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Clinical presentation, risk factors and use of antibiotics in urinary tract infections
RENAL AND UROLOGICAL SURGERY III
Clinical presentation, risk factors and use of antibiotics in urinary tract infections
virulence of threatening pathogens is normally balanced by host protective mechanisms. This balance may be disturbed by risk factors. Sometimes microorganisms enter the urinary tract without causing problems. This is called asymptomatic bacteriuria and is no longer regarded as a type of urinary tract infection (UTI), although treatment is recommended under certain circumstances like in pregnancy and before invasive urological procedures. The presence of pathogens in the urine is considered to be a risk factor for a clinical infection.1,2 Local and systemic symptoms may arise when pathogens invade the urothelium. The higher up in the urinary tract the invasion takes place, the more serious is the clinical situation. The most severe condition is when urinary tract pathogens enter the blood stream and cause urosepsis. A doctor who is seeing a patient suspected of having a UTI must assess clinical diagnosis, available treatment measures and prognosis. The primary concern is to protect kidney function. A concern of increasing importance is to protect the environment against collateral damage from antibiotics. The aim of this paper is to present recent recommendations on severity assessment, and use of antibiotics to prevent and treat urinary tract infections. Severity assessment is based on clinical presentation, risk factors and antibiotic treatment options.
Truls E Bjerklund Johansen Rasmus Nilsson Zafer Tandogdu Florian Wagenlehner
Abstract The European Section for Infections in Urology (EAU) has introduced a new concept of severity assessment of urinary tract infections (UTI). The assessment is based on clinical presentation, patient risk factors and availability of effective antibiotics. Instead of the old classification of uncomplicated and complicated UTI, ESIU suggests to describe risk factors by means of phenotyping. In this paper we present the new classification and give practical recommendations on antibiotic treatment of the most common community acquired and hospital acquired urinary tract infections. Antibiotics have been prescribed so extensively that resistant bacteria have made prophylaxis and treatment of urinary tract infections a more difficult task. Prophylaxis during surgical procedures should be prescribed according to the risk of infective complications. The most important criterion is the contamination category of the procedure. Basically there are four categories: clean, clean-contaminated, contaminated and dirty, but in urology the clean-contaminated category is subdivided depending on whether the urinary tract or the gastrointestinal tract is opened. International guidelines consider pharmacokinetic and pharmacodynamics features of antibiotics and global resistance data. These recommendations may therefore need local adaptations. Urologists, microbiologists and infectious disease specialists should meet in every hospital to adapt their own guidelines according to local resistance data.
Materials and methods The main reference for the present review is the EAU guidelines on urinary infections which are being updated on an annual basis.3 A special update of EAU guidelines was made in 2010 in collaboration with the ICUD (International Consultation on Urological Diseases). This update was based on a systematic review of 3600 references by 123 authors including the systematic literature reviews reported by the international Cochrane collaboration.4,5 Another important source of information is the database and publications from the annual Global Prevalence studies on Infections in Urology (GPIU) that have been run by ESIU for 10 years in a row.6 We have also considered recent publications in leading medical journals.
Keywords Antibiotic treatment; clinical presentation; ORENUC; prophylaxis; risk factors; urinary tract infections
Clinical presentation Introduction
According to EAU/ESIU definitions a patient is diagnosed as having a symptomatic UTI if: there are clinical symptoms indicative of UTI and pathogens can be verified or suspected by culture, microscopy, dipstick or PCR-techniques, or the diagnosis or an appropriate therapy of symptomatic UTI is made by a physician upon clinical evaluation.1,2 A UTI is classified as cystitis (CY), pyelonephritis (PN) and urosepsis (US). Urethritis (UR) and male accessory gland infections (‘male adnexitis’ or MA, e.g. prostatitis) are usually dealt with separately, because the clinical presentations are quite different.2 The clinical presentation of the three UTI entities discussed here (CY, PN, US) are presented in Table 1. A PN is always more severe than a CY and a US is always more severe than the two former conditions. In addition, PN can present as a mild and moderate infection, which usually can be treated by oral antimicrobials in an outpatient setting, and as a severe infection with systemic reactions like nausea and vomiting, which usually
Microorganisms always threaten to invade the urinary tract. Billions of them are coming out of the anal opening near by. The
Truls E Bjerklund Johansen MD PhD is Professor, Department of Urology, Oslo University Hospital, Oslo, Norway. Conflicts of interest: none declared. Rasmus Nilsson MD is a urologist at Telemark Hospital, Skien, Norway. Conflicts of interest: none declared. Zafer Tandogdu MD holds an EAU scholarship at Newcastle University, Medical School, Northern Institute for Cancer Research (NICR), Newcastle upon Tyne, UK. Conflicts of interest: none declared. Florian Wagenlehner MD is Professor at the Department of Urology, University of Giessen, Giessen, Germany. Conflicts of interest: none declared.
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Clinical presentation of cystitis (CY), pyelonephritis (PN) and urosepsis (US) and grading of severity2 Acronym
Clinical diagnosis
Clinical symptoms
Grade of severity
CY-1
Cystitis
1
PN-2
Mild and moderate pyelonephritis
PN-3
Severe pyelonephritis
US-4
Urosepsis (simple)a
US-5
Severe urosepsisa
US-6
Uroseptic shocka
Dysuria, frequency, urgency, suprapubic pain; sometimes unspecific symptoms Fever, flank pain, CVA tenderness; sometimes unspecific symptoms with or without symptoms of CY As PN-2, but in addition nausea and vomiting with or without symptoms of CY (>2 SIRS criteria must be met for US-4 diagnosis) Temperature > 38 C or < 36 C Heart rate > 90 beats min Respiratory rate > 20 breaths/min or PaCO2 < 32 mmHg (<4.3 kPa) WBC > 12,000 cells/mm3 or < 4,000 cells/mm3 or 10% immature (band) forms With or without symptoms of CY or PN As US-4, but in addition associated with organ dysfunction, hypoperfusion or hypotension. Hypoperfusion and perfusion abnormalities may include but are not limited to lactic acidosis, oliguria or an acute alteration of mental status AS US-4 or US-5, but in addition with hypotension despite adequate fluid resuscitation along with the presence of perfusion abnormalities that may include, but are not limited to, lactic acidosis, oliguria, or an acute alteration in mental status. Patients who are on inotropic or vasopressor agents may not be hypotensive at the time that perfusion abnormalities are measured.
2
3 4
5
6
Note: Hypotension due to urosepsis is defined as a systolic blood pressure of <90 mmHg or a reduction of >40 mmHg from baseline in the absence of other causes of hypotension. a Urosepsis is defined as sepsis originating from the urogenital tract. CVA, costovertebral angle; SIRS, systemic inflammatory response syndrome; WBC, white blood cell.
Table 1
new concept of phenotyping to better describe the different groups of risk factors of UTI.1e3 Risk factors related to UTI will modify the patient’s prognosis. The diagnostic work-up in patients with UTI is about detecting risk factors that need to be considered or eliminated to achieve treatment aims. ESIU has suggested to phenotype risk factors in UTI by means of the so-called ORENUC system (Table 2). The system has six main categories. Each category is referred to by a letter. All letters together make up the name ORENUC. Table 2 presents examples of risk factors in each category. The list of risk factors in this table is not complete. Phenotyping of risk factors is also relevant before a surgical procedure, like for example a prostate biopsy. A history of UTI during the recent 6 months and asymptomatic bacteriuria are important category U risk factors, while having had an indwelling catheter is a category C risk factor.
needs initial parenteral therapy and hospitalization. For urosepsis the severity grading of sepsis in general use is: sepsis, severe sepsis and septic shock. Recently the ESIU suggested ascribing each of the clinical presentations a severity grade in Arabic letters.1 The clinical presentation is always the most important prognostic criterion.
Risk factors Many categories of risk factors are described in literature on UTI, such as risk factors for getting UTI, risk factors for recurrences, risk factors for serious complications, risk factors for kidney failure, etc. Long and often overlapping lists of risk factors have been described within a concept of UTIs being either uncomplicated or complicated.7,8 The ESIU found this old concept not sufficiently reflecting the clinical needs, and introduced a
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Host risk factors in urinary tract infections categorized according to the ORENUC system1,2 Phenotype
Category of risk factor
Examples of risk factors
O R
NO known risk factor Risk factors for Recurrent UTI, but no risk of more severe outcome
E
Extra-urogenital risk factors with risk of more severe outcome
N
Nephropathic diseases with risk of more severe outcome
U
Urological risk factors with risk of more severe outcome, which can be resolved during therapy
C
Permanent urinary Catheter and non resolvable urological risk factors with risk of more severe outcome
Otherwise healthy premenopausal women Sexual behaviour (frequency, spermicide), Hormonal deficiency in postmenopause Secretor type of certain blood groups Well-controlled diabetes mellitus Prematurity, newborn Pregnancy Male gender Badly controlled diabetes mellitus Relevant immunosuppression (not well defined) Relevant renal insufficiency (not well defined) Polycystic nephropathy Interstitial nephritis (e.g. due to analgetics) Ureteral obstruction due to a ureteral stone Well controlled neurogenic bladder disturbances Transient short-term external urinary catheter Asymptomatic bacteriuria Long-term external urinary catheter Non resolvable urinary obstruction Badly controlled neurogenic bladder disturbances
Table 2
complication can be found in existing databases. Table 3 shows the risk of infective complications related to one of the most common urological procedures, prostate biopsy.3,11,12 Patient-related risk factors as described in the ORENUC system will modify the procedure-related risk of infection in a given patient. All factors need to be addressed when risk assessment is done before a surgical procedure.
The risk of developing infective complications after surgical procedures is usually described in a separate system known as Contamination categories (Box 1). The most important factors for assessment of contamination category have been the age of the surgical wound, if bodily tracts are opening during surgery, spillage of its contents, and signs of infection or devitalized tissue.9 The concept of contamination categories was developed during World War II in order to evaluate prognosis and risk of infection after injuries. Since then large databases have been built that give the infection rate in each category and confirm the validity of the classification principle also in modern surgery.10 However, modern urological surgery differs significantly from war injuries and open surgery. Therefore the ESIU recently worked out their own definitions of contamination categories in urology. The categories are still based on characteristics of the surgical field, but a new criterion has been added according to which bodily tract that is entered or opened and the duration of the procedure. All surgical procedures may be ascribed a contamination category. Once the category is defined, the risk of infective
Antibiotic stewardship The overall aim of antibiotic treatment in UTI is to restore a normal balance between pathogens and the host. This either means getting rid of the pathogens, or causing the pathogens to withdraw to their habitats outside the urinary tract, or even inside urothelial cells. Not all pathogens will receive a lethal dose of antibiotics and some may survive. While resting in their trenches some pathogens are even capable of developing resistance mechanisms to classes of antibiotics such as betalactams and spread to other hosts. This is what collateral damage is about. With a generation time of only 20 minutes new genes are multiplied at high speed thus making pathogens appear as intelligent creatures. As long as the number of available antibiotics is limited and resistance increases, our chance of giving effective prophylaxis and treatment is steadily being reduced. This is why antibiotic stewardship is important.13 Over the past ten years we have seen a rise in multiresistant pathogens such as extended spectrum betalactamase producing strains (ESBL), vancomycin resistant strains and methicillin resistant staphylococci (MRSA). Recently the first omniresistant bacteria NDM-1, was described in urine cultures in UK.14 Within a short time the pathogen spread to most European countries.
Classical definitions of surgical field contamination I. II. III. IV.
Clean Clean-contaminated Contaminated Dirty
Box 1
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Biopsy routes, contamination categories and risk of infection without prophylaxis in prostate biopsies3,11 Biopsy route
Contamination category
Transperineal
Clean Clean-contaminated
Transperineal
Contaminated
Transrectal Transrectal
Contaminated Dirty
Key criteria
Sterile urine No history UTI/UGI Sterile urine History of UTI/UGI Sterile urine Bacteriuria Urethral catheter
Risk of infection <5% 5e10% 10e15% 10e15% 15e40%
UGI, urogenital infection (i.e. prostatitis); UTI, urinary tract infection.
Table 3
normalization of reflux, the children are outpatients and there are no foreign bodies present. What seems to be an inconsistence of principles as to antibiotic use in children and in perioperative prophylaxis reflects the relative lack of high level evidence in this field.
Knowledge about the clinical course of urinary tract infections with multiresistant or omniresistant pathogens is still limited, but the perspectives give reasons for concern. Urologists should be aware of the antibiotic prescription policy for community acquired UTIs as this may enhance the development of resistant strains that may be brought into hospitals. Today up to 100% of patients in a urology ward may be receiving antibiotics for prophylaxis or treatment. This means that urology departments are high-risk zones for development of resistant uropathogens. If effective antibiotics are not available, natural host defence is the only protection against spread of infection. Risk factors will make spread of infection more likely. In many developing countries there is poor availability of antibiotics, and in some regions even in Europe today available antibiotics are no longer effective because of high resistance rates. Therefore the ESIU recommended that availability of effective antibiotics should be included in the assessment of severity and prognosis for a case of UTI, and suggested a three letter scale, aec, describing the different combinations of pathogen susceptibility and availability of effective antibiotics.1 This concept is however, not fully developed.
Short-term perioperative prophylaxis Hospital acquired urinary tract infections are seen in about 11% of patients in urology departments.6 When this occurs after surgical procedures it is because pathogens are resistant to the antibiotics used for prophylaxis. EAU guidelines are based on evidence from pharmacokinetic, pharmacodynamic and international studies of pathogens and resistance. However, the GPIU studies have shown that urologists do not always adhere to the EAU guidelines recommendations.17 As a rule the urologist should sit down with the local microbiologist and infectious disease specialist to work out prophylaxis regimens based on local culture results of hospital acquired UTI and regional results of community acquired UTI. Designing prophylactic regimens is a dynamic process and the regimens should be changed with a few years’ interval. The most potent antibiotics such as aminoglycosides and carbapenems should be reserved for treatment. Perioperative prophylaxis is a short-term administration ensuring adequate serum levels at the time of maximal exposure to possible pathogens. Sometimes administration may be prolonged for up to three days. However, antibiotics are not recommended for prophylaxis in patients waiting for catheter removal, for example after radical prostatectomy or cystectomy. The risk of infective complications following urological surgery may be foreseen by the contamination category of the procedure. Prophylaxis is not generally recommended in clean procedures where the risk of infective complications is less than 5%,3 but individual risk factors may modify the overall risk and justify prophylaxis also in clean procedures. The antibiotics most commonly recommended for prophylaxis in endourological procedures are trimethoprim sulphametoxazol, second generation cephalosporins, aminopenicillin plus a betalactamase inhibitor and fluoroquinolones. For open surgical procedures the most commonly recommended antibiotics are trimethoprim sulphametoxazol, second or third generation cephalosporins, aminopenicillin plus a betalactamase inhibitor and metronidazole.3 Amikacin is frequently used in Asia, while second and third generation cephalosporins are often used in South
Use of antibiotics in urology Antibiotics are prescribed in three different situations in urology: prophylaxis suspected UTI UTI with an identified pathogen. Suspected UTI is the main reason for prescribing antibiotics in urology accounting for 50% of cases, while the two other groups account for about 25% each.15 Prophylaxis may be given as longterm administration to prevent recurrent UTI like in children and as short-term administration to prevent infective complications after surgical procedures. Long-term prophylaxis in children There is evidence to support long-term administration of oral antibiotics in children at risk of kidney damage.3,16 The concept of prophylaxis in children with recurrent UTI is different from the concept of perioperative prophylaxis. Important characteristics are that the patients are children, the situation we try to prevent is end-stage kidney disease, the urinary tract is undergoing physiological development during prophylaxis including
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America and Africa.17 For details on contamination categories and recommended prophylactic regimens the reader is referred to the Guidelines of the European Association of Urology.3 Antibiotic prophylaxis in prostate biopsies represents a special challenge in terms of which antibiotic to use, especially in repeat biopsies, and the timing of administration in outpatient procedures.18 Most guidelines recommend fluoroquinolones for prophylaxis in prostate biopsies, but the increase of fluoroquinolone resistance has raised the question of appropriateness of the current recommendation.3 As a rule extended courses is not recommended after prostate biopsies. Doing culture tests of rectal swabs may help developing a better tailored prophylaxis.
pyelonephritis an oral therapy of 10e14 days is usually sufficient. A fluoroquinolone for 7e10 days can be recommended as first-line therapy if the resistance rate of E. coli is still below 10%. If the fluoroquinolone dosage is increased, the treatment can probably be reduced to 5 days. However, increasing rates of fluoroquinolone resistant E. coli already found in the community area in some parts of the world restrict the empiric use of fluoroquinolones. A third generation oral cephalosporin (e.g. cefpodoxime proxetil or ceftibuten) may be an alternative. However, available studies demonstrated only equivalent clinical, but not microbiological, efficacy compared with ciprofloxacin. Because of increasing E. coli resistance rates above 10%, cotrimoxazole is not suitable for empiric therapy in most areas, but can be used as test conform therapy when susceptibility of the pathogen is already known. Amoxiclav is not recommended as a drug of first choice for empiric oral therapy of acute pyelonephritis. It is, however, recommended when susceptibility testing shows a susceptible Grampositive organism. In communities with high rates of fluoroquinolone resistant and ESBL producing E. coli (>10%), an initial empiric therapy with an aminoglycoside or a carbapenem has to be considered until susceptibility testing demonstrates that oral drugs can also be used. Hospital admission should be considered if risk factors cannot be ruled out by available diagnostics and/or the patient has clinical signs and symptoms of sepsis. After improvement, the patient can be switched to an oral regimen using one of the abovementioned antibacterials, if active against the infecting organism, to complete the 1e2 week course of therapy.19 Patients with severe pyelonephritis who cannot take oral medication because of systemic symptoms like nausea and vomiting, have to be treated initially with one of the following parenteral antibiotics depending on the local resistance rates of E. coli: a parenteral fluoroquinolone, in communities with resistance rates of E. coli to fluoroquinolones <10% a third generation cephalosporin, in communities with resistance rates of ESBL producing E. coli <10% an aminopenicillin plus a betalactamase inhibitor in case of a known susceptible Gram-positive pathogen an aminoglycoside or a carbapenem in communities with resistance rates to fluoroquinolones and/or ESBL producing E. coli >10%. In women whose pyelonephritis symptoms do not improve within 3 days, or that resolve and then recur within 2 weeks, a repeat urine culture, antimicrobial susceptibility testing and an appropriate investigation, such as renal ultrasound, computertomography or scan, should be performed. In the patient with no urological abnormality, it should be assumed that the infecting organism is not susceptible to the agent originally used and an alternative tailored therapy should be considered based on culture results. For those patients who have a symptomatic relapse with the same pathogen as the initial infecting strain, diagnosis of uncomplicated pyelonephritis should be reconsidered and further diagnostic steps are necessary.3
Suspected UTI Suspected UTI always means that treatment is started on an empirical basis, and usually the situation has to be reassessed once the identity and susceptibility of the pathogen is known. According to both US and European guidelines it is acceptable to diagnose UTI by patient history and clinical examination only and to initiate treatment on this basis, which should be tailored as soon as urine culture results are available. In the majority of community acquired UTI the identity and susceptibility of the pathogen is unknown at the time when treatment is started. Primary care physicians must however, acquaint themselves with local resistance figures because only drugs with a general resistance in the population of <20% are recommended as first-line therapy. In terms of hospital acquired UTI we advocate waiting for evidence from urinalysis and culture if clinically suitable, otherwise empirical treatment for suspected UTI is considered. All general recommendations have to be modified by patient related risk factors. Community acquired cystitis without known risk factors: according to known susceptibility patterns, the following antibiotics can be considered the drugs of first choice in many countries, where available: fosfomycin trometamol 3 g as a single dose pivmecillinam 400 mg bid for 3 days and nitrofurantoin macrocrystal 100 mg bid for 5 days. Cotrimoxazole 160/800 mg bid for 3 days or trimethoprim 200 mg for 5 days should only be considered as the first choice in areas with known resistance rates of Escherichia coli below 20%. Alternative antibiotics are ciprofloxacin 250 mg bid, ciprofloxacin ER 500 mg qd, levofloxacin 250 mg qd, norfloxacin 400 mg bid and ofloxacin 200 mg bid, each as a 3-day course. However, collateral effects have to be considered. Symptomatology may be sufficient for routine follow-up. In treated patients where symptoms do not resolve and in patients with early relapse (<2 weeks) urine culture and antimicrobial susceptibility testing should be performed for guidance of therapy.19 Community acquired acute pyelonephritis without known risk factors: due to lack of suitable surveillance studies the spectrum and susceptibility patterns of uropathogens causing uncomplicated cystitis has to be used as guide for empiric therapy in a given country. However, Staphylococcus saprophyticus is to be less considered in acute pyelonephritis as compared to acute cystitis. In mild and moderate cases of acute uncomplicated
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Antibiotic treatment of HAUTI and urosepsis: the goal of antibiotic therapy of hospital acquired UTIs (HAUTI) is not only to cure the patient but also to contain the spread of infection and
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Urologists prescribe a huge amount of antibiotics, 50% for prophylaxis, 25% for suspected UTI and 25% for confirmed infections with known pathogens. The best way to develop prophylactic regimens is for the urologist, microbiologist and infectious disease specialist to work together. Increasing resistance among urinary tract pathogens necessitates prudent use of antibiotics. Fluoroquinolones still hold a key position in prophylaxis and treatment of urinary tract infections, but care must be taken because of world-wide increase of resistant uropathogens and to avoid overuse causing further collateral damage to the patients. Special attention should be paid to avoid infective complications after prostate biopsies. Rectal swabs before intervention may help developing a better tailored prophylaxis. A
prevent the emergence of resistant mutants. Susceptibility testing should be carried out in any case of HAUTI, and if possible the results should be awaited before treatment. However, in severe infections an initial empiric therapy must be instigated immediately after microbiological sampling. Susceptibility testing can serve in these cases to narrow the antibiotic coverage. Provisional microbiological findings can lead to early stratification of pathogens and allow a more tailored empiric antibiotic therapy. Prudent use of antimicrobials may also help to reduce the selection of resistant pathogens to a minimum. Antibiotics with an enlarged antibacterial spectrum are necessary for initial empiric treatment. The empiric parenteral treatment could start with: a cephalosporin group 3a a fluoroquinolone with good renal excretion or an aminopenicillin in combination with a betalactamase inhibitor. If clinical improvement fails after two to three days, treatment should be switched to: a pseudomonas active acylaminopenicilline/betalactamase-inhibitor a group 3b cephalosporin or a carbapenem. Other reasons for treatment failure, such as persistent risk factors, other infections or noninfectious sources, should also be taken into account and be re-evaluated. Regional variations in resistance must also be considered for empiric treatment. The use of parenteral antibiotics is determined by the general condition of the patient (e.g. nausea, vomiting) and the severity of the infection; oral antibiotics can be continued as soon as the clinical situation has improved. After the results of the susceptibility testing have arrived, the antibiotic treatment should be aligned accordingly. Treatment duration should continue for at least three to five days beyond defervescence, depending on the removal of the risk factor. However, this recommendation does not hold true for the treatment of pyelonephritis with abscess formation or chronic bacterial prostatitis, which should usually continue for several weeks.19,20 HAUTIs are frequently complicated by the presence of a biofilm in which pathogens adhere to anatomical structures of the urinary tract - stones, foreign materials or necrotic tissue - and are embedded in organic (exopolysaccharide) and anorganic (phosphate) material. Therefore it is necessary to elevate antibiotic concentrations by 10- to 100-fold in order to inhibit or kill the pathogens. Such increased antibiotic concentrations are often not clinically achievable. Fluoroquinolones and macrolides (only effective against Gram-positive bacteria) exhibit a specific effect on the biofilm formation, which, however, is usually not sufficient to eradicate the pathogens. Therefore, antimicrobial therapy in complicated UTIs may only kill the bacteria dissolved from the biofilm (planktonic form) and thus inhibit spread of the infectious process. An accompanying urological therapy must aim to remove the biofilm.21
REFERENCES 1 Bjerklund Johansen Truls E, Botto Henry, Cek Mete, et al. Critical review of current definitions of urinary tract infections and proposal of an EAU/ESIU classification system. IJAA 2011; 38(suppl): 64e70. 2 Bjerklund Johansen TE, Botto H, Cek M, et al. Criteria for healthcare associated urinary tract infections: an EAU/ESIU update on current definitions. Chapter 10.2. In: Naber KG, Scaeffer AJ, Heyns CF, Matsumoto T, Shoskes DA, Bjerklund Johansen TE, eds. Urogenital infections (textbook 1182pp). International Consultation on Urological Diseases (ICUD) and European Association of Urology, 2010; 567e74. ISBN: 978-90-79754-41-0, Arnheim. 3 Grabe M, Bjerklund Johansen TE, Botto H, et al. Guidelines on urological infections. EAU guidelines 2013 edition, pp.1e100. Arnheim. European Association of Urology, 2013. ISBN/EAN: 978-90-79754-717. 4 Naber KG, Scaeffer AJ, Heyns CF, et al. Urogenital infections (textbook 1182pp). International Consultation on Urological Diseases (ICUD) and European Association of Urology, 2010. ISBN: 978-90-79754-410, Arnheim. 5 www.thecochranelibrary.com. 6 Johansen TEB, Cek M, Tenke P, Stratchounski L, Svendsen MV, Naber K, on behalf of the PEP and PEAP-study investigators and the Board of the European Society of Infections in Urology. Hospital acquired urinary tract infections in urology departments: pathogens, susceptibility and antibiotics given. Data from the PEP and PEAPstudies. Int J Antimicrob Agents 2006; 28S: 91e107. 7 Rubin USE, Andriole VT, Davis RJ, Stamm WE. Evaluation of new antiinfective drugs for the treatment of UTI. Clin Infect Dis 1992; 15: 216. 8 Rubin UH, Shapiro ED, Andriole VT, Davis RJ, Stamm WE, with a modification by a European Working Party (Norrby SR). General Guidelines for the evaluation of new anti-infective drugs for the treatment of urinary tract infection. Taufkirchen, Germany: The European Society of Clinical Microbiology and Infectious diseases, 1993; 240e310. 9 Howard JM, Barker WF, Culbertson WR, et al. Postoperative wound infections: the influence of ultraviolet irradiation of the operating room and of various other factors. Ann Surg 1964; 160(suppl): 1e192. 10 Culver DH, Horan TC, Gaynes RP, et al. Surgical wound infection rates by wound class, operative procedure, and patient risk index. Am J Med 1991; 91(suppl 3B): 152Se1157.
Conclusions Severity scoring in UTI is based on clinical presentation, risk factors and availability of effective antibiotics. Risk factors may be classified by the ORENUC system.
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11 Grabe M, Botto H, Cek M, et al. Preoperative assessment of the patient and risk factors for infectious complications and tentative classification of surgical field contamination of urological procedures. World J Urol 2012; 30: 39e50. 12 Bjerklund Johansen TE. Update on urinary tract infections: how to prevent infective complications after prostate biopsies. Urology News 2010; 15: 6e9. 13 Wagenlehner Florian ME, Bartoletti Ricardo, Cek M, et al. Antibiotic stewardship e a call for action by the urological community. Eur Urol 2013; 64: 358e60. 14 Elias J, Schoen C, Heinze G, et al. Nosocomial outbreak of VIM-2 metallo-ß-lactamase-producing Pseudomonas aeruginosa associated with retrograde urography. Clin Microbiol Infect 2010; 16: 1494e500. 15 Johansen TEB, Cek M, Tenke P, Stratchounski L, Svendsen MV, Naber K, on behalf of the PEP and PEAP-study investigators and the board of the European Society of Infections in Urology. Prevalence of hospital acquired urinary tract infections in urology departments: data from the PEP and PEAP-studies. Eur Urol 2007; 51: 1100e12. 16 Arant Jr BS. Vesicoureteral reflux and evidence-based management. J Pediatr 2001; 139: 620e1. 17 Cek M, Tandogdu Z, Naber K, et al. Antimicrobial prophylaxis in urology departments 2005e2010. Eur Urol 2013; 63: 386e94. 18 Wagenlehner FME, van Ostrum E, Tenke P, et al. Infective complications after prostate biopsy: outcome of the Global Prevalence Study of Infections in Urology (GPIU). Eur Urol 2013; 63: 521e7.
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19 Wagenlehner FME, Cek M, Kiyota H, Bjerklund Johansen TE. Epidemiology, treatment and prevention of healthcare associated urinary tract infections. Chapter 10.3. In: Naber KG, Scaeffer AJ, Heyns CF, Matsumoto T, Shoskes DA, Bjerklund Johansen TE, eds. Urogenital infections. Arnheim: International Consultation on Urological Diseases (ICUD) and European Association of Urology, 2010; 575e88. 20 Wagenlehner FME, Platz A, Weidner W. Urosepsis e from the view of the urologist. Chapter 11.4. In: Naber KG, Scaeffer AJ, Heyns CF, Matsumoto T, Shoskes DA, Bjerklund Johansen TE, eds. Urogenital Infections. Arnheim: International Consultation on Urological Diseases (ICUD) and European Association of Urology, 2010; 630e44. 21 Tenke P, Koves B, Nagy K. Urinary catheters and drainage systems: prevention and treatment of urinary tract infections. Chapter 9.3. In: Naber KG, Scaeffer AJ, Heyns CF, Matsumoto T, Shoskes DA, Bjerklund Johansen TE, eds. Urogenital Infections. Arnheim: International Consultation on Urological Diseases (ICUD) and European Association of Urology, 2010; 532e40.
Acknowledgements The authors wish to acknowledge with thanks Drs Peter Tenke, Mete Cek and Kurt Naber for their critical review of this article during its preparation.
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Clinical presentation, risk factors and use of antibiotics in urinary tract infections
virulence of threatening pathogens is normally balanced by host protective mechanisms. This balance may be disturbed by risk factors. Sometimes microorganisms enter the urinary tract without causing problems. This is called asymptomatic bacteriuria and is no longer regarded as a type of urinary tract infection (UTI), although treatment is recommended under certain circumstances like in pregnancy and before invasive urological procedures. The presence of pathogens in the urine is considered to be a risk factor for a clinical infection.1,2 Local and systemic symptoms may arise when pathogens invade the urothelium. The higher up in the urinary tract the invasion takes place, the more serious is the clinical situation. The most severe condition is when urinary tract pathogens enter the blood stream and cause urosepsis. A doctor who is seeing a patient suspected of having a UTI must assess clinical diagnosis, available treatment measures and prognosis. The primary concern is to protect kidney function. A concern of increasing importance is to protect the environment against collateral damage from antibiotics. The aim of this paper is to present recent recommendations on severity assessment, and use of antibiotics to prevent and treat urinary tract infections. Severity assessment is based on clinical presentation, risk factors and antibiotic treatment options.
Truls E Bjerklund Johansen Rasmus Nilsson Zafer Tandogdu Florian Wagenlehner
Abstract The European Section for Infections in Urology (EAU) has introduced a new concept of severity assessment of urinary tract infections (UTI). The assessment is based on clinical presentation, patient risk factors and availability of effective antibiotics. Instead of the old classification of uncomplicated and complicated UTI, ESIU suggests to describe risk factors by means of phenotyping. In this paper we present the new classification and give practical recommendations on antibiotic treatment of the most common community acquired and hospital acquired urinary tract infections. Antibiotics have been prescribed so extensively that resistant bacteria have made prophylaxis and treatment of urinary tract infections a more difficult task. Prophylaxis during surgical procedures should be prescribed according to the risk of infective complications. The most important criterion is the contamination category of the procedure. Basically there are four categories: clean, clean-contaminated, contaminated and dirty, but in urology the clean-contaminated category is subdivided depending on whether the urinary tract or the gastrointestinal tract is opened. International guidelines consider pharmacokinetic and pharmacodynamics features of antibiotics and global resistance data. These recommendations may therefore need local adaptations. Urologists, microbiologists and infectious disease specialists should meet in every hospital to adapt their own guidelines according to local resistance data.
Materials and methods The main reference for the present review is the EAU guidelines on urinary infections which are being updated on an annual basis.3 A special update of EAU guidelines was made in 2010 in collaboration with the ICUD (International Consultation on Urological Diseases). This update was based on a systematic review of 3600 references by 123 authors including the systematic literature reviews reported by the international Cochrane collaboration.4,5 Another important source of information is the database and publications from the annual Global Prevalence studies on Infections in Urology (GPIU) that have been run by ESIU for 10 years in a row.6 We have also considered recent publications in leading medical journals.
Keywords Antibiotic treatment; clinical presentation; ORENUC; prophylaxis; risk factors; urinary tract infections
Clinical presentation Introduction
According to EAU/ESIU definitions a patient is diagnosed as having a symptomatic UTI if: there are clinical symptoms indicative of UTI and pathogens can be verified or suspected by culture, microscopy, dipstick or PCR-techniques, or the diagnosis or an appropriate therapy of symptomatic UTI is made by a physician upon clinical evaluation.1,2 A UTI is classified as cystitis (CY), pyelonephritis (PN) and urosepsis (US). Urethritis (UR) and male accessory gland infections (‘male adnexitis’ or MA, e.g. prostatitis) are usually dealt with separately, because the clinical presentations are quite different.2 The clinical presentation of the three UTI entities discussed here (CY, PN, US) are presented in Table 1. A PN is always more severe than a CY and a US is always more severe than the two former conditions. In addition, PN can present as a mild and moderate infection, which usually can be treated by oral antimicrobials in an outpatient setting, and as a severe infection with systemic reactions like nausea and vomiting, which usually
Microorganisms always threaten to invade the urinary tract. Billions of them are coming out of the anal opening near by. The
Truls E Bjerklund Johansen MD PhD is Professor, Department of Urology, Oslo University Hospital, Oslo, Norway. Conflicts of interest: none declared. Rasmus Nilsson MD is a urologist at Telemark Hospital, Skien, Norway. Conflicts of interest: none declared. Zafer Tandogdu MD holds an EAU scholarship at Newcastle University, Medical School, Northern Institute for Cancer Research (NICR), Newcastle upon Tyne, UK. Conflicts of interest: none declared. Florian Wagenlehner MD is Professor at the Department of Urology, University of Giessen, Giessen, Germany. Conflicts of interest: none declared.
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Clinical presentation of cystitis (CY), pyelonephritis (PN) and urosepsis (US) and grading of severity2 Acronym
Clinical diagnosis
Clinical symptoms
Grade of severity
CY-1
Cystitis
1
PN-2
Mild and moderate pyelonephritis
PN-3
Severe pyelonephritis
US-4
Urosepsis (simple)a
US-5
Severe urosepsisa
US-6
Uroseptic shocka
Dysuria, frequency, urgency, suprapubic pain; sometimes unspecific symptoms Fever, flank pain, CVA tenderness; sometimes unspecific symptoms with or without symptoms of CY As PN-2, but in addition nausea and vomiting with or without symptoms of CY (>2 SIRS criteria must be met for US-4 diagnosis) Temperature > 38 C or < 36 C Heart rate > 90 beats min Respiratory rate > 20 breaths/min or PaCO2 < 32 mmHg (<4.3 kPa) WBC > 12,000 cells/mm3 or < 4,000 cells/mm3 or 10% immature (band) forms With or without symptoms of CY or PN As US-4, but in addition associated with organ dysfunction, hypoperfusion or hypotension. Hypoperfusion and perfusion abnormalities may include but are not limited to lactic acidosis, oliguria or an acute alteration of mental status AS US-4 or US-5, but in addition with hypotension despite adequate fluid resuscitation along with the presence of perfusion abnormalities that may include, but are not limited to, lactic acidosis, oliguria, or an acute alteration in mental status. Patients who are on inotropic or vasopressor agents may not be hypotensive at the time that perfusion abnormalities are measured.
2
3 4
5
6
Note: Hypotension due to urosepsis is defined as a systolic blood pressure of <90 mmHg or a reduction of >40 mmHg from baseline in the absence of other causes of hypotension. a Urosepsis is defined as sepsis originating from the urogenital tract. CVA, costovertebral angle; SIRS, systemic inflammatory response syndrome; WBC, white blood cell.
Table 1
new concept of phenotyping to better describe the different groups of risk factors of UTI.1e3 Risk factors related to UTI will modify the patient’s prognosis. The diagnostic work-up in patients with UTI is about detecting risk factors that need to be considered or eliminated to achieve treatment aims. ESIU has suggested to phenotype risk factors in UTI by means of the so-called ORENUC system (Table 2). The system has six main categories. Each category is referred to by a letter. All letters together make up the name ORENUC. Table 2 presents examples of risk factors in each category. The list of risk factors in this table is not complete. Phenotyping of risk factors is also relevant before a surgical procedure, like for example a prostate biopsy. A history of UTI during the recent 6 months and asymptomatic bacteriuria are important category U risk factors, while having had an indwelling catheter is a category C risk factor.
needs initial parenteral therapy and hospitalization. For urosepsis the severity grading of sepsis in general use is: sepsis, severe sepsis and septic shock. Recently the ESIU suggested ascribing each of the clinical presentations a severity grade in Arabic letters.1 The clinical presentation is always the most important prognostic criterion.
Risk factors Many categories of risk factors are described in literature on UTI, such as risk factors for getting UTI, risk factors for recurrences, risk factors for serious complications, risk factors for kidney failure, etc. Long and often overlapping lists of risk factors have been described within a concept of UTIs being either uncomplicated or complicated.7,8 The ESIU found this old concept not sufficiently reflecting the clinical needs, and introduced a
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Host risk factors in urinary tract infections categorized according to the ORENUC system1,2 Phenotype
Category of risk factor
Examples of risk factors
O R
NO known risk factor Risk factors for Recurrent UTI, but no risk of more severe outcome
E
Extra-urogenital risk factors with risk of more severe outcome
N
Nephropathic diseases with risk of more severe outcome
U
Urological risk factors with risk of more severe outcome, which can be resolved during therapy
C
Permanent urinary Catheter and non resolvable urological risk factors with risk of more severe outcome
Otherwise healthy premenopausal women Sexual behaviour (frequency, spermicide), Hormonal deficiency in postmenopause Secretor type of certain blood groups Well-controlled diabetes mellitus Prematurity, newborn Pregnancy Male gender Badly controlled diabetes mellitus Relevant immunosuppression (not well defined) Relevant renal insufficiency (not well defined) Polycystic nephropathy Interstitial nephritis (e.g. due to analgetics) Ureteral obstruction due to a ureteral stone Well controlled neurogenic bladder disturbances Transient short-term external urinary catheter Asymptomatic bacteriuria Long-term external urinary catheter Non resolvable urinary obstruction Badly controlled neurogenic bladder disturbances
Table 2
complication can be found in existing databases. Table 3 shows the risk of infective complications related to one of the most common urological procedures, prostate biopsy.3,11,12 Patient-related risk factors as described in the ORENUC system will modify the procedure-related risk of infection in a given patient. All factors need to be addressed when risk assessment is done before a surgical procedure.
The risk of developing infective complications after surgical procedures is usually described in a separate system known as Contamination categories (Box 1). The most important factors for assessment of contamination category have been the age of the surgical wound, if bodily tracts are opening during surgery, spillage of its contents, and signs of infection or devitalized tissue.9 The concept of contamination categories was developed during World War II in order to evaluate prognosis and risk of infection after injuries. Since then large databases have been built that give the infection rate in each category and confirm the validity of the classification principle also in modern surgery.10 However, modern urological surgery differs significantly from war injuries and open surgery. Therefore the ESIU recently worked out their own definitions of contamination categories in urology. The categories are still based on characteristics of the surgical field, but a new criterion has been added according to which bodily tract that is entered or opened and the duration of the procedure. All surgical procedures may be ascribed a contamination category. Once the category is defined, the risk of infective
Antibiotic stewardship The overall aim of antibiotic treatment in UTI is to restore a normal balance between pathogens and the host. This either means getting rid of the pathogens, or causing the pathogens to withdraw to their habitats outside the urinary tract, or even inside urothelial cells. Not all pathogens will receive a lethal dose of antibiotics and some may survive. While resting in their trenches some pathogens are even capable of developing resistance mechanisms to classes of antibiotics such as betalactams and spread to other hosts. This is what collateral damage is about. With a generation time of only 20 minutes new genes are multiplied at high speed thus making pathogens appear as intelligent creatures. As long as the number of available antibiotics is limited and resistance increases, our chance of giving effective prophylaxis and treatment is steadily being reduced. This is why antibiotic stewardship is important.13 Over the past ten years we have seen a rise in multiresistant pathogens such as extended spectrum betalactamase producing strains (ESBL), vancomycin resistant strains and methicillin resistant staphylococci (MRSA). Recently the first omniresistant bacteria NDM-1, was described in urine cultures in UK.14 Within a short time the pathogen spread to most European countries.
Classical definitions of surgical field contamination I. II. III. IV.
Clean Clean-contaminated Contaminated Dirty
Box 1
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Biopsy routes, contamination categories and risk of infection without prophylaxis in prostate biopsies3,11 Biopsy route
Contamination category
Transperineal
Clean Clean-contaminated
Transperineal
Contaminated
Transrectal Transrectal
Contaminated Dirty
Key criteria
Sterile urine No history UTI/UGI Sterile urine History of UTI/UGI Sterile urine Bacteriuria Urethral catheter
Risk of infection <5% 5e10% 10e15% 10e15% 15e40%
UGI, urogenital infection (i.e. prostatitis); UTI, urinary tract infection.
Table 3
normalization of reflux, the children are outpatients and there are no foreign bodies present. What seems to be an inconsistence of principles as to antibiotic use in children and in perioperative prophylaxis reflects the relative lack of high level evidence in this field.
Knowledge about the clinical course of urinary tract infections with multiresistant or omniresistant pathogens is still limited, but the perspectives give reasons for concern. Urologists should be aware of the antibiotic prescription policy for community acquired UTIs as this may enhance the development of resistant strains that may be brought into hospitals. Today up to 100% of patients in a urology ward may be receiving antibiotics for prophylaxis or treatment. This means that urology departments are high-risk zones for development of resistant uropathogens. If effective antibiotics are not available, natural host defence is the only protection against spread of infection. Risk factors will make spread of infection more likely. In many developing countries there is poor availability of antibiotics, and in some regions even in Europe today available antibiotics are no longer effective because of high resistance rates. Therefore the ESIU recommended that availability of effective antibiotics should be included in the assessment of severity and prognosis for a case of UTI, and suggested a three letter scale, aec, describing the different combinations of pathogen susceptibility and availability of effective antibiotics.1 This concept is however, not fully developed.
Short-term perioperative prophylaxis Hospital acquired urinary tract infections are seen in about 11% of patients in urology departments.6 When this occurs after surgical procedures it is because pathogens are resistant to the antibiotics used for prophylaxis. EAU guidelines are based on evidence from pharmacokinetic, pharmacodynamic and international studies of pathogens and resistance. However, the GPIU studies have shown that urologists do not always adhere to the EAU guidelines recommendations.17 As a rule the urologist should sit down with the local microbiologist and infectious disease specialist to work out prophylaxis regimens based on local culture results of hospital acquired UTI and regional results of community acquired UTI. Designing prophylactic regimens is a dynamic process and the regimens should be changed with a few years’ interval. The most potent antibiotics such as aminoglycosides and carbapenems should be reserved for treatment. Perioperative prophylaxis is a short-term administration ensuring adequate serum levels at the time of maximal exposure to possible pathogens. Sometimes administration may be prolonged for up to three days. However, antibiotics are not recommended for prophylaxis in patients waiting for catheter removal, for example after radical prostatectomy or cystectomy. The risk of infective complications following urological surgery may be foreseen by the contamination category of the procedure. Prophylaxis is not generally recommended in clean procedures where the risk of infective complications is less than 5%,3 but individual risk factors may modify the overall risk and justify prophylaxis also in clean procedures. The antibiotics most commonly recommended for prophylaxis in endourological procedures are trimethoprim sulphametoxazol, second generation cephalosporins, aminopenicillin plus a betalactamase inhibitor and fluoroquinolones. For open surgical procedures the most commonly recommended antibiotics are trimethoprim sulphametoxazol, second or third generation cephalosporins, aminopenicillin plus a betalactamase inhibitor and metronidazole.3 Amikacin is frequently used in Asia, while second and third generation cephalosporins are often used in South
Use of antibiotics in urology Antibiotics are prescribed in three different situations in urology: prophylaxis suspected UTI UTI with an identified pathogen. Suspected UTI is the main reason for prescribing antibiotics in urology accounting for 50% of cases, while the two other groups account for about 25% each.15 Prophylaxis may be given as longterm administration to prevent recurrent UTI like in children and as short-term administration to prevent infective complications after surgical procedures. Long-term prophylaxis in children There is evidence to support long-term administration of oral antibiotics in children at risk of kidney damage.3,16 The concept of prophylaxis in children with recurrent UTI is different from the concept of perioperative prophylaxis. Important characteristics are that the patients are children, the situation we try to prevent is end-stage kidney disease, the urinary tract is undergoing physiological development during prophylaxis including
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America and Africa.17 For details on contamination categories and recommended prophylactic regimens the reader is referred to the Guidelines of the European Association of Urology.3 Antibiotic prophylaxis in prostate biopsies represents a special challenge in terms of which antibiotic to use, especially in repeat biopsies, and the timing of administration in outpatient procedures.18 Most guidelines recommend fluoroquinolones for prophylaxis in prostate biopsies, but the increase of fluoroquinolone resistance has raised the question of appropriateness of the current recommendation.3 As a rule extended courses is not recommended after prostate biopsies. Doing culture tests of rectal swabs may help developing a better tailored prophylaxis.
pyelonephritis an oral therapy of 10e14 days is usually sufficient. A fluoroquinolone for 7e10 days can be recommended as first-line therapy if the resistance rate of E. coli is still below 10%. If the fluoroquinolone dosage is increased, the treatment can probably be reduced to 5 days. However, increasing rates of fluoroquinolone resistant E. coli already found in the community area in some parts of the world restrict the empiric use of fluoroquinolones. A third generation oral cephalosporin (e.g. cefpodoxime proxetil or ceftibuten) may be an alternative. However, available studies demonstrated only equivalent clinical, but not microbiological, efficacy compared with ciprofloxacin. Because of increasing E. coli resistance rates above 10%, cotrimoxazole is not suitable for empiric therapy in most areas, but can be used as test conform therapy when susceptibility of the pathogen is already known. Amoxiclav is not recommended as a drug of first choice for empiric oral therapy of acute pyelonephritis. It is, however, recommended when susceptibility testing shows a susceptible Grampositive organism. In communities with high rates of fluoroquinolone resistant and ESBL producing E. coli (>10%), an initial empiric therapy with an aminoglycoside or a carbapenem has to be considered until susceptibility testing demonstrates that oral drugs can also be used. Hospital admission should be considered if risk factors cannot be ruled out by available diagnostics and/or the patient has clinical signs and symptoms of sepsis. After improvement, the patient can be switched to an oral regimen using one of the abovementioned antibacterials, if active against the infecting organism, to complete the 1e2 week course of therapy.19 Patients with severe pyelonephritis who cannot take oral medication because of systemic symptoms like nausea and vomiting, have to be treated initially with one of the following parenteral antibiotics depending on the local resistance rates of E. coli: a parenteral fluoroquinolone, in communities with resistance rates of E. coli to fluoroquinolones <10% a third generation cephalosporin, in communities with resistance rates of ESBL producing E. coli <10% an aminopenicillin plus a betalactamase inhibitor in case of a known susceptible Gram-positive pathogen an aminoglycoside or a carbapenem in communities with resistance rates to fluoroquinolones and/or ESBL producing E. coli >10%. In women whose pyelonephritis symptoms do not improve within 3 days, or that resolve and then recur within 2 weeks, a repeat urine culture, antimicrobial susceptibility testing and an appropriate investigation, such as renal ultrasound, computertomography or scan, should be performed. In the patient with no urological abnormality, it should be assumed that the infecting organism is not susceptible to the agent originally used and an alternative tailored therapy should be considered based on culture results. For those patients who have a symptomatic relapse with the same pathogen as the initial infecting strain, diagnosis of uncomplicated pyelonephritis should be reconsidered and further diagnostic steps are necessary.3
Suspected UTI Suspected UTI always means that treatment is started on an empirical basis, and usually the situation has to be reassessed once the identity and susceptibility of the pathogen is known. According to both US and European guidelines it is acceptable to diagnose UTI by patient history and clinical examination only and to initiate treatment on this basis, which should be tailored as soon as urine culture results are available. In the majority of community acquired UTI the identity and susceptibility of the pathogen is unknown at the time when treatment is started. Primary care physicians must however, acquaint themselves with local resistance figures because only drugs with a general resistance in the population of <20% are recommended as first-line therapy. In terms of hospital acquired UTI we advocate waiting for evidence from urinalysis and culture if clinically suitable, otherwise empirical treatment for suspected UTI is considered. All general recommendations have to be modified by patient related risk factors. Community acquired cystitis without known risk factors: according to known susceptibility patterns, the following antibiotics can be considered the drugs of first choice in many countries, where available: fosfomycin trometamol 3 g as a single dose pivmecillinam 400 mg bid for 3 days and nitrofurantoin macrocrystal 100 mg bid for 5 days. Cotrimoxazole 160/800 mg bid for 3 days or trimethoprim 200 mg for 5 days should only be considered as the first choice in areas with known resistance rates of Escherichia coli below 20%. Alternative antibiotics are ciprofloxacin 250 mg bid, ciprofloxacin ER 500 mg qd, levofloxacin 250 mg qd, norfloxacin 400 mg bid and ofloxacin 200 mg bid, each as a 3-day course. However, collateral effects have to be considered. Symptomatology may be sufficient for routine follow-up. In treated patients where symptoms do not resolve and in patients with early relapse (<2 weeks) urine culture and antimicrobial susceptibility testing should be performed for guidance of therapy.19 Community acquired acute pyelonephritis without known risk factors: due to lack of suitable surveillance studies the spectrum and susceptibility patterns of uropathogens causing uncomplicated cystitis has to be used as guide for empiric therapy in a given country. However, Staphylococcus saprophyticus is to be less considered in acute pyelonephritis as compared to acute cystitis. In mild and moderate cases of acute uncomplicated
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Urologists prescribe a huge amount of antibiotics, 50% for prophylaxis, 25% for suspected UTI and 25% for confirmed infections with known pathogens. The best way to develop prophylactic regimens is for the urologist, microbiologist and infectious disease specialist to work together. Increasing resistance among urinary tract pathogens necessitates prudent use of antibiotics. Fluoroquinolones still hold a key position in prophylaxis and treatment of urinary tract infections, but care must be taken because of world-wide increase of resistant uropathogens and to avoid overuse causing further collateral damage to the patients. Special attention should be paid to avoid infective complications after prostate biopsies. Rectal swabs before intervention may help developing a better tailored prophylaxis. A
prevent the emergence of resistant mutants. Susceptibility testing should be carried out in any case of HAUTI, and if possible the results should be awaited before treatment. However, in severe infections an initial empiric therapy must be instigated immediately after microbiological sampling. Susceptibility testing can serve in these cases to narrow the antibiotic coverage. Provisional microbiological findings can lead to early stratification of pathogens and allow a more tailored empiric antibiotic therapy. Prudent use of antimicrobials may also help to reduce the selection of resistant pathogens to a minimum. Antibiotics with an enlarged antibacterial spectrum are necessary for initial empiric treatment. The empiric parenteral treatment could start with: a cephalosporin group 3a a fluoroquinolone with good renal excretion or an aminopenicillin in combination with a betalactamase inhibitor. If clinical improvement fails after two to three days, treatment should be switched to: a pseudomonas active acylaminopenicilline/betalactamase-inhibitor a group 3b cephalosporin or a carbapenem. Other reasons for treatment failure, such as persistent risk factors, other infections or noninfectious sources, should also be taken into account and be re-evaluated. Regional variations in resistance must also be considered for empiric treatment. The use of parenteral antibiotics is determined by the general condition of the patient (e.g. nausea, vomiting) and the severity of the infection; oral antibiotics can be continued as soon as the clinical situation has improved. After the results of the susceptibility testing have arrived, the antibiotic treatment should be aligned accordingly. Treatment duration should continue for at least three to five days beyond defervescence, depending on the removal of the risk factor. However, this recommendation does not hold true for the treatment of pyelonephritis with abscess formation or chronic bacterial prostatitis, which should usually continue for several weeks.19,20 HAUTIs are frequently complicated by the presence of a biofilm in which pathogens adhere to anatomical structures of the urinary tract - stones, foreign materials or necrotic tissue - and are embedded in organic (exopolysaccharide) and anorganic (phosphate) material. Therefore it is necessary to elevate antibiotic concentrations by 10- to 100-fold in order to inhibit or kill the pathogens. Such increased antibiotic concentrations are often not clinically achievable. Fluoroquinolones and macrolides (only effective against Gram-positive bacteria) exhibit a specific effect on the biofilm formation, which, however, is usually not sufficient to eradicate the pathogens. Therefore, antimicrobial therapy in complicated UTIs may only kill the bacteria dissolved from the biofilm (planktonic form) and thus inhibit spread of the infectious process. An accompanying urological therapy must aim to remove the biofilm.21
REFERENCES 1 Bjerklund Johansen Truls E, Botto Henry, Cek Mete, et al. Critical review of current definitions of urinary tract infections and proposal of an EAU/ESIU classification system. IJAA 2011; 38(suppl): 64e70. 2 Bjerklund Johansen TE, Botto H, Cek M, et al. Criteria for healthcare associated urinary tract infections: an EAU/ESIU update on current definitions. Chapter 10.2. In: Naber KG, Scaeffer AJ, Heyns CF, Matsumoto T, Shoskes DA, Bjerklund Johansen TE, eds. Urogenital infections (textbook 1182pp). International Consultation on Urological Diseases (ICUD) and European Association of Urology, 2010; 567e74. ISBN: 978-90-79754-41-0, Arnheim. 3 Grabe M, Bjerklund Johansen TE, Botto H, et al. Guidelines on urological infections. EAU guidelines 2013 edition, pp.1e100. Arnheim. European Association of Urology, 2013. ISBN/EAN: 978-90-79754-717. 4 Naber KG, Scaeffer AJ, Heyns CF, et al. Urogenital infections (textbook 1182pp). International Consultation on Urological Diseases (ICUD) and European Association of Urology, 2010. ISBN: 978-90-79754-410, Arnheim. 5 www.thecochranelibrary.com. 6 Johansen TEB, Cek M, Tenke P, Stratchounski L, Svendsen MV, Naber K, on behalf of the PEP and PEAP-study investigators and the Board of the European Society of Infections in Urology. Hospital acquired urinary tract infections in urology departments: pathogens, susceptibility and antibiotics given. Data from the PEP and PEAPstudies. Int J Antimicrob Agents 2006; 28S: 91e107. 7 Rubin USE, Andriole VT, Davis RJ, Stamm WE. Evaluation of new antiinfective drugs for the treatment of UTI. Clin Infect Dis 1992; 15: 216. 8 Rubin UH, Shapiro ED, Andriole VT, Davis RJ, Stamm WE, with a modification by a European Working Party (Norrby SR). General Guidelines for the evaluation of new anti-infective drugs for the treatment of urinary tract infection. Taufkirchen, Germany: The European Society of Clinical Microbiology and Infectious diseases, 1993; 240e310. 9 Howard JM, Barker WF, Culbertson WR, et al. Postoperative wound infections: the influence of ultraviolet irradiation of the operating room and of various other factors. Ann Surg 1964; 160(suppl): 1e192. 10 Culver DH, Horan TC, Gaynes RP, et al. Surgical wound infection rates by wound class, operative procedure, and patient risk index. Am J Med 1991; 91(suppl 3B): 152Se1157.
Conclusions Severity scoring in UTI is based on clinical presentation, risk factors and availability of effective antibiotics. Risk factors may be classified by the ORENUC system.
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11 Grabe M, Botto H, Cek M, et al. Preoperative assessment of the patient and risk factors for infectious complications and tentative classification of surgical field contamination of urological procedures. World J Urol 2012; 30: 39e50. 12 Bjerklund Johansen TE. Update on urinary tract infections: how to prevent infective complications after prostate biopsies. Urology News 2010; 15: 6e9. 13 Wagenlehner Florian ME, Bartoletti Ricardo, Cek M, et al. Antibiotic stewardship e a call for action by the urological community. Eur Urol 2013; 64: 358e60. 14 Elias J, Schoen C, Heinze G, et al. Nosocomial outbreak of VIM-2 metallo-ß-lactamase-producing Pseudomonas aeruginosa associated with retrograde urography. Clin Microbiol Infect 2010; 16: 1494e500. 15 Johansen TEB, Cek M, Tenke P, Stratchounski L, Svendsen MV, Naber K, on behalf of the PEP and PEAP-study investigators and the board of the European Society of Infections in Urology. Prevalence of hospital acquired urinary tract infections in urology departments: data from the PEP and PEAP-studies. Eur Urol 2007; 51: 1100e12. 16 Arant Jr BS. Vesicoureteral reflux and evidence-based management. J Pediatr 2001; 139: 620e1. 17 Cek M, Tandogdu Z, Naber K, et al. Antimicrobial prophylaxis in urology departments 2005e2010. Eur Urol 2013; 63: 386e94. 18 Wagenlehner FME, van Ostrum E, Tenke P, et al. Infective complications after prostate biopsy: outcome of the Global Prevalence Study of Infections in Urology (GPIU). Eur Urol 2013; 63: 521e7.
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19 Wagenlehner FME, Cek M, Kiyota H, Bjerklund Johansen TE. Epidemiology, treatment and prevention of healthcare associated urinary tract infections. Chapter 10.3. In: Naber KG, Scaeffer AJ, Heyns CF, Matsumoto T, Shoskes DA, Bjerklund Johansen TE, eds. Urogenital infections. Arnheim: International Consultation on Urological Diseases (ICUD) and European Association of Urology, 2010; 575e88. 20 Wagenlehner FME, Platz A, Weidner W. Urosepsis e from the view of the urologist. Chapter 11.4. In: Naber KG, Scaeffer AJ, Heyns CF, Matsumoto T, Shoskes DA, Bjerklund Johansen TE, eds. Urogenital Infections. Arnheim: International Consultation on Urological Diseases (ICUD) and European Association of Urology, 2010; 630e44. 21 Tenke P, Koves B, Nagy K. Urinary catheters and drainage systems: prevention and treatment of urinary tract infections. Chapter 9.3. In: Naber KG, Scaeffer AJ, Heyns CF, Matsumoto T, Shoskes DA, Bjerklund Johansen TE, eds. Urogenital Infections. Arnheim: International Consultation on Urological Diseases (ICUD) and European Association of Urology, 2010; 532e40.
Acknowledgements The authors wish to acknowledge with thanks Drs Peter Tenke, Mete Cek and Kurt Naber for their critical review of this article during its preparation.
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