Effect of Adjuvant Treatment With Compound Cranberry Extract Tablets in Acute Bacterial Cystitis.
Effect of Adjuvant Treatment With Compound Cranberry Extract Tablets in Acute Bacterial Cystitis.
In conventional treatment for non-complicated bacterial cystitis, 3-day oral antibiotics
 could achieve good cure rate. However, severe lower urinary tract symptoms were most
 bothersome and only could be partially relieved by NSAID, detrusor muscle relaxants, minor
 tranquilizer or pyridium. Some medication associated side effects were complained while
 receiving adjuvant medication treatment, including gastro-intestinal discomfort, dry mouth,
 blurred vision, lethargy, or allergic reactions. The irritative bladder symptoms from bladder
 inflammation had great impact on the quality of life and well tolerable adjuvant therapy
 would have clinical benefit to reduce the discomfort from the bladder.

 In the past years, cranberry juice or its extract has been proven to have protective effect
 on urothelium to prevent further bacterial ascending infection. The commercial cranberry
 extract tablets have good tolerability and showed good effect on symptoms reliving and
 infection protection on several clinical observation. In acute bladder infection, we could
 expect the bioactive components in cranberry could reduce the virulence of pathogens and
 assist to eradicate pathogens and to stable the urothelium. In literature review, only little
 works focusing on the symptoms relief in acute cystitis patients. To clarify the clinical
 benefit on lower urinary symptoms relieving, we attempt to conduct a randomized double-blind
 placebo-controlled trial to evaluate the effect of a compound cranberry extract tablet as an
 adjunctive modality in treating acute uncomplicated bacterial cystitis in otherwise healthy
 female patients.
Introduction

 Acute bacterial cystitis is a common and bothersome disease with a rapid onset nature.
 Uncomplicated cystitis occurs in patients without anatomical or physiological anomaly in the
 lower urinary tract. Although the infection is not life threatening in immuno-competent
 patients, the associated lower urinary tract symptoms cause massive impact on the
 quality-of-life of the victims. The voiding symptoms, such as urinary frequency, urgency,
 dysuria and suprapubic pain, were associated with the inflammatory response to microbial
 invasion. In most clinical scenario, 3-day empirical oral antimicrobial treatment could
 eradicate the pathogen efficiently.1,2 However, the lower urinary tract symptoms were not
 eradicated effectively by antibiotics only. In daily clinical practice, several symptomatic
 relieving treatments were applied while acute infection presented, including pyridine and
 anticholinergic agents. However, several side effects were complained according to the
 medication.

 In lower urinary tract infection, the virulence of the pathogen was the major factor
 associated with colonization and invasion in the urinary tract mucosa. The adherence of the
 pathogen to the urothelium is the crucial step in the urinary tract infection.3 Several
 studies revealed good anti-adherence effect of the cranberry juice.4-7 In several clinical
 studies, cranberry juice has been proven to be an protective effect in bacterial cystitis8
 and the role of cranberry juice in preventing urinary tract infection was well
 established.9,10 Cranberry is a rich source of bioactive compounds, such as phenolic acid and
 several organic acids, which have been proven playing major anti-bacterial effect.11

 In literature reviewing, the clinical application of cranberry juice or extract tablet was
 focusing on the preventive role on chronic or repeated urinary tract infection. The effect to
 reduce bacteriuria and pyuria has been mentioned.12 However, the effect on lower urinary
 tract symptom relieving effect of the food supplement cranberry was not established. In this
 study, we try to evaluate the clinical efficacy of a commercial compound cranberry extract in
 treating acute uncomplicated cystitis as an adjunctive role. The compound tablet contained
 900mg per tablet, including 600% concentrated cranberry extract 150mg, vitamin C 70mg,
 Rhizoma extract (Acrobio TS®) 150mg, Flos extract (Acrobio GL®) 60mg, lactose and mannitol
 490mg. The compound has been on the market in Taiwan as a food supplement and was well
 tolerable. We conducted a double-blind, randomized, placebo-controlled trial to evaluate the
 adjuvant effect of compound cranberry extract on the symptomatic relieving effect.

 Material and Methods

 Study Method:

 We prepare to conduct a paralleled-group, double-blind, placebo-controlled, randomized
 clinical trial to evaluate the effect of a compound cranberry extract tablet as an adjunctive
 modality in treating acute uncomplicated bacterial cystitis in otherwise healthy female
 patients. The treatment arm will receive standard 3-day oral antibiotics plus 7-day compound
 cranberry extract tablets (UmayC) and the control arm will receive standard 3-day oral
 antibiotics plus 7-day identical placebo.

 Study Processes:

 1. Participant recruitment During study period, we will recruit 60 volunteer female
 patients visiting the urological outpatient clinics in Min-Sheng General Hospital for
 uncomplicated acute bacterial cystitis to join our trial. The age limitation was 20 to
 65 years old and the acute cystitis was diagnosed by the clinical symptoms, physical
 exams and pyuria (WBC>5/HPF) on urinalysis.

 The exclusion criteria: recent (less than one month) urinary tract infection or
 partially treated acute cystitis; anatomical or function disease of the lower urinary
 tract; patients received radical pelvic surgery; associated bladder stone disease; upper
 urinary tract anomaly or urolithiasis; systemic infection with body temperature higher
 than 38°C; known allergic reaction to cranberry or vitamin C; pregnant or prepare to be
 pregnant, or diabetic patients.

 2. Objectives and outcome measurements We try to evaluate the symptom relieving effect of
 compound cranberry extract as an adjuvant therapeutic modality. The study hypothesis is
 the compound cranberry extract tablet as an adjuvant treatment for uncomplicated acute
 bacterial cystitis with 3-day empirical antibiotics will reduce the irritative bladder
 symptoms (urinary frequency, urinary urgency, and dysuria and suprapubic pain).

 We conducted a Frequency-Urgency-Pain (FUP) score to evaluate the irritative lower
 urinary tract symptoms. Another 10-point Likert scales from 0 (none) to 9 (severe)
 questionnaire will be used to evaluate every individual symptom. A modified diary method
 was used to evaluate the symptoms change during the whole evaluation period. 3 in-face
 questionnaire interviews will be preformed on day 1, 4, and 8 by the study assistants. A
 brief form questionnaire will be done by telephone on day 2 and 3. The primary outcome
 of this study is the proportion of symptoms relief (based on FUP and individual symptom
 scale evaluation) after 3-day and 7-day treatments. The secondary outcome variables were
 the pyuria eradication rate after 3- and 7-day therapy and the time to symptoms relief.
 Possible adverse effect was recorded and reported.

 3. Sample size and randomization In this study, we will recruit 60 participants to detect
 the difference between the intervention and control groups with a 0.05 one-sided
 significance level and a 80% power. These participants will be randomly assigned to each
 group according to a pre-set random permuted blocks procedure. Efficacy analysis will be
 conducted according to the intension-to-treat principle.

 4. Intervention Intervention group will receive 3-day oral trimethoprim/sulfamethoxazole
 (80/400mg) 2 tablets twice a day on day 1 to 3 plus oral compound cranberry extract
 tablets (UmayC, 900mg) 2 tablets three times a day on day 1 to 7. The control group will
 received same oral antibiotics plus identical placebo prescribed as the same protocol of
 intervention arm. For patients with known allergic reaction to sulfa drug, the empirical
 antibiotics will be replaced by cephalexin (250mg) 2 capsules four times a day.

 Study Processes:

 After participant enrollment with inform consent, detail medical history will be collected,
 including basic physiological data (body weight and height), major medical disease (diabetes,
 cerebral vascular disease, or neurological disorder), major operation history (neurological
 and pelvic surgery), recent medication records (including recent antibiotics treatment),
 child-baring history, sexual activity, fluid drinking history, and socio-economical and
 education status.

 A voiding symptoms questionnaire, including FUP score and 10-point Likert scales symptomatic
 questions, will be done by in-face interview by study assistants. Random urine bacterial
 culture will be collected before medical treatment. The participants will be requested to
 receive 2 telephone interviews on day 2 and 3 by the study assistants and to return for
 urinalysis and 2nd in-face questionnaire on day 4 after complete antibiotics treatment. The
 clinical follow up will be arranged on day 8 by the physicians and urinalysis will be done
 again.

 Adverse event reporting and patient safety All participants will receive close follow up
 protocol for adverse event reporting. Any discomfort associated with the medical treatment
 will be recorded on daily interview record and be reported. Interruption of the trial and
 intervention decoding will be performed immediately once an intolerable side effect happened.
Inclusion Criteria:

 -  female patient with non-complicated acute bacterial cystitis

 Exclusion Criteria:

 -  recent (less than one month) urinary tract infection

 -  partially treated acute cystitis

 -  anatomical or function disease of the lower urinary tract

 -  patients received radical pelvic surgery

 -  associated bladder stone disease

 -  upper urinary tract anomaly or urolithiasis

 -  systemic infection with body temperature higher than 38°C

 -  known allergic reaction to cranberry or vitamin C

 -  pregnant or prepare to be pregnant.