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International Journal of Phytomedicine and Phytotherapy

Table 1 Overview of clinical studies with symptomatic treatment options (multimodal phytotherapy and NSAIDs) versus antibiotic treatment in uncomplicated lower urinary tract infections

From: UTI − quo vadis? New alternatives to treat uncomplicated urinary tract infections

 Wagenlehner et al., 2018 [4]Gágyor et al., 2015 [14]Bleidorn et al., 2010 [15]Vik et al., 2018 [16]Kronenberg et al., 2017 [17]
MedicationBNO 1045 vs. fosfomycin (FT)Ibuprofen vs. fosfomycinIbuprofen vs. ciprofloxacinIbuprofen vs. pivmecillinamDiclofenac vs. norfloxacin
Study designaDouble-blind, controlled, double-dummy, parallel group, randomized, multicentre, multinational Phase IIIDouble-blind, randomized, multicentre, comparative effectiveness trial with two parallel active treatment armsDouble-blind, randomized, controlled equivalence trialDouble-blind, randomized, parallel-group, multicentre, non-inferiority trialDouble-blind, randomized, controlled non-inferiority trial
Inclusion criteriabSum score of the three main uUTI symptoms (dysuria, pollakiuria and urgency) reported on the ACSS-typical domain on Day 1 is ≥6, leukocyturia on Day 1, confirmed by positive dipstickDysuria and/or frequency/urgency of micturition, with or without lower abdominal painAt least one of the main UTI symptoms, dysuria and frequencyDysuria combined with either increased urinary frequency or urinary urgency, or both, with or without visible haematuriaOne or more symptoms of acute lower UTI (dysuria, frequency, macrohaematuria, cloudy or smelly urine) or self-diagnosed symptomatic cystitis in combination with a positive urine dipstick test for nitrite or/and leucocytes
Exclusion criteriabHistory of recurrent infection of the urinary tractUTI within the past 2 weeksUTI within the last 2 weeksSymptoms of UTI within the last 4 weeksRecurrent UTI (> 3 infections during the past 12 months)
Number of patientsn = 325 (BNO 1045), n = 334 (FT)n = 241 (ibuprofen), n = 243 (FT)n = 40 (ibuprofen), n = 39 (ciprofloxacin)n = 194 (ibuprofen), n = 189 (pivmecillinam)n = 133 (diclofenac), n = 120 (norfloxacin)
Duration in days1–380–280–280–280–30
Dosage and duration of administrationBNO 1045, 7 days, 2 tablets TID
Fosfomycin trometamol (FT), single dose on Day 1 (3 g)
ibuprofen, 3 days, 1 tablet (400 mg) TID
fosfomycin trometamol (FT), single dose on Day 1 (3 g)
ibuprofen, 3 days, 1 tablet (400 mg) TID
ciprofloxacin, 3 days, 1 tablets (250 mg) BID
ibuprofen, 3 days, 1 tablet (600 mg) TID
pivmecillinam, 3 days, 1 tablet (200 mg) TID
diclofenac, 3 days, 1 tablet (75 mg) BID
norfloxacin, 3 days, 1 tablet (400 mg) BID
ParacetamolAllowedNot reportedNot reportedAt patients’ discretion. There is the possibility that intake of paracetamol may have masked symptomatic progression of upper UTI.Not reported
Visits/calls* (days)1,4*,8,381*,3*,5*,7*,280, 4, 7, 28?30*
Symptom scaleACSS questionnaire: Mean sum scores of the ACSS-typical domain between Days 1 and 38
Typical symptoms (n = 6) of lower uUTIs (ACSS-typical), where 0 = no symptoms, 1 = mild, 2 = moderate, and 3 = severe symptoms
Dysuria, frequency/urgency of micturition, and low abdominal pain, each on a five point scale from 0 to 4.Intensity of main symptoms - dysuria, frequency, low abdominal pain - was recorded, scoring each symptom from 0 (none) to 4 (very strong)Patient diary for recording daily symptoms, diary was based on a previously validated versionThe self-report questionnaire used to ascertain the severity of symptoms was developed based on questionnaires described by Clayson et al. and Little et al.
Women rated the severity of five UTI symptoms (dysuria, frequency, urgency, abdominal pain when passing urine, pain or tenderness in the lower back or loin) daily from days 0 to 10 in a diary and on day 30 by telephone interview on a Likert scale from 0 to 6, with their composite score ranging from 0 to 30. Symptom resolution was defined as 2 or less points (slight, very slight, or no problems) on all five components. Complete absence of symptoms was defined as 0 points on all components.
Primary endpoint(s)Additional antibiotic intake between days 1–38Total number of courses of antibiotics on days 0–28, burden of symptoms on days 0–7 as area under the curveSymptom resolution on day 4Proportion of patients who felt cured by day 4, as assessed based on a patient diaryResolution of symptoms at day 3 (72 h after randomization and 12 h after intake of the last study drug)
Secondary endpointsbACSS questionnaire assessments at days 4, 8 and 38Numbers of adverse eventsBurden of symptoms on days 4 and 7 (based on the sum score of all symptoms), symptom resolution on day 7 and frequency of relapsesProportion of patients in need of secondary treatment with antibiotics and cases of pyelonephritisUse of any antibiotic (including norfloxacin and fosfomycin as trial drugs) up to day 30 (ITT)
StatisticsNon-inferiority margin (− 15%)Superiority in the first and non-inferiority (125%) in the second co-primary endpointRough estimate of equivalence of ibuprofen and ciprofloxacin for uUTI regarding symptom resolution Non-inferiority margin (−15%)
Main ResultAntibiotic Reduction of 85%.
Non-inferiority demonstrated.
Clinical benefit on reduction of the main ACSS-typical symptoms was observed after 3 days of treatment.
More cases of pyelonephritis in the non-antibiotic group.
Fosfomycin: 243 study antibiotic + 34 additional for UTI.
Ibuprofen: 81 additional for UTI -- > Antibiotic Reduction of 67%.
Symptom burden sum score decreased in both groups (Day 0: 6 -- > Day 7: < 1) -- > non-inferiority margin of 125% exceeded.
Higher burden of symptoms.
More cases of pyelonephritis in the non-antibiotic group.
Assumption of non-inferiority is supported, but confirmation by further trials needed.Ibuprofen was inferior to pivmecillinam for treating uUTI, reducing the use of antibiotics came at the cost of stronger symptom burden, longer duration of symptoms, and more complications.Diclofenac is inferior to norfloxacin for symptomatic relief in UTI and is likely to be associated with an increased risk of pyelonephritis.
SymptomsSymptom decline comparable in both groups (statistical significance in favour of fosfomycin on Day 4)Symptoms lasted 1 day longer in the ibuprofen group.
Day 4: 56% in fosfomycin group symptom-free vs. 39% in the ibuprofen group.
As for symptom resolution, 58.3% of patients in the ibuprofen group and 51.5% in the ciprofloxacin group were completely free of symptoms on Day 4 (difference non-significant). On Day 7, the proportion of symptom-free patients had increased further in both groups, without a significant difference between groups. The course of symptoms in terms of mean symptom sum scores: with respect to Day 4, the difference in total sum scores was − 0.33 score points (95% CI (− 1.13; + 0.47)) in the PP analysis (primary analysis). The corresponding ITT analysis resulted in a difference of 0.50 (95% CI: (− 1.31; + 0.31). With regard to general impairment, there were no significant differences between the ibuprofen and ciprofloxacin groups. In particular, no difference could be shown between groups for the course of dysuria.Patients in the pivmecillinam group generally felt cured sooner than the patients in the ibuprofen group.
The median duration of symptoms was 6 days in the ibuprofen group and 3 days in the pivmecillinam group.
The median time until resolution of symptoms was 4 days in the diclofenac group, compared with 2 days in the norfloxacin group.
Safety5 cases of pyelonephritis (BNO 1045) vs. 1 case (fosfomycin)5 cases of pyelonephritis (ibuprofen) vs. 1 case (fosfomycin)
One gastrointestinal haemorrhage in the ibuprofen group
58 non-serious adverse events (32 ibuprofen, 26 ciprofloxacin)7 SAEs during the trial, 1 in the pivmecillinam group and 6 in the ibuprofen group. 5 patients developed a febrile UTI and 7 patients developed pyelonephritis, all initially treated with ibuprofen6 cases of pyelonephritis (diclofenac) vs. 0 (norfloxacin)
RecurrenceThe AB rates were comparable across the different reasons for additional AB intake during the clinical trial (persistent or worsening symptoms: BNO 1045: 66.0% and FT: 67.7%; recurrent symptoms: BNO 1045: 23.4% and FT: 25.8%; no symptoms reported: BNO 1045: 10.6% and FT: 6.5%).Comparable in both groups, but significant more recurrences after day 14 in the FT group (11% vs. 6%)The surprisingly high number of patients presenting again with persistent/recurrent symptoms while taking ciprofloxacin (18%) might indicate that antibiotic treatment takes a few days to resolve symptoms, a fact which may have worried trial patients who did not know which drug they were taking.Comparing the subgroup with recurrent UTIs (i.e., 3 or more UTIs during the previous 12 months) to the subgroup with 0 ± 2 UTIs within the last 12 months, the highest symptom burden over 6 days was observed in the recurrent UTI patients treated with ibuprofen.
The difference in symptom burden between the treatment groups was greater for those with recurrent UTIs, but significant in both subgroups.
Recurrent UTI: 4% diclofenac vs. 3% norfloxacin
Recurrent UTI was defined as additional visits after day 14 because of recurrent UTI symptoms after symptoms had resolved by day 10, and the physician decided to treat with antibiotics.
LimitationsMicrobiological data (but not mandatory for uUTIs)Inclusion was biased towards patients with less severe symptoms -- > results only applicable to patients with mild to moderate symptoms, rather than all uUTI
Neither symptom score or measurement of the area under the curve were validated -- > relevance for affected patients was not formally proved
Small sample size, pilot trialHigh dosage of ibuprofen, low dosage of pivmecillinamRescue antibiotic (fosfomycin) could be taken at patients’ discretion after day 3
Symptom resolution ≠ complete absence of symptoms
ConclusionTrial may inform treatment choices and encourage wider adoption of antibiotic alternatives, such as BNO 1045, for the treatment of lower uUTIs in routine clinical practiceNon-inferiority not achieved, no general recommendation of the “ibuprofen first approach”Results support the assumption of non-inferiority, but further trials or an adequately powered trial is necessary.Until we can identify those women in need of antibiotic treatment to prevent complications, ibuprofen alone cannot be recommended to women with uUTIs.Trial failed to detect non-inferiority of NSAIDs compared with antibiotics for symptom control.
Symptomatic treatment of lower urinary tract infections prolongs symptom duration and is likely to be associated with an increased risk of pyelonephritis.
  1. aAs reported in the publication
  2. bNot a complete list