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Urologia 2014 ; 81 (4): 222-227 DOI: 10.5301/uro.5000092
ISSN 0391-5603
Focus ON
Nosocomial urinary tract infections: a review Valerio Iacovelli, Gabriele Gaziev, Luca Topazio, Pierluigi Bove, Giuseppe Vespasiani, Enrico Finazzi Agrò Department of Urology, Tor Vergata University, Rome - Italy
Abstract Nosocomial urinary tract infections are a common complication in healthcare systems worldwide. A review of the literature was performed in June 2014 using the Medical Literature Analysis and Retrieval System Online (MEDLINE) database, through either PubMed or Ovid as a search engine, to identify publications regarding nosocomial urinary tract infections (NUTIs) definition, epidemiology, etiology and treatment. According to current definitions, more than 30% of nosocomial infections are urinary tract infections (UTIs). A UTI is defined ‘nosocomial’ (NUTI) when it is acquired in any healthcare institution or, more generally, when it is related to patient management. The origin of nosocomial bacteria is endogenous (the patient’s flora) in two thirds of the cases. Patients with indwelling urinary catheters, those undergoing urological surgery and manipulations, long-stay elderly male patients and patients with debilitating diseases are at high risk of developing NUTIs. All bacterial NUTIs should be treated, whether the patient is harboring a urinary catheter or not. The length of treatment depends on the infection site. There is abundance of important guidance which should be considered to reduce the risk of NUTIs (hand disinfection with instant hand sanitizer, wearing non-sterile gloves permanently, isolation of infected or colonized catheterized patients). Patients with asymptomatic bacteriuria can generally be treated initially with catheter removal or catheter exchange, and do not necessarily need antimicrobial therapy. Symptomatic patients should receive antibiotic therapy. Resistance of urinary pathogens to common antibiotics is currently a topic of concern. Keywords: Urinary tract infections, Nosocomially acquired urological infections, Catheter-associated urinary tract infections
Introduction A hospital-acquired infection (HAI) or nosocomial infection is an infection whose development is favored by a hospital environment, such as one acquired by a patient during a hospital visit or one developing among hospital staff. HAI is sometimes described as a healthcare-associated infection to emphasize that infections can be correlated with health care in various settings (not just hospitals). Hospital-acquired infections are a major challenge to patient safety. Device-associated infections (i.e., ventilatorassociated pneumonia, catheter-associated urinary tract infection, and central catheter-associated bloodstream infection) account for 25.6% of all health care-associated Accepted: September 13, 2014 Published online: November 12, 2014 Corresponding author: Luca Topazio School of Specialization in Urology Tor Vergata University V.le Oxford, 81 00133 Rome, Italy [email protected]
infections; together, device-associated infections and surgical-site infections (21.8%) account for 47.4% of all health care-associated infections (239 of 504 infections) (1). It is estimated that in 2011, a total of 721800 hospital-acquired infections occurred in the U.S. (1); similar data have been reported from Europe (2). The estimated costs to the U.S. healthcare budget are $5 billion to $10 billion annually (3). The strains retrieved from these patients are even more resistant (4). This review aims to highlight the current clinical urological knowledge about definition, epidemiology and risk factors, pathogenesis, etiology, prevention and treatment of the nosocomial or nosocomially acquired urological infections (NUTIs or NAUTIs).
Materials and Methods A review of the literature was performed in June 2014 using the Medical Literature Analysis and Retrieval System Online (MEDLINE) database, through either PubMed or Ovid as a search engine, to identify publications regarding NUTIs definition, epidemiology, etiology and treatment. English language full text articles were included for review, and non-English articles were included if they provided an English abstract. We gave preference to the Cochrane Central Register of Con© 2014 Wichtig Publishing
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trolled Trials and also considered other relevant publications until May 2014. Reports written by the European Centre for Disease Prevention and Control (ECDC) and the American Centers for Disease Control and Prevention (CDC) were carefully analyzed. The keywords queried included: nosocomial infections, urinary tract infections, urinary catheter, UTI, NUTI, NAUTI.
Results Definition Firstly introduced in 1957, UTI definition was based on the bacterial count (5). Kass developed the concept of significant bacteriuria (>105 cfu/mL) in the context of pyelonephritis in pregnancy (6). UTI is a commonly used term, which has the advantage to immediately describe the site of infection. Although this concept introduced quantitative microbiology into the diagnosis of infectious diseases, and is therefore still of general importance, it has recently become clear that there is no fixed bacterial count that is indicative of significant bacteriuria, which can be applied to all kinds of UTIs and in all circumstances. The most widely used definitions of UTI are those developed by the Centers for Disease Control and Prevention (CDC) in the USA in 1988 (7) and updated in 2008 (8), the Infectious Diseases Society of America (IDSA) in 1992 (9), and by the European Society for Clinical Microbiology and Infectious Diseases (ESCMID) in 1993 (10). The purpose of the CDC definitions is to define and report healthcare-associated (nosocomial) UTI. In the 1988 edition, UTIs comprised symptomatic UTI, asymptomatic bacteriuria (ASB) and other infections of the urinary tract. Currently, the concept of ASB has been revisited. The removal of ASB may lead to define strictly symptomatic UTI (SUTI). In 2003, the Consensus Conference on nosocomial urinary tract infections underlined that the term ‘colonization of the urinary tract’ is preferable to that of ‘asymptomatic bacteriuria’. Colonization is defined as the presence of one (or several) microorganism in the urinary tract without clinical manifestations (11). Following this Consensus Conference, UTIs identified the invasion of tissues by one (or several) microorganic species, inducing an inflammatory response as well as signs and symptoms whose nature and intensity vary according to the terrain (11). The European Association of Urology recommends on one hand to microbiologically define the UTI (12, 13), and on the other hand to report not only the results, but also which methods and standards were applied, such as the European Committee for Antimicrobial Susceptibility Testing (EUCAST) (14, 15), or the National Committee for Clinical Laboratory Standards (NCCLS) (16). A UTI is said ‘nosocomial’ or ‘nosocomially acquired’ (NUTI or NAUTI) when it is acquired in any healthcare institution or, more generally, when it is related to patient management (11). Virtually, all healthcare-associated UTIs are caused by instrumentation of the urinary tract. Catheter-associated urinary tract infections are commonly called CAUTI.
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Epidemiology and risk factors Between 15% and 25% of hospitalized patients may receive short-term indwelling urinary catheters (17, 18). In many cases, catheters are placed for inappropriate indications, and healthcare providers are often unaware that their patients have catheters, leading to prolonged unnecessary use (19-21). According to current ECDC studies, around 31.2% of HAI are nosocomial urinary tract infections (NUTIs) (2). Most patients with nosocomial urinary tract infections (UTIs) have either had genitourinary or urological manipulation (ca. 10-20%) or permanent urethral catheterization (ca. 80%), or both (22). Morbidity and mortality from CAUTI are considered to be relatively low compared to other HAIs. The high prevalence of urinary catheter use leads to a large cumulative burden of infections with resulting infectious complications and deaths. Based on American data, an estimated 17% to 69% of CAUTI may be preventable with recommended infection control measures, which means that up to 380,000 infections and 9000 deaths related to CAUTI per year could be prevented (23). The presence of an indwelling urethral catheter allows continuous access of organisms into the urinary tract. In 2001, Bouza et al. estimated the incidence of NUTI in Europe. A total of 141 hospitals from 25 European countries participated in the study. The total number of new NAUTI episodes on the day of the study was 298, representing an incidence of 3.55 episodes/1000 patient-days and an estimated prevalence of 10.65/1000. The Authors described that 22.8% of patients had no ‘classic’ UTI-predisposing factors. Catheterassociated UTI (CAUTI) was present in 187 patients (62.8%). A closed drainage system was used in only 78.5% of catheterized patients. The indication for bladder catheterization was not considered adequate in 7.6% of cases and continuation of bladder catheterization was considered unnecessary in 31.3%. Opening of the closed drainage system was the most frequent major error in catheter management (16.8%). Antimicrobial treatment was not considered adequate in 19.8% of all cases (24). More recently, in 2007 Bjerklund Johansen et al. registered the prevalence of NAUTIs in urology sections in Europe and Asia. A total of 6033 hospitalized patients in 194 different urology departments were screened in two internet-based studies. The Authors concluded that the prevalence of NAUTI was 10% in the Pan European Prevalence (PEP) study, 14% in the Pan EuroAsian Prevalence (PEAP) study, and 11% in the combined analysis. It was shown that most NUTIs were catheter associated in 74% of the cases (4). In 2014, the European Centre for Disease Prevention and Control presented the results of a prevalence survey of healthcare associated infections. The ECDC registered a very heterogeneous situation in Europe. Although the overall median percentage of urinary catheter use was low (6.3%), it was reported by 33.3% and 17.9% in the Czech Republic and Greece, respectively (2). Multivariate analyses have emphasized that the duration of catheterization is the most important risk factor in the development of catheter-associated bacteriuria (25-27). Other risk factors include: colonization of the drainage bag, catheter
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and periurethral segment, diabetes mellitus, female gender, impaired renal function, poor quality of catheter care, including its insertion outside of an operating room and lack of antimicrobial therapy (28-31). Pathogenesis The urethral catheter can inhibit or bypass certain defense mechanisms that would normally prevent or minimize bacteria-epithelial cell interactions, e.g. the glycosaminoglycan (GAG) layer and biofilm formation. The source of microorganisms causing CAUTI can be endogenous, typically via meatal, rectal, or vaginal colonization, or exogenous, such as via contaminated equipment or healthcare staff’s hands. Microbial pathogens can enter the urinary tract either by the extraluminal route, via migration along the outside of the catheter in the periurethral mucous sheath, or by the intraluminal route, via movement along the internal lumen of the catheter from a contaminated collection bag or catheter-drainage tube junction. The relative contribution of each route in the pathogenesis of CAUTI is not well known (32). Bacteria can enter the urinary tract in catheterized patients at the time of catheter insertion. This is especially common in patients who have inadequate cleansing of the perineum and distal urethra, especially in patients on intermittent clean catheterization where only a limited attempt is made to cleanse the ‘entry points’ before introducing the catheter. It is, however, doubtful whether such cleansing is in general of any benefit, but in hospitalized patients the introduction of organisms at the time of catheterization could be critical. Up to 20% of individuals are colonized immediately after catheterization (25, 26, 31). The formation of biofilms by urinary pathogens on the surface of the catheter and drainage system occurs universally with prolonged duration of catheterization. Over time, the urinary catheter becomes colonized with microorganisms living in a sessile state within the biofilm, making them resistant to antimicrobials and host defenses and virtually impossible to eradicate without removing the catheter (33). Specifically, type 1 fimbriae contribute to catheter-associated urinary tract infections caused by Escherichia coli (34). Etiology Gram-negative organisms predominate in hospital-acquired urinary tract infections, almost all of which are associated with urethral catheterization. After the second day of catheterization, it is estimated that the risk of bacteriuria increases by 5 to 10% per day. The majority of bacteriuria cases are asymptomatic, and the most effective management is the catheter removal rather than an antibiotic treatment. In rare cases, local and systemic complications ensue, and antibiotic treatment should be initiated (35). In 1982, Warren et al. described the relationship between methods of catheterization and the risk of CAUTI (36). After single (straight) catheterization, bacteriuria develops in 1-5% of cases (17, 27, 35, 36). Short-term catheterization usually identifies a catheter left in place for less than 7 days (27). Between 15% and 25% of patients admitted to hospital may be
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catheterized for 2-4 days during their stay (17, 27). Between 10% and 30% will develop bacteriuria (25). Most episodes of short-term catheter-associated bacteriuria are asymptomatic and are caused by single organisms; 15% may be polymicrobial (22), reflecting the prevailing flora in hospital or community environments. When indwelling catheterization lasts for more than 28 days it is defined as ‘long-term’ or ‘chronic’. Unfortunately, there is no consensus on the classification of indwelling catheters in place for 8-29 days. The patient with a long-term indwelling catheter is at high risk of morbidity due to this procedure. Bacteriuria with at least one strain is universal, whilst most patients are infected with two or more strains (31-38). Most CAUTIs derive from the patient’s own colonic flora (25). The commonest infecting organism is E. coli (31). In 2001, the Co-operative Group of the European Study Group on Nosocomial Infections evaluated 141 hospitals of different sizes, 98 from EU countries and 43 from non-EU countries, serving an estimated population of 99,759,000 patients. The number of microorganisms isolated from NAUTI episodes was 340. Gram-positive bacteria represented 21.2% of all isolates, whereas Gram-negative bacteria were 65.9%. Yeasts were 12.9%. The five most commonly isolated microorganisms were Escherichia coli (35.3%), Enterococcus sp. (15.2%), Candida sp. (12.9%), Klebsiella sp. (9.8%) and Pseudomonas aeruginosa (5.4%). Overall, 14.1% of the episodes were polymicrobial (13.1% in EU countries versus 16% in nonEU countries; P>0.05) (24). In 2004, Bjerklund Johansen et al. of the European Society of Infections in Urology (ESIU-EAU) collected data from two internet-based studies on NAUTI in hospitalized urological patients presented together: the Pan European Prevalence (PEP) study, which was a 1-day prevalence study in November 2003; and the Pan Euro-Asian Prevalence (PEAP) study, which was carried out in November 2004. Overall, 93 and 101 hospitals from the two studies, respectively, completed the hospital questionnaires and provided patient information for the present study. NAUTI was diagnosed according to the Centers for Disease Control and Prevention (CDC) criteria in 727 of the 6033 patients hospitalized on the study days in urological departments. The most commonly reported pathogen was Escherichia coli (31%), followed by species of Pseudomonas (13%), Enterococcus (10%), Klebsiella (10%), Enterobacter (6%) and Proteus (6%). Candida spp. and Pseudomonas spp. occurred significantly more frequently as causative agents in urosepsis than in other types of infections (4). The most frequent pathogens associated with CAUTI (combining both ASB and SUTI) in hospitals reporting to the National Healthcare Safety Network (NHSN) between 20062007 were Escherichia coli (21.4%) and Candida spp. (21.0%), followed by Enterococcus spp. (14.9%), Pseudomonas aeruginosa (10.0%), Klebsiella pneumoniae (7.7%), and Enterobacter spp. (4.1%). A smaller proportion was caused by other gram-negative bacteria and Staphylococcus spp. (39). In 2014, Latour et al. of the ECDC published their survey. Between April and May 2013, 1181 long-term care facilities in 19 European countries (including three UK administrations) participated in the HALT-2 point prevalence survey of HAIs and antimicrobial use in Europe. Data were collected from each site on a single day. In total, 77,264 residents met the eligibility criteria. Referring to NUTIs, 604 etiological microor© 2014 Wichtig Publishing
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ganisms were reported in total. The most frequently isolated bacteria were: Escherichia coli (34.4%), Enterococcus (10.2%), Proteus mirabilis (8.1%), Pseudomonas aeruginosa (6.8%), Klebsiella pneumoniae (6.7%). In 2014, the World Health Organization (WHO) published a report that examines, for the first time, the current status of surveillance and information on antibacterial resistance (ABR), at country level worldwide. One of the key findings and public health implications of ABR is the very high rate of resistance observed in bacteria that cause common healthcare associated and community-acquired infections, especially UTIs, in all WHO regions. Antimicrobial resistance among urinary pathogens is an ever-increasing problem. WHO report collected a response including data, or information that no national data were available, returned from 129 of the 194 WHO Member States that responded to the survey (66%). Of these, 114 provided some data for at least one bacteria-antibacterial drug resistance combination. In Western Countries, Escherichia Coli is resistant to fluoroquinolones in 8-48% and to third-generation cephalosporins in 3-43% of the cases. Infections with Klebsiella Pneumoniae are particularly common in hospitals among vulnerable individuals. Similarly to E. coli, K. pneumoniae acquires resistance to multiple antibacterial drugs mainly through horizontal transfer of mobile genetic elements such as transposons or plasmids. Klebsiella is an emerging problem because the ESBL-positive (Extended Spectrum Beta Lactamase) strains are resistant to all extended beta-lactam antibacterial drugs such as cephalosporins. Although for these strains the carbapenems are the main remaining treatment option, K. pneumonia is also the main trigger of infections caused by carbapenem-resistant bacteria worldwide (0-68%) (40). Prevention In 2010, Gould et al. published the guideline for the prevention of catheter-associated urinary tract infections (32). At first, they pointed out that the clinical significance of ASB in catheterized patients is undefined. Approximately 75% to 90% of patients with ASB do not develop a systemic inflammatory response or other signs or symptoms to suggest infection. Moreover, ASB monitoring and treatment do not represent an effective prevention measure for SUTI as treatment of ASB has not been shown to be clinically beneficial and is associated with the selection of antimicrobial-resistant organisms. With regard to catheters or collecting systems it is important to highlight some key points: 1. Minimize urinary catheter use and duration in all patients, particularly when the mortality risk may be higher due to catheterization, such as in the elderly and in patients with severe illness; 2. Hydrophilic catheters might be preferable to standard catheters for patients requiring intermittent catheterization; 3. Perform the aseptic insertion of the urinary catheter, maintain a closed drainage system; 4. Urinary catheter systems with preconnected, sealed catheter-tubing junctions are suggested for use; 5. Instillation of antiseptic or antimicrobial solutions into © 2014 Wichtig Publishing
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urinary drainage bags is not recommended; 6. Unless clinical indications exist (e.g., in patients with bacteriuria upon catheter removal post urologic surgery), do not use systemic antimicrobials routinely as prophylaxis for UTI in patients requiring either short- or long-term catheterization. According to the Cochrane database for patients using intermittent catheterization, there is limited evidence suggesting that antibiotic prophylaxis decreases the rate of bacteriuria (asymptomatic and symptomatic) (41). Adherence to these basic recommendations could significantly decrease the risk of catheter-associated urinary tract infections. Vanhems et al. in a 10-year study of infection control and surveillance practices emphasizing some of these principles, showed a decrease of 70% over time in the risk of urinary tract infections in an intensive care unit population (42). In 2014, Tenke et al. reviewed the latest advances in the field of catheter care and the management of CAUTIs. The Authors underlined that the most efficient methods to prevent CAUTIs are to avoid unnecessary catheterizations and to remove catheters as soon as possible. The use of different reminder systems and the implementation of infection control programs can effectively decrease CAUTIs, although their introduction can be challenging. No evidence to support the routine use of antimicrobial-impregnated catheters has been described, but the use of hydrophilic-coated catheters for clean intermittent catheterization can effectively reduce infections. Preliminary results with chlorhexidine-coated catheters are promising. In cases of serious catheter-associated UTI in patients with a history of previous antibiotic therapy or healthcare-associated bacteremia, empirical antibiotic treatment should be initiated with activity against multiresistant uropathogens (43). Treatment Treatment of NUTIs needs to be considered separately for patients with ASB and for those with SUTI. In general, ASB in catheterized patients should not be treated. Removal of the catheter allows resolution of bacteriuria in one third to one half of cases (31). The European and Asian guidelines recommend treatment of asymptomatic bacteriuria in the following circumstances: 1. For patients undergoing urological surgery or implantation of prostheses; 2. When treatment may be part of a plan to control nosocomial infections due to a particularly virulent organism prevailing in a treatment unit; 3. For patients who have a high risk of serious infectious complications (e.g., patients who are immunosuppressed); 4. For infections originating by strains causing a high incidence of bacteremia (e.g., S. marcescens). The treatment of symptomatic urinary tract infections is usually more straightforward. Clinical symptoms and signs, such as frequency, dysuria, or suprapubic pain directly attributable to an infection, are an indication for treatment. The most common symptom attributed to a urinary tract infection in hospitalized patients is usually fever. If the patient
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is systemically ill, empiric antibiotics should be started, based on knowledge of the local bacterial ecology, and then tailored according to a definitive culture and susceptibility results. However, in patients with nosocomial urinary tract infections, who may have indwelling urinary catheters and highly resistant pathogens, the perception that bacterial susceptibilities are unimportant may not necessarily be accurate. Thus, clinical judgment and the patient’s response to therapy dictate the degree to which susceptibility data are used for the direct treatment of symptomatic urinary tract infections in hospitalized patients (44).
Discussion UTIs are the most common type of healthcare-associated infections reported to the National Healthcare Safety Network (NHSN) and by the ECDC and WHO. Among UTIs acquired within the hospital environment, approximately 75% are associated with a urinary catheter. Between 15-25% of hospitalized patients receive urinary catheters during their hospital stay. Therefore, NUTIs are a major cause of morbidity in hospitalized patients in general, and in post-operative surgical patients in particular. Nowadays, active surveillance on epidemiology, etiology, prevention and treatment of NUTIs is mandatory due to the increase of clinical cases worldwide. Treatment may be complicated by the development of resistant bacteria not adequately followed by new antibiotics and other strategies of care. Several national and international studies have been reported regarding every aspect concerning NUTIs. Every single institution must have an infectious control system and protocols about the prevention and treatment of NUTIs, in order to firstly geographically focalize differences in microorganisms and their resistance and, secondly, to allow global metanalysis and best practice guidelines. Nosocomial urinary tract infections are a common complication in healthcare systems worldwide. The use of urinary catheters is the major risk factor for the development of these infections. Discontinuation of catheterization as soon as possible is a plausible key to avoiding nosocomial urinary tract infections. Patients with asymptomatic bacteriuria can generally be treated initially with catheter removal or catheter exchange, and do not necessarily need antimicrobial therapy. Symptomatic patients should receive antibiotic therapy. Resistance of urinary pathogens to common antibiotics is currently a topic of concern.
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Disclosures Informed consent: The manuscript does not report the results of an experimental investigation on human subjects. Financial support: The study has not been supported by private or public sources, grants or funds. Conflict of interest: None of the authors have proprietary interests.
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Urologia 2014 ; 81 (4): 222-227 DOI: 10.5301/uro.5000092
ISSN 0391-5603
Focus ON
Nosocomial urinary tract infections: a review Valerio Iacovelli, Gabriele Gaziev, Luca Topazio, Pierluigi Bove, Giuseppe Vespasiani, Enrico Finazzi Agrò Department of Urology, Tor Vergata University, Rome - Italy
Abstract Nosocomial urinary tract infections are a common complication in healthcare systems worldwide. A review of the literature was performed in June 2014 using the Medical Literature Analysis and Retrieval System Online (MEDLINE) database, through either PubMed or Ovid as a search engine, to identify publications regarding nosocomial urinary tract infections (NUTIs) definition, epidemiology, etiology and treatment. According to current definitions, more than 30% of nosocomial infections are urinary tract infections (UTIs). A UTI is defined ‘nosocomial’ (NUTI) when it is acquired in any healthcare institution or, more generally, when it is related to patient management. The origin of nosocomial bacteria is endogenous (the patient’s flora) in two thirds of the cases. Patients with indwelling urinary catheters, those undergoing urological surgery and manipulations, long-stay elderly male patients and patients with debilitating diseases are at high risk of developing NUTIs. All bacterial NUTIs should be treated, whether the patient is harboring a urinary catheter or not. The length of treatment depends on the infection site. There is abundance of important guidance which should be considered to reduce the risk of NUTIs (hand disinfection with instant hand sanitizer, wearing non-sterile gloves permanently, isolation of infected or colonized catheterized patients). Patients with asymptomatic bacteriuria can generally be treated initially with catheter removal or catheter exchange, and do not necessarily need antimicrobial therapy. Symptomatic patients should receive antibiotic therapy. Resistance of urinary pathogens to common antibiotics is currently a topic of concern. Keywords: Urinary tract infections, Nosocomially acquired urological infections, Catheter-associated urinary tract infections
Introduction A hospital-acquired infection (HAI) or nosocomial infection is an infection whose development is favored by a hospital environment, such as one acquired by a patient during a hospital visit or one developing among hospital staff. HAI is sometimes described as a healthcare-associated infection to emphasize that infections can be correlated with health care in various settings (not just hospitals). Hospital-acquired infections are a major challenge to patient safety. Device-associated infections (i.e., ventilatorassociated pneumonia, catheter-associated urinary tract infection, and central catheter-associated bloodstream infection) account for 25.6% of all health care-associated Accepted: September 13, 2014 Published online: November 12, 2014 Corresponding author: Luca Topazio School of Specialization in Urology Tor Vergata University V.le Oxford, 81 00133 Rome, Italy [email protected]
infections; together, device-associated infections and surgical-site infections (21.8%) account for 47.4% of all health care-associated infections (239 of 504 infections) (1). It is estimated that in 2011, a total of 721800 hospital-acquired infections occurred in the U.S. (1); similar data have been reported from Europe (2). The estimated costs to the U.S. healthcare budget are $5 billion to $10 billion annually (3). The strains retrieved from these patients are even more resistant (4). This review aims to highlight the current clinical urological knowledge about definition, epidemiology and risk factors, pathogenesis, etiology, prevention and treatment of the nosocomial or nosocomially acquired urological infections (NUTIs or NAUTIs).
Materials and Methods A review of the literature was performed in June 2014 using the Medical Literature Analysis and Retrieval System Online (MEDLINE) database, through either PubMed or Ovid as a search engine, to identify publications regarding NUTIs definition, epidemiology, etiology and treatment. English language full text articles were included for review, and non-English articles were included if they provided an English abstract. We gave preference to the Cochrane Central Register of Con© 2014 Wichtig Publishing
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trolled Trials and also considered other relevant publications until May 2014. Reports written by the European Centre for Disease Prevention and Control (ECDC) and the American Centers for Disease Control and Prevention (CDC) were carefully analyzed. The keywords queried included: nosocomial infections, urinary tract infections, urinary catheter, UTI, NUTI, NAUTI.
Results Definition Firstly introduced in 1957, UTI definition was based on the bacterial count (5). Kass developed the concept of significant bacteriuria (>105 cfu/mL) in the context of pyelonephritis in pregnancy (6). UTI is a commonly used term, which has the advantage to immediately describe the site of infection. Although this concept introduced quantitative microbiology into the diagnosis of infectious diseases, and is therefore still of general importance, it has recently become clear that there is no fixed bacterial count that is indicative of significant bacteriuria, which can be applied to all kinds of UTIs and in all circumstances. The most widely used definitions of UTI are those developed by the Centers for Disease Control and Prevention (CDC) in the USA in 1988 (7) and updated in 2008 (8), the Infectious Diseases Society of America (IDSA) in 1992 (9), and by the European Society for Clinical Microbiology and Infectious Diseases (ESCMID) in 1993 (10). The purpose of the CDC definitions is to define and report healthcare-associated (nosocomial) UTI. In the 1988 edition, UTIs comprised symptomatic UTI, asymptomatic bacteriuria (ASB) and other infections of the urinary tract. Currently, the concept of ASB has been revisited. The removal of ASB may lead to define strictly symptomatic UTI (SUTI). In 2003, the Consensus Conference on nosocomial urinary tract infections underlined that the term ‘colonization of the urinary tract’ is preferable to that of ‘asymptomatic bacteriuria’. Colonization is defined as the presence of one (or several) microorganism in the urinary tract without clinical manifestations (11). Following this Consensus Conference, UTIs identified the invasion of tissues by one (or several) microorganic species, inducing an inflammatory response as well as signs and symptoms whose nature and intensity vary according to the terrain (11). The European Association of Urology recommends on one hand to microbiologically define the UTI (12, 13), and on the other hand to report not only the results, but also which methods and standards were applied, such as the European Committee for Antimicrobial Susceptibility Testing (EUCAST) (14, 15), or the National Committee for Clinical Laboratory Standards (NCCLS) (16). A UTI is said ‘nosocomial’ or ‘nosocomially acquired’ (NUTI or NAUTI) when it is acquired in any healthcare institution or, more generally, when it is related to patient management (11). Virtually, all healthcare-associated UTIs are caused by instrumentation of the urinary tract. Catheter-associated urinary tract infections are commonly called CAUTI.
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Epidemiology and risk factors Between 15% and 25% of hospitalized patients may receive short-term indwelling urinary catheters (17, 18). In many cases, catheters are placed for inappropriate indications, and healthcare providers are often unaware that their patients have catheters, leading to prolonged unnecessary use (19-21). According to current ECDC studies, around 31.2% of HAI are nosocomial urinary tract infections (NUTIs) (2). Most patients with nosocomial urinary tract infections (UTIs) have either had genitourinary or urological manipulation (ca. 10-20%) or permanent urethral catheterization (ca. 80%), or both (22). Morbidity and mortality from CAUTI are considered to be relatively low compared to other HAIs. The high prevalence of urinary catheter use leads to a large cumulative burden of infections with resulting infectious complications and deaths. Based on American data, an estimated 17% to 69% of CAUTI may be preventable with recommended infection control measures, which means that up to 380,000 infections and 9000 deaths related to CAUTI per year could be prevented (23). The presence of an indwelling urethral catheter allows continuous access of organisms into the urinary tract. In 2001, Bouza et al. estimated the incidence of NUTI in Europe. A total of 141 hospitals from 25 European countries participated in the study. The total number of new NAUTI episodes on the day of the study was 298, representing an incidence of 3.55 episodes/1000 patient-days and an estimated prevalence of 10.65/1000. The Authors described that 22.8% of patients had no ‘classic’ UTI-predisposing factors. Catheterassociated UTI (CAUTI) was present in 187 patients (62.8%). A closed drainage system was used in only 78.5% of catheterized patients. The indication for bladder catheterization was not considered adequate in 7.6% of cases and continuation of bladder catheterization was considered unnecessary in 31.3%. Opening of the closed drainage system was the most frequent major error in catheter management (16.8%). Antimicrobial treatment was not considered adequate in 19.8% of all cases (24). More recently, in 2007 Bjerklund Johansen et al. registered the prevalence of NAUTIs in urology sections in Europe and Asia. A total of 6033 hospitalized patients in 194 different urology departments were screened in two internet-based studies. The Authors concluded that the prevalence of NAUTI was 10% in the Pan European Prevalence (PEP) study, 14% in the Pan EuroAsian Prevalence (PEAP) study, and 11% in the combined analysis. It was shown that most NUTIs were catheter associated in 74% of the cases (4). In 2014, the European Centre for Disease Prevention and Control presented the results of a prevalence survey of healthcare associated infections. The ECDC registered a very heterogeneous situation in Europe. Although the overall median percentage of urinary catheter use was low (6.3%), it was reported by 33.3% and 17.9% in the Czech Republic and Greece, respectively (2). Multivariate analyses have emphasized that the duration of catheterization is the most important risk factor in the development of catheter-associated bacteriuria (25-27). Other risk factors include: colonization of the drainage bag, catheter
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and periurethral segment, diabetes mellitus, female gender, impaired renal function, poor quality of catheter care, including its insertion outside of an operating room and lack of antimicrobial therapy (28-31). Pathogenesis The urethral catheter can inhibit or bypass certain defense mechanisms that would normally prevent or minimize bacteria-epithelial cell interactions, e.g. the glycosaminoglycan (GAG) layer and biofilm formation. The source of microorganisms causing CAUTI can be endogenous, typically via meatal, rectal, or vaginal colonization, or exogenous, such as via contaminated equipment or healthcare staff’s hands. Microbial pathogens can enter the urinary tract either by the extraluminal route, via migration along the outside of the catheter in the periurethral mucous sheath, or by the intraluminal route, via movement along the internal lumen of the catheter from a contaminated collection bag or catheter-drainage tube junction. The relative contribution of each route in the pathogenesis of CAUTI is not well known (32). Bacteria can enter the urinary tract in catheterized patients at the time of catheter insertion. This is especially common in patients who have inadequate cleansing of the perineum and distal urethra, especially in patients on intermittent clean catheterization where only a limited attempt is made to cleanse the ‘entry points’ before introducing the catheter. It is, however, doubtful whether such cleansing is in general of any benefit, but in hospitalized patients the introduction of organisms at the time of catheterization could be critical. Up to 20% of individuals are colonized immediately after catheterization (25, 26, 31). The formation of biofilms by urinary pathogens on the surface of the catheter and drainage system occurs universally with prolonged duration of catheterization. Over time, the urinary catheter becomes colonized with microorganisms living in a sessile state within the biofilm, making them resistant to antimicrobials and host defenses and virtually impossible to eradicate without removing the catheter (33). Specifically, type 1 fimbriae contribute to catheter-associated urinary tract infections caused by Escherichia coli (34). Etiology Gram-negative organisms predominate in hospital-acquired urinary tract infections, almost all of which are associated with urethral catheterization. After the second day of catheterization, it is estimated that the risk of bacteriuria increases by 5 to 10% per day. The majority of bacteriuria cases are asymptomatic, and the most effective management is the catheter removal rather than an antibiotic treatment. In rare cases, local and systemic complications ensue, and antibiotic treatment should be initiated (35). In 1982, Warren et al. described the relationship between methods of catheterization and the risk of CAUTI (36). After single (straight) catheterization, bacteriuria develops in 1-5% of cases (17, 27, 35, 36). Short-term catheterization usually identifies a catheter left in place for less than 7 days (27). Between 15% and 25% of patients admitted to hospital may be
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catheterized for 2-4 days during their stay (17, 27). Between 10% and 30% will develop bacteriuria (25). Most episodes of short-term catheter-associated bacteriuria are asymptomatic and are caused by single organisms; 15% may be polymicrobial (22), reflecting the prevailing flora in hospital or community environments. When indwelling catheterization lasts for more than 28 days it is defined as ‘long-term’ or ‘chronic’. Unfortunately, there is no consensus on the classification of indwelling catheters in place for 8-29 days. The patient with a long-term indwelling catheter is at high risk of morbidity due to this procedure. Bacteriuria with at least one strain is universal, whilst most patients are infected with two or more strains (31-38). Most CAUTIs derive from the patient’s own colonic flora (25). The commonest infecting organism is E. coli (31). In 2001, the Co-operative Group of the European Study Group on Nosocomial Infections evaluated 141 hospitals of different sizes, 98 from EU countries and 43 from non-EU countries, serving an estimated population of 99,759,000 patients. The number of microorganisms isolated from NAUTI episodes was 340. Gram-positive bacteria represented 21.2% of all isolates, whereas Gram-negative bacteria were 65.9%. Yeasts were 12.9%. The five most commonly isolated microorganisms were Escherichia coli (35.3%), Enterococcus sp. (15.2%), Candida sp. (12.9%), Klebsiella sp. (9.8%) and Pseudomonas aeruginosa (5.4%). Overall, 14.1% of the episodes were polymicrobial (13.1% in EU countries versus 16% in nonEU countries; P>0.05) (24). In 2004, Bjerklund Johansen et al. of the European Society of Infections in Urology (ESIU-EAU) collected data from two internet-based studies on NAUTI in hospitalized urological patients presented together: the Pan European Prevalence (PEP) study, which was a 1-day prevalence study in November 2003; and the Pan Euro-Asian Prevalence (PEAP) study, which was carried out in November 2004. Overall, 93 and 101 hospitals from the two studies, respectively, completed the hospital questionnaires and provided patient information for the present study. NAUTI was diagnosed according to the Centers for Disease Control and Prevention (CDC) criteria in 727 of the 6033 patients hospitalized on the study days in urological departments. The most commonly reported pathogen was Escherichia coli (31%), followed by species of Pseudomonas (13%), Enterococcus (10%), Klebsiella (10%), Enterobacter (6%) and Proteus (6%). Candida spp. and Pseudomonas spp. occurred significantly more frequently as causative agents in urosepsis than in other types of infections (4). The most frequent pathogens associated with CAUTI (combining both ASB and SUTI) in hospitals reporting to the National Healthcare Safety Network (NHSN) between 20062007 were Escherichia coli (21.4%) and Candida spp. (21.0%), followed by Enterococcus spp. (14.9%), Pseudomonas aeruginosa (10.0%), Klebsiella pneumoniae (7.7%), and Enterobacter spp. (4.1%). A smaller proportion was caused by other gram-negative bacteria and Staphylococcus spp. (39). In 2014, Latour et al. of the ECDC published their survey. Between April and May 2013, 1181 long-term care facilities in 19 European countries (including three UK administrations) participated in the HALT-2 point prevalence survey of HAIs and antimicrobial use in Europe. Data were collected from each site on a single day. In total, 77,264 residents met the eligibility criteria. Referring to NUTIs, 604 etiological microor© 2014 Wichtig Publishing
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ganisms were reported in total. The most frequently isolated bacteria were: Escherichia coli (34.4%), Enterococcus (10.2%), Proteus mirabilis (8.1%), Pseudomonas aeruginosa (6.8%), Klebsiella pneumoniae (6.7%). In 2014, the World Health Organization (WHO) published a report that examines, for the first time, the current status of surveillance and information on antibacterial resistance (ABR), at country level worldwide. One of the key findings and public health implications of ABR is the very high rate of resistance observed in bacteria that cause common healthcare associated and community-acquired infections, especially UTIs, in all WHO regions. Antimicrobial resistance among urinary pathogens is an ever-increasing problem. WHO report collected a response including data, or information that no national data were available, returned from 129 of the 194 WHO Member States that responded to the survey (66%). Of these, 114 provided some data for at least one bacteria-antibacterial drug resistance combination. In Western Countries, Escherichia Coli is resistant to fluoroquinolones in 8-48% and to third-generation cephalosporins in 3-43% of the cases. Infections with Klebsiella Pneumoniae are particularly common in hospitals among vulnerable individuals. Similarly to E. coli, K. pneumoniae acquires resistance to multiple antibacterial drugs mainly through horizontal transfer of mobile genetic elements such as transposons or plasmids. Klebsiella is an emerging problem because the ESBL-positive (Extended Spectrum Beta Lactamase) strains are resistant to all extended beta-lactam antibacterial drugs such as cephalosporins. Although for these strains the carbapenems are the main remaining treatment option, K. pneumonia is also the main trigger of infections caused by carbapenem-resistant bacteria worldwide (0-68%) (40). Prevention In 2010, Gould et al. published the guideline for the prevention of catheter-associated urinary tract infections (32). At first, they pointed out that the clinical significance of ASB in catheterized patients is undefined. Approximately 75% to 90% of patients with ASB do not develop a systemic inflammatory response or other signs or symptoms to suggest infection. Moreover, ASB monitoring and treatment do not represent an effective prevention measure for SUTI as treatment of ASB has not been shown to be clinically beneficial and is associated with the selection of antimicrobial-resistant organisms. With regard to catheters or collecting systems it is important to highlight some key points: 1. Minimize urinary catheter use and duration in all patients, particularly when the mortality risk may be higher due to catheterization, such as in the elderly and in patients with severe illness; 2. Hydrophilic catheters might be preferable to standard catheters for patients requiring intermittent catheterization; 3. Perform the aseptic insertion of the urinary catheter, maintain a closed drainage system; 4. Urinary catheter systems with preconnected, sealed catheter-tubing junctions are suggested for use; 5. Instillation of antiseptic or antimicrobial solutions into © 2014 Wichtig Publishing
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urinary drainage bags is not recommended; 6. Unless clinical indications exist (e.g., in patients with bacteriuria upon catheter removal post urologic surgery), do not use systemic antimicrobials routinely as prophylaxis for UTI in patients requiring either short- or long-term catheterization. According to the Cochrane database for patients using intermittent catheterization, there is limited evidence suggesting that antibiotic prophylaxis decreases the rate of bacteriuria (asymptomatic and symptomatic) (41). Adherence to these basic recommendations could significantly decrease the risk of catheter-associated urinary tract infections. Vanhems et al. in a 10-year study of infection control and surveillance practices emphasizing some of these principles, showed a decrease of 70% over time in the risk of urinary tract infections in an intensive care unit population (42). In 2014, Tenke et al. reviewed the latest advances in the field of catheter care and the management of CAUTIs. The Authors underlined that the most efficient methods to prevent CAUTIs are to avoid unnecessary catheterizations and to remove catheters as soon as possible. The use of different reminder systems and the implementation of infection control programs can effectively decrease CAUTIs, although their introduction can be challenging. No evidence to support the routine use of antimicrobial-impregnated catheters has been described, but the use of hydrophilic-coated catheters for clean intermittent catheterization can effectively reduce infections. Preliminary results with chlorhexidine-coated catheters are promising. In cases of serious catheter-associated UTI in patients with a history of previous antibiotic therapy or healthcare-associated bacteremia, empirical antibiotic treatment should be initiated with activity against multiresistant uropathogens (43). Treatment Treatment of NUTIs needs to be considered separately for patients with ASB and for those with SUTI. In general, ASB in catheterized patients should not be treated. Removal of the catheter allows resolution of bacteriuria in one third to one half of cases (31). The European and Asian guidelines recommend treatment of asymptomatic bacteriuria in the following circumstances: 1. For patients undergoing urological surgery or implantation of prostheses; 2. When treatment may be part of a plan to control nosocomial infections due to a particularly virulent organism prevailing in a treatment unit; 3. For patients who have a high risk of serious infectious complications (e.g., patients who are immunosuppressed); 4. For infections originating by strains causing a high incidence of bacteremia (e.g., S. marcescens). The treatment of symptomatic urinary tract infections is usually more straightforward. Clinical symptoms and signs, such as frequency, dysuria, or suprapubic pain directly attributable to an infection, are an indication for treatment. The most common symptom attributed to a urinary tract infection in hospitalized patients is usually fever. If the patient
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is systemically ill, empiric antibiotics should be started, based on knowledge of the local bacterial ecology, and then tailored according to a definitive culture and susceptibility results. However, in patients with nosocomial urinary tract infections, who may have indwelling urinary catheters and highly resistant pathogens, the perception that bacterial susceptibilities are unimportant may not necessarily be accurate. Thus, clinical judgment and the patient’s response to therapy dictate the degree to which susceptibility data are used for the direct treatment of symptomatic urinary tract infections in hospitalized patients (44).
Discussion UTIs are the most common type of healthcare-associated infections reported to the National Healthcare Safety Network (NHSN) and by the ECDC and WHO. Among UTIs acquired within the hospital environment, approximately 75% are associated with a urinary catheter. Between 15-25% of hospitalized patients receive urinary catheters during their hospital stay. Therefore, NUTIs are a major cause of morbidity in hospitalized patients in general, and in post-operative surgical patients in particular. Nowadays, active surveillance on epidemiology, etiology, prevention and treatment of NUTIs is mandatory due to the increase of clinical cases worldwide. Treatment may be complicated by the development of resistant bacteria not adequately followed by new antibiotics and other strategies of care. Several national and international studies have been reported regarding every aspect concerning NUTIs. Every single institution must have an infectious control system and protocols about the prevention and treatment of NUTIs, in order to firstly geographically focalize differences in microorganisms and their resistance and, secondly, to allow global metanalysis and best practice guidelines. Nosocomial urinary tract infections are a common complication in healthcare systems worldwide. The use of urinary catheters is the major risk factor for the development of these infections. Discontinuation of catheterization as soon as possible is a plausible key to avoiding nosocomial urinary tract infections. Patients with asymptomatic bacteriuria can generally be treated initially with catheter removal or catheter exchange, and do not necessarily need antimicrobial therapy. Symptomatic patients should receive antibiotic therapy. Resistance of urinary pathogens to common antibiotics is currently a topic of concern.
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Disclosures Informed consent: The manuscript does not report the results of an experimental investigation on human subjects. Financial support: The study has not been supported by private or public sources, grants or funds. Conflict of interest: None of the authors have proprietary interests.
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