|Year : 2022 | Volume
| Issue : 5 | Page : 82-88
Expert group opinion for urinary tract infection in solid organ transplant recipients in South Asia
Sishir Gang1, Abhyuday Rana2, Shyam Bihari Bansal2
1 Department of Nephrology, Muljibhai Patel Urological Hospital, Nadiad, Gujarat, India
2 Department of Nephrology and Renal Transplant Medicine, Medanta Kidney and Urology Institute, Medanta Medicity, Gurugram, Haryana, India
|Date of Submission||29-Oct-2021|
|Date of Acceptance||14-Feb-2022|
|Date of Web Publication||18-Oct-2022|
Dr. Sishir Gang
Department of Nephrology, Muljibhai Patel Urological Hospital, Nadiad - 387 001, Gujarat
Source of Support: None, Conflict of Interest: None
Urinary tract infection (UTI) is one of the common infections in solid organ transplant recipients and the most common infection in kidney transplant recipients. UTI in the early posttransplant period is associated with significant morbidity and graft dysfunction. Female gender, advanced age, presence of urinary tract abnormalities, and diabetes mellitus are some of the risk factors for UTI. The emergence of multi-drug resistant bacteria has made the treatment difficult and one needs to be aware of the local antibiotic resistance pattern when treating empirically. These patients should be treated adequately and those with recurrent UTI would need long-term prophylaxis. Asymptomatic bacteriuria should only be treated if it occurs within the first 2–3 months of transplant, otherwise, it can lead to the emergence of the resistant organism without any benefit. To reduce the risk of UTI after transplant, the Foley's catheter should be removed within 3–5 days, DJ stent should be removed within 2–3 weeks and the recipient should be kept on routine prophylaxis for 6 months.
Keywords: Kidney transplant, solid organ transplant, South Asia, urinary tract infection
|How to cite this article:|
Gang S, Rana A, Bansal SB. Expert group opinion for urinary tract infection in solid organ transplant recipients in South Asia. Indian J Transplant 2022;16, Suppl S1:82-8
|How to cite this URL:|
Gang S, Rana A, Bansal SB. Expert group opinion for urinary tract infection in solid organ transplant recipients in South Asia. Indian J Transplant [serial online] 2022 [cited 2022 Dec 9];16, Suppl S1:82-8. Available from: https://www.ijtonline.in/text.asp?2022/16/5/82/358657
| Introduction|| |
Urinary tract infection (UTI) is a common infection in solid organ transplant (SOT) recipients and the most frequent infectious complication in kidney transplant recipients (KTRs)., UTI continues to be the major cause of morbidity and graft dysfunction in the early postoperative period., In the multicenter RESITRA registry, the incidence of bacterial UTIper 100 transplantation-days was 4.5 for kidney, 2.2 for kidney-pancreas, 0.6 for liver, 0.7 for heart, and 0.2 for lung transplant recipients. In view of the emergence of antibiotic-resistant organisms, it is desirable to develop strategies for the prevention and appropriate treatment of this infection. This review will provide current knowledge about epidemiology, risk factors, treatment and prevention of UTI in SOT recipients with particular emphasis on KTRs.
| Definitions|| |
The definition of UTI in SOT recipients is similar to those in the general population. However, all symptomatic UTI whether lower or upper tract is considered complicated UTI. The definitions provided in [Table 1] are adapted from reference.
| Epidemiology|| |
The reported incidence of UTI infection in KT recipients varies from 23% to 75%. This wide variation is probably due to non-uniform diagnostic criteria, different antibiotic prophylaxis regimens, varying duration of follow-up, immunosuppressive regimen, and clustering of infections due to local outbreaks. About 30% of all hospitalizations for sepsis in KTRs are due to UTI of which 80% occur within the first 3 months and are associated with poor graft function. Late infections are more frequent in women compared to men. The prevalence of recurrent UTIs varies from 4% to 10%. Two recent studies from North and South India showed UTI prevalence of 32.86% and 41.9%, respectively, among KTR.,
| Risk Factor for Urinary Tract Infection|| |
The risk factors for the development of post-transplant UTI in SOT recipients are multifactorial and are determined by the interaction between host factors, pathologic agents, anatomical abnormalities, pre-transplant patient characteristics, the donor source, peri-operative need for catheterization, and immunosuppression. The risk factors for UTI can be classified into pretransplant and post-transplant and are listed in [Table 2]. Both female gender and advanced age are suggested to be risk factors for UTI in pre- and posttransplant period, however, there are conflicting data about it., Diabetes mellitus is not only associated with bacterial infection but is also an important risk factor for Candida albicans infection.
|Table 2: Risk factors for urinary tract infection in renal transplant recipient|
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The other pretransplant risk factor for posttransplant UTI are recurrent UTI before transplant, urological abnormalities in the recipient, and polycystic kidney diseases.
Deceased donor and use of expanded criteria donor are risk factors found to be associated with increased risk of UTI. In KTRs, unlike native ureters, the transplant ureter is short and often refluxing. This increases the risk of pyelonephritis. Prolonged bladder catheterization, problems in the ureteral anastomosis, and ureteral stenting for a period greater than 4 weeks is associated with increased risk of UTI, hence early removal is recommended.
Apart from recipient characteristics and peri-operative factors, the dose and type of immunosuppression also determine the risk of UTI. The use of mycophenolate mofetil and anti-thymocyte globulin has been found to be associated with increased risk of UTI., Episodes of delayed graft function or rejection and need for additional immunosuppression also predispose to UTI. Serum creatinine levels >2 mg/dL and prednisone dose >20 mg/d are considered risk factors for late UTI (>6 months post-transplantation).
| Microbiology|| |
Gram-negative organisms are the predominant cause of UTI in KTRs. Escherichia coli is the most common organism followed by Klebseilla pneumonia, Pseudomonasaeruginosa, Enterococcus, Enterobacter cloacae, and Proteus sp. Gram-positive bacteria such as Staphylococcus saprophyticus, Streptococcus species, and Corynebacteriumurealyticum can occasionally cause UTIs. In a study by Hase et al., the most common organism isolated for complicated UTI from a single center from India was E. coli (53%) followed by Klebsiella pneumoniae (24.40%), Enterococcus (12.24%), Pseudomonas (4.08%), candida in two (4.08%), and Proteus (2%).
C. albicans is the predominant fungus responsible for UTI in KT recipients, most notably in diabetic recipients. Candiduria though frequent is often asymptomatic, however rarely it causes ascending infection, obstruction due to fungal balls and candidemia.
BK virus (BKV) is an important pathogen in KT recipients but largely remains asymptomatic except in the setting of ureteral stenosis. Although BKV associated hemorrhagic cystitis is well-described in hematopoietic stem cell transplant recipients, this is relatively uncommon in KT recipients.
In the last decade, with the widespread use of antibiotics in the community and hospital setting there has been an increased incidence of multi-drug resistance bacteria in transplant patients. In the Spanish registry study RESTIRA, 26% of symptomatic E. coli infections were caused by ESBL (Extended Spectrum Beta Lactamases)-producing organisms. The study from Brazil also shows 45% incidence of ESBL-producing organisms, especially in those with recurrent UTI. Similar study in complicated UTIs from India revealed 58% of isolates were ESBL producers, whereas 4% were pan resistant. Recent meta-analysis by Michail has shown that one in ten transplant patients will develop UTI with ESBL-producing organism with increased risk of recurrence. There are several reports of Carbapenem-resistant Klebsiella pneumonia UTI in SOT. They are not only associated with recurrent UTIs but are also often the cause of mortality.,
| Clinical Manifestations|| |
Clinical presentation can vary from asymptomatic bacteriuria (AB) to complicated acute pyelonephritis.
AB is the presence of > 105 bacterial colony-forming units per milliliter (CFU/mL) in the urine without urinary or systemic symptoms which mostly signifies contamination or colonization.
Simple cystitis is positive urine culture (>103 CFU/ml) and lower urinary symptoms such as dysuria, frequency, or urgency but no systemic symptoms and no indwelling device. Complicated UTI/pyelonephritis includes significant growth of a uropathogen (104 CFU/ml) and at least one of the following: fever, chills, graft tenderness, hemodynamic instability, leukocytosis, or evidence of bacteremia with the same organism as in the urine culture or associated prostatitis. UTIs associated with structural or functional abnormalities of the genitourinary tract, indwelling ureteric stents, bladder catheters, or nephrostomy tubes are also included in complicated UTIs. All patients with any systemic symptoms are classified as complicated UTIs. Recurrent UTI includes ≥3 UTIs (/reinfection/relapse) in the prior 12-month period.
In general, these UTIs are associated with >10WBCs/mm3 in urine but <10 WBCs does not rule out UTI. It is important to note that signs and symptoms of UTIs may be subtle in transplant recipients due to the immunosuppressants and being a denervated graft. Hence, a thorough clinical and laboratory evaluation is needed and any new febrile illness with asymptomatic rise of creatinine should prompt a search for UTI, even in absence of urinary tract specific symptoms [Table 1].
| Diagnosis of Urinary Tract Infection|| |
Definitive diagnosis of UTI requires microbiological confirmation by urine culture. Midstream urine specimen should be obtained, after cleaning the perineum/glans with antiseptic wipes, in a sterile container. In patients unable to provide midstream specimen, straight catheterization for obtaining urine specimen is also an appropriate option. For patients with short-term indwelling catheters, the sample should be obtained by puncturing the catheter port. For the patient with long-term indwelling catheter, a midstream urine sample should be obtained after removing the catheter or from the newly placed catheter.
| Screening|| |
Though many transplant centers routinely screen for the presence of AB, the data supporting the benefit of this practice is uncertain. If screening is undertaken, it should be limited to the first three months following the kidney transplant. This will avoid unnecessary treatment and selection of drug-resistant bacteria. The American Society of Transplantation Infectious Diseases Community of Practice advises not to treat ASB occurring more than 3 months after KT unless there is an increase in serum creatinine. Most centers recommend screening for ASB every 2–4 weeks till 12 weeks posttransplant.
| Diagnosis|| |
The standard quantitative criterion for the diagnosis of UTI with voided specimens is an organism count of ≥105 CFU/mL of a potential uro-pathogen. In patients with UTI, pyuria should be present on urine microscopy. A Patient with UTI should undergo appropriate imaging studies. Ultrasound or noncontrast computed tomography (CT) scan should be done to rule out any structural abnormalities. Uroflowmetry and in men trans-rectal sonography should be done to rule out outflow obstruction.
- Urine culture collection technique is important. A midstream urine sample is collected in a sterile container after the use of antiseptic wipes to clean the perineum/glans
- In patients unable to perform these steps, straight catheterization to obtain a urine specimen can be considered. For patients with indwelling catheters (>2 weeks), the sample should be obtained from after removing the catheter or after inserting the new catheter
- Transplant patients should not be screened for AB
- For diagnosis of UTI, urine culture should be positive with >105 CFU/ml with pyuria in urine analysis
- UTI in a transplant patient requires appropriate imaging studies/uroflowmetry to rule out structural abnormality.
| Treatment of Urinary Tract Infection|| |
Treatment of UTI in posttransplant period depends on the symptomatology, duration after transplantation, site, and severity of infection. However, it must be borne in mind that in view of the immunosuppressed state the correlation between symptoms, signs, and effect on graft function may be poor. The choice of anti-bacterial treatment is guided by the local epidemiology, culture, and sensitivity of the infecting organism. In patient with sepsis, reduction or discontinuation of anti-proliferative immunosuppression should be considered. Imaging studies (ultrasound/CT scan/transrectal sonography) and uroflowmetry should be done to determine any structural or functional abnormality of the urogenital system.
| Asymptomatic Bacteriuria|| |
AB is common after kidney transplant. It was believed, albeit with limited evidence that it is a risk factor for progression to UTI, graft pyelonephritis, graft dysfunction, and graft loss.
Two recent prospective studies did not show any benefit of treating AB., Among the retrospective studies the outcome has been mixed. Some report possible benefits and some report either no benefit or possible harm in form of selecting drug-resistant strains.,,,,
Most trials have excluded patients in the first 1 to 3 months following kidney transplant. In view of inadequate data and theoretical concerns about progression to symptomatic UTI or graft dysfunction, it may be prudent to treat AB in the early months following transplantation, especially if they are associated with pyuria. After 3 months it is not recommended to screen for or treat AB. Treating such patients risks the selection and emergence of more resistant organisms, however an exception can be made for the treatment of persistent ASB in patients with, who develop impairment of renal function due to the rare occurrence of asymptomatic pyelonephritis.
| Symptomatic Urinary Tract Infection|| |
Urine analysis, urine, and blood cultures should be drawn to determine antibiotic susceptibility, before the administration of antibiotics. Urinary catheters should be preferably removed or changed. Ultrasound of the graft and native kidney should be done to rule out structural abnormalities and asses post void residue. Choice of empiric antibiotics should be based on the local epidemiology of resistance and prior susceptibilities in previous episodes of UTI. Once the antibiotic susceptibilities are known, the therapy should be de-escalated to the narrowest spectrum.
For patients with cystitis and no evidence of systemic effects such as fever, leukocytosis, allograft tenderness, or graft dysfunction, an oral antibiotic is suitable. Either oral fluoroquinolone, oral third-generation cephalosporin, nitrofurantoin are appropriate choices. The duration of treatment should be 7–10 days. Single-dose or short course of 3 days is not preferred. In view of increasing resistance to the above medications, oral fosfomycin (3-gram powder of fosfomycin dissolved in a glass of water), two or three doses given 48 h apart is preferred by many transplant physicians. However, in view of limited oral options and increasing resistance fosfomycin should be used only if other options are not available.,,,
For patients with severe infection, the initial choice of antibiotics is intravenous third-generation cephalosporin (cefaperazone, ceftazidime) or piperacillin/tazobactam or a carbapenem (meropenem or doripenem).
Further, the incidence of multi-drug resistant UTIs is growing. They are associated with increased mortality, graft failure, and recurrence., For these patients, a combination therapy is indicated. A regimen combining a carbapenem plus one or two fully active drugs (including colistin, an aminoglycoside, or fosfomycin) is recommended if carbapenem minimum inhibitory concentration (MIC) is <8 mg/L. Carbapenems are not recommended if the MIC is >16 mg/L. Between 8 and 16, the role of carbapenem is uncertain.
| Recurrent Urinary Tract Infection|| |
Thorough evaluation should be undertaken to rule out any structural or functional abnormality of the urinary tract [Figure 1]. Prostate and native kidney as a source of infection should also be considered. In patients with autosomal dominant kidney disease, PET scans may be done to look for infected cysts.
|Figure 1: Evaluation of recurrent urinary tract infection in kidney transplant recipient|
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Both urine and blood cultures should be drawn. Intravenous third-generation cephalosporin or carbapenem should be initiated. The choice may take into consideration the bacteriology and susceptibility of the previous episode. The duration of antibiotics is uncertain but many experts believe that a course of 4–6 weeks should be administered.
To prevent recurrent UTI in women they should be counseled about frequent voiding, adequate hydration and to void after sexual intercourse.
Consideration may be given to use low-dose nitrofurantoin or trimethoprim for long-term prophylaxis. Attempts should be made to stop and observe for relapse after 3–6 months. Long-term prophylaxis is required in many patients as stoppage is associated with relapse.
- AB in transplant recipients should not be treated after 3 months posttransplant
- Choice of empiric antibiotics for treatment of UTI should be based on the local epidemiology of resistance and prior susceptibilities in previous episodes of UTI. Once the antibiotic susceptibilities are known, the therapy should be de-escalated to the narrowest spectrum
- Patients with cystitis only should be treated with oral antibiotics for 7–10 days
- Patients with pyelonephritis/complicated UTI need intravenous treatment for 2–3 weeks
- For multidrug-resistant UTI, regimen combining a carbapenem plus one or two fully active drugs (including colistin, an aminoglycoside, or fosfomycin) is recommended
- Patients with recurrent UTI need a thorough evaluation for lower urinary tract to rule out any structural/functional abnormality
- A longer 4–6 weeks course of antibiotics can be considered in patients with recurrent UTI. Consideration may be given to use low dose nitrofurantoin or trimethoprim for long term prophylaxis
| Prevention of Urinary Tract Infection|| |
Longer the duration of urinary catheterization higher the incidence of UTI. Early removal of the urinary catheter within 3–5 days has been associated with reduced rates of early UTI.,, Antibiotic administration before catheter removal may help to reduce the rate of UTI.
Meta-analysis of randomized control trials recommends the routine use of a prophylactic transplant ureteric stent to reduce major urological complications, although at a slightly higher risk of UTI infection. Early removal, within 2 weeks, may mitigate this problem to some extent.
| Prophylactic Antibiotics|| |
Trimethoprim/sulfamethaxazole (TMP) SMX) which is recommended as prophylaxis against Pneumocystis jirovecii pneumonia for the first 6–12 months, is also helpful to prevent UTI. However, its role is uncertain now with widespread resistance to TMP/SMX. Nitrofurantoin or ciprofloxacin may be considered if the patient is allergic to TMP/SMX. The use of long-term prophylaxis was found to be useful in one study, however it is not supported by others due to fear of the increased risk of resistance and is not recommended at present.
| Screening for Urinary Tract Infection in Transplant Candidates and Donors|| |
A thorough history of urinary complaints such as dysuria, double voiding, straining, incomplete voiding, fever, history of previous urological procedures should be sought from the recipients. Urine routine, culture, and an ultrasound KUB are done in all prospective transplant recipients and donors before taking for surgery. Any symptomatic episode of UTI should be adequately treated in donor or recipient before taking them for surgery. Recipients without any previous history of UTI, normal urine examination, and normal imaging require no further work-up. Patients with a history of UTI, abnormal USG (dilated ureter, kidney stones, bladder abnormalities) should be further evaluated with noncontrast/contrast CT of KUB for stone and hydronephrosis, micturating cystourethrogram in case of dilated ureters or abnormal bladder to rule out reflux/urethral stricture/posterior urethral valve. An uroflow and bladder scan should be done in patients with a history of long-standing diabetes or if suspicion of neurogenic bladder, however sometimes it might not be possible due to small urine output, then one might need urodynamic studies to know the status of the bladder.
- Early urinary catheter removal, i. e., within 3–5 days posttransplant and early ureteric stent removal, i. e., within 2–3 weeks should be considered to decrease the chances of posttransplant UTI
- TMP/SMX prophylaxis first 6–12 months posttransplant might help reduce the incidence of early posttransplant UTI. Nitrofurantoin or ciprofloxacin may be considered if the patient is allergic to TMP/SMX.
| Conclusions|| |
UTI is a common infection in SOT recipients and is the most frequent bacterial complication following kidney transplantation. It is associated with significant morbidity and has an impact on graft function. Early in the transplant period, AB may be treated, however, it is not recommended to screen or treat AB after 3 months of transplantation. Symptomatic UTI should be promptly treated with narrow-spectrum culture-sensitive antibiotics. Multidrug-resistant organism requires combination therapy. Thorough evaluation should be undertaken in patient with recurrent infection for structural or functional abnormality of the urinary tract. Preventive strategies, especially reducing the duration of indwelling tubes are important to prevent UTIs. There are still many controversial issues in posttransplant UTI and future research should be directed to see any benefit of long-term prophylaxis, follow-up of AB, use of combination therapy for MDR UTI, and role of the urinary microbiota in relation to UTI.
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Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2]