By Richard R. Watkins, MD, MS, FACP, FIDSA

Associate Professor of Internal Medicine, Northeast Ohio Medical University; Division of Infectious Diseases, Cleveland Clinic Akron General, Akron, OH

Dr. Watkins reports that he has received research support from Allergan.

SYNOPSIS: A randomized, open-label, superiority trial found that daily antibiotic prophylaxis for patients who use clean, intermittent self-catheterization reduced symptomatic urinary tract infections by 48% over a 12-month period. Antibiotic resistance became prevalent in urinary isolates from the group receiving prophylaxis compared to controls.

SOURCE: Fisher H, Oluboyede Y, Chadwick T, et al. Continuous low-dose antibiotic prophylaxis for adults with repeated urinary tract infections (AnTIC): A randomised, open-label trial. Lancet Infect Dis 2018;18:957-968.

Recurrent urinary tract infections (UTIs) in patients who practice clean, intermittent self-catheterization (CISC) are a frequent dilemma in clinical practice. Although meticulous technique is recommended, pragmatically this is difficult to maintain long term. Fisher and colleagues sought to determine whether daily antibiotic prophylaxis is an effective strategy to prevent UTIs in patients who self-catheterize.

The randomized, open-label, parallel group trial was conducted in the community in coordination with 51 organizations in the United Kingdom. Subjects were eligible for participation if they had either two or more symptomatic UTIs related to CISC within the preceding 12 months or at least one UTI that required hospitalization. Exclusion criteria included inability to tolerate the prescribed antibiotic prophylaxis, and women who intended to become pregnant, who were pregnant, or were breastfeeding. Patients who were taking an antibiotic for prophylaxis already were told to discontinue the medication for three months prior to randomization. Researchers allocated subjects randomly in a 1:1 ratio to receive either antibiotic prophylaxis (experimental group) or no prophylaxis (control group). The antibiotics prescribed were nitrofurantoin 50 mg daily, trimethoprim 100 mg daily, or cephalexin 250 mg daily. Investigators assessed tolerability for the chosen antibiotic during a one-month review. If necessary, one of the alternative antibiotics was substituted. Subjects also submitted a perirectal swab at baseline, six months, and 12 months. Those who completed at least six months of follow-up were included in the analysis of the primary outcome, which was the incidence of symptomatic UTIs treated with antibiotics during the 12 months of participation in the study. The cost-effectiveness of antibiotic prophylaxis was expressed as the incremental cost per UTI avoided.

The experimental group included 203 subjects and the control group included 201 participants. The incidence of symptomatic UTIs treated with antibiotics in the experimental group was 1.3 cases per person year (95% confidence interval [CI], 1.1-1.6) and 2.6 cases (95% CI, 2.3-2.9) in the control group. The incidence rate ratio was 0.52 (95% CI, 0.44-0.66) in favor of prophylaxis. This rate indicated a 48% reduction in UTI incidence. However, the number of febrile UTIs was small in both groups: 15 cases in the experimental group and 22 cases in the control group. Also, the incidence of asymptomatic bacteriuria and hospital admission for a UTI did not differ between the groups. During the 12 months, the median number of symptomatic UTIs observed was one in the experimental group and two in the control group. The prophylaxis was well tolerated, with only 22 minor adverse events recorded. Most commonly, these were gastrointestinal symptoms and rashes.

At baseline, the frequency of antimicrobial resistance (AMR) of urinary isolates to eight antibiotics commonly prescribed for treating UTIs was similar in the two groups. However, during the trial, resistance became more common in the isolates from subjects in the experimental group. Indeed, there was no evidence of any change in AMR in the control group over the 12-month period. The level of resistance in E. coli cultured from perirectal swabs remained the same for both groups throughout the 12-month study period. Finally, the economic analysis showed a slight potential benefit for antibiotic prophylaxis, although the authors did not consider the potential cost of increasing AMR.

COMMENTARY

The study by Fisher and colleagues provides good evidence that antibiotic prophylaxis for patients who use CISC is effective in preventing UTIs. However, the difficulty is balancing this benefit vs. the high likelihood that prophylaxis will increase the spread of AMR. In light of the latter concern, a careful review of the study’s design reveals some limitations that make the choice to use prophylaxis less straightforward. First, the treating physicians were aware of the patient’s study group, which may have introduced bias into their treatment decisions. Second, the primary outcome was based on patient-reported symptoms, which are not always reliable in diagnosing UTIs in this patient population. Third, patients in the control group did not receive a placebo, and this could have led to an overestimation of their UTIs. Finally, the economic benefit of prophylaxis was modest and did not take into account the increase in spread of AMR at the societal level.

Should all patients who use CISC receive antibiotic prophylaxis? I believe the answer is no and that a more nuanced approach is necessary. For example, the researchers found that despite repeated UTIs, their effect on patient well-being was low. One approach might be to offer prophylaxis to patients with more severe symptoms, to those who experience more episodes than others, or to those with more frequent hospitalizations. Further research is needed to more clearly identify subgroups of CISC users for whom the benefits of antibiotic prophylaxis outweigh the risks.

An alternative to daily prophylaxis is self-start therapy, which involves providing patients with a supply of an antibiotic at home that they can start as soon as they begin to have UTI symptoms. This strategy also theoretically may promote AMR, but antibiotic cycling among two or three classes every year or two may reduce the risk. Cranberry extracts have proven to be ineffective in this population and should not be recommended. Finally, although the potential of methenamine hippurate is appealing, there currently is no strong evidence that this agent is beneficial in preventing UTIs in patients who use CISC.