Open Forum Infectious Diseases MAJOR ARTICLE Antibiotic Treatment Versus No Treatment for Asymptomatic Bacteriuria in Kidney Transplant Recipients: A Multicenter Randomized Trial Downloaded from https://academic.oup.com/ofid/article/6/6/ofz243/5494787 by Universitat Autònoma de Barcelona user on 11 February 2022 Núria Sabé,1 Isabel Oriol,1 Edoardo Melilli,2 Anna Manonelles,2 Oriol Bestard,2 Carolina Polo,2 Ibai Los Arcos,3 Manel Perelló,4 Dolors Garcia,5 Lluís Riera,6 Cristian Tebé,7 Òscar Len,3 Francesc Moreso,4 Josep M Cruzado,2 and Jordi Carratalà1 1 Department of Infectious Diseases, Hospital Universitari de Bellvitge-IDIBELL, Spanish Network for Research in Infectious Diseases (REIPI), and Clinical Sciences Department, Faculty of Medicine, University of Barcelona, L’Hospitalet de Llobregat, Spain; 2Department of Nephrology, Hospital Universitari de Bellvitge-IDIBELL, and Clinical Sciences Department, Faculty of Medicine, L´Hospitalet de Llobregat, Barcelona, Spain; 3Department of Infectious Diseases, Hospital Universitari Vall d’Hebron-VHIR, Spanish Network for Research in Infectious Diseases (REIPI), Barcelona, Spain; 4Department of Nephrology, Hospital Universitari Vall d’Hebron-VHIR, Barcelona, Spain; 5Department of Microbiology, Hospital Universitari de Bellvitge-IDIBELL, L´Hospitalet de Llobregat, Barcelona, Spain; 6Department of Urology, Hospital Universitari de Bellvitge-IDIBELL, Barcelona, Spain; 7Statistical Assessment Service at Bellvitge Biomedical Research Institute (IDIBELL) and Department of Basic Sciences, Universitat Rovira i Virgili, L’Hospitalet de Llobregat, Barcelona, Spain Background. Whether antibiotic treatment of asymptomatic bacteriuria (AB) can prevent acute graft pyelonephritis (AGP) in kidney transplant (KT) recipients has not been elucidated. Methods. In this multicenter, open-label, nonblinded, prospective, noninferiority, randomized controlled trial, we compared antibiotic treatment with no treatment for AB in KT recipients in the first year after transplantation when urinary catheters had been removed. The primary endpoint was the occurrence of AGP. Secondary endpoints included bacteremic AGP, cystitis, susceptibility of urine isolates, graft rejection, graft function, graft loss, opportunistic infections, need for hospitalization, and mortality. Results. We enrolled 205 KT recipients between 2013 and 2015. AB occurred in 41 (42.3%) and 46 (50.5%) patients in the treatment and no treatment groups, respectively. There were no differences in the primary endpoint in the intention-to-treat popu- lation (12.2% [5 of 41] in the treatment group vs 8.7% [4 of 46] in the no treatment group; risk ratio, 1.40; 95% confidence interval, 0.40–4.87) or the per-protocol population (13.8% [4 of 29] in the treatment group vs 6.7% [3 of 45] in the no treatment group; risk ratio, 2.07, 95% confidence interval, 0.50–8.58). No differences were found in secondary endpoints, except for antibiotic suscepti- bility. Fosfomycin (P = .030), amoxicillin-clavulanic (P < .001) resistance, and extended-spectrum β-lactamase production (P = .044) were more common in KT recipients receiving antibiotic treatment for AB. Conclusions. Antibiotic treatment of AB was not useful to prevent AGP in KT recipients and may increase antibiotic resistance. However, our findings should be regarded with caution, due to the small sample size analyzed. Key words. asymptomatic bacteriuria; kidney transplantation; pyelonephritis. INTRODUCTION population and is often complicated by acute graft dysfunction Urinary tract infection is the most common complication in requiring hospitalization [6, 7]. Cytomegalovirus (CMV) infec- kidney transplant (KT) recipients, notably in the first months after tion, rejection, chronic allograft dysfunction, and mortality have KT, with an incidence that varies from 6% to 83% depending on also been associated with AGP in some studies [4, 5, 8–11]. whether symptomatic or asymptomatic infections are considered Infections due to multidrug-resistant (MDR) organisms have [1–5]. The most serious manifestation is acute graft pyelone- become a serious problem in KT recipients [12] because of their phritis (AGP), which is the leading cause of bacteremia in this association with higher complication and recurrences rates [13, 14]. Moreover, MDR infections require treatment with last re- sort antibiotics that are usually associated with more adverse Received 20 March 2019; editorial decision 15 May 2019; accepted 20 May 2019. events, including nephrotoxicity, which may be increased by the Correspondence: N. Sabé, MD, Department of Infectious Diseases, Hospital Universitari concomitant use of calcineurin inhibitors [15]. Given this wor- de Bellvitge-IDIBELL, Feixa LLarga, s/n, 08907 L’Hospitalet de Llobregat, Barcelona, Spain (nfsabe@bellvitgehospital.cat). risome scenario, effective strategies of antibiotic stewardship are Open Forum Infectious Diseases® urgently needed to reduce resistance rates while maintaining © The Author(s) 2019. Published by Oxford University Press on behalf of Infectious Diseases patient safety. When considering this, however, it is important Society of America. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/ that we acknowledge the key role of antibiotic pressure as the by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any major driver for the selection of MDR bacteria. medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Measures are needed to prevent AGP after KT, and the po- DOI: 10.1093/ofid/ofz243 tential preventive role of antibiotic treatment for asymptomatic Treatment for Asymptomatic Bacteriuria in Kidney Transplants • ofid • 1 bacteriuria (AB) remains controversial [16, 17]. At present, the AB was documented. If AB occurred during follow-up, anti- management of AB in KT recipients varies between transplant biotic treatment was prescribed for 5–7 days according to the centers [18] and due to a lack of solid evidence [19–22]. However, susceptibility of the microorganism isolated in urine culture. recently published guidelines provide recommendations against If fosfomycin was used, a shorter antibiotic course of 1–3 days screening and treating AB episodes after KT, especially within the was considered appropriate. To avoid the interference of foreign first month following KT [23, 24]. Moreover, a randomized trial bodies, study interventions only began when urethral and ure- found no apparent benefit from screening and treating AB in 112 teral catheters had been removed. From KT to removal of uri- KT recipients beyond the second month after transplantation [25]. nary catheters, the decision whether to treat AB with antibiotics Downloaded from https://academic.oup.com/ofid/article/6/6/ofz243/5494787 by Universitat Autònoma de Barcelona user on 11 February 2022 In this multicenter, randomized controlled trial (RCT), we aimed was made by the attending physician. to test the hypothesis that no treatment for AB in KT recipients would be noninferior to antibiotic treatment in the prevention of AGP. Follow-up and Outcomes Assessments Clinical follow-up was performed by transplant physicians METHODS in outpatient settings at the following posttransplantation intervals: weekly in the first month, every 2 weeks from the Design and Study Endpoints second to third month, once monthly from the third to sixth This prospective, multicenter, open-label, nonblinded, month, and every 3 months from the sixth to the twelfth month. noninferiority RCT was conducted from January 2013 to It was ensured that essential data about outcomes were regis- September 2015. We compared the efficacies of antibiotic treat- tered and that all necessary urinary and blood samples were col- ment and no treatment of AB to prevent AGP in KT recipients lected and analyzed. If the patients required other medical visits during the first year posttransplantation and after urinary or needed hospitalization, the investigators evaluated them and catheters removal. The primary study endpoint was the in- relevant data were collected. cidence of the first episode of AGP. Secondary endpoints in- Urine cultures and blood analysis of graft function were cluded AGP-related bacteremia, cystitis, acute graft rejection, done at every follow-up visit, plus when the attending physi- opportunistic infections, hospitalization due to any cause, graft cian considered testing necessary. Quantitative urine cultures function, graft loss, mortality, and antimicrobial susceptibility were analyzed in cystine lactose electrolyte deficient agar with of microorganisms isolated in urine cultures. a 0.001 mL calibrated loop. Antibiotic susceptibility of isolated microorganisms was assessed by the disk-diffusion method, Setting and Study Population and the minimum inhibitory concentration was determined. The study was performed centrally in 2 university hospitals If urine cultures were contaminated, they were considered with active renal transplant programs in Barcelona. Patients negative and not repeated. Urine cultures were performed if were identified at each participating hospital by checking daily symptoms of urinary infection were present, and blood cultures if a KT had been performed. Consecutive KT recipients were were performed if AGP was suspected clinically. eligible for enrolment if they were aged 18 years or older, had To evaluate the primary endpoint, all episodes of AGP during fol- received a KT in the previous month, and if they or their legal low-up were carefully evaluated and recorded. Secondary endpoints surrogate provided written informed consent. Patients were also were registered. For all episodes of AB, isolated organisms and excluded from inclusion if they were already included in another antibiotic susceptibilities were recorded. All antibiotics prescribed clinical trial in which the treatment of AB was recommended or in patients assigned to the antibiotic group were recorded. if they did not provide informed consent. Definitions Randomization and Allocation Concealment Randomization was performed by computer-generated random AB was considered present if a patient without symptoms pro- code allocation with a block size of ten. The program randomly vided a single, clean-catch voided urine specimen with 1 bac- assigned participants on a 1:1 basis to 2 parallel groups in 2 treat- terial isolate present at ≥105 colony-forming units/mL. Cystitis ment arms, stratified by hospital site. A biostatistician held the was diagnosed if bacteriuria was present with symptoms of random code centrally. One investigator in each hospital opened dysuria, frequency, and urinary urgency, without meeting the the sealed and sequentially numbered opaque envelopes for the criteria for AGP. Acute graft pyelonephritis was defined by the randomly assigned patients who had provided written informed simultaneous presence of fever with bacteriuria or bacteremia, consent and met the study criteria. No attempt was made to conceal or both, and 1 or more of the following: renal allograft tender- study arm intervention from patients or treating clinicians. ness, chills, or criteria for cystitis [21]. Contaminated urine culture was defined as a culture of urinary sample that grows Intervention 3 or more different types of bacteria. Allograft rejection was Patients fulfilling the inclusion requirements were randomly diagnosed based on impaired renal function with suggestive assigned to receive antibiotic treatment or no treatment when findings on renal biopsy. Graft loss was defined as loss of kidney 2 • ofid • Sabé et al function necessitating chronic dialysis. Opportunistic infection Medicines and Health Products. In accordance with Spanish legisla- was considered when any infection due to an opportunistic tion governing clinical trials (RD 223/2004), this study had liability pathogen occurred during study follow-up (ie, CMV, BK virus). insurance covering possible damages to patients during their partic- Hospitalization was defined as any hospital admission due to ipation in the study (HDI Hannover International, Spanish branch, causes other than AGP. Mortality was defined as death due to policy number 130/002/001691). any cause during study follow-up. RESULTS Exclusion Criteria Before Trial Intervention Study Population Downloaded from https://academic.oup.com/ofid/article/6/6/ofz243/5494787 by Universitat Autònoma de Barcelona user on 11 February 2022 We excluded patients with graft loss or who were lost to fol- The flow chart for study inclusion is shown in Figure 1. In total, low-up before urinary catheters were removed, as well as 402 KTs were performed in the participating hospitals during patients with surgical complications that prolonged the need the study period. Among these, 205 KT recipients were enrolled for urinary catheters. KT recipients without documented AB in the study and underwent randomization, wherein 102 were during follow-up also were excluded. assigned to the antibiotic treatment group and 103 were assigned to the no treatment group. The median time from KT to study Statistical Analysis inclusion was 4 days (interquartile range [IQR] 3–7). Before The sample size was estimated based on the hypothesis that no protocol intervention, a further 17 KT recipients were excluded treatment would be noninferior to antibiotic treatment at affecting for different reasons. All of these patients were excluded early the incidence of AGP in KT recipients with AB. The required after KT and before urinary catheters were removed. Among sample size was estimated for a noninferiority of 15% between the remaining 188 KT recipients, AB did not occur in 101 the 2 management strategies and a probability that AGP would during follow-up (53.7%), so these were also excluded. occur in 20%. This indicated that 100 patients would be neces- sary per group to achieve an estimated power of 65.8%, allowing ITT and PP Populations for the likelihood that 40% of randomized patients would be During the 12 month follow-up period, AB was documented in excluded for not presenting with AB or for other reasons. 41 patients in the antibiotic treatment group and in 46 patients in Data were collected and anonymously entered in a dedicated the no treatment group. The median follow-up from the first ep- database that was reviewed periodically by descriptive analysis isode of AB in the ITT population was 302 days (IQR 244–321.5) to detect illogical data. The baseline characteristics and outcome in antibiotic treatment group and 277 days (IQR 226.5–329) in measures were compared by the χ2 test for categorical variables no treatment group, while in the PP population it was 308 days and t test or nonparametric Mann-Whitney test for contin- (IQR 223–323) in antibiotic treatment group and 281 days (IQR uous variables, as appropriate. Noninferiority was defined as 226–330) in no treatment group. The median time between KT the upper limit of the 1-sided, 97.5% confidence interval (CI) and the first episode of AB was 58 days (IQR 46–121) in anti- of the difference in the incidence of AGP in KT recipients be- biotic treatment group and 68 days (IQR 44.75–117.25) in no tween study groups being <15%. All statistical analyses were treatment group. In the PP population, the mean days between performed with R (version 3.4.1 for Windows). KT and the first episode of AB was 53 days (IQR 44.5–117.5) in The intention-to-treat (ITT) population was defined as KT antibiotic treatment group and 68 days (IQR 44.5–113) in the no recipients who developed AB within 12 months of follow-up after treatment group of AB. The baseline characteristics of the ITT urethral and ureteral catheter removal. The per-protocol (PP) populations were comparable and are detailed in Table 1. In 12 population comprised the ITT population that received antibiotic KT recipients assigned to receive antibiotic treatment, no antibi- treatment or no treatment for AB according to randomization. otic was prescribed despite AB being identified; also, a single KT recipient assigned to the no treatment group received antibiotic Ethical Issues therapy when AB was present. Consequently, the PP population This trial is registered with the US National Library of Medicine at included 29 KT recipients in the antibiotic treatment group and https://clinicaltrials.gov/ as study number NCT01771432 and was 45 KT recipients in the no treatment group. No differences were conducted according to the principles of the Declaration of Helsinki found in baseline characteristics of the PP population. (2008) and current Spanish legislation (Real decreto 223/2004). The principal investigator or collaborator at each site obtained written Urine Cultures informed consent from all patients (or legal representatives if they In the ITT population, the mean number of urine cultures lacked capacity) before enrollment. The study data were identified obtained per KT recipient with AB was 7.5 and 7.8 in the an- by a code, maintaining patient confidentiality in accordance with tibiotic treatment and no treatment groups, respectively. The current legislation. The trial protocol, the informed consent form, mean number of positive urine cultures was comparable in each and information sheet received research ethics committee approval. group with AB (2.7 in the antibiotic treatment group and 2.8 Clinical trial authorization was granted by the Spanish Agency for in the no treatment group). More than 70% of KT recipients in Treatment for Asymptomatic Bacteriuria in Kidney Transplants • ofid • 3 402 Kidney transplant recipients assessed for eligibility 197 excluded: Declined to participate 40 Graft loss 36 Already included in another clinical trial 121 Downloaded from https://academic.oup.com/ofid/article/6/6/ofz243/5494787 by Universitat Autònoma de Barcelona user on 11 February 2022 205 randomized Antibiotic treatment if asymptomatic No treatment if asymptomatic bacteriuria was documented bacteriuria was documented 102 103 61 excluded: 57 excluded: Graft loss 3 Graft loss 4 Surgical complications Surgical complications precluding urinary catheters precluding urinary catheters removal 1 removal 7 Loss of follow up 1 Frequent antibiotic use due to respiratory infection 1 No asymptomatic bacteriuria No asymptomatic bacteriuria occurred during follow up 56 occurred during follow up 45 Kidney transplant recipients with INTENTION-TO-TREAT Kidney transplant recipients with asymptomatic bacteriuria POPULATION asymptomatic bacteriuria 41 46 12 kidney transplant recipients 1 kidney transplant recipients did not receive antibiotic received antibiotic therapy therapy for all episodes of asmptomatic bacteriuria Evaluable patients PER-PROTOCOL Evaluable patients 29 POPULATION 45 Figure 1. Flow Diagram of the Study each group had 2 or more episodes of AB during follow-up. The (38 of 83 episodes) in no treatment group, excluding urine mean number of contaminated urine cultures obtained per KT cultures performed in the twelfth month after KT as no screening recipient in the ITT population was 1.1 in the antibiotic treat- urine cultures were performed thereafter. Considering all AB ment group and 1.5 in the no treatment group. In the ITT pop- episodes, independently of the group assigned, the success rate ulation, 114 episodes of AB were documented in the treatment in clearing AB was 34.2 % (25 of 73 episodes) in AB episodes group and 77 (67.5%) were treated with antibiotics. In the no treated with antibiotics and 46.9% (54 of 115 episodes) in those treatment group, 129 episodes of AB occurred and 4 (3.1%) of without antibiotic treatment. them were treated with antibiotics. In the ITT population prior to ureteral catheter removal, In the PP population, the success rate in clearing AB in anti- 25 KT recipients in the treatment group had 40 episodes of biotic treatment group was 36.2% (25 of 69 episodes) and 45.7% AB and 24 KT recipients in the no treatment group had 38 4 • ofid • Sabé et al Table 1. Baseline Characteristics in Intention-to-Treat Population Antibiotic Treatment of Asymptomatic No Treatment of Asymptomatic Bacteriuria n = 41 Bacteriuria n = 46 n % n % Male sex 15 36.6 21 45.7 Age, years, mean ± SD 61.048 ± 11.582 60.194 ± 11.412 Type of donor Living donor 10 24.4 6 13.0 Downloaded from https://academic.oup.com/ofid/article/6/6/ofz243/5494787 by Universitat Autònoma de Barcelona user on 11 February 2022 Decreased donor 31 75.6 40 87.0 Etiology of renal impairment Unknown 7 17.1 12 26.1 Diabetic nephropathy 9 22.0 8 17.4 Kidney polycystic disease 5 12.2 9 16.9 Glomerulonephritis 6 14.6 7 15.2 Nephroangiosclerosis 4 9.8 2 4.3 Other 10 24.4 8 17.4 Previous kidney transplant 11 26.8 7 15.2 Diabetes mellitus Before kidney transplant 10 24.4 13 28.3 After kidney transplant 7 17.1 5 10.9 Preemptive transplant 8 19.5 6 13.0 Previous hemodialysis 30 73.0 34 73.9 Previous peritoneal dialysis 3 7.3 6 13.0 Months in dialysis, mean ± SD 31.900 ± 36.848 24.181 ± 30.801 Donor positive/recipient negative CMV serostatus 1 2.4 5 10.9 Complications during admission after kidney transplant 22 53.7 24 52.2 Delayed graft function 7 17.9 12 29.3 Reintervention 1 2.6 3 7.3 ICU admission 7 18.4 3 7.3 Acute rejectiona 3 7.3 2 4.3 Days of admission for kidney transplant, mean ± SD 14.926 ± 7.705 12.434 ± 7.960 Immunosuppressive treatment Monoclonal antibodies 15 55.6 23 50.0 Antithymocyte globulin 15 36.6 21 45.7 Plasmapheresis 4 9.8 2 4.3 Intravenous immunoglobulin 8 19.5 6 13.0 Corticosteroids 40 97.5 46 100 Corticosteroids at discharge 40 97.5 43 93.5 Calcineurin inhibitors 40 97.6 45 97.8 Mycophenolate 39 95.1 45 97.8 TMP-SMX prophylaxis 41 100 45 97.8 Days of TMP-SMX prophylaxis, mean ± SD 117.289 ± 54.343 100.069 ± 37.750 CMV prophylaxis with valganciclovir 22 53.7 25 54.3 Days of bladder catheterization, mean ± SD 8.125 ± 4.303 8.577 ± 4.648 Days of double-J catheterization, mean ± SD 35.124 ± 7.467 35.065 ± 5.405 Abbreviations: CMV, cytomegalovirus; ICU, intensive care unit; SD, standard deviation; TMP-SMX, trimethoprim-sulfamethoxazole. a Only rejection episodes occurring before trial intervention was initiated were considered in this variable. episodes of AB. Antibiotic treatment was prescribed in 45% (18 -7.39%–21.64%). In intention to treat analysis results were of 40) episodes of AB in the treatment group and in 47% (18 of similar with a difference in the AGP incidence of 3.50% 38) episodes of AB in the no treatment group before urinary (97.5% CI, -9.40%–16.41%) (Tables 2 and 3). Prior AB due to catheters were removed. the microorganism that caused AGP occurred in 7 episodes in the ITT population (4 of 6 in the antibiotic treatment group Primary Endpoint and 3 of 6 in the no treatment group) and 5 episodes in the In the PP analysis, the number of patients with AGP was 4 PP population (3 of 5 in the treatment group and 2 of 4 in the of 29 in the treated group and 3 of 45 in the untreated group. no treatment group). Characteristics of AGP episodes are de- The difference in the AGP incidence was 7.13% (97.5% CI, tailed in Table 4. Treatment for Asymptomatic Bacteriuria in Kidney Transplants • ofid • 5 Table 2. Study Outcomes in Intention-to-Treat Population Antibiotic Treatment No Treatment if if Asymptomatic Asymptomatic Bacteriuria n = 41 Bacteriuria n = 46 n % n % P value RR 95% CI Primary endpoint KT recipients with acute graft pyelonephritisa 5 12.2 4 8.7 .59 1.40 0.40–4.87 Secondary endpoints Downloaded from https://academic.oup.com/ofid/article/6/6/ofz243/5494787 by Universitat Autònoma de Barcelona user on 11 February 2022 Bacteremic pyelonephritis 1 2.4 3 6.5 .36 0.37 0.036–3.588 Cystitisb 6 14.6 3 6.5 .215 2.24 0.60–8.40 Opportunistic infections 9 22.0 10 21.7 .98 1.01 0.46–2.24 Cytomegalovirus infectionc 9 22.0 10 21.7 .98 1.01 0.46-2.24 BK virus infection 2 4.9 0 .13 Rejection episodesd 1 2.4 2 4.3 .63 0.56 0.05–5.96 Need for hospital admissione 22 53.7 26 56.5 .83 0.95 0.65–1.39 Abbreviations: CI, confidence interval; KT, kidney transplant; RR, risk ratio. a One KT recipient in the antibiotic treatment group and 2 KT recipients in the nontreatment group had 2 episodes of acute graft pyelonephritis (AGP). The median days from transplantation to the first episode of AGP were 61 days in the antibiotic treatment group and 121.5 days in the nontreatment group. b Two KT recipients in the antibiotic treatment group and 1 recipient in the nontreatment group had 2 episodes of cystitis. c Two KT recipients in the treatment group and 3 patients in the nontreatment group had 2 episodes of cytomegalovirus (CMV) infection. Antibiotic group (no.): viremia (11) and viral syndrome (1); nontreatment group (no.): viremia (10), viral syndrome (1), and digestive disease (1). d Only rejection episodes occurring after trial intervention was initiated were considered in this variable. e Admission due to AGP is not considered in this variable. Twelve (26.1%) KT recipients in the treatment group and 8 (19.5%) patients in the nontreatment group needed 2 or more hospital admissions for events other than episodes of AGP. Antibiotic group (no.): renal biopsy per protocol (19), congestive heart failure (2), renal impairment (4), CMV disease (1), lymphocele (1), pneumonia (2), and diarrhea (1); nontreatment group (no.): renal biopsy per protocol (22), congestive heart failure (5), renal impairment (1), CMV disease (2), lymphocele (2), pneumonia (1), diarrhea (1), and Clostridium difficile colitis (1). Secondary Endpoints causes other than AGP, or in the rates of opportunistic infections Secondary study endpoints in the ITT and PP populations or acute graft rejection. There were no graft losses or deaths. are detailed in Tables 2, 3, and Figure 2. During follow-up, no The incidence of a first episode of symptomatic urinary tract in- differences were found between the 2 populations in the in- fection in treatment versus no treatment group of AB in the ITT cidence rates of bacteremic AGP or cystitis, in the estimated population was 10 of 41 (24.3%) versus 7 of 46 (15.2%) (P = .280; glomerular filtration rates, in the hospital admission rates for RR, 1.60; 95% CI, 0.67–3.82) and in the PP population it was 7 Table 3. Study Outcomes in Per-Protocol Population Antibiotic Treatment No Treatment if if Asymptomatic Asymptomatic Bacteriuria n = 29 Bacteriuria n = 45 n % n % P value RR 95% CI Primary endpoint KT recipients with acute graft pyelonephritisa 4 13.8 3 6.7 .31 2.07 0.50–8.58 Secondary endpoints Bacteremic pyelonephritis 0 2 4.4 .25 Cystitisb 4 13.8 3 6.7 .31 2.07 0.50–8.58 Opportunistic infections 5 17.2 10 22.2 .77 0.78 0.30–2.04 Cytomegalovirus infectionc 5 17.2 10 22.2 .77 0.78 0.30–2.04 BK virus infection 2 6.9 0 .07 Rejection episodesd 1 3.4 2 4.4 .83 0.78 0.07–8.17 Need for hospital admissione 16 55.8 26 57.8 1 0.95 0.63–1.44 Abbreviations: CI, confidence interval; KT, kidney transplant; RR, risk ratio. a One KT recipient in the antibiotic treatment group and 1 recipient in the nontreatment group had 2 episodes of acute graft pyelonephritis (AGP). The median days from transplantation to the first episode of AGP were 63 days in the antibiotic treatment group and 169 days in the nontreatment group. b Two KT recipients in the antibiotic treatment group and 1 recipient in the nontreatment group had 2 episodes of cystitis. c Two KT recipients in the treatment group and 3 patients in the nontreatment group had 2 episodes of cytomegalovirus (CMV) infection. Antibiotic group (no.): viremia (7) and viral syndrome (1); nontreatment group (no.): viremia (10), viral syndrome (1), and digestive disease (1). d Only rejection episodes occurring after trial intervention was initiated were considered in this variable. e Admission due to AGP is not considered in this variable. Twelve (26.7%) KT recipients in the treatment group and 7 (24.1%) patients in the nontreatment group need 2 or more hospital admissions different from episodes of AGP. Antibiotic group (no.): renal biopsy per protocol (13), congestive heart failure (1), renal impairment (4), CMV disease (1), and pneumonia (2). Nontreatment group (no.): renal biopsy per protocol (22), congestive heart failure (4), renal impairment (1), CMV disease (1), lymphocele (2), pneumonia (1), and Clostridium difficile colitis (1). 6 • ofid • Sabé et al Table 4. Characteristics of Acute Graft Pyelonephritis Episodes in Patients Included in the Study AGP due to the Previous Microorganism Antibiotic Days Since Kidney Bacteremic Complications Related Patient Study Group Isolated in AB Urine Cultures Treatment for AB Transplant AGP to AGP Episode 1 Antibiotic Yes Yes 284 No Renal insufficiency treatment 2 Antibiotic Yes Yes 61 No Renal insufficiency treatment Downloaded from https://academic.oup.com/ofid/article/6/6/ofz243/5494787 by Universitat Autònoma de Barcelona user on 11 February 2022 2 Antibiotic Yes Yes 344 No Renal insufficiency treatment 3 Antibiotic No 65 No No treatment 4 Antibiotic No 98 No Renal insufficiency treatment 5a Antibiotic Yes No 72 Yes No treatment 6 No treatment No 303 No No 6 No treatment No 326 No Renal insufficiency 7 No treatment Yes No 219 Yes Renal insufficiency 8 No treatment Yes No 169 Yes No 9a No treatment No 74 Yes Renal insufficiency 9a No treatment Yes Yes 330 No Renal insufficiency Abbreviations: AB, asymptomatic bacteriuria; AGP, acute graft pyelonephritis. a Patients 5 and 9 were included in the ITT population but not in the PP population. of 29 (24.1%) versus 6 of 45 (13.3%) (P = .233; RR, 1.81; 95% CI, group and 2 of 2 in the no treatment group). As cystitis in patients 0.68–4.85). We counted 4 episodes of bacteremic AGP in patients with previous same-microorganism AB, we observed 7 episodes in with previous same-microorganism AB in the ITT population (1 the ITT population (7 of 8 in the antibiotic treatment group and 0 of 1 in the antibiotic treatment group and 2 of 3 in the no treatment of 4 in the no treatment group) and 6 episodes in the PP population group) and 2 episodes in the PP population (0 of 0 in the treatment (6 of 7 in the treatment group and 0 of 4 in the no treatment group). A B 50 50 40 40 eGFR eGFR 30 30 20 20 Antibiotic treatment of asymptomatic bacteriuria Antibiotic treatment of asymptomatic bacteriuria Non-treatment of asymptomatic bacteriuria Non-treatment of asymptomatic bacteriuria 0 1 2 3 4 5 6 9 12 0 1 2 3 4 5 6 9 12 Months Months Figure 2. Evolution of Estimated Glomerular Filtration Rate During 12-Month Follow-up in Intention-to-Treat and in Per-Protocol Populations Abbreviation: eGFR, estimated glomerular filtration rate mL/min/1.73m2. Treatment for Asymptomatic Bacteriuria in Kidney Transplants • ofid • 7 The identification and antibiotic susceptibility of in the antibiotic treatment groups in both the ITT and the PP microorganisms isolated in urine cultures of patients with AB populations. (Table 5) are detailed in Table 5 for the ITT and PP populations. The most Antibiotic Treatment for Asymptomatic Bacteriuria frequent microorganism in each group was Escherichia coli, The antibiotics prescribed by isolate susceptibility in urine followed by Klebsiella pneumoniae and Enterococcus faecalis. cultures are detailed in Table 5 for the ITT and the PP The number of KT recipients who experienced an extended- populations. No serious adverse reactions were associated with spectrum beta-lactamase (ESBL)-producing bacteria at some any antibiotic prescriptions in patients with AB. point during the study follow-up was 8 (19.5%) in treatment Downloaded from https://academic.oup.com/ofid/article/6/6/ofz243/5494787 by Universitat Autònoma de Barcelona user on 11 February 2022 group versus 7 (15.2%) in no treatment group of AB in the ITT population and 5 (17.2%) in treatment group versus 6 (13.3%) DISCUSSION in no treatment group of AB in the PP population. When all In this noninferiority, multicenter RCT of KT recipients with isolates of AB episodes were considered, fosfomycin-resistant AB, we found no significant differences in the incidence of isolates (22.7% vs 12.4% in the ITT population; P = .030, and AGP in the first year after transplantation between a group 23.4% vs 10.2% in the PP population; P = .007), ESBL-producing receiving antibiotic treatment and a group receiving no treat- Enterobacteriaceae (24.5% vs 13.3% in the ITT population; ment. However, antibiotic susceptibility testing suggests P = .044, and 21.1% vs 11.0% in the PP population; P = .067), that this approach may increase antibiotic resistance rates. and amoxicillin-clavulanate resistant Enterobacteriaceae However, our findings should be regarded with caution due (52.1% vs 26.7% in the ITT population; P < .001, and 51.3% to the small sample size analyzed that confers low level of vs 22.0% in the PP population; P < .001) were more common statistical power. Table 5. Isolated Microorganisms, Susceptibility Patterns, and Antibiotics Administered in Asymptomatic Bacteriuria Episodes in Intention-to-Treat and in Per-Protocol Population Intention-to-Treat Population Per-Protocol Population Antibiotic No Antibiotic No Treatment Treatment of Treatment Treatment of AB AB of AB of AB 119 Isolates 137 Isolates 92 Isolates 128 Isolates n (%) n (%) n (%) n (%) Isolated microorganisms in urine samples of AB episodes Gram negative 102 113 81 107 Escherichia coli 43 (36.1) 74 (54.0) 40 (43.5) 71 (55.4) Klebsiella pneumoniae 37 (31.1) 24 (17.5) 26 (28.2) 24 (18.7) Enterobacter aerogenes 6 (5.0) 2 (1.5) 5 (5.4) 2 (1.6) Morganella morganii 4 (3.3) 2 (1.5) 2 (2.2) 0 Proteus mirabillis 3 (2.5) 2 (1.5) 2 (2.2) 2 (1.6) Other enterobacteriaceae 1 (0.8) 1 (0.7) 1 (1.1) 1 (0.7) Pseudomonas aeruginosa 8 (6.7) 8 (5.8) 5 (5.4) 7 (5.5) Gram positive 17 24 11 21 Enterococcus faecalis 13 (10.9) 19 (13.8) 8 (8.7) 17 (13.3) Enterococcus faecium 1 (0.8) 1 (0.7) 1 (1.1) 1 (0.7) Other Gram-positive microorganisms 3 (2.5) 4 (2.9) 2 (2.2) 3 (2.3) Antibiotic susceptibility of isolated microorganisms in urine samples of AB episodes Ciprofloxacin resistant Gram-negative bacilli 61/102 (59.8) 73/113 (64.6) 48/81 (59.2) 62/107 (57.9) Fosfomycin-resistant microorganisms 27/119 (22.7) 17/137 (12.4) 22/94 (23.4) 13/128 (10.2) TMP-SMX–resistant enterobacteriaceae 78/94 (82.9) 77/105 (73.3) 62/76 (81.6) 67/100 (67.0) Amoxicillin-clavulanate–resistant enterobacteriaceae 49/94 (52.1) 28/105 (26.7) 39/76 (51.3) 22/100 (22.0) ESBL-producing enterobacteriaceae 23/94 (24.5) 14/105 (13.3) 16/76 (21.0) 11/100 (11.0) MDR Pseudomonas aeruginosa 4/8 (50.0) 5/8 (62.5) 3/5 (60.0) 4/7 (57.1) Antibiotics administered for asymptomatic bacteriuria episodes Cefuroxime 17 1 16 0 Amoxicillin-clavulanate 8 0 8 0 Ciprofloxacin 20 0 18 0 Fosfomycin 32 4 30 0 Abbreviations: AB, asymptomatic bacteriuria; ESBL, extended-spectrum beta-lactamase; MDR, multidrug resistant; TMP-SMX, trimethoprim-sulfamethoxazole. 8 • ofid • Sabé et al Some retrospective studies have shown a higher incidence of physicians of considering and treating positive urine culture subsequent AGP in KT recipients with AB, even though anti- results in asymptomatic patients, especially when the utility biotic treatment was given at the asymptomatic stage [26, 27]. of this practice is not clearly established. Protocol deviations Increased urine cytokines have also been documented in KT were due to failure in revising urine culture results in some recipients with AB, suggesting that it may reflect an occult in- cases by the attending physician and, in a few cases, isolation of flammatory process in the renal allograft [28, 29]. Given that microorganisms without oral antibiotic treatment options. AB in KT recipients has therefore been associated with the In conclusion, our results suggest that antibiotic treatment of development of symptomatic infection, other retrospective AB has no use in the prevention of AGP among KT recipients Downloaded from https://academic.oup.com/ofid/article/6/6/ofz243/5494787 by Universitat Autònoma de Barcelona user on 11 February 2022 studies have assessed the usefulness of giving antibiotics to after urinary catheters are removed in the first year after trans- KT recipients with AB. However, results have been conflicting. plantation. In addition, antibiotic treatment of AB may increases Although some authors have shown that antibiotic therapy antibiotic resistance in urine isolates. However, the study limita- may prevent symptomatic urinary infections [30], others have tions regarding sample size require further randomized studies shown no differences in the progression toward symptomatic to corroborate our findings. infection between treated and untreated AB episodes [31, 32]. Acknowledgments Moreover, other research has observed a higher risk of symp- N.S., J.M.C., and J.C. participated in the performance of the research, tomatic infections in KT recipients receiving antibiotic therapy research design, writing the article, and data analysis. I.O., E.M., O.L., and for AB [33]. In a recent RCT comparing antibiotic treatment F.M. participated in performance of the research, writing the article, and with no treatment for AB in 112 KT recipients beyond the data analysis. I.L.A., M.P., Ll.R., and A.M. participated in performance of the research and data analysis. C.P. participated in performance of the second month after transplantation, no differences were seen research and research design; D.G. participated in performance of the re- in the incidence of AGP or lower urinary tract infections [25]. search; and C.T. participated in data analysis. It has been suggested that rejection and allograft dysfunc- Financial support. This study was supported by a grant from Fondo de Investigaciones Sanitarias (FIS PI11 1540) and by the Plan Nacional tion may be associated with urinary infections [4, 5, 8–11]. de I+D+i and the Instituto de Salud Carlos III, Subdirección General de Nevertheless, antibiotic treatment of AB had no benefit in the Redes y Centros de Investigación Cooperativa, Ministerio de Economía incidence of rejection or allograft function within the first year y Competitividad, and the Spanish Network for Research in Infectious Diseases (REIPI RD12/0015; REIPI RD16/0016), which is co-financed after transplantation in our trial. Our findings concur with by European Development Regional Fund’s “A Way to Achieve Europe.” those encountered by other investigators [25, 31–33]. I.O. also received a research grant from the University of Barcelona. The selection of MDR organisms by the widespread use of Potential conflicts of interest. All authors: No reported conflicts of antibiotics is of increasing concern. Given the high prevalence of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to AB in KT recipients, antibiotic treatment in these cases could sig- the content of the manuscript have been disclosed. nificantly affect antimicrobial resistance rates in this vulnerable population. We observed higher antibiotic resistance rates in the References urine isolates of KT recipients who received treatment for AB more 1. Sorto R, Irizar SS, Delgadillo G, Alberú J, Correa-Rotter R, Morales- Buenrostro LE. Risk factors for urinary tract infections during the first year after often than in those who did not receive treatment and this differ- kidney transplantation. Transplant Proc 2010; 42:280–1. ence was not observed in the first episode of AB. However, this 2. Säemann M, Hörl WH. Urinary tract infection in renal transplant recipients. Eur J Clin Invest 2008; 38(Suppl 2):S58–65. finding does not allow for firm assertions due to the small number 3. Muñoz P. Management of urinary tract infections and lymphocele in renal trans- of patients included. Moreover, this conflict with data from a pre- plant recipients. Clin Infect Dis 2001; 33(Suppl 1):S53–7. 4. Valera B, Gentil MA, Cabello V, Fijo J, Cordero E, Cisneros JM. Epidemiology of vious study [25], in which higher antibiotic resistance rates were urinary infections in renal transplant recipients. Transplant Proc 2006; 38:2414–5. not seen in the isolates from KT recipients treated for AB. 5. Fiorante S, Fernández-Ruiz M, López-Medrano F, et al. Acute graft pyelonephritis in renal transplant recipients: incidence, risk factors and long-term outcome. Our study had some limitations that should be acknowl- Nephrol Dial Transplant 2011; 26:1065–73. edged. A percentage of KT during the study period were not 6. Linares L, García-Goez JF, Cervera C, et al. Early bacteremia after solid organ transplantation. Transplant Proc 2009; 41:2262–4. eligible due to inclusion in other trials, mainly related to immu- 7. Silva M Jr, Marra AR, Pereira CA, Medina-Pestana JO, Camargo LF. Bloodstream nosuppressive therapies. The planned study sample size was not infection after kidney transplantation: epidemiology, microbiology, associated achieved, in part, because the expected incidence of AGP was risk factors, and outcome. Transplantation 2010; 90:581–7. 8. Dupont PJ, Manuel O, Pascual M. Infection and chronic allograft dysfunction. overestimated during study design. The low incidence of AGP Kidney Int 2010; 78(Suppl 119):S47–53. in KT recipients documented in the study could be explained 9. Pellé G, Vimont S, Levy PP, et al. Acute pyelonephritis represents a risk factor impairing long-term kidney graft function. Am J Transplant 2007; 7:899–907. as only patients without urinary catheters were included and, 10. Kamath NS, John GT, Neelakantan N, Kirubakaran MG, Jacob CK. Acute graft in addition, KT recipients with urological complications were pyelonephritis following renal transplantation. Transpl Infect Dis 2006; 8:140–7. 11. Lorenz EC, Cosio FG. The impact of urinary tract infections in renal transplant excluded. We know the small sample size limits any categorical recipients. Kidney Int 2010; 78:719–21. conclusion about the results. Second, there was poor protocol 12. Origüen J, Fernández-Ruiz M, López-Medrano F, et al. Progressive increase of re- sistance in Enterobacteriaceae urinary isolates from kidney transplant recipients compliance for KT recipients with AB assigned to the antibi- over the past decade: narrowing of the therapeutic options. Transpl Infect Dis otic treatment group, reflecting the inconvenience for attending 2016; 18:575–84. Treatment for Asymptomatic Bacteriuria in Kidney Transplants • ofid • 9 13. Bodro M, Sanclemente G, Lipperheide I, et al. Impact of antibiotic resistance on 22. Parasuraman R, Julian K; AST Infectious Diseases Community of Practice. the development of recurrent and relapsing symptomatic urinary tract infection Urinary tract infections in solid organ transplantation. Am J Transplant 2013; in kidney recipients. Am J Transplant 2015; 15:1021–7. 13(Suppl 4):327–36. 14. Alevizakos M, Nasioudis D, Mylonakis E. Urinary tract infections caused by 23. Nicolle LE, Gupta K, Bradley SF, et al. Clinical practice guideline for the manage- ESBL-producing Enterobacteriaceae in renal transplant recipients: a systematic ment of asymptomatic bacteriuria: 2019 update by the Infectious Diseases Society review and meta-analysis. Transpl Infect Dis 2017; 19:e12759. of America [published online ahead of print March 21, 2019]. Clin Infect Dis 15. Cervera C, van Delden C, Gavaldà J, Welte T, Akova M, Carratalà J; ESCMID Study 2019; doi:10.1093/cid/ciy1121. Group for Infections in Compromised Hosts. Multidrug-resistant bacteria in solid 24. Goldman JD, Julian K. Urinary tract infections in solid organ transplant organ transplant recipients. Clin Microbiol Infect 2014 (Suppl 7); 20:S49–73. recipients: guidelines from the American Society of Transplantation Infectious 16. Coussement J, Abramowicz D. Should we treat asymptomatic bacteriuria after Diseases Community of Practice [published online ahead of print February renal transplantation? Nephrol Dial Transplant 2014; 29:260–2. 21, 2019]. Clin Tranplant 2019; doi:10.1111/ctr.13507. 17. Coussement J, Scemla A, Abramowicz D, Nagler EV, Webster AC. Antibiotics for 25. Origüen J, López-Medrano F, Fernández-Ruiz M, et al. Should asymptomatic bac- Downloaded from https://academic.oup.com/ofid/article/6/6/ofz243/5494787 by Universitat Autònoma de Barcelona user on 11 February 2022 asymptomatic bacteriuria in kidney transplant recipients. Cochrane Database teriuria be systematically treated in kidney transplant recipients? Results from a Syst Rev 2018; 2:CD011357. randomized controlled trial. Am J Transplant 2016; 16:2943–53. 18. Coussement J, Maggiore U, Manuel O, et al; European Renal Association- 26. Fiorante S, López-Medrano F, Lizasoain M, et al. Systematic screening and treat- European Dialysis Transplant Association (ERA-EDTA) Developing Education ment of asymptomatic bacteriuria in renal transplant recipients. Kidney Int 2010; Science and Care for Renal Transplantation in European States (DESCARTES) 78:774–81. Working Group and the European Study Group for Infections in Compromised 27. Gołębiewska JE, Dębska-Ślizień A, Rutkowski B. Treated asymptomatic bac- Hosts (ESGICH) of the European Society of Clinical Microbiology and Infectious teriuria during first year after renal transplantation. Transpl Infect Dis 2014; Diseases (ESCMID). Diagnosis and management of asymptomatic bacteriuria in 16:605–15. kidney transplant recipients: a survey of current practice in Europe. Nephrol Dial 28. Ciszek M, Paczek L, Bartłomiejczyk I, Mucha K. Urine cytokines profile in Transplant 2018; 33:1661–8. renal transplant patients with asymptomatic bacteriuria. Transplantation 2006; 19. Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. 81:1653–7. KDIGO clinical practice guideline for the care of kidney transplant recipients. Am 29. Sadeghi M, Daniel V, Naujokat C, et al. Strong inflammatory cytokine response J Transplant 2009; 9(Suppl 3):S1–55. in male and strong anti-inflammatory response in female kidney transplant 20. Nicolle LE, Bradley S, Colgan R, Rice JC, Schaeffer A, Hooton TM; Infectious recipients with urinary tract infection. Transpl Int 2005; 18:177–85. Diseases Society of America; American Society of Nephrology; American 30. Kotagiri P, Chembolli D, Ryan J, Hughes PD, Toussaint ND. Urinary tract Geriatric Society. Infectious Diseases Society of America guidelines for the diag- infections in the first year post-kidney transplantation: potential benefits of nosis and treatment of asymptomatic bacteriuria in adults. Clin Infect Dis 2005; treating asymptomatic bacteriuria. Transplant Proc 2017; 49:2070–5. 40:643–54. 31. Moradi M, Abbasi M, Moradi A, Boskabadi A, Jalali A. Effect of antibiotic therapy 21. Vidal E, Cervera C, Cordero E, et al; Study Group of Infection in Transplant on asymptomatic bacteriuria in kidney transplant recipients. Urol J 2005; 2:32–5. Recipients (GESITRA) of the Spanish Society of Infectious Diseases, Clinical 32. El Amari EB, Hadaya K, Bühler L, et al. Outcome of treated and untreated asymp- Microbiology (SEIMC), Spanish Network for Research in Infectious Diseases tomatic bacteriuria in renal transplant recipients. Nephrol Dial Transplant 2011; (REIPI). Executive summary. Management of urinary tract infection in solid organ 26:4109–14. transplant recipients: consensus statement of the Group for the Study of Infection 33. Green H, Rahamimov R, Goldberg E, et al. Consequences of treated versus un- in Transplant Recipients (GESITRA) of the Spanish Society of Infectious Diseases treated asymptomatic bacteriuria in the first year following kidney transplan- and Clinical Microbiology (SEIMC) and the Spanish Network for Research in tation: retrospective observational study. Eur J Clin Microbiol Infect Dis 2013; Infectious Diseases (REIPI). Enferm Infecc Microbiol Clin 2015; 33:680–7. 32:127–31. 10 • ofid • Sabé et al