What are the best strategies for Urinary Tract Infections and asymptomatic bacteriuria in patients with a renal transplantation?
No recommendation can be made about screening and treatment of ASB in renal transplant patients. Experts are of the opinion that it may be appropriate to screen and start treatment for bacteriuria in the early postoperative period and up to 6 months post transplant.
Prophylaxis given for Pneumocystis jiroveci with low-dose TMP-SMX reduces the risk of early UTI and is recommended for the first 6-9 months after renal transplantation.
Treatment of UTI in renal transplant patients should be according to the general guidelines for treatment of complicated UTI, but in the first 3 months after transplantation empirical treatment with the combination of amoxicillin and ciprofloxacin is recommended.
No recommendation can be made about changing immunosuppressive drugs from one class to another to prevent a recurrence of UTI.
In the choice of antibiotics for treatment of recurrent UTI the increased risk for ESBL-related infections should be considered. Therefore, earlier culture results and fluoroquinolone use in the last < 30 days have to be checked.
Removal of the urinary catheter should be done as soon as appropriate.
In case of a UTI the JJ stent should be removed if possible and the urine must be cultured.
In patients with recurrent UTI further investigations for anatomical abnormalities, bladder dysfunction or infection of the native kidneys should be initiated.
It is important to note that several antimicrobial agents can interact with immunosuppressants, especially with calcineurine-inhibitors. Therefore, interactions have to be checked.
This guideline does not include individual introductions to each module. A general introduction can be found in the attachments under the heading 'related'.
UTI are the most common infectious complications after kidney transplantation [(118) B]. The highest incidence of UTI is in the first 3 months after transplantation [(119). A1].
Induction therapy with antithymocyte globulin compared to induction therapy with basiliximab increases the risk of UTI in the first year after transplantation, with similar graft and patient survival.. [(125) A2]
With the use of prophylaxis with TMP-SMX for PJP the incidence of UTI has decreased [(135) A1]
In a double-blind RCT prophylaxis with high-dose TMP-SMX (320/1600 daily in 2 gifts) decreased the incidence of UTI to 25% compared to 49% in the patients with a moderate (160/800 daily) or low dose (80/400 daily)[(138) A2].
ASB episodes are associated with pyelonephritis and with rejection [(134) B].
Treatment of ASB in renal transplants does not show any benefit on graft function [(134) B; (135) B].
A meta-analysis showed no significant difference in graft loss with prophylactic use of antibiotics in the first 6 months after renal transplantation. However, prophylaxis lowered the risk for developing sepsis with bacteremia by 87% (RR 0.13, 95% CI 0.02-0.7) and the risk for developing bacteriuria (symptomatic or asymptomatic) by 60% (RR 0.41, 95% CI 0.31-0.56) [(128) A1].
The most frequently isolated micro-organisms in the first 3 months after transplantation appear to be the Escherichia Coli , Pseudomonas aeruginosa and enterococci [(120) C; (130) C; (132) D].
Early (< 3 days) removal of urinary catheters reduces the risk of UTI in the post-transplantation period [(140) C; (141) D].
Early UTI in the first 6 months after transplantation are more commonly associated with pyelonephritis, bacteremia and relapse (127) D; (137) D].
Recurrent UTI and acute graft pyelonephritis are associated with a poorer graft and patient outcome [(130) C; (131) B; (129) A2].
The incidence of UTI with ESBL-producing micro-organisms increases with the number of recurrent UTI [(133) B].
Although cranberry juice may have some inhibitory effect on CYP3A activity, no interference with cyclosporine levels has been found [(142) C].
UTIs are the most common infectious complications after renal transplantation, accounting for 45-70% of all infections. The incidence of recurrent UTI (≥ 3 year) is reported to range from 6-18% (118).
The highest incidence of UTI is in the first 3 months after transplantation, which may be related to surgical trauma, presence of urinary catheters and ureteric stents, as well as high doses of immunosuppressive drugs (119). In several retrospective cohort studies the major risk factors for UTI include female gender, time on hemodialysis, diabetes mellitus, pretransplant UTIs, indwelling bladder catheters, anatomic abnormalities of the kidney, intra-operative ureteric stenting, rejection episodes, cytomegalovirus and BK virus infection, re-transplantation, polycystic kidney disease, postmortal donor, ASB and possibly the amount and kind of immunosuppression (120), (118), (121), (122).
Vesico-ureteric reflux (VUR) to the transplanted kidney appears to be a unique risk factor for this group of patients, occurring in 47% of transplant recipients with recurrent UTIs (118). This VUR is a consequence of the kidney transplantation surgery, which causes disruption of the normal valve of the ureteric orifice.
There are conflicting results on the role of immunosuppressive drugs in the risk of UTI in renal transplant patients. In one retrospective cohort study, treatment with mycophenolate mofetil was associated with a higher incidence of UTI compared to azathioprine-based therapy (123), whereas others found an increased incidence of UTI in azathioprine-treated patients (124). Induction therapy with antithymocyte globulin compared to induction therapy with basiliximab showed to increase the risk of UTI in the first year after transplantation, with similar graft and patient survival (125), (126).
No clinical data are available on the benefit of changing immunosuppressive drugs from one class to another to prevent one recurrence of UTI; therefore, no recommendations can be made on this topic.
Especially lower UTIs in the first 6 months after transplantation (early UTI) have a higher risk of complications, because these early infections are more commonly associated with pyelonephritis, bacteremia, and relapse (127), (128). Recurrent UTI, and especially acute graft pyelonephritis (AGPN) and bacteremia, are associated with a poorer graft and poorer patient outcome (129). In a prospective study in 177 renal transplant patients, AGPN did not alter graft or recipient survival but, compared to patients with uncomplicated UTIs, patients with AGPN exhibited a significant decrease in creatinine clearance, already detected after 1 year (MDRD-GFR: AGPN: 39.5 ± 12.5; uncomplicated UTI: 54.6 ± 21.7 mL/min/1.73 m2, P< 0.01) and still persistent (about 50%) 4 years after transplantation (130). This trend was also demonstrated in a large analysis of data from the United States Renal Data System (USRDS) in 28,942 patients (131). In that analysis, late UTI was significantly associated with an increased risk of subsequent death in Cox regression analysis (P < 0.001; adjusted hazard ratio [HR], 2.93; 95% confidence interval [CI], 2.22, 3.85); and adjusted HR for graft loss was 1.85 (95% CI, 1.29, 2.64). The association of UTI with death persisted after adjusting for cardiac and other infectious complications, and regardless of whether UTI was assessed as a composite of outpatient/inpatient claims, primary hospitalized UTI, or solely outpatient UTI.
The most frequently isolated micro-organisms in the first months after transplantation are E. coli, P. aeruginosa and enterococci (120), (130), (132). The risk for infection with ESBL-producing micro-organisms increases significantly with recurrent episodes of UTI, as shown in retrospective studies (133).
In a prospective analysis of urine cultures in 89 patients during 1 year after kidney transplantation, 151 episodes of bacteriuria were detected in 49 patients, of which 65% was ASB, 13% a lower UTI and 22% an upper UTI (Golebiewska et al. 2985-90). In a retrospective single-center study in 388 renal transplant patients bacteriuria was noted in 57% of the female and 21% of the male patients. Bacteriuria correlated positively with the dose of prednisolone and mycophenolate acid (122).
ASB can impair renal function in kidney transplant patients, probably due to cumulative inflammatory damage (132), (127).
In another retrospective study the impact of ASB on renal transplant outcome was analysed in 189 renal transplant recipients. A total of 2-5 ASB episodes were independent factors associated with pyelonephritis, whereas more than 5 episodes was a factor associated with rejection (134). Only a few studies have addressed the problem of ASB in renal transplant recipients; however, in neither of these studies were the frequency of ASB screening or the parameters to evaluate renal function specified. In a more recent study, no benefit on graft function was demonstrated by treatment of ASB (135).
With the use of antibiotic prophylaxis against Pneumocytis jiroveci pneumonia (PJP) with TMP-SMX the incidence of UTI has decreased (135).
A recent meta-analysis showed no significant difference in graft loss (risk ratio [RR] 0.99, 95% CI 0.91-1.81) with prophylactic use of antibiotics in the first 6 months after renal transplantation. However, prophylaxis lowered the risk for developing sepsis with bacteremia by 87% (RR 0.13, 95% CI 0.02-0.7) and the risk for developing bacteriuria (symptomatic or asymptomatic) by 60% (RR 0.41, 95% CI 0.31-0.56; 3 trials). Symptomatic UTI and pyelonephritis were not reported. No significant reduction was found in all-cause mortality, and adverse events rates and conflicting results were reported for the development of resistant bacteria (128). In most of the transplantation centers prophylaxis with TMP-SMX (480-960 mg once daily) for 6-12 months after the kidney transplant is used as PJP prophylaxis. This is in accordance with the recommendations of the guideline of the Kidney Disease: Improving Global Outcomes (KDIGO) from 2009 (136), because this prophylaxis showed to be beneficial also for prevention of UTI (137), (128), (138). Some studies showed a similar protection for UTI with the use of ciprofloxacin or 1 month ofloxacin prophylaxis after transplantation (139); however, this regimen does not protect against PJP.
In an RCT, trial prophylaxis with high-dose TMP-SMX (320/1600 daily in 2 gifts) decreased the incidence of UTI to 25% compared to 49% in the patients with a moderate (160/800 daily) or low dose (80/400 daily) (138).
Besides TMP-SMX prophylaxis, a good surgical technique and early removal of urinary catheters have a large impact on reducing the risk for UTI after kidney transplantation. Early removal (< 3 days) reduced the rate of UTI to 14%, compared to a rate of 74% in patients with a late removal (>7 days) of the urinary catheter (140), (141).
Recurrent UTI in renal transplant patients
Recurrent UTI (rUTI) in renal transplant patients is difficult to treat. The general recommendations for rUTI can also be applied for renal transplant patients, although none of these interventions (like cranberries or topical estragen) have been thoroughly studied in this group of patients. Although cranberry juice may have some inhibitory effect on CYP3A activity, no interference with cyclosporine levels has been found (142).
There is no specific literature concerning the choice of agent and duration of antibiotic treatment in renal transplant patients. Especially lower UTIs in the first 6 months after transplantation (early UTI) have a higher risk of complications, because these early infections are more commonly associated with pyelonephritis, bacteremia, and relapse (127), (128). For that reason it is recommended that all patients with UTIs in the first 6 months after renal transplantation with clinical and laboratory evidence suggestive of kidney allograft pyelonephritis, should be hospitalized and treated with intravenous antibiotics (KDIGO AmJ Transplant 2009;9(suppl 3):S59-62).
Although it seems reasonable that the immunodeficient state of the renal transplant patients plays an important role in the pathogenesis of recurrent UTI in these patients, no robust data are available on the best choice of immunosuppressive drugs in these patients, or possible benefits of switching between classes of immunosuppressive drugs.
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This guideline does not include evidence tables.
In general the treatment of UTI in renal transplant patients is not different from the treatment in non-transplants; for these patients we refer to the paragraph on empirical treatment and duration of treatment.
However, in the first 3 months after transplantation P. aeruginosa and enterococci are more frequently isolated and empirical treatment must cover these micro-organisms (120), (130), (132). Because of the nephrotoxicity of gentamicin, the Guideline committee recommends to cover these agents with a combination of amoxicillin and ciprofloxacin.
Prevention of UTI after kidney transplantation also needs a thorough management of structural and functional urinary tract abnormalities in the pre-transplant period, which sometimes even justifies nephrectomy of the native kidneys, especially in patients with recurrent UTI in polycystic kidney disease and in patients with VUR to their native kidneys.
In the face of a relapsing UTI in a renal transplant recipient, functional or anatomic abnormalities must be excluded (e.g. stone, obstructive uropathy, poorly functioning bladder, or urodynamic disorders following complication of ureterovesical anastomosis). The most common findings include ureteral reflux, strictures at the ureterovesical junction, neurogenic bladder, and subvesical obstruction, especially in men aged over 60 years. Early removal (< 3 days) of the catheter to reduce the rate of UTI is often not possible, because the junction between ureter and bladder is not healed 3 days after the transplantation (140), (141).
Evidence to support screening recommendations in the post renal transplant period is incomplete. Experts think that it may be appropriate to screen and start treatment for bacteriuria in the early postoperative period and up to 6 months post transplant. However, continued screening for and treatment of ASB in a clinically stable renal transplant recipient beyond 6 months does not seem beneficial given the lack of impact of bacteriuria on graft survival (143). Because of these conflicting results, no clear recommendation can be made for screening and treatment of ASB in renal transplant or other solid organ transplant recipients, which is in concordance with the IDSA guidelines on the Diagnosis and treatment of ASB (73).
In case of an early UTI and presence of a JJ ureteral stent it should be assumed that, despite antibiotic treatment, the urine will (latently) remain infected as long as a corpus alienum is present in the urinary tract. This stent should be removed if possible and the urine must be cultured. In cases of recurrent pyelonephritis experts recommend to administer prolonged courses of antibiotics up to several days after removal of the stent.
Depending on the context, additional investigations might be indicated, such as ultrasound study of the native and transplanted kidneys, positron emission tomography (PET) or computer tomography (CT) scan, cystoscopy or micturating cystogram. One should keep in mind that the native kidneys can be a source for recurrent infections, especially in patients with pre-transplant rUTI.
Because of toxicity, the Guideline committee will not recommend high-dose TMP-SMX (320/1600 daily in 2 gifts) as prophylaxis against UTI, despite the decreased incidence of UTI (138).
Authorization date and validity
Last review : 01-03-2013
Last authorization : 01-03-2013
This guideline was developed and approved by representatives of the professional medical societies, mentioned in the introduction and methods sections and therefore represents the current professional standard in 2013. The guideline contains general recommendations. It is possible that, in individual cases, these recommendations do not apply. Applicability of the guideline in clinical practice resorts to the responsibility of every individual practitioner. Facts or circumstances may occur, in which deviation of the guideline is justified, in order to provide optimal quality of care for the patient.
Initiative and authorization
Development of this guideline was supported and financed by the SKMS (Kwaliteitsgelden Medisch Specialisten).
Scope and target group
The objective of these guidelines is to update clinicians with regard to important advances and controversies in the antibiotic treatment of patients with complicated urinary tract infections (UTIs).
The guidelines described here cover the empirical antimicrobial therapy of adult patients (for this guideline 12 years or older) with a complicated UTI admitted to a hospital (emergency room or ward) in the Netherlands. Uncomplicated UTIs are treated predominantly by the general practitioner. For the relevant guidelines, see the recently updated Standard for Urinary Tract Infections of the Dutch Society of General Practitioners (NHG). We have tried to adhere to this standard insofar as possible. Urethritis and epididymitis are not included in this guideline.
The Guidelines give a general therapy advice for all UTI with systemic symptoms because, at first presentation of a patient, it is not always possible to differentiate between an acute prostatitis, pyelonephritis or urosepsis. In addition, this differentiation has no consequences for the choice of empirical antimicrobial therapy. Apart from these general guidelines, we give specific advice for certain groups of patients separately.
Members of the guideline panel
Preparation of the guideline text was carried out by a multidisciplinary committee consisting of experts, delegated from the professional societies for infectious diseases (VIZ), medical microbiology (NVMM), hospital pharmacists (NVZA), urology (NVU), gynaecology (NVO), nephrology (NFN) and general practice (NHG). After consultation with the members of these professional societies, the definitive guideline was drawn up by the delegates and approved by the board of SWAB.
- Dr. S.E. Geerlings (coordinator, SWAB), Internal Medicine/Infectious Diseases specialist, Department of Internal Medicine, Division of Infectious Diseases, Academic Medical Center, Amsterdam
- Dr. C. van Nieuwkoop (VIZ, NIV), Internal Medicine, Emergency Medicine and Infectious Diseases specialist, Department of Internal Medicine, Hagaziekenhuis, the Hague
- E. van Haarst (NVU), Urologist, Department of Urology, St. Lucas Andreas Hospital, Amsterdam
- Dr. M. van Buren (NFN), Internal Medicine and Nephrology specialist, Department of Internal Medicine, Hagaziekenhuis, the Hague
- Dr. B.J. Knottnerus (NHG), General Practitioner, Department General Practice, Academic Medical Center, Amsterdam
- Dr. E. E. Stobberingh (NVMM), Medical microbiologist, Lab Medical Microbiology, Maastricht Univerisity Medical Center, Maastricht
- Prof. dr. C.J. de Groot (NVOG), Gynaecologist, Department of Obstetrics and Gynaecology, Vrije Universiteit Medical Center, Amsterdam
- Prof. dr. J.M. Prins (SWAB), Internal Medicine/Infectious Diseases specialist, Department of Internal Medicine, Division of Infectious Diseases, Academic Medical Center, Amsterdam
The Guideline committee would also like to thank Frederique Bemelman (nephrologist) for her comments on the chapter about renal transplantation and Albert Vollaard (infectious disease specialist) for his comments on the subchapter about methenamine.
Declaration of interest
The SWAB employs strict guidelines with regard to potential conflicts of interests as described in the SWAB Format for Guideline Development (www.swab.nl). Members of the preparatory committee reported the following potential conflicts of interest:
SE Geerlings: for the RCTs mentioned in the reference numbers 84 en 168 (Beerepoot et al.): Ref 84: Cranberry capsules and placebo capsules for this trial were delivered by Springfield Nutraceuticals, Oud Beijerland, The Netherlands. Ref 168: Chr Hansen A/S, Denmark has the patents for Lactobacillus rhamnosus GR-1 and Lactobacillus reuteri RC-14 and donated the placebo capsules for this trial.
E v Haarst: has received speaker fees on a national urological symposium from GlaxoSmithKline, the manufacturer of amoxicillin-clavulanic acid.
Other authors: no potential conflicts of interest declared.
This guideline does not include patient involvement.
Method of development
This guideline does not include an implementation strategy.
Methods and proces
This guideline was drawn up according to the recommendations for evidence-based development of guidelines (6), (Evidence-Based Richtlijn-Ontwikkeling (EBRO) and Appraisal of Guidelines Research and Evaluation (AGREE), www.agreecollaboration.org). The guidelines are derived from a review of literature based on the 9 key questions concerning the treatment of UTI. Studies were assigned a degree of evidential value according to the handbook of the Dutch Institute for Healthcare Improvement (Centraal Begeleidingsorgaan/Kwaliteitsinstituut voor de gezondheidszorg, CBO) (CBO. Evidence-based Richtlijnontwikkeling, handleiding voor werkgroepleden. Utrecht: CBO; 2007). Conclusions were drawn, completed with the specific level of evidence, according to the grading system adopted by SWAB (Table 1 and 2). The only exception concerns Nethmap, an annual report from which the resistance surveillance data were used. The Guideline committee cannot give Nethmap a level of evidence and decided to use an asterix (*), but is of the opinion that the results can be given substantial weight, since the surveillance data described in Nethmap cover 30% of the Dutch population. Subsequently, specific recommendations were formulated.
In order to develop recommendations for the optimal treatment of UTI, the literature was searched for the key questions. For each question a literature search was performed in the PubMed database (January 1966 to January 2012) as well as in the Cochrane Register of Controlled Trials (CENTRAL). For resistance surveillance data NethMap 2011 was used, and for the interpretation of susceptibility test results, in addition, reports of the European Committee on Antimicrobial Susceptibility Testing (EUCAST) were used. When scientific verification could not be found, the guideline text was formulated on the basis of the opinions and experiences of the members of the Guideline committee.
Searches are available upon request. Please contact the Richtlijnendatabase.