Leitner L, Sybesma W, Chanishvili N, Goderdzishvili M, Chkhotua A, Ujmajuridze A, Schneider MP, Sartori A, Mehnert U, Bachmann LM, Kessler TM. Bacteriophages for treating urinary tract infections in patients undergoing transurethral resection of the prostate: a randomized, placebo-controlled, double-blind clinical trial. BMC Urol. 2017;17:90.
BACKGROUND: Urinary tract infections (UTI) are among the most prevalent microbial diseases and their financial burden on society is substantial. The continuing increase of antibiotic resistance worldwide is alarming. Thus, well-tolerated, highly effective therapeutic alternatives are urgently needed. Although there is evidence indicating that bacteriophage therapy may be effective and safe for treating UTIs, the number of investigated patients is low and there is a lack of randomized controlled trials.
METHODS AND DESIGN: This study is the first randomized, placebo-controlled, double-blind trial investigating bacteriophages in UTI treatment. Patients planned for transurethral resection of the prostate are screened for UTIs and enrolled if in urine culture eligible microorganisms ≥104 colony forming units/mL are found. Patients are randomized in a double-blind fashion to the 3 study treatment arms in a 1:1:1 ratio to receive either: a) bacteriophage (i.e. commercially available Pyo bacteriophage) solution, b) placebo solution, or c) antibiotic treatment according to the antibiotic sensitivity pattern. All treatments are intended for 7 days. No antibiotic prophylaxes will be given to the double-blinded treatment arms a) and b). As common practice, the Pyo bacteriophage cocktail is subjected to periodic adaptation cycles during the study. Urinalysis, urine culture, bladder and pain diary, and IPSS questionnaire will be completed prior to and at the end of treatment (i.e. after 7 days) or at withdrawal/drop out from the study. Patients with persistent UTIs will undergo antibiotic treatment according to antibiotic sensitivity pattern.
DISCUSSION: Based on the high lytic activity and the potential of resistance optimization by direct adaptation of bacteriophages, and considering the continuing increase of antibiotic resistance worldwide, bacteriophage therapy is a very promising treatment option for UTIs. Thus, our randomized controlled trial investigating bacteriophages for treating UTIs will provide essential insights into this potentially revolutionizing treatment option.
Urinary tract infections (UTIs) are very common. In the U.S., as the authors point out, UTIs account for over 7 million doctor visits and cost $1.6 billion annually. Typically, treatment involves increased fluid intake, usually accompanied by antibiotics. The problem is that those antibiotics are often associated with adverse events and the development of antibiotic resistance.
The authors describe, in brief, the history of bacteriophages during the past century, including the fact that bacteriophage use and study has continued in Eastern Europe, while essentially disappearing from the literature in Western Europe and North America. Within the past two decades, however, there has been an increasing interest in bacteriophage therapy in the west, with a few very small studies of phage for urinary and diabetic foot wound infections.
This team of researchers have therefore designed a prospective, controlled and randomized clinical trial of intra-vesicular phage therapy (phage directly into the bladder) for the treatment of UTI/s. Their operating hypotheses are: 1) intravesical bacteriophage treatment in patients with UTIs due to E. coli and other uropathogens, will show a 40% increase in success rate (normalization of urine culture defined as no evidence of bacteria, i.e. <104 colony forming units/mL) as compared to placebo treatment within 7 days. 2) bacteriophage treatment will be non-inferior to antibiotic treatment in terms of treatment success rates, with a non-inferiority margin of 35%.
There is another issue that must be considered when discussing the context of this publication: This article describes a research project which has not yet been performed. It is a study that has not even yet been started (at least not at the time it was written). This is most uncommon for several reasons. First and foremost, many researchers do not want to “give away” their research plans and designs for fear that others may perform the work before they themselves have a chance to finish and publish it. Second, most readers want to know about the results and implications of studies already completed more than they want to know about studies still being planned.
The “findings” of this publication are really the methods by which the researches have decided to pursue their investigation. So here is what they plan to do: a randomized, placebo-controlled, double-blinded
Three-armed clinical trial of intravesicular bacteriophage (Pyo bacteriophage solution: commercially available and registered in Georgia) vs placebo vs antibiotics, for the treatment of UTI in patients undergoing transurethral prostatectomy with susceptible microorganisms (Enterococcus spp., Escherichia coli, Proteus mirabilis, Pseudomonas aeruginosa, Staphylococcus spp., and Streptococcus spp.). The study will be carried out at at the Tzulukidze National Center of Urology (TNCU), Tbilisi, Georgia. Pyo bacteriophage solution is produced by the Eliava Institute of Bacteriophages, Microbiology, and Virology in Tbilisi (EIBMV), Georgia. During the study, continuous adaption cycles will be carried out at EIBMV to enhance the treatment effect. Study design and statistical analysis will be performed by staff at the Neuro-Urology, Spinal Cord Injury Center & Research, University of Zürich, Balgrist University Hospital,
Zürich, Switzerland. Based on a set of performance assumptions and a power goal of 0.8, the sample size was calculated to be 27 subjects in each arm, for a total of 81 evaluable patients. Rather than enroll a larger set number of patients to compensate for whatever attrition may occur, the researchers plan simply to “replace” those subjects lost prematurely with new enrollees.
Urinary tract infections are common, and many can pose a serious threat to life. The clinical situation being studied in this proposed research (namely, UTI’s in men undergoing trans-urethral resection of the prostate – TURP) is not common, but does fall into the category of serious and difficult-to-treat UTI. Many have had multiple infections by the time they are scheduled for TURP, and therefore frequently have infections with antibiotic-resistant organisms. So, in that sense, the study population being addressed is representative of the patients in whom phage therapy should be considered. This is a strong “plus” for the study.
Actually, I cannot think of a strong negative with regard to this study design. I find it unusual that the team would not set out to enroll 85 or 90 patients to ensure that they still meet their goal of 81 evaluable patients, despite the few who are likely not to complete the study. Enrolling more patients to make up for those who drop out is an unusual way to design the study, but as long as the replacements are invited to participate in a random fashion (for example, the very next patients who are eligible, in order of presentation), then the study can maintain its status as a randomized trial. The fact that study duration is so short (just one week from initiation to final data collection) means that recruiting additional subjects should not delay the completion of the study by any appreciable amount of time.
Throughout my reading of the manuscript, I have been wondering: why is this group publishing their study methods before they actually conduct the study? The cynical answer would be: to get another publication! But I think there is more to it. The study group is from Tbilisi, Georgia, where phage therapy is already well accepted. One of the participants (Eliava Institute) is the manufacturer of the product being tested. By publishing this manuscript, which is essentially a study protocol, the authors are essentially providing a template as well as a stimulus for other researchers to do the same or similar studies. This could have significant benefit for the study participants . . . and significant benefits for the rest of us. Sincerely, I hope others in the infectious disease community consider doing phage studies like this or on other populations. The authors are correct in drawing our attention to the fact that we need more prospective, randomized clinical trials. But we particularly need more trials in the West.
So I am now inspired to do what I can, independently or through the BTER Foundation, to support more well-designed clinical trials of phage therapy in North America. What about you??
-Reviewed by: Dr. Ronald Sherman