Case Commentary: Unlocking the Potential of Bacteriophage to Prevent Recurrent Urinary Tract Infections after Kidney Transplantation

ABSTRACT

Recurrent urinary tract infections (UTIs) are common in kidney transplant recipients, and novel prevention approaches are needed. The case presented by Le et al. (Antimicrob Agents Chemother, in press) describes a patient with recurrent UTIs due to extended-spectrum β-lactamase-producing Klebsiella pneumoniae who was successfully treated with bacteriophage therapy. This commentary highlights the potential for bacteriophage therapy to prevent recurrent UTIs, as well as outstanding questions that require further investigation.

INTRODUCTION

Urinary tract infections (UTIs) are the most common infections after kidney transplantation and are responsible for 30% to 40% of hospitalizations for sepsis and bacteremia (1–3). Up to one-third of kidney transplant recipients who have a UTI will develop recurrent UTIs (4–6). Recurrent UTIs cause substantial morbidity and lead to allograft impairment and repeated courses of antibacterial therapies. This in turn leads to infections due to increasingly multidrug-resistant (MDR) organisms (4).

Current approaches to preventing recurrent UTIs after kidney transplantation include lifestyle modifications, evaluation for correctable anatomical abnormalities that increase UTI risk, methenamine hippurate, and vaginal estrogen for postmenopausal women (7, 8). Unfortunately, these strategies are often ineffective, and many patients are placed on long-term antibiotic prophylaxis to prevent recurrent episodes of UTI and sepsis (9). Long-term antibiotic prophylaxis has damaging effects on the gut microbiome and increases the risk of developing infections due to MDR pathogens, such as extended-spectrum-β-lactamase (ESBL)-producing bacteria (10). These bacteria are often resistant to all oral agents, leading to frequent hospitalizations for intravenous antibiotics (11). Novel approaches to preventing recurrent UTIs in kidney transplant recipients are urgently needed that will not exacerbate antimicrobial resistance or gut microbiome health.

This case report highlights the potential of bacteriophage therapy, as an alternative to antibiotic prophylaxis, to prevent recurrent UTIs in kidney transplant recipients (12). It describes a kidney and liver transplant recipient who had recurrent episodes of UTI and sepsis due to ESBL-producing Klebsiella pneumoniae that led to impaired graft function. She was treated with an intravenous cocktail of three bacteriophages twice daily for 4 weeks and did not have a recurrent UTI in the ensuing 6 months. While she eventually had episodes of cystitis, these episodes were due to K. pneumoniae strains that were susceptible to oral antibiotics, and she did not require intravenous therapy.

This report adds to the growing number of published cases of kidney transplant recipients with recurrent UTIs due to ESBL-producing organisms who were successfully treated with bacteriophage cocktails to prevent UTI recurrence (13–15). Bacteriophage therapy to eradicate the gut or urinary reservoir of a uropathogen is a promising alternative to prevent recurrent UTIs compared to conventional antibiotics because phage is selective only for the uropathogen and does not kill healthy commensal bacteria (16). Furthermore, unlike acutely ill patients with septic shock, patients with recurrent UTIs typically have time to wait for the lengthy period currently required to obtain and administer strain-specific bacteriophages.

While these reports offer promise, fundamental questions remain that must be answered for bacteriophage to become a viable clinical option to prevent recurrent UTIs. First, it is important to learn strategies to minimize the risk of developing resistance to therapeutic bacteriophages. In this report, although phage therapy was temporarily effective in preventing UTIs, the patient eventually had a UTI due to a K. pneumoniae that was resistant to all three bacteriophages in the phage cocktail. Potential strategies to minimize the emergence of resistance to bacteriophages include identifying phages active against a broad range of strains within a given species, using larger numbers of phages in therapeutic cocktails, and using modern tools to engineer phages to which bacteria are less likely to be able to develop resistance (17, 18). Second, the pharmacokinetics and pharmacodynamics of therapeutic bacteriophages require additional investigation. Patients with recurrent UTIs can have both gut and urine reservoirs for uropathogens (19). This case report did not evaluate stool concentrations of bacteriophage, the likely reservoir for recurrent UTIs in kidney transplant recipients (20). Further investigation is needed to determine how bacteriophage therapy may differentially affect the different uropathogen species in the gut and urine reservoirs. In this report, the patient received the phage by twice daily intravenous infusions for 4 weeks. Oral bacteriophage preparations would be a more convenient strategy to prevent recurrent UTIs, but concerns exist over the ability of oral bacteriophages to survive acidic environments and achieve therapeutic concentrations in stool (21). Another option would be to instill bacteriophage therapy directly into the bladder to maximize the exposure of the phages to pathogenic bacteria. A recent randomized trial showed that intravesicular bacteriophage therapy yielded similar microbiologic outcomes to antibiotic therapy in patients with UTI undergoing transurethral prostate resection (22). We also need to better understand host immune inactivation of bacteriophages. In this report, partial serum neutralization occurred within 1 week after initiation of treatment. Other reports have found complete inactivation of bacteriophage within 2 weeks (23). It remains to be seen whether other routes of administration such as bladder or enema administration could evade the immune system response and be more effective in the setting of repeated administrations. Lastly, while the bacteriophage therapy appears to have eliminated the ESBL-producing K. pneumoniae in this patient, the patient still had recurrent UTIs due to a K. pneumoniae strain that was susceptible to oral antibiotics. Further strategies are needed to fully remove uropathogens from the gut and urine reservoirs to decrease the risk of UTI recurrence.

Individual case reports of successful bacteriophage therapy do not constitute proof of efficacy, particularly given that unsuccessful case reports may not be published. Therefore, once the above issues have been addressed, it is critical that bacteriophage therapy is subjected to a randomized trial that is sufficiently powered to detect potential clinical benefit in kidney transplant recipients with recurrent UTIs. Such a trial would be a major step in bringing the potential power of bacteriophages closer to patient care.

The views expressed in this article do not necessarily reflect the views of the journal or of ASM.