of the 30 studies included showed that bacteriophage therapy successfully decreased or halted bacterial growth.
Safety
7. Safety data on bacteriophage therapy came from the four systematic reviews described under the clinical effectiveness subheading above. Not all of the studies included in the reviews reported safety outcomes, hence the number of included studies and patient numbers differ between the clinical effectiveness and safety sections.
8. The most recent systematic review (51 studies; nine comparative; n=731) found that, based on a pooled analysis of nine RCTs, patients treated with bacteriophage therapy were less likely to experience adverse events than those in the control group (7.6% vs 14.9%; 9 RCTs). No adverse events were reported in the observational studies. A pooled analysis of case series found an adverse event rate comparable to that observed in the RCTs.
9. The second systematic review (20 studies; n=51) noted that eight of the 20 studies included reported adverse events associated with bacteriophage therapy, finding that adverse events occurred in 8% of treatment episodes, all of which were considered to be minor: elevation of liver function tests, mild pruritis associated with an elevation of Tumour Necrosis Factor alpha, or redness and pain.
10. The third systematic review (15 studies; n=1,095) included three studies in patients with burn wound infections that found no adverse events, five studies in patients with chronic wound or ulcer infections, four of which identified no adverse events, and eight studies in patients with dermatological infections, seven of which did note adverse events. Adverse events were described on an individual study basis, were relatively mild and were not thought to be directly related to bacteriophage therapy. Adverse event data from this review was primarily from studies conducted between 1929 and 1987 and therefore should be interpreted with caution.
11. The fourth systematic review (22 studies; n=not reported) reported that 20 studies found no adverse events. The remaining two studies noted subsequent infections after treatment, eczema, increased pain, nausea and vomiting, but had limited data to confirm whether these were related to bacteriophage therapy. No studies reported an association between phage administration and death.
Patient and social aspects
12. The literature on patient and social aspects is limited to a single study on patient preferences around bacteriophage therapy and antibiotic therapy for diabetic foot ulcer infections. The study explored patient awareness and concern about antibiotic resistance, and perceptions of
bacteriophage therapy, through a survey (n=55) and focus group (n=5) with Scottish patients and found that:
a. patients’ levels of concern about antibiotic versus bacteriophage therapy were not statistically significantly different
b. after reading information about bacteriophage therapy, 87% of patients stated they would accept bacteriophage therapy if it was recommended by their doctor
c. all focus group participants were supportive of bacteriophage therapy, and four of the five strongly expressed a willingness to use bacteriophage therapy in lieu of intravenous antibiotics if possible, citing ease of use, the potential not to be admitted to hospital and the likelihood of a significantly reduced side effect profile.
13. The views of patients were captured via a patient organisation submission received from Antibiotic Research UK which noted that:
a. patients with antibiotic resistant infections feel there is a lack of acceptance or confirmation of their ongoing suffering and a need to travel to private clinics in England, or even abroad, to access alternative treatments
b. recurrent and resistant infection's dramatically reduce quality of life for patients and their families. They severely affect mental health; many patients say life is not worth living and admit to having suicidal thoughts.
c. antibiotic resistant infections represent an economic burden for patients through being unable to work and to the NHS due to long-term care needs.
Cost effectiveness
14. No published cost effectiveness evidence was identified during the literature search. An economic model was therefore developed by SHTG to inform the recommendations on the use of bacteriophage therapy for the treatment of patients with difficult to treat bacterial infections.
15. The economic evaluation estimated the cost effectiveness of bacteriophage therapy plus standard of care versus standard of care only for the treatment of adults with severe treatment-refractory diabetic foot infections who were at risk of amputation despite conventional antibiotic therapy. This population represents a subset of the overall patient population who may be suitable for bacteriophage therapy, and was selected for analysis
based on the availability clinical expertise to inform the analysis.
16. Base case results indicate that bacteriophage therapy plus standard of care is less costly and more effective than standard of care only. The cost savings associated with bacteriophage therapy plus standard of care stem from a lower proportion of patients requiring minor or major lower extremity amputation, leading to an overall lower cost of care and higher quality-adjusted life years (QALYs). Of note:
a. probabilistic sensitivity analysis estimated that bacteriophage therapy plus standard of care has approximately an 85% probability of being cost effective using a willingness to pay threshold of £20,000 per QALY.
b. individual scenario analyses indicate that the cost effectiveness of bacteriophage therapy plus standard of care versus standard of care only is relatively stable, with the majority of scenarios estimating that bacteriophage therapy plus standard of care remains a dominant (that is, less costly and more effective) treatment strategy despite changes in key parameters.
c. the cost effectiveness of bacteriophage therapy plus standard of care was less clear when a number of conservative assumptions regarding its clinical effectiveness and cost were combined (for example, a 75% reduction in the probability of clinical resolution and a 200% increase in the cost of treatment).
What were we asked to look at?
SHTG was asked to evaluate the clinical effectiveness, cost effectiveness, safety and patient experience of bacteriophage therapy in patients whose clinical needs are not met by antibiotics (for example, where bacteria have developed resistance to multiple antibiotics).
Why is this important?
The incidence of antimicrobial tolerant and resistant bacterial infections is increasing worldwide, contributing to the strain on healthcare services due to longer hospital stays, rising medical costs and increased mortality. During 2016, it was estimated that multi-drug resistant bacterial infections alone caused 700,000 deaths globally each year; if current practices continue this figure is expected to rise to 10 million deaths by 2050. Bacteriophage therapy represents an option to address this problem in the near future.
