The Safety and Efficacy of Phage Therapy for Infections in Cardiac and Peripheral Vascular Surgery: A Systematic Review.

New approaches to managing infections in cardiac and peripheral vascular surgery are required to reduce costs to patients and healthcare providers. Bacteriophage (phage) therapy is a promising antimicrobial approach that has been recommended for consideration in antibiotic refractory cases. We systematically reviewed the clinical evidence for phage therapy in vascular surgery to support the unlicensed use of phage therapy and inform future research. Three electronic databases were searched for articles that reported primary data about human phage therapy for infections in cardiac or peripheral vascular surgery. Fourteen reports were eligible for inclusion, representing 40 patients, among which an estimated 70.3% of patients (n = 26/37) achieved clinical resolution. A further 10.8% (n = 4/37) of patients showed improvement and 18.9% (n = 7/37) showed no improvement. Six of the twelve reports that commented on the safety of phage therapy did not report adverse effects. No adverse effects documented in the remaining six reports were directly linked to phages but reflected the presence of manufacturing contaminants or release of bacterial debris following bacterial lysis. The reports identified by this review suggest that appropriately purified phages represent a safe and efficacious treatment option for infections in cardiac and peripheral vascular surgery.

Phage therapy: Awareness and demand among clinicians in the United Kingdom.

Bacterial resistance or tolerance to antibiotics is costly to patients and healthcare providers. With the impact of antibiotic resistance forecast to grow, alternative antimicrobial approaches are needed to help treat patients with antibiotic refractory infections and reduce reliance upon existing antibiotics. There is renewed interest in bacteriophage (phage) therapy as a promising antimicrobial strategy. We therefore performed the first multi-specialty survey about phage therapy and the first such survey among clinicians in the United Kingdom. An anonymous 10-question survey of clinicians from medical and surgical specialties in two Scottish Health Boards was performed. The 90 respondents spanned 26 specialties and were predominantly consultants (73.3%). The respondents were concerned about antibiotic resistance in their clinical practice; 83 respondents estimated having seen 711 patients in the last 12 months whose infections were refractory to antibiotics (delaying or preventing resolution). Over half (58.8%) of the respondents had previously heard of phage therapy. Staphylococci, Pseudomonas and E. coli were identified as the highest cross-specialty priorities for the development of phage therapy. Together, 77 respondents estimated seeing 300 patients in the last 12 months for whom phage therapy may have been appropriate (an average of 3.9 patients per clinician). Most respondents (71.1%, n = 90) were already willing to consider using phage therapy in appropriate cases. Additional comments from the respondents affirmed the potential utility of phage therapy and highlighted a need for more information. The results of this survey demonstrate substantial demand for and willingness to use phage therapy in appropriate cases, both from individual clinicians and across specialties. Demand from a wide range of specialties illustrates the broad clinical utility of phage therapy and potential scope of impact. Widening access to phage therapy could deliver substantial clinical and financial benefits for patients and health authorities alike.

Managing Patient and Clinician Expectations of Phage Therapy in the United Kingdom.

Bacteriophage (phage) therapy is a promising alternative antimicrobial approach which has the potential to transform the way we treat bacterial infections. Phage therapy is currently being used on a compassionate basis in multiple countries. Therefore, if a patient has an antibiotic refractory infection, they may expect their clinician to consider and access phage therapy with the hope of improvement. The expectations of clinicians may be similar and may also include expectations around data collection. However, there are multiple biological and practical barriers to fulfilling patient and clinician expectations. While it is possible to access phage therapy, the path to acquisition is not straightforward and expectations therefore need to be managed appropriately to avoid raising false hope and undermining confidence in phage therapy. Phage scientists have an important contribution to make in educating clinicians and the broader public about phage therapy. However, it is clinicians that are responsible for managing the expectations of their patients and this relies on clear communication about the barriers and limitations.

The Safety and Efficacy of Phage Therapy: A Systematic Review of Clinical and Safety Trials.

Trials of phage therapy have not consistently reported efficacy. This contrasts with promising efficacy rates from a sizeable and compelling body of observational literature. This systematic review explores the reasons why many phage trials have not demonstrated efficacy. Four electronic databases were systematically searched for safety and/or efficacy trials of phage therapy. Sixteen trials of phage therapy were included, in which 378 patients received phage. These were divided into historical (pre-2000; N = 3; n = 76) and modern (post-2000; N = 13; n = 302) trials. All 13 modern trials concluded that phage therapy was safe. Six of the 13 modern trials were exclusively safety trials. Seven modern trials investigated both safety and efficacy; efficacy was observed in two. Two of three historical trials did not comment on safety, while adverse effects in the third likely reflected the use of phage preparations contaminated with bacterial debris. None of the historical trials contained evidence of efficacy. The evidence from trials is that phage therapy is safe. For efficacy to be observed a therapeutic amount of the right phage(s) must be delivered to the right place to treat infections containing enough susceptible bacterial cells. Trials that have not demonstrated efficacy have not fulfilled one or more elements of this principle.

The microbiology of diabetic foot infections: a meta-analysis.

BACKGROUND: Diabetic foot ulcers are a common complication of poorly controlled diabetes and often become infected, termed diabetic foot infection. There have been numerous studies of the microbiology of diabetic foot infection but no meta-analysis has provided a global overview of these data. This meta-analysis aimed to investigate the prevalence of bacteria isolated from diabetic foot infections using studies of any design which reported diabetic foot infection culture results. METHODS: The Medline, EMBASE, Web of Science and BIOSIS electronic databases were searched for studies published up to 2019 which contained microbiological culture results from at least 10 diabetic foot infection patients. Two authors independently assessed study eligibility and extracted the data. The main outcome was the prevalence of each bacterial genera or species. RESULTS: A total of 112 studies were included, representing 16,159 patients from which 22,198 microbial isolates were obtained. The organism most commonly identified was Staphylococcus aureus, of which 18.0% (95% CI 13.8-22.6%; I2 = 93.8% [93.0-94.5%]) was MRSA. Other highly prevalent organisms were Pseudomonas spp., E. coli and Enterococcus spp. A correlation was identified between Gross National Income and the prevalence of Gram positive or negative organisms in diabetic foot infections. CONCLUSION: The microbiology of diabetic foot infections is diverse, but S. aureus predominates. The correlation between the prevalence of Gram positive and negative organisms and Gross National Income could reflect differences in healthcare provision and sanitation. This meta-analysis has synthesised multiple datasets to provide a global overview of the microbiology of diabetic foot infections that will help direct the development of novel therapeutics.

Patient perceptions of phage therapy for diabetic foot infection.

Infections of diabetic foot ulcers are common, generally recalcitrant and often complicated by antibiotic resistance. Alternative antimicrobial strategies are needed. Phage therapy is a promising alternative that is being rediscovered. Despite phage therapy's 100-year history, there have been no investigations into patient thoughts and concerns. This study aimed to explore patient awareness of and concern about antibiotic resistance and gain insight into the perceptions of phage therapy among a patient group that could potentially benefit from phage therapy. Patients with an active or resolved (healed or amputated) diabetic foot ulcer were eligible to participate. A survey was distributed digitally to eligible patients across Scotland via the NHS Research Scotland Diabetes Network and hard copies were available in diabetic foot clinics at the Royal Infirmary of Edinburgh and Queen Elizabeth University Hospital, Glasgow. A focus group of five survey respondents was held in Glasgow. Fifty-five survey responses were obtained. There was a high level of awareness (76.4%; N = 55) and concern (83.3%; N = 54) about antibiotic resistance. While largely aware of viruses, most patients had not heard of phage or phage therapy. Patients were no more concerned about phage than antibiotic therapy, with most suggesting more information could alleviate any concerns. Patient acceptability of phage therapy was high, a finding confirmed by the focus group. Patients are concerned about antibiotic resistance and supportive of 'new' antimicrobials. We have demonstrated that patients are supportive, enthusiastic and accepting of phage therapy. Although 'Western' phage therapy remains in its infancy, an understanding of patient ideas, concerns and expectations will be important in eventually shaping and successfully reintroducing phage therapy.

The Safety and Efficacy of Phage Therapy for Superficial Bacterial Infections: A Systematic Review.

Superficial bacterial infections, such as dermatological, burn wound and chronic wound/ulcer infections, place great human and financial burdens on health systems globally and are often complicated by antibiotic resistance. Bacteriophage (phage) therapy is a promising alternative antimicrobial strategy with a 100-year history of successful application. Here, we report a systematic review of the safety and efficacy of phage therapy for the treatment of superficial bacterial infections. Three electronic databases were systematically searched for articles that reported primary data about human phage therapy for dermatological, burn wound or chronic wound/ulcer infections secondary to commonly causative bacteria. Two authors independently assessed study eligibility and performed data extraction. Of the 27 eligible reports, eight contained data on burn wound infection (n = 156), 12 on chronic wound/ulcer infection (n = 327) and 10 on dermatological infections (n = 1096). Cautionary pooled efficacy estimates from the studies that clearly reported efficacy data showed clinical resolution or improvement in 77.5% (n = 111) of burn wound infections, 86.1% (n = 310) of chronic wound/ulcer infections and 94.14% (n = 734) of dermatological infections. Over half of the reports that commented on safety (n = 8/15), all published in or after 2002, did not express safety concerns. Seven early reports (1929-1987), described adverse effects consistent with the administration of raw phage lysate and co-administered bacterial debris or broth. This review strongly suggests that the use of purified phage to treat superficial bacterial infections can be highly effective and, by various routes of administration, is safe and without adverse effects.

The prevalence of methicillin-resistant Staphylococcus aureus among diabetic patients: a meta-analysis.

AIMS: Diabetic patients have multiple risk factors for colonisation with methicillin-resistant Staphylococcus aureus (MRSA), a nosocomial pathogen associated with significant morbidity and mortality. This meta-analysis was conducted to estimate the prevalence of MRSA among diabetic patients. METHODS: The MEDLINE, Embase, BIOSIS, and Web of Science databases were searched for studies published up to May 2018 that reported primary data on the prevalence of MRSA in 10 or more diabetic patients. Two authors independently assessed study eligibility and extracted the data. The main outcomes were the pooled prevalence rates of MRSA colonisation and infection among diabetic populations. RESULTS: Eligible data sets were divided into three groups containing data about the prevalence of MRSA colonisation or in diabetic foot or other infections. From 23 data sets, the prevalence of MRSA colonisation among 11577 diabetics was 9.20% (95% CI, 6.26-12.63%). Comparison of data from 14 studies that examined diabetic and non-diabetic patients found that diabetics had a 4.75% greater colonisation rate (P < 0.0001). From 41 data sets, the prevalence of MRSA in 10994 diabetic foot infection patients was 16.78% (95% CI, 13.21-20.68%). Among 2147 non-foot skin and soft-tissue infections, the MRSA prevalence rate was 18.03% (95% CI, 6.64-33.41). CONCLUSIONS: The prevalence of MRSA colonisation among diabetic patients is often higher than among non-diabetics; this may make targeted screening attractive. In the UK, many diabetic patients may already be covered by the current screening policies. The prevalence and impact of MRSA among diabetic healthcare workers requires further research. The high prevalence of MRSA among diabetic foot infections may have implications for antimicrobial resistance, and should encourage strategies aimed at infection prevention or alternative therapies.