Methods

• Study design: parallel, placebo‐controlled, double‐blind RCT (3:1)

• Study duration: not reported

• Duration of follow‐up: 1 year

Participants

• Country: USA

• Setting: single institution, outpatient

• Adults with spinal cord injuries for ≥ 1 year, neuropathic bladders requiring catheterization (indwelling or intermittent catheters), ≥ to 2 symptomatic UTI in preceding year

• Number: treatment group (21); control group (6)

• Mean age, range (years): treatment group (52, 27 to 71); control group (52, 28 to 74)

• Sex: all males

• Comorbidities: not reported

• Exclusion criteria: supravesical urinary diversion; VUR; obstructing urolithiasis; indwelling nephrostomy catheter; extra urogenital infections requiring prolonged antibiotics; uncontrolled DM; immunosuppression; children

Interventions

Treatment group

• Intravesical instillation: 30 mL of E. coli 83972 suspension (10⁶ CFU/mL of saline) for 2 hours, then drained. Twice/d for 3 consecutive days

Control group

• Intravesical instillation: 30 mL of sterile saline for 2 hours, then drained. Twice/d for 3 consecutive days

Outcomes

• Symptomatic UTI: significant bacteriuria (≥ 10⁵ CFU/mL) and pyuria (> 10 WBC/HPF) plus one or more of the following signs or symptoms for which no other aetiology could be identified:

  • Fever, suprapubic or flank discomfort, bladder spasm, increased spasticity and worsening dysreflexia

Notes

• Only males were enrolled with no female enrolment

• Results are confusing, initially mentioned that 62% of patients in treatment group compared to 100% of patients in control group developed at least 1 episode of UTI during the 1‐year follow‐up (P = 0.7). However, when survival analysis via Kaplan‐Meier curves were done, the patients who were unsuccessfully colonised in the treatment group were considered part of placebo group for statistical comparison. When groups were adjusted, study reported 46% in treatment group versus 93% in placebo group develop at least 1 episode of UTI during the 1‐year follow‐up with Kaplan‐Meier curves showing better survival for those successfully colonised (P = 0.002)

• Funding source: Rehabilitation Research and Development Service grant from Department of Veterans Affairs, Paralysed Veterans of America Spinal Cord Research Foundation, US Public Health Service

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Study was described as randomised, method of randomisation was not reported

Allocation concealment (selection bias)

Unclear risk

Insufficient information to permit judgement

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Stated that patients were blinded. It was stated that nurse administering the bladder instillation was not blinded

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Stated clearly that evaluator was blinded to randomisation group

Incomplete outcome data (attrition bias)
All outcomes

High risk

All patients accounted for up to 1 year follow‐up. For patients randomised into the treatment group, if they failed inoculation, they were then combined with the patients in the placebo group for statistical comparisons. High risk of bias as it not fully intention to treat

Selective reporting (reporting bias)

High risk

Only adverse event reported was one participant had autonomic dysreflexia. Generally stated that there was lack of evidence of septicaemia and UTI attributable to E. coli 83972

Other bias

Low risk

Study appears free of other biases

Methods

• Study design: parallel, placebo‐controlled, double‐blind RCT

• Study duration: not reported

• Duration of follow‐up: 1 year

Participants

• Country: USA

• Setting: outpatient, multicenter (6)

• Adults with spinal cord injuries for ≥ 1 year, neuropathic bladders requiring catheterization (indwelling or intermittent catheters) or external collection device, ≥ to 2 symptomatic UTI in preceding year

• Number (randomised/analysed): treatment group (45/17); control group (14/10)

• Mean age, range (years): treatment group (48, 29 to 78); control group (56, 30 to 85)

• Sex: all males

• Comorbidities: not reported

• Exclusion criteria: obstructing urolithiasis; history of autonomic dysreflexia within previous 3 months; supravesical urinary diversion; VUR; bladder volume < 50 mL; nephrostomy tube; vascular or urologic implants; infection‐prone congenital or acquired cardiac disease; uncontrolled DM; immunocompromised, extra‐urogenital infections requiring prolonged antibiotics; pregnant and fertile women engaging in unprotected intercourse; inability to provide inform consent; persons judged unreliable in maintaining follow‐up; children

Interventions

Treatment group

• Intravesical instillation: 10 mL saline with E. coli HU2117 bacteria (10⁶ CFU/mL) via catheter. Catheter was clamped for 1 hour, then drained. Inoculation occurred twice in 1 day for 3 consecutive days

Control group

• Intravesical instillation: 10 mL of normal saline via catheter. Catheter was clamped for 1 hour, then drained. Inoculation occurred twice in 1 day for 3 consecutive days

Outcomes

• Symptomatic UTI: bacteriuria (> 10⁵ CFU/mL) and pyuria (> 10 WBC/HPF), fever (oral temp > 100°F) plus one or more of the following signs or symptoms for which no other aetiology could be identified:

  • Suprapubic or flank discomfort, bladder spasm, increased spasticity and worsening dysreflexia

Notes

• 27 patients that they analysed were males. Authors did report that they enrolled 5 female patients in the initial 45 patients but none of the females had successful inoculation

• Results reported were not intention to treat, more drop outs in the treatment than placebo group

• Analysis was only conducted on patients who had the 1 year follow‐up

• Kaplan‐Meier survival curves showed better survival to UTI in patients with successful bladder colonisation of E. coli HU2117 than those on placebo (P = 0.04)

• Authors also reported average number of episodes of UTI/patient‐year was lower in the treatment group (0.50) versus control group (1.68) (P = 0.02)

• Funding: National Institute of Health

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Clearly stated randomisation was computer generated for each centre

Allocation concealment (selection bias)

Low risk

Stated that placebo inoculum visually identical to bacterial inoculum

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Clearly stated patients and investigators were blinded

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Clearly stated outcome assessors were blinded

Incomplete outcome data (attrition bias)
All outcomes

High risk

Clinical characteristics of the 27 patients who were followed up till 1 year was similar. However, no characteristics of the 32 patients who had initial bladder inoculation but dropped out was mentioned. There were more drop outs in the treatment than placebo group 28 versus 4. Authors did mention that patient compliance with inoculation protocol was low to account for the reason that losses to follow‐up was higher in the treatment group

Although 59 patients received bladder inoculation, only 27 patients were evaluated and analysed up to the 1 year follow‐up period. The survival analysis were only based on patients who completed the one year follow‐up period and did not account for the loss to follow‐ups; high risk of bias as not fully intention to treat

Selective reporting (reporting bias)

High risk

No reporting of adverse events except that female gender was associated with bladder colonisation failure

Other bias

Low risk

Study appears free of other biases

Methods

• Study design: crossover RCT (3:1)

  • Phase 1: blinded, randomised and placebo controlled crossover study

  • Phase 2: blinded, observational and placebo controlled.

• Study duration: 4 years

• Duration of follow‐up: 24 months

Participants

• Country: Sweden

• Setting: outpatient, single centre

• Adults with incomplete bladder emptying; 3 or more microbiologically proven UTI/year, 2 years prior to the study; optimal conservative measurements including clean intermittent catheterization to empty bladder; all 20 patients were recorded to have voiding dysfunction with at least 11 patients having neurological causes of bladder dysfunction.

• Number

  • Phase 1: treatment group (13); control group (11)

  • Phase 2: treatment group (11); control group (13)

• Mean age, range (years): 56.7, 32 to 84

• Sex (M/F): 8/12

• Comorbidities: none reported

• Exclusion criteria: upper UTI; renal deterioration; hydronephrosis; untreated bladder outflow obstruction; urinary calculi; immunosuppression; urological malignancies

Interventions

Treatment group

• Intravesical instillation: 30 mL of E. coli 83972 (10⁵ CFU/mL); inoculation occurred once/d for 3 days

Control group

• Intravesical instillation: 30 mL of saline; inoculation occurred once/d for 3 days

Outcomes

• Self‐reported UTI symptoms

  • Suprapubic pain/discomfort, malaise, fever, chills, urgency, leakage, abnormal urine, autonomic dysreflexia or spasticity

• Urine samples were taken for culture, the definition of uropathogenic growth was not defined

Notes

• Patients who were unsuccessfully inoculated were not included in analysis. In Phase 1, median time to UTI were longer with successful E. coli 83972 colonisation than non E. coli colonisation ‐ 11.3 versus 5.7 months (P = 0.01). Phase 2 number of reported UTI was lower in patients with successful E. coli 83972 colonisation than those without (13 versus 35, P = 0.009)

• Funding: grants from Coloplast, Riksforbundet for Trafik och Polioskadade, Swedish Strategic Programme against antibiotic resistance, Region Skane FoU, Foundations of Gosta Jonsson, Hillevi Fries, Per‐‐Olof Strom and Greta Ekholm

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computer generated randomisation list

Allocation concealment (selection bias)

Low risk

Wullt corresponded in 2015 that both active and placebo inoculum have the same appearance, a clear fluid that could not be differentiated by a non‐informed observer

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Patient were blinded as to the nature of inoculum; investigators were aware of whether patients were in intervention or control arm.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Wullt corresponded in 2015 that study team was unaware of urine culture results but were aware of patient's symptoms in view of outcome being self‐reported UTI symptoms. Wullt corresponded in 2015 that the investigator who surveyed the urine culture was aware of type of inoculum

Incomplete outcome data (attrition bias)
All outcomes

High risk

Patients with unsuccessful colonisation post inoculation were excluded from analysis ‐ not fully intention to treat ‐ only analysed 20/26 patients. Wullt corresponded in 2015 that an intention‐to‐treat analysis was not conducted due to the small number of patients enrolled

Selective reporting (reporting bias)

High risk

Only reported that it is safe due to absence of pyelonephritis. In a later article published in 2014, the authors reported symptomatic UTI in 2 patients who were successfully inoculated with E. coli 83972

Other bias

Low risk

Study appears free of other biases