What is the optimal empirical treatment strategy concerning the choice of drug, also for patients with an increased risk for Extended-Spectrum Beta-Lactamase (ESBL)-producing Enterobacteriaceae?
In patients suspected of having a complicated UTI, a urine culture and susceptibility test should always be performed.
Amoxicillin, co-amoxiclav, TMP and TMP-SMX are not suitable for the empirical treatment of complicated UTI.
The combination of amoxicillin + an aminoglycoside, a 2nd generation cephalosporin + an aminoglycoside or a 3rd generation cephalosporin intravenously can be recommended as empirical treatment of complicated UTI.
Ciprofloxacin can only be recommended when the whole treatment is given orally, when patients do not require hospitalization or when the patient has an anaphylaxis for beta-lactam antibiotics, provided that the local resistance percentages are < 10%.
Ciprofloxacin and other fluoroquinolones are not suitable for the empirical treatment of complicated UTI in patients from the urology department or when patients have used fluoroquinolones in the last 6 months.
If the prevalence of fluoroquinolone resistance is thought to exceed 10%, an initial 1-time intravenous dose of a long-acting antimicrobial, such as a 3rd generation cephalosporin or an aminoglycoside, is recommended while resistance data are pending.
If the prevalence of fluoroquinolone resistance is thought to be higher than 10% and the patient has contra indications for 3rd generation cephalosporins or an aminoglycoside, ciprofloxacin can be prescribed as an empirical treatment in women with an uncomplicated pyelonephritis.
In the event of hypersensitivity to penicillin, a 3rd generation cephalosporin can still be prescribed, with the exception of systemic anaphylaxis in the past.
In patients with a UTI with systemic symptoms empirical treatment should cover ESBL in the initial treatment only in patients who are colonised with ESBL-producing micro-organisms. The resistance pattern of the ESBL strain should guide empirical therapy.
When the results of the urine culture are known, therapy must be adjusted and if possible narrowed down. If the clinical condition of the patient allows it and if the patient does not vomit, oral therapy can be prescribed.
If the patient no longer has symptoms, there is no indication for follow-up cultures.
This guideline does not include individual introductions to each module. A general introduction can be found in the attachments under the heading 'related'.
Escherichia coli is the causative organism in most cases of complicated UTIs.
E. coli isolated from patients presenting to unselected outpatient hospital departments (not urology or intensive care units) have high resistance percentages to amoxicillin, co-amoxiclav, trimethoprim and trimethoprim-sulfamethoxazole (TMP-SMX).
E. coli isolated from patients presenting to unselected outpatient hospital departments (not urology or intensive care units) have to ciprofloxacin a resistance rate of 17%, but in isolates from patients from general practice offices this is 10% and in isolates from urology departments it is 25%. The resistance percentages of norfloxacin, levofloxacin and moxifloxacin are similar to those of ciprofloxacin.
E. coli isolated from patients presenting to unselected outpatient hospital departments show the following resistance percentages to intravenous antimicrobial agents: gentamicin 8%, second-generation cephalosporin 13%, all third-generation cephalosporins 5%, and “last line” antimicrobial agents: piperacilin-tazobactam 8%, imipenem and meronepenem 0.03%.
Evaluating the SWAB guideline from 2006, the combination of amoxicillin and gentamicin is the most adequate (inadequate treatment rate of 6%). Second-generation cephalosporins had the highest inadequate treatment rate, i.e. 24%; the inadequate treatment rate for third-generation cephalosporins was 18%, for co-amoxiclav 14% and for ciprofloxacin it was 23%. Leaving out enterococci decreased the inadequate treatment rate, third-generation cephalosporins were now adequate in 10% of cases [(Spoorenberg submitted) C].
CAUSATIVE MICRO-ORGANISMS AND RESISTANCE
Although there is a greater diversity of causative micro-organisms in complicated UTIs than in uncomplicated UTIs, Escherichia coli remains in most cases of complicated UTIs the causative organism. Using the Infectious Diseases Surveillance Information System on Antimicrobial Resistance (ISIS-AR) and data selected from patients in the urology and internal medicine departments of 19 Dutch hospitals (Spoorenberg et al. submitted), we found the following causative micro-organisms: E. coli (45-62%), Enterococcus spp. (7-15%), Proteus mirabilis (6-8%), and Klebsiella pneumoniae (7-9%).
The most useful resistance data on the above-mentioned micro-organisms were provided by the report “Nethmap” (www.swab.nl) and ISIS-AR.
In Nethmap, information has been collected on the prevalence of resistance against antibiotics in the Netherlands in the period up to 2010. The interpretation of susceptibility test follows the guidelines of the European Committee on Antimicrobial Susceptibility Testing (EUCAST). For treatment of a UTI with systemic symptoms the antimicrobial drug must achieve high concentrations in urine, kidney tissue and prostate. Therefore, nitrofurantoin and fosfomycin are not registered for the treatment of a UTI with systemic symptoms.
On the basis of resistance data from 2009/2010 (Nethmap 2011), E. coli isolated from patients presenting to unselected outpatient hospital departments have high resistance percentages for amoxicillin, co-amoxiclav, trimethoprim (TMP) and of trimethoprim-sulfamethoxazole (TMP-SMX) (Table 1). For ciprofloxacin the resistance percentage was 17% for E. coli isolated from patients presenting to unselected outpatient hospital departments (not urology or intensive care units), but in isolates from patients from urology departments it was 25%. The most important risk factor for ciprofloxacin resistance was the use of this agent in the last 6 months (7) (odds ratio (OR) 17.5, 95% confidence interval (CI) 6.0-50.7). The resistance percentages of norfloxacin, levofloxacin and moxifloxacin are similar to those of ciprofloxacin.
For intravenous antibiotics the resistance percentages of E.coli isolated from patients presenting to unselected outpatient hospital departments (not urology or intensive care units) are shown in Table 1.
Table 1 Data from Nethmap (SWAB) and *the Infectious Diseases Surveillance Information System on Antimicrobial Resistance (ISIS-AR) of 32,785 (first urine) isolates from 26,711 patients (complicated UTI was defined as a urine-isolate from a hospitalised patient).
Resistance percentages 2009/2010
ciprofloxacin (unselected departments)
cefuroxime (2nd generation cephalosporin)
3rd generation cephalosporins (cefotaxime)
imipenem and meronepenem
amoxicillin + third-generation cephalosporins
co-amoxiclav + gentamicin
GP = general practitioner
Other uropathogens (K. pneumoniae, P. mirabilis) showed (besides their intrinsic resistance) comparable resistant patterns, with the exception of co-amoxiclav for which the resistance percentages were 11-12%.
To evaluate the adequacy of the SWAB guideline for antimicrobial treatment of complicated UTI from 2006, a study was performed in the urology and internal medicine departments of 19 Dutch hospitals. Patients from these hospitals were representative for the patient population in Dutch hospitals since university, teaching and non-teaching hospitals located throughout the Netherlands participated. We considered a guideline-recommended or prescribed empirical therapy to be adequate if the cultured uropathogen was reported to be susceptible to the recommended or prescribed antibiotic. A guideline-recommended or prescribed empirical therapy was considered to be inadequate in case of resistance or inadequate coverage of the cultured uropathogen.
We evaluated all patients with a complicated UTI without other conditions (n=810). The combination of amoxicillin and gentamicin was the most adequate (inadequate treatment rate of 6%) Second-generation cephalosporins had the highest inadequate treatment rate, i.e. 24% (inadequate coverage 16%, resistance 8%), the inadequate treatment rate for third-generation cephalosporins was 18% (inadequate coverage 16%, resistance 2%), for co-amoxiclav 14% (inadequate coverage 7%, resistance 7%) and for ciprofloxacin it was 23% (inadequate coverage 9%, resistance 14%). Enterococcus species usually have low virulence, and it is debatable whether they should be covered in empirical therapy. Leaving out enterococci (7% of all uropathogens) decreased the inadequate treatment rate for some regimens: third-generation cephalosporins were now adequate in 10% of cases. All other regimens remained inadequate in > 10% of patients (Spoorenberg et al., submitted).
Search and select
Resistance data were obtained from the report Nethmap 2011 (www.swab.nl) and from the Infectious Diseases Surveillance Information System on Antimicrobial Resistance (ISIS-AR).
For other articles the databases of Pubmed and the Cochrane Library were searched.
Keywords: urinary tract infection AND treatment
Limits: Last 2 years for Pubmed (IDSA guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women were published in 2011) (3)), English, adults, humans, clinical trials, guideline, meta-analysis, RCT
Pubmed: 101 results, all titles screened, 1 abstract screened, 1 additional article included.
Cochrane Library: 35 results, all titles screened, 0 abstracts screened, 0 reviews included.
Articles on antimicrobial agents which are not available in the Netherlands, or on the treatment of uncomplicated UTIs, were excluded.
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This guideline does not include evidence tables.
Optimal therapy for UTI with systemic symptoms depends on the severity of illness at presentation, as well as local resistance patterns and specific host factors (such as allergies). In addition, urine culture and susceptibility testing should be performed, and initial empirical therapy should be tailored and followed by (oral) administration of an appropriate antibiotic agent on the basis of the isolated uropathogen.
Collateral damage, a term describing ecological adverse effects of antimicrobial therapy, such as the selection of drug-resistant organisms and colonization or infection with multidrug-resistant organisms, has been associated with the use of broad-spectrum antimicrobial agents (3). Therefore, last line antimicrobial agents like piperacilin-tazobactam, imipenem and meropenem are not recommended as first choice empirical therapy.
EMPIRICAL TREATMENT: DRUG OF CHOICE
In the recent updated IDSA guidelines for the treatment of uncomplicated UTI, it is recommended that the resistance percentages of causative micro-organisms must be below 20% to consider an agent suitable for empirical treatment of a lower UTI and must be below 10% for treatment of an upper UTI. Considering the resistance percentages of amoxicillin, co-amoxiclav, TMP and TMP-SMX, we can conclude that these agents are not suitable for the empirical treatment of pyelonephritis in a normal host and, therefore, also not for treatment of all other complicated UTIs. The same applies to ciprofloxacin and other fluoroquinolones in patients from the urology departments.
Therefore, patients with a UTI with systemic symptoms requiring hospitalization should be initially treated with an intravenous antimicrobial regimen, such as an aminoglycoside, with or without amoxicillin or a second generation cephalosporin; or a third generation cephalosporin or extended-spectrum penicillin, with or without an aminoglycoside. The choice between these agents should be based on local resistance data, and the regimen should be tailored on the basis of susceptibility results (3). These recommendations are not only suitable for pyelonephritis but for all complicated UTIs.
In view of the high degree of resistance, in particular among patients admitted to the department of urology, fluoroquinolones are not automatically suitable as empirical antimicrobial therapy, especially when the patient has used ciprofloxacin in the last 6 months (7). Therefore, this agent can only be recommended as empirical treatment when the patient is not seriously ill and it is considered safe to start initial oral treatment or if the patient has had an anaphylactic reaction to β-lactam antibiotics.
Oral ciprofloxacin (500 mg twice daily, with or without an initial 400-mg dose of intravenous ciprofloxacin) is an appropriate choice for therapy in patients not requiring hospitalization when the prevalence of resistance of community uropathogens to fluoroquinolones is not known to exceed 10%. If the prevalence of fluoroquinolone resistance is thought to exceed 10%, an initial 1-time intravenous dose of a long-acting antimicrobial, such as 1 g of ceftriaxone or an aminoglycoside, is recommended (3) while resistance data are pending. However, a study in women with uncomplicated pyelonephritis showed there were no differences in the clinical success rates of women with a ciprofloxacin susceptible E. coli compared to those with a ciprofloxacin resistant E. coli (8). After a follow-up of 4-7 days, and 14-21 days after completion of therapy, the clinical success rates were 87.0% vs. 76.9% (P=0.14) and 98.6% vs. 94.9% (P=0.18) for the ciprofloxacin susceptible and ciprofloxacin resistant groups, respectively. Therefore, it seems that in women with uncomplicated pyelonephritis, even in higher percentages of ciprofloxacin resistance, ciprofloxacin can be prescribed as an empirical treatment (8).
Because there is only a small chance that cross-hypersensitivity exists between penicillin derivatives and cephalosporins (9), the Guideline committee is of the opinion that in the event of hypersensitivity for penicillin derivatives (a rash but not a systemic anaphylactic reaction), a 3rd generation cephalosporin can still be prescribed. If -lactam antibiotics have caused anaphylaxis in the past, a fluoroquinolone is recommended.
If the clinical condition of the patient allows it and if the patient does not vomit, then oral therapy can be prescribed (10), (11). If the patient no longer has symptoms, there is no indication for follow-up cultures.
When to cover ESBL in the empiric regimen?
In the SWAB guidelines for antibacterial therapy of adult patients with sepsis (SWAB 2010) the following recommendations are made:
- In (departments of) hospitals with a high prevalence of Extended-Spectrum Beta-Lactamase (ESBL)-producing Enterobacteriaceae, a carbapenem with anti-pseudomonal activity (imipenem/meropenem) should be chosen as empirical antibacterial therapy if an infection caused by ESBL-producing bacteria is suspected. As no critical prevalence level has been identified, risk factors of ESBL infection should be used to target empirical therapy on an individual patient basis.
- In patients with community-acquired and nosocomial sepsis and prior use of cephalosporins or quinolones within 30 days before presentation and/or colonized with ESBL-producing micro-organisms, the antibacterial regimen should also be active against ESBL-producing micro-organisms. This can be achieved by the addition of an aminoglycoside to the regimen or by the use of a carbapenem.
The background of these recommendations is the assumption that inadequate empirical coverage will result in a delay of start of effective therapy, and a resulting excess mortality. For patients with bacteremia caused by ESBL-producing Enterobacteriaceae this assumption proved to be correct (12). However, in this meta-analysis the increased relative risk for mortality was not corrected for confounding. In general, mortality is low in patients with UTI, and for UTI patients no excess mortality could be demonstrated for ESBL compared to non-ESBL producing strains (13), (14). In a Dutch study on antibiotic treatment and outcome in patients with ESBL-producing Enterobacteriaceae bacteremia, urosepsis and intra-abdominal infections were major sources of bacteremia. After correcting for confounding, adequacy of antibiotic treatment within 24 hours was not associated with increased 30-day mortality (WC Rottier et al.. Submitted).
For these reasons, the Guideline committee recommends to cover ESBL in the initial treatment only in patients who are colonized with ESBL-producing micro-organisms. In that case, the resistance pattern of the ESBL strain should guide empirical therapy.
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.