A multicenter,randomized controlled clinical trial of Pseudomonas aeruginosa injection for prevention of recurrent urinary tract infections
Objective To investigate the clinical efficacy and safety of Pseudomonas aeruginosa injection in preventing reurrent urinary tract infection in women.Methods This was a multicenter,randomized,open,positive-controlled,non-inferiority trial involving female patients with recurrent urinary tract infections(rUTIs)who were admitted to 11 medical centers in China.Inclusion criteria:①Aged 18-70 years,with verifiable clinical data showing at least 3 episodes of acute UTIs within 1 year and at least 2 episodes within 6 months,and cured by antimicrobial therapy;② At the time of enrollment,the patients had no obvious symptoms of urinary tract irritation,normal white blood cell count in midstream urine routine(within the normal range of laboratory standards of each unit)or ≤3HP by centrifuge microscopy,negative leucocyte esterase and nitrite,and negative urine culture;③No abnormal urinary anatomic function(such as urinary obstruction,calculus or congenital urinary malformation)and residual urine volume ≤50 ml were detected by B-ultrasound of urinary system;④Informed consent signed by the person or agent;⑤Clear consciousness,able to answer questions independently,according to the requirements of the test plan to complete the research questionnaire.Exclusion criteria:① Patients allergic to the above drugs;② Any complex signs of urinary tract infection or pyelonephritis(manifested as low back pain,fever ≥37.3℃,systemic symptoms);③Drugs affecting immune function were used within 7 days before randomization;④Patients with basic diseases of urinary system such as obstruction,calculus,urinary stenosis,vesicoureteral reflux or other functional abnormalities,urine diversion,indwelling catheter or stent tube or intermittent catheterization;⑤Combined with or existing systemic lupus erythematosus,AIDS and other diseases that can lead to systemic immune function abnormalities;@Patients who are known or suspected to be pregnant,breastfeeding,or planning a pregnancy within 3 months of stopping the drug;⑦Patients with malignant tumors and mental patients;⑧Persons who have received any other investigational drug treatment or participated in another interventional clinical trial within 4 weeks prior to screening;⑨ Failure to comply with the trial protocol or other conditions deemed unsuitable for enrollment by the investigator.Patients were randomly divided into 2 groups.The experimental group was given Pseudomonas aeruginosa injection for 5 times,0.5 ml for the first time,and 1 ml/time per week for the following 4 weeks.The control group was given fosfomycin aminotriol 3g orally,once every 10 days,for 9 consecutive times.The patients were followed up for 6 to 8 months,during which urinary tract symptoms developed and routine urine tests showed abnormally elevated white blood cells,which was defined as recurrent UTIs.Urine routine,liver and kidney function,and urinary secretory immunoglobulin A(SIgA)were reviewed 0-2 days(V2)after the 5th administration of the experimental group and the 4th administration of the control group.Urine routine and urine SIgA were reviewed at(90±10)d(V3)and(180±10)d(V4)after treatment.At(270±10)d(V5)after treatment,the recurrence(re-infection caused by the same species of bacteria)or re-infection(re-infection caused by non-same species of bacteria)of the two groups were compared,and non-inferiority analysis was performed,and the non-inferiority threshold was set at 0.2.Results From March 2021 to May 2022,a total of 152 rUTIs patients were enrolled in this study,including 80 patients in the experimental group,71 patients in the intention-to-analysis set(ITT)and 66 patients in the protocol analysis set(PPS).In the control group,72 cases met ITT in 69 cases and PPS in 67 cases.There were no significant differences in age,body mass index,marital status,duration of urinary tract infection,history of diabetes,history of previous major surgery,history of infection,and urinary SIgA between the two groups(all P＞0.05).The recurrence rates of the experimental group and the control group at V5 time point were 44.78％(30/67)and 42.65％(29/68),respectively(P=0.803)(ITT data set analysis results showed that the difference in recurrence rates between the two groups was 0.0213(95％CI-0.1460-0.1886,P=0.0048).PPS data set analysis showed that the difference of recurrence rate between the two groups was-0.0021(95％CI-0.1711-0.1670,P=0.0109),and the recurrence rate of the experimental group was not worse than that of the control group.At V2 time points,there were no significant differences in liver and kidney function indexes between test group and control group(P＞0.05).At V2 to V4 time points,urinary SIgA of test group and control group were 0.90(0.37,2.89)mg/L and 1.32(0.34,3.08)mg/L,1.54(0.44,3.23)mg/L and 1.71(0.27,2.92)mg/L,1.11(0.65,3.42)mg/L and 2.18(0.43,3.26)mg/L,there was no statistical significance(P＞0.05).The incidence of adverse events in the experimental group was 30.0％(24/80),including 14 cases of redness,pain and discomfort at the injection site,5 cases of fever,2 cases of allergic rash,and 1 case of urticaria,headache and constipation each.The incidence of adverse events in the control group was 5.6％(4/72),all of which were diarrhea,and the difference between the two groups was statistically significant(P＜0.01).No life-threatening serious adverse events occurred in both groups,and all adverse events were self-healing without additional intervention.Conclusions Compared with fosfomycin aminotriol,Pseudomonas aeruginosa injection has the same clinical effect in preventing rUTI and has good safety.
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