ARTICLE IN PRESS
Actas Urol Esp. 2015;xxx(xx):xxx---xxx
Actas Urológicas Españolas www.elsevier.es/actasuro
Consensus document of the Spanish Urological Association on the management of uncomplicated recurrent urinary tract infections夽 L. Prieto a,∗ , M. Esteban b , J. Salinas c , J.M. Adot d , S. Arlandis e , L. Peri f , J.M. Cozar g , Grupo de trabajo para las recomendaciones en el diagnóstico y manejo de las infecciones del tracto urinario recurrentes no complicadas. Realizado bajo los auspicios nola de Urología 2013 de la Asociación Espa˜ a
Servicio de Urología, Hospital Universitario de Elche, Alicante, Spain Servicio de Urología, Hospital Nacional de Parapléjicos de Toledo, Toledo, Spain c Servicio de Urología, Hospital Clínico San Carlos, Madrid, Spain d Servicio de Urología, Hospital General Universitario, Burgos, Spain e Servicio de Urología, Hospital Universitari i Politècnic la Fe, Valencia, Spain f Servicio de Urología, Hospital Clínico de Barcelona, Barcelona, Spain g Servicio de Urología, Hospital Virgen de las Nieves, Granada, Spain b
Received 2 September 2014; accepted 7 October 2014
KEYWORDS Urinary tract infection; Bacteriuria; Recurrence; Consensus; Managing disease
Abstract Introduction: The clinical manifestations of urinary infections, commonly mild and uncomplicated, have resulted in a generally empirical therapeutic decision-making process, which does not help ﬁght resistances to antibacterial agents, thus causing a high rate of recurrence. Objective: This study seeks to reduce the clinical variability in the diagnosis and treatment of uncomplicated recurrent urinary tract infections (RUTIs). Material and method: The consensus document was developed using a nominal group methodology, using scientiﬁc evidence on RUTIs extracted from a systematic (noncomprehensive) literature review, along with the expert judgment of specialists and their experience in clinical practice. Results: RUTIs are considered the manifestation of at least 3 episodes of uncomplicated infection, with a positive culture in the past 12 months, in addition to (for men) the absence of structural or functional abnormalities. We maintain that the treatment should be empiric when suspecting RUTIs (prior to obtaining a urine sample for culture) in those patients who have a high probability of recurrence, associated risk factors and/or urinary or general symptoms,
夽 Please cite this article as: Prieto L, Esteban M, Salinas J, Adot JM, Arlandis S, Peri L, et al. Documento de consenso de la Asociación Espa˜ nola de Urología en el manejo de las infecciones del tracto urinario recurrentes no complicadas. Actas Urol Esp. 2015. http://dx.doi.org/10.1016/j.acuro.2014.10.003 ∗ Corresponding author. E-mail address: prieto [email protected]
2173-5786/© 2014 AEU. Published by Elsevier España, S.L.U. All rights reserved.
ACUROE-712; No. of Pages 10
ARTICLE IN PRESS
L. Prieto et al. such as fever and chills. Homogeneous criteria are recommended for the diagnosis and treatment in order to ﬁght the increased rates of resistance that the microorganisms develop against antimicrobial agents. Conclusion: Imprecision in the identiﬁcation of the infection requires a search for agreements on homogenized criteria and decision algorithms that guide the management of these patients. © 2014 AEU. Published by Elsevier España, S.L.U. All rights reserved.
PALABRAS CLAVE Infección del tracto urinario; Bacteriuria; Recurrencia; Consenso; Manejo enfermedad
Documento de consenso de la Asociación Espa˜ nola de Urología en el manejo de las infecciones del tracto urinario recurrentes no complicadas Resumen Introducción: Las manifestaciones clínicas de las infecciones urinarias, habitualmente leves y no complicadas, ha ocasionado que la toma de decisiones terapéuticas sea generalmente empírica, lo que no ayuda a combatir las resistencias a los antibacterianos, relacionándose con una alta tasa de recurrencias. Objetivo: Este trabajo pretende reducir la variabilidad clínica en el diagnóstico y tratamiento de las infecciones del tracto urinario recurrentes (ITUR) no complicadas. Material y método: El documento de consenso se realizó mediante metodología grupo nominal, utilizando evidencias cientíﬁcas sobre ITUR extraídas de una revisión sistemática (no exhaustiva) de la literatura, junto al juicio experto de especialistas y a su experiencia en práctica clínica. Resultados: Se considera ITUR la manifestación de al menos 3 episodios de infección no complicada con cultivo positivo en los últimos 12 meses, a˜ nadiéndose, en el caso de los hombres, la ausencia de anormalidades estructurales o funcionales. Se mantiene que el tratamiento bajo sospecha de ITUR debe ser empírico, previo a la obtención de una muestra de orina para el cultivo, en aquellos pacientes que presenten una alta probabilidad de recurrencia, factores de riesgo asociados y/o sintomatología urinaria o general, como ﬁebre o escalofríos. Se recomiendan criterios homogéneos para el diagnóstico y tratamiento con el propósito de combatir el incremento de las tasas de resistencia que los microorganismos desarrollan contra los agentes antimicrobianos. Conclusión: La imprecisión en la identiﬁcación de la infección hace necesario sensibilizar la búsqueda de acuerdos para homogeneizar criterios y algoritmos de decisión que guíen en el manejo de estos pacientes. © 2014 AEU. Publicado por Elsevier España, S.L.U. Todos los derechos reservados.
Introduction In Europe, little evidence is available on the prevalence of urinary tract infections (UTIs), their impact on quality of life, the economic consequences in terms of resource use and on healthcare costs. In the US, UTIs are responsible for over 7 million medical visits each year, including over 2 million for cystitis alone.1 Approximately 15% of all community-prescribed antibiotics are dispensed for treating UTIs, with an estimated annual cost of over 1000 million dollars.2 Besides, UTIs account for more than 100,000 hospital admissions annually,1 represent at least 40% of all nosocomial infections and are, in the majority of cases, catheter associated.2---4 Most UTIs occur in the lower urinary tract and their clinical manifestations are usually mild and without complications. Nearly one half of women experience a UTI in their lifetime, and 20% of them will even experience several UTI episodes. This translates into a high prevalence rate and their recurrence makes them become recurrent UTIs (RUTI).5---8 Their high incidence, morbidity and the need for treatment before microbiological results are available entail
that treatment decisions in the case of uncomplicated UTIs are generally taken in an empirical manner.9,10 In order to ensure the correct treatment of uncomplicated UTIs, it is necessary to know their causes, the germs involved and the most common resistances associated with the latter, with a low resistance index (<10---20%) and a guideline promoting therapeutic compliance being thus required.11,12 A key goal for the National Healthcare System (NHS) must be the development of consensus documents and protocols rooted in evidence-based medicine which would provide guidelines for the homogenization and rational use of antibiotics, thus aiming at reducing bacterial resistance responsible for therapeutic failures. The Spanish Association of Urology (AEU) has drawn up this consensus document on the management of uncomplicated RUTIs with the following goals: (1) to unify criteria and to standardize decision making in the management of uncomplicated RUTIs; (2) to raise awareness among the scientiﬁc community about the suitability of approaching these processes on the basis of the evidence available, for greater effectiveness and care equity and (3) to contribute to the proper and safe use of available treatments
ARTICLE IN PRESS
Consensus document of the Spanish Urological Association and to the improvement of healthcare quality indicators in these patients. This document is addressed to any medical or health professional diagnosing and/or dealing with this condition: urologists, family physicians and gynecologists, including nursing staff.
3 Consensus protocol •
Preparation of consensus protocol with objectives, areas, basic thematic index, and work methodology
Methods and materials The Methodological Manual for the Development of Clinical Practice Guidelines of the NHS13 was followed for the production of this document. We used a consensus methodology derived from the nominal group technique which included the scientiﬁc evidence available on RUTI, selected on the basis of a ‘‘non-exhaustive’’ systematic review of the literature guided by experts. The paper was developed with the cooperation of 3 groups: (1) a scientiﬁc committee made up of 3 experts (SC); (2) a group working on recommendations (GR) consisting of the members of the SC and 3 more urologists and (3) a group for validating recommendations (GVR), with 21 more experts on urology, all of whom were led by a coordinator. The SC oversaw the quality of the processes and the consensus methodology. The GR was responsible for the assessment and selection of the contents of the literature review, as well as for the development of recommendations. The GVR was designed to obtain a broader more representative assessment of the recommendations made by the GR. Fig. 1 shows the process followed for drawing up the consensus document. A subject index was created for consultation (SIc) including the questions to be answered, on the basis of an expanded subject index (eSI) proposed by the GR and using the PICO framework,14 which facilitates the development of well-structured clinical questions, at those points where it was deemed appropriate. On the basis of the SIc and following a framework protocol deﬁning limits and search criteria, we performed the literature review, where those consensus documents, literature reviews and guidelines published over the last 5 years in leading journals were prioritized (Fig. 2). After that, critical reading and a summary of contents were made. In the evidence assessment process, we prioritized internal validity, the magnitude of the response and the clinical relevance of the results, as well as their applicability to speciﬁc clinical circumstances, in accordance with the reality of the NHS. The ﬁnal document included the recommendations made by the GR and agreed upon by the GR and the GVR. This paper outlines a selection of the main recommendations. Each recommendation was classiﬁed according to the level of evidence (LoE) and the grade of recommendation (GoR) referred to in the original publication or, failing that, in accordance with the categorization criteria for the LoE and GoR of the Centre for Evidence-Based Medicine (Oxford), as modiﬁed by Sackett.15 Those reaching an agreement rate of over 70% between members of the GR with regard to usefulness (U) and applicability (A) assessment were established as formal recommendations for the process; the ﬁnal percentage of agreement obtained is shown along with the formulation of the recommendation. First-round recommendations were assessed by 19 experts, whereas second-round ones were assessed by a total of 23 experts.
Non-comprehensive systematic review Development of the advisory thematic index (aTI). Development of search matrices (application of the PICO method) Carrying out of search matrices
• • •
Critical reading and synthesis • •
Critical reading and synthesis of the information Validation of the document of synthesis of evidence by means of face-to-face expert meeting
Development of recommendations (CC and GER) • • •
Selection of evidences and recommendations Formulation of new recommendations. Classification of evidence and grading of recommendations.
Validation of recommendations • • •
First round of individual assessment of the recommendations regarding applicability and utility, using a questionnaire. (GVR) Group validation in face-to-face meeting of dissenting recommendations in first round. (CC, GER and GVR) Second round of individual assessment of dissenting recommendations by means of questionnaire. (C, GER and GVR)
Figure 1 Process followed for the preparation of the consensus document.
Results Deﬁnition of urinary tract infection UTIs are classiﬁed into uncomplicated, complicated and sepsis, although they can also be classiﬁed according to their severity and pattern of occurrence. The European Association of Urology (EAU)16 classiﬁes them by deﬁning their clinical presentation, degree of severity, risk factors and pathogenesis. Table 1 shows a series of deﬁnitions prepared by the panel of experts.
Deﬁnition of recurrence It is recommended to consider RUTI in women with at least 3 episodes of uncomplicated infection with a positive culture in the past 12 months, whereas in the case of men RUTIs are deﬁned as at least 3 episodes of uncomplicated infection with a positive culture in the past 12 months with no structural or functional abnormalities16 (LoE/GoR: 4/C, U: 100%, A: 100%). Similarly, it is considered appropriate to draw a distinction between recurrences (recurrence of bacteriuria
ARTICLE IN PRESS
L. Prieto et al. Table 1
Deﬁnitions of UTIs.
Analytical criteria Bacteriuria Signiﬁcant bacteriuria Hidden bacteriuria Asymptomatic bacteriuria Urinary infection
According to its location Bladder bacteriuria Lower urinary infection Lower urinary infection Upper urinary tract infection or pyelonephritis According to clinical expression Voiding syndrome or bacterial cystitis Urethral syndrome or non-bacterial cystitis Uncomplicated infection Complicated infection
It is the presence of bacteria in urine >100,000 CFU/ml of freshly voided urine or any amount by suprapubic puncture Signiﬁcant bacteriuria in a population apparently healthy >100,000 CFU/ml in 2 urine samples in patients with no voiding symptoms >100,000 CFU/ml of a single pathogen in a sample of urine in patients with urinary symptoms
Bacteria in urine obtained by catheterization or suprapubic puncture Bacteria in urine collected directly from the renal pelvis or ureter Cystitis, urethritis, and prostatitis Pelvis and renal parenchyma
Symptomatic bacteriuria Urethral tract symptoms without bacteriuria If it happens on a normal urinary tract If it happens in a urinary tract with structural, functional, or anatomic abnormalities, which condition the self-perpetuation of infections: stones, bladder catheterization, neurogenic bladder, polycystic kidney disease, diabetes, immunosuppression, pregnancy, recent instrumentation of the urinary tract
UTI: urinary tract infections; ml: milliliter; CFU: colony forming units.
following treatment due to the same germ that had been primarily isolated) and re-infections (recurrence of posttreatment bacteriuria with a different germ)17 (LoE/GoR: 4/C, U: 100%, A: 100%). However, it is recommend to
consider those infections where bacteria are not eradicated after 7---14 days of supervised treatment17 (LoE/GoR: 4/C, U: 94.7%, A: 89.5%) as persistent UTIs, and not as RUTIs.
Diagnosis Exploitation of search matrices: 1032 citations
Discarding of duplicates: 385 citations
Screening based on title, abstract and type of study 84 articles and guidelines to perform critical reading
The resulting document of recommendations referred 95 articles by adding subsidiary references to the extracted contents.
Selection of references.
In order to conﬁrm UTIs in a patient reporting the presence of one or more symptoms, it is recommended to use the algorithm published by Kodner et al.18 both in the case of women and men, and to follow the diagnostic criteria as modiﬁed in accordance with the recommendations of the Infectious Diseases Society of America and the European Association of Clinical Microbiology and Infectious Diseases, published in the EAU guidelines.16 Although no clear evidence suggesting that greater patient care would prevent UTI recurrence has been found, there seems to be some kind of relationship between recurrence rates and the quality time spent on patient care. In primary care, and with the goal of preventing any recurrences, it is recommended in patients with UTI, before starting any therapeutic approach, to have an access to a detailed medical history on their pathological background and a clinical sequence expressing the current patient situ√ ation (LoE/GoR: 4/C , U: 95.5%, A: 59.1%). Besides, it is important to examine risk factors in those patients with recurrent urinary infections and without any evident predisposing factors19 (LoE/GoR: 4/C, U: 89.5%, A: 89.5%). A well-targeted medical history on irritative urinary symptomatology is deemed sufﬁcient for the diagnosis of RUTI. In order to get a correct diagnosis, the panel of
ARTICLE IN PRESS
Consensus document of the Spanish Urological Association Table 2
Recommendations of diagnostic tests.
Recommendations on the use of diagnostic tests
Recurrent urinary infections must be diagnosed by urine culture
For the assessment of RUTI, excretory urography, cystography, or cystoscopy are not recommended The diagnosis of acute uncomplicated cystitis can be carried out with a high probability based on a focused history of irritative urinary symptoms (dysuria, frequency, and urgency) and the absence of vaginal discharge or irritation, in women who have no other risk factors of complicated UTI
U: 100% A: 100% U: 89.5% A: 94.7% U: 94.7%
Patients who present with atypical symptoms of acute uncomplicated cystitis or uncomplicated acute pyelonephritis, as well as those who do not respond to appropriate antimicrobial therapy should be considered for further diagnostic studies
A: 89.5% U: 100%
Urologic evaluation should be performed routinely in adolescents and men with febrile UTI after 72 h of treatment, pyelonephritis, or recurrent infection, or when a complication in the clinical picture is suspected
A: 100% U: 100%
A: 100% Given the need to rule out urinary obstruction or renal lithiasis, in the context of a RUTI, it is recommended that an evaluation of the upper urinary tract is performed with renal and urinary tract ultrasound
Recommendations in the diagnosis of asymptomatic bacteriuria In women, a ≥105 CFU/ml count of a microorganism in a sample of evacuated urine is diagnosis of bacteriuria
A: 94.7% % U: 89.5% A: 89.5%
In men, ≥103 CFU/ml count of a microorganism in a sample of evacuated urine is diagnosis of bacteriuria In patients with indwelling urethral catheters, a ≥105 CFU/ml count is diagnostic of bacteriuria
In the case of a urine sample collected through the introduction and removal of a probe, a ≥100 CFU/ml count is compatible with bacteriuria Pyuria in the absence of signs or symptoms in a person with bacteriuria should not be interpreted as symptomatic infection or as an indication of antibiotic treatment
U: 94.7% A: 94.7% U: 89.5% A: 78.9% U: 84.2% A: 84.2% U: 94.7% A: 100%
A: applicability; RG: recommendation grade; UTI: urinary tract infections; RUTI: recurrent urinary tract infections; ml: milliliter; LE: level of evidence; U: usefulness; CFU: colony forming units. Source: Eitel et al.16
participating experts decided to validate the recommendations set out in the EAU guidelines,16 for both UTI and asymptomatic bacteriuria (Table 2), which imply starting with a test strip in asymptomatic patients or in patients with suspected uncomplicated UTI. On the other hand, in the case of patients with suspected complicated UTI or at risk of UTI, a urine culture and an antibiogram, and even ultrasound testing or other additional tests (computed tomography, excretory urography or gammagraphy) are recommended in order to rule out other conditions. There are no guidelines or speciﬁc indications regarding imaging studies in women with UTI but without any other underlying medical or anatomical conditions.18 The indications for using ultrasound are recurrent urinary infections which are not due to coital activity, persistent hematuria associated with urinary infections, acute pyelonephritis, or kidney function tests. The panel of experts was unanimous in recommending ultrasound as a ﬁrst-line diagnostic test, in the case of pregnant women, excluding those tests using X√ rays, except in exceptional circumstances (LoE/GoR: 4/C ,
U: 100%, A: 100%). Plain urological X-ray is only recommended in the case of suspected lithiasis (LoE/GoR: 4/C, U: 94.7%, A: 100%). With regard to urodynamic studies (UDS), the opinion of the panel of experts was that they must be taken into consideration if any dysfunction of the lower urinary tract is suspected, either given the clinical picture or due to postvoiding residual urine. UDS, particularly video urodynamic testing, are recommended in the event of neurogenic dys√ function (LoE/GoR: 4/C , U: 100%, A: 77.3%). Table 3 shows recommendations for the diagnosis of speciﬁc RUTI scenarios.
Treatment Changing certain habits might have an inﬂuence on the remission of UTIs, so it is therefore recommended to instruct √ patients through educational measures (LoE/GoR: 4/C , U: 94.7%, A: 100%), which must be individualized according to the patient’s proﬁle (Table 4).
ARTICLE IN PRESS
L. Prieto et al. Table 3
Scenarios of recurrence in the diagnosis of RUTI.
Young women with sexual activity and recurrences after a ﬁrst episode of cystitis Although they have no abnormalities in the urinary tract, it is acceptable to make a dipstick analysis rather than formal urinary microscopy when there is suspicion of acute uncomplicated cystitis16 (LE/RG: 2a/B, U: 94.7%, A: 89.5%) Elderly patients It is possible that the urological symptoms may be masked by other general symptoms due to showing neurological changes, adding confounding factors in the clinical expression at the beginning of cystitis or even without this condition27,28 , so it is recommended to evaluate this possibility of masking the speciﬁc clinic of cystitis and reducing the monitoring of non-speciﬁc symptoms √ (LE/RG: 2a/B , U: 94.7%, A: 89.5%) Patients with neurogenic voiding dysfunction They will require a urine culture, including antibiotic sensitivity to guide therapy. It is important to obtain serum analysis and assessment of the general medical condition Pregnant women Special attention should be given to pregnant women, since they have a higher risk of asymptomatic bacteriuria (2---12%), which entails twice the risk of premature delivery and 50% higher that the newborn is underweight29 Patients with urinary catheters Urinary tract infections in patients with urinary catheters currently pose a clinical, epidemiological, and therapeutic problem of utmost importance, since they are an important reservoir of multiresistant microorganisms, easily transferable to other patients, and cause infections often difﬁcult to treat Elderly, immunocompromised, or with congenital malformations of the kidneys patients30 CT or ultrasound are usually required in elderly, immunocompromised, or with congenital malformations of the kidneys patients30 A: applicability; RG: recommendation grade; RUTI: recurrent urinary tract infections; LE: level of evidence; U: usefulness.
In case of RUTI, as well as in the event of suspected uncomplicated UTI, starting empirical therapy must be considered, prior to the collection of a urine sample for culture in those patients with a high probability of recurrence, associated risk factors and/or urinary or general symptoma√ tology, such as fever and chills (LoE/GoR: 4/C , U: 94.7%, A: 94.7%). In the case of asymptomatic bacteriuria, discerning when one must be undergo treatment and when not is complicated. The panel of experts validated the following recommendations made by the EAU16 (Table 5). Treatment for RUTIs in their ﬁrst recurrence is the same as for other cases of uncomplicated cystitis. According to the existing European sensitivity patterns, single-dose fosfomycin trometamol 3 g, pivmecillinam 400 mg bid for 3 days16 (LoE/GoR: 1a/A, U: 94.7%, A: 94.7%) and macrocrystalline nitrofurantoin 100 mg twice daily for 5 days16
Table 4 habits.
Educational measures and healthy changes of
To To To To
drink at least 2l of liquids a day (preferably water) completely empty the bladder at least every 3 h defecate every day to limit perianal contamination wipe from front to back after urinating or defecating to avoid self-contamination To maintain pre- and post-coital genital hygiene (postcoital urination whenever possible) To avoid routine use of intimate deodorants, douches, or other irritants such as ovules, spermicides, diaphragms, etc. To prioritize shower to bath, avoiding foaming salts, bath oils, perfumes, or other irritating chemicals in the water To preferably use underwear cotton To avoid coffee, tea, and alcohol since they tend to irritate the bladder
Source: Martin et al.24 and Gonzalez-Chamorro et al.26
(LoE/GoR: 2a/B, U: 94.7%, A: 94.7%) are regarded as drugs of ﬁrst choice in those countries where available. As to the scope of this paper, the GR advises to follow the recommendations on uncomplicated cystitis in women made by the EAU20 (Table 6). In male patients and healthy premenopausal women, the occurrence of re-infections is quite common after a ﬁrst episode of cystitis. In these patients, a wait-and-see approach is recommended as long as bacteriuria is asymptomatic. However, cotrimoxazole 160/800 mg twice daily for Table 5 Recommendations in the treatment of asymptomatic bacteriuria. Screening and treatment of asymptomatic bacteriuria are recommended in the following cases Pregnant women (LE/RG: 1a/A, U: 100%, A: 100%) Before a genitourinary invasive intervention where there is a risk of bleeding mucosa (LE/RG: 1b/A, U: 100%, A: 100%) Screening and treatment of asymptomatic bacteriuria are not recommended in the following cases Postmenopausal women (LE/RG: 1b/A, U: 94.7%, A: 100%) Diabetic women (LE/RG: 1b/A, U: 94.7%, A: 100%) Healthy men (LE/RG: 2b/B, U: 94.7%, A: 100%) Residents in assistance center in the long term (LE/RG: 1a/A, U: 94.7%, A: 100%) Patients with indwelling urethral catheter (LE/RG: 1b/A, U: 94.7%, A: 100%) Patients with nephrostomy tubes or ureteral endoprostheses (LE/RG: 4/C, U: 100%, A: 100%) Patients with spinal lesions (LE/RG: 1b/A, U: 100%, A: 100%) Patients with candiduria (LE/RG: 1b/A, U: 94.7%, A: 100%) Patients undergoing a kidney transplant after the ﬁrst 6 months (LE/RG: 2b/B, U: 84.2%, A: 89.5%) A: applicability; RG: recommendation grade; LE: level of evidence; U: usefulness. Source: Eitel et al.16
ARTICLE IN PRESS
Consensus document of the Spanish Urological Association Table 6
Recommendations for the treatment of RUTI.
Fosfomycin trometamol in a single-unit dose of 3 g
Sulfamethoxazoletrimethoprim, 800/160 mg/12 h for 3 days (in areas with resistance to E. coli below 20%) Norﬂoxacin, 400 mg/12 h for 3 days Ciproﬂoxacin, 250 mg/12 h for 3 days Amoxicillin-clavulanate, 500/125 mg/8 h for 5 days Ceﬁxime, 400 mg/24 h for 3 days Nitrofurantoin, 50---100 mg/8 h for 5---7 days
RUTI: recurrent urinary tract infections.
3 days or trimethoprim 200 mg for 5 days should be regarded as drugs of ﬁrst choice only in regions with known E. coli resistance rates lower than 20%16 (LoE/GoR: 1a/A, U: 94.7%, A: 94.7%). In pregnant women, uncomplicated UTIs must always be treated. If there is asymptomatic bacteriuria, treatment with single-dose fosfomycin trometamol, with beta-lactams (amoxicillin---clavulanic acid and cephalosporins) for 5 days or with nitrofurantoin for 7 days20 is recommended (LoE/GoR: IIa/A----Agency for Healthcare Research and Quality [AHQR]----2a/B----Sackett----, U: 100%, A: 100%). On the other hand, quinolones are not recommended and cotrimoxazole should be avoided between the ﬁrst and third months of pregnancy20 (NE/GR: C----AHQR----4/C----Sackett----, U: 100%, A: 100%). In postmenopausal women, single-dose fosfomycin trometamol is the ﬁrst-choice treatment and amoxicillin---clavulanic acid every 8 h for 5 days is the second-choice treatment.
Prevention In order to prevent the recurrence of uncomplicated UTIs, the use of antibiotics in the prophylaxis of RUTIs should be considered for those women where different antibiotic patterns have not proven successful16 (LoE/GoR: 4/C, U: 100%, A: 100%). Antibiotic prophylaxis can be continuously administered or following a post-coital pattern. The EAU recommends to conﬁrm the eradication of a previous UTI with a negative urine culture one or two weeks after treatment16 (LoE/GoR: 4/C, U: 100%, A: 89.5%). However, according to some studies, it is only effective during antibiotic intake, recurrences thus occurring again when treatment is complete.21 With regard to non-antibiotic preventive options, the use of both hyaluronic acid (HA) and chondroitin sulfate (CS) are key components since they are part of the glycosaminoglycan (GAG) layer protecting the urothelium, given that damage of this layer might increase bacterial adherence and, therefore, the risk of infection.22 Both components
7 Table 7
Options to prevent RUTI.
Instillations of hyaluronic acid in combination with chondroitin sulfate They signiﬁcantly reduce the rate of UTI without serious side effects versus placebo, improving symptoms and quality of life of patients with RUTI31 Bladder instillation of HA and HA-CS in combination appears as a promising therapeutic option and provides a good tolerability proﬁle in patients of different ages32 (LE/RG: 4/C, U: 100% A: 78.9%) GAG treatment is, therefore, an alternative to the widespread use of antibiotics, although occasionally they are not well accepted by patients through their route of administration (LE/RG: 4/C, U: 100% A: 78.9%) Prevention with blueberries There is research that suggests that blueberries prevent the adhesion of bacteria (particularly E. coli) to uroepithelial cells that line the bladder wall. However, the body of evidence suggests that blueberry products, compared with placebo, do not provide beneﬁts in most population groups, and in some subgroups the beneﬁt is likely to be very small33 Immunoprevention As for the immunoprevention by protein extracts of bacteria or prevention with probiotics, the expert panel intends to follow the recommendations of the EAU16 in places where such probiotic products are accessible. Immunoprevention in RUTI can be used of ﬁrst intention, but nearly always having previously tested bacteriostatic antibiotic treatments. The understanding of the pathogenesis and mechanisms of action of vaccines is expanding showing more and more effectiveness. A: applicability; HA: hyaluronic acid; CS: chondoitin sulphate; EAU: European Association of Urology; GAG: glycosaminoglycans; RG: recommendation grade; LE: level of evidence; U: usefulness.
enable repair of the protective urothelial lining, reduce urothelial permeability and are indicated in any clinical situation of damage of the GAG layer,23 although new ongoing studies must conﬁrm this indication. Table 7 summarizes treatment options for recurrence prevention.
Patient follow-up The lack of bibliographic references detailing a speciﬁc follow-up plan in patients with RUTI reﬂects the evident variability in the management of these patients. However, the panel of experts agreed that follow-up must comprise clinical and bacteriological monitoring over a period of between 3 months and one year, with discharge being considered when both bacteriological (according to age) and clinical criteria regard a patient as asymptomatic. To that end, analyses and urine cultures must be carried out √ (LoE/GoR: 4/C , U: 100%, A: 94.7%). Emphasizing the fact that patients must be subject to examination when symptoms persist or reappear after ﬁnishing treatment, it is recommended to follow the recommendations made by the EAU16 (Table 8).
ARTICLE IN PRESS
L. Prieto et al. Table 8
Recommendations in the follow-up of UTI.
Recommendations in the follow-up of uncomplicated UTI
A priori, systematically performing urine analyses or urine cultures after treatment in asymptomatic patients is not indicated In women whose symptoms do not improve within 3 days, or in those who resolve and reappear within 2 weeks, new urine cultures, antimicrobial susceptibility testing, and appropriate additional tests, such as renal ultrasound, CT, or renal scintigraphy should be performed
U: 94.7% A: 94.7% U: 100%
In these patients without urological abnormalities, butin whom the symptoms recur, it must be assumed that the infecting microorganism is not sensitive to the drug originally used and an alternative treatment should be considered adapted in the light of the results of the cultures
A: 84.2% U: 100%
In patients with recurrence of the same pathogen, uncomplicated UTI diagnosis should be reconsidered. The diagnostic steps are needed to rule out complicating factors Recommendations in the follow-up of UTI in pregnant women In pregnant women, in addition, we recommend getting urine cultures shortly after the end of treatment of asymptomatic bacteriuria and symptomatic UTI during pregnancy
A: 94.7% U: 100%
% U: 100% A: 100%
A: applicability; RG: recommendation grade; UTI: urinary tract infection; LE: level of evidence; U: usefulness. Source: Eitel et al.16
In order to assess the effectiveness of any treatment intended to treat RUTIs, it is necessary to select appropriate indicators. The panel of experts did not consider QoL questionnaires to be appropriate; however, they deﬁned time to recurrence, the number of infections per year (UTI episodes/year) and effectiveness upon the patient’s clinical record as indicators for assessing effectiveness (LoE/GoR: √ 4/C , U: 100%, A: 94.7%).
Criteria for referral There are, though they are not followed, referral guidelines for patients with uncomplicated RUTIs, although in the review carried out by Kodner et al.18 it was suggested that most patients with uncomplicated RUTIs can be treated by family physicians. However, the panel of experts recommends to refer the patient to a urologist so that he makes a ﬁrm diagnosis of those patients with suspected RUTI √ (LoE/GoR: 4/C , U: 84.2%, A: 89.5%). It is also recommended to refer patients when there is suspicion of organic and/or functional urinary tract alterations, previous surgical procedures on it or symptoms during the periods with √ no UTI (LoE/GoR: 4/C , U: 100%, A: 94.7%). Once a patient is diagnosed with uncomplicated RUTI, follow-up should be supervised by both the primary care physician and the urologist, with close monitoring of these patients over the next √ 12 months (LoE/GoR: 4/C , U: 78%, A: 89.4%).
Discussion Conceptually, UTI involves a microbial infestation of the urinary tract which surpasses the capability of the host’s defense mechanisms, causes morphological or functional alterations and an immune response that is not always evident. The presence of recurrences in uncomplicated UTIs is partly due to the high variability of therapeutic criteria and to the necessity of starting treatment before microbiological results are available, which increases resistance to different
agents. For this reason, in clinical practice, it is important to homogenize decision-making criteria in the management of UTI. The GAG layer plays a major role in the protection of epithelial cells from the bladder. Damage of this layer might increase bacterial adherence and, therefore, the risk of infection.22 It has been speculated that bacteria invading those epithelial cells could be a factor causing UTI recurrence and that they act as a stimulus for interstitial cystitis.24 On the other hand, there is a clear association between antibiotic use and the resistance level, both at an individual and communal level,25 which currently even affects broad-spectrum antibiotics such as ﬂuoroquinolones and cephalosporins. Rational antibiotic treatment is therefore important to prevent the occurrence of bacterial resistance responsible for therapeutic failures. During the preparation of this document, new therapeutic alternatives were proposed. This is the case, for example, of new immunotherapy products, which although can be regarded as a more comfortable treatment than instillations, it should be taken into consideration that they do not usually make a urine culture negative. Their usefulness, however, may lie in those patients with recurrences which are always caused by the same germ. Another innovation discussed was the existence of a new format of pre-ﬁlled syringes containing high concentrations of HA and CS and calcium, which make self-administration easier. This format can also be usefulness for nursing practice as it increases comfort and administration safety, since less manipulation involves a lower risk of infection due to contamination. With this paper, we aimed at sorting, classifying and disclosing the evidence available in order to guide and unify diagnostic---therapeutic criteria to facilitate decision-making through the development of expert recommendations. Although it should be mentioned that the development of consensus documents through nominal groups might limit the guarantee of representativeness of some participants, since some experts’ opinions may bias the opinion of others. On the other hand, due to the
ARTICLE IN PRESS
Consensus document of the Spanish Urological Association characteristics and limits of the systematic review of the literature, as well as to the screening of scientiﬁc documents, some kind of newness or prominent old references might have been left out.
9 Francisco Serrano, Luis Rodríguez Villamil, Raúl Vozmediano and Carmen Zubiaur.
References Conclusions RUTI should be considered upon the manifestation of at least 3 episodes of uncomplicated infection with a positive culture in the past 12 months, and with an absence of structural or functional abnormalities in the case of men. Those infections where bacteria are not eradicated after 7---14 days of treatment will be regarded as persistent UTIs. Before getting treatment, it is recommended to take a detailed medical history, to collect information on their pathological background and to instruct patients through educational measures, although starting empirical therapy prior to the collection of urine for culture can be considered, in patients with a high probability of recurrence and in the case of UTIs during pregnancy. The ﬁrst-choice treatment is fosfomycin trometamol in a single dose of 3 g, although other options aimed at prevention can be considered, such as bladder instillations of HA in combination with HA-CS or immunotherapy.
Funding The development of this work has been done with the logistical support of Laboratorios Gebro Pharma S.A.
Conﬂict of interest Drs. S. Arlandis and J.M. Adot have worked as lecturers in symposia sponsored by Gebro Pharma S.A. The remaining authors declare no conﬂicts of interest.
Acknowledgements The authors wish to thank the team of GOC Networking for their support and collaboration in the development of this document and Laboratorios Gebro Pharma S.A. for their continued and consistent support to the project.
Appendix A. Working group for the recommendations in the diagnosis and management of recurrent uncomplicated infections of the urinary tract. Conducted under the auspices of the Spanish Association of Urology 2013. Coordinator: Manuel Esteban; scientiﬁc committee: José Manuel Cozar, Jesús Salinas, Luis Prieto; group making recommendations: José María Adot, Salvador Arlandis, José Manuel Cozar, Lluís Peri, Luis Prieto and Jesús Salinas; Group validating recommendations: Pedro Blasco, Miguel Ángel Bonillo, Salvador Bustamante, David Castro, José Luis Gago, Antonio Gómez, José Luis Gutiérrez Ba˜ nos, Antonio Hualde, Miguel Jiménez Cidre, Manuel Enrique Leva, Fernanda Lorenzo, Blanca Madurga, Carlos Muller, Manuel Rapariz, Carlos Rioja, Enrique Robles, Eduardo Vicente, Javier Sánchez Rodríguez Losada,
1. Foxman B. Epidemiology of urinary tract infections: incidence, morbidity, and economic costs. Am J Med. 2002;113:5S---13S. 2. Mazzulli T. Resistance trends in urinary tract pathogens and impact on management. J Urol. 2002;168:1720---2. 3. Gales AC, Jones RN, Gordon KA, Sader HS, Wilke WW, Beach ML, et al. Activity and spectrum of 22 antimicrobial agents tested against urinary tract infection pathogens in hospitalized patients in Latin America: report from the second year of the SENTRY antimicrobial surveillance program (1998). J Antimicrob Chemother. 2000;45:295---303. 4. Ruden H, Gastmeier P, Daschner FD, Schumacher M. Nosocomial and community-acquired infections in Germany. Summary of the results of the First National Prevalence Study (NIDEP). Infection. 1997;25:199---202. 5. Foxman B, Gillespie B, Koopman J, Zhang L, Palin K, Tallman P, et al. Risk factors for second urinary tract infection among college women. Am J Epidemiol. 2000;151:1194---205. 6. Spahn DR, Bouillon B, Cerny V, Coats TJ, Duranteau J, Fernandez-Mondejar E, et al. Management of bleeding and coagulopathy following major trauma: an updated European guideline. Crit Care. 2013;17:R76. 7. Valdevenito SJ. Recurrent urinary tract infection in women. Rev Chilena Infectol. 2008;25:268---76. 8. Malhotra A, Lindberg M, Faust GG, Leibowitz ML, Clark RA, Layer RM, et al. Breakpoint proﬁling of 64 cancer genomes reveals numerous complex rearrangements spawned by homology-independent mechanisms. Genome Res. 2013;23: 762---76. 9. Nicolle LE. Empirical treatment of acute cystitis in women. Int J Antimicrob Agents. 2003;22:1---6. 10. Baerheim A. Empirical treatment of uncomplicated cystitis. BMJ. 2001;323:1197---8. 11. Hooton TM. Practice guidelines for urinary tract infection in the era of managed care. Int J Antimicrob Agents. 1999;11: 241---5. 12. Naber KG. Treatment options for acute uncomplicated cystitis in adults. J Antimicrob Chemother. 2000;46:23---7. 13. Fehlings D, Switzer L, Agarwal P, Wong C, Sochett E, Stevenson R, et al. Informing evidence-based clinical practice guidelines for children with cerebral palsy at risk of osteoporosis: a systematic review. Dev Med Child Neurol. 2012;54:106---16. 14. van Loveren C, Aartman IH. The PICO (patient--intervention---comparison---outcome) question. Ned Tijdschr Tandheelkd. 2007;114:172---8. 15. Marchetti AP, Johansson KP, McLendon GL. AgBr photophysics from optical studies of quantum conﬁned crystals. Phys Rev B Condens Matter. 1993;47:4268---75. 16. Eitel C, Wilton SB, Switzer N, Cowan K, Exner DV. Baseline delayed left ventricular activation predicts long-term clinical outcome in cardiac resynchronization therapy recipients. Europace. 2012;14:358---64. 17. American College of Obstetricians and Gynecologists. ACOG practice bulletin no. 91: treatment of urinary tract infections in nonpregnant women. Obstet Gynecol. 2008;111:785---94. 18. Kodner CM, Thomas Gupton EK. Recurrent urinary tract infections in women: diagnosis and management. Am Fam Physician. 2010;82:638---43. 19. Nicolle LE. Complicated urinary tract infection in adults. Can J Infect Dis Med Microbiol. 2005;16:349---60. 20. Ackroyd S, Swirsky D, Kay CL, Parapia LA. A case of myelomatous meningitis. Br J Haematol. 2004;126:627.
ARTICLE IN PRESS
10 21. Albert X, Huertas I, Pereiro II, Sanfelix J, Gosalbes V, Perrota C. Antibiotics for preventing recurrent urinary tract infection in non-pregnant women. Cochrane Database Syst Rev. 2004:CD001209. 22. Parsons CL. Epithelial coating techniques in the treatment of interstitial cystitis. Urology. 1997;49:100---4. 23. Shao Y, Shen ZJ, Rui WB, Zhou WL. Intravesical instillation of hyaluronic acid prolonged the effect of bladder hydrodistention in patients with severe interstitial cystitis. Urology. 2010;75:547---50. 24. Martin WJ, Gipson TG, Conliffe MA, Cotton WG, Dove LF, Rice JM. Histocompatibility difference between C3HfeB/HeN and C3H/HeN mice: tumour induced in C3HfeB/HeN mice expresses C3H/HeN-associated alloantigen. J Immunogenet. 1978;5:255---60. 25. Gyssens IC. Antibiotic policy. Int J Antimicrob Agents. 2011;38:11---20. 26. Gonzalez-Chamorro F, Palacios R, Alcover J, Campos J, Borrego F, Damaso D. Urinary tract infections and their prevention. Actas Urol Esp. 2012;36:48---53. 27. Sun PZ, Benner T, Kumar A, Sorensen AG. Investigation of optimizing and translating pH-sensitive pulsed-chemical exchange saturation transfer (CEST) imaging to a 3 T clinical scanner. Magn Reson Med. 2008;60:834---41.
L. Prieto et al. 28. Loeb M, Brazil K, Lohfeld L, McGeer A, Simor A, Stevenson K, et al. Effect of a multifaceted intervention on number of antimicrobial prescriptions for suspected urinary tract infections in residents of nursing homes: cluster randomised controlled trial. BMJ. 2005;331:669. 29. Macejko AM, Schaeffer AJ. Asymptomatic bacteriuria and symptomatic urinary tract infections during pregnancy. Urol Clin North Am. 2007;34:35---42. 30. Neal DE Jr. Complicated urinary tract infections. Urol Clin North Am. 2008;35:13---22. 31. Damiano R, Quarto G, Bava I, Ucciero G, de Domenico R, Palumbo MI, et al. Prevention of recurrent urinary tract infections by intravesical administration of hyaluronic acid and chondroitin sulphate: a placebo-controlled randomised trial. Eur Urol. 2011;59:645---51. 32. De Vita D, Antell H, Giordano S. Effectiveness of intravesical hyaluronic acid with or without chondroitin sulfate for recurrent bacterial cystitis in adult women: a meta-analysis. Int Urogynecol J. 2013;24:545---52. 33. Jepson RG, Williams G, Craig JC. Cranberries for preventing urinary tract infections. Cochrane Database Syst Rev. 2012;10:CD001321.