Effect of antibiotics on urine leakage in women with refractory detrusor overactivity: A phase IIb randomized trial

Abstract

Aim: Because bacterial cystitis is common in women with refractory detrusor overactivity, the aim was to compare the efficacy of 6 weeks of rotating antibiotics versus placebo, in conjunction with an anticholinergic, in controlling the symptoms of urge incontinence. Methods: In a multicenter phase IIb double-blinded randomized placebocontrolled trial, women with urodynamically proven refractory detrusor overactivity were randomized in a 2:1 ratio of antibiotics versus placebo for 6 weeks, in addition to darifenacin for 6 months. Any woman with disabling cystitis symptoms was given appropriate antibiotics ("clinical override"). The primary outcome was the degree of urge incontinence change at 6 weeks and 6 months on 24-h pad test. Secondary outcomes were changes in leaks and voids per day measured on 3-day bladder diary and quality of life measures. Microbiological data were collected at all visits. Results: Although 278 women were screened, only 36 were randomized and 33 (91.7%) completed the trial. Leakage on 24-h pad test decreased at 6 months by 75 g in patients receiving antibiotics versus 35 g in placebo. Cure of urge incontinence occurred at 6 months in 10/21 (48%) of antibiotics versus 2/12 (17%) of placebo. Clinical override, necessitating treatment of cystitis, occurred in 41.6% of placebo versus 16.7% of the antibiotic group by 6 months. Conclusion: Despite the small sample size, the study showed a significant reduction in pad leakage and leaks per day over 24 h in the active treatment group over a 6-month period. Nearly half of patients on placebo had disabling urinary tract infection symptoms that required clinical override treatment.

Urinary cytokines in women with refractory detrusor overactivity: A longitudinal study of rotating antibiotic versus placebo treatment

“…Patients and urine samples for this study came from the women who participated a doubleblind, placebo-controlled, randomised clinical trial [29]. Selection criteria included postmenopausal status and >50 years of age with symptoms of overactive bladder (severe urgency, frequency, nocturia).…”

“…All participants provided written informed consent and the protocol was approved by the Ethics review committee (protocol CT13/003 Wollongong; HREC14/193 South East Sydney; registered with the Australia and New Zealand Clinical Trials Registry (ACTRN12613000285752)). Based on Simons two-stage design, to detect a biological effect of antibiotic therapy on urinary leakage, for an 80% power with 95% confidence, 120 trial participants were needed with a planned interim analysis after 33 enrolled patients [29]. Participants were randomised via minimization method at a 2:1 ratio of antibiotic therapy to placebo.…”

“…small sample size of the RCT. The trial was halted post interim analysis because of low recruitment (due mainly to the arrival of a new treatment, botulinum toxin injections that was highly attractive to patients) and also because of ethical concerns that many patients on placebo needed antibiotic therapy ("clinical override", for details see ref 29). Nevertheless, a clinical benefit was seen at the pre-designed interim analysis.…”

“…Both demonstrated improvements in urinary leakage and urgency symptoms, but cytokine responses were not studied. Recently, a randomised placebo controlled trial (RCT) of antibiotics in patients with refractory DO has demonstrated a significant improvement in patient symptoms, including a decrease in leakage (on 24-hour pad test) and voids per day (on bladder diary) in the antibiotic treated patients, and improvements in scores related to urinary urgency and symptom bother [29]. The response of cytokine levels to antibiotic therapy has not been studied.…”

“…The aims of the current study were to make use of the consecutive series of urine samples collected from women with refractory DO who participated in a RCT of rotating antibiotic therapy [29], and to determine the effect of bacteriuria, and antibiotic treatment, on the levels of urinary cytokines in such women. The urinary cytokines chosen were IL-1α, IL-1 receptor antagonist, IL-4, IL-6, IL-8, IL-10, CXCL10 (IP-10), MCP-1 and TNF-α.…”