Clean intermittent catheterization (CIC) is considered the method of choice for bladder emptying when neurological or non-neurological causes make normal voiding impossible or incomplete . The outcome is overall good, also in the long-term. There is no one best technique nor one best material for CIC, as both depend greatly on anatomical, social and economic factors for an individual patient . The most frequent complication of CIC is UTI. Incidence figures for UTI vary widely in the literature, owing to different definition criteria, various methods used for evaluation, different CIC techniques used, different frequencies of urine analysis, the administration of prophylaxis, the group of patients studied and probably other factors as well. A review of the literature shows that most studies do not provide a high level of evidence [3,4].
For the present review we gathered information on different aspects of UTI to guide future research on clearer recommendations for the prevention of UTI in patients who perform CIC. A literature search was conducted, after which data were presented to the expert group, and discussion followed, both through meetings in person and by email.
DEFINITIONS AND SEVERITY GRADING OF UTI IN CIC
When micro-organisms enter the urinary tract without causing symptoms, this is defined as asymptomatic bacteriuria. This is no longer regarded as a UTI, although treatment is recommended under certain circumstances, such as in pregnancy and before invasive urological procedures. The presence of pathogens in the urine is, however, considered to be a risk factor for a clinical infection . If pathogens invade the urothelium, local and systemic symptoms may arise. Symptomatic UTI is defined as the presence of significant bacteriuria in a patient with signs or symptoms attributable to the urinary tract and no alternate source. Clinical presentation depends on the part of the urinary tract (lower or upper) in which the invasion takes place. The virulence of threatening pathogens is normally balanced by host protective mechanisms, but this balance may be disturbed by risk factors.
Assessment of a patient suspected of having a UTI is based on clinical diagnosis, prognosis and available treatment measures. Recently, the European Association of Urology (EAU)/European Section for Infection in Urology (ESIU) published new definitions of UTI and recommendations on severity assessment . Severity assessment is based on clinical presentation, risk factors and antibiotic treatment options. A UTI is classified as cystitis (CY), pyelonephritis (PN) and urosepsis (US). Urethritis and male accessory gland infections (male adnexitis, e.g. prostatitis) are usually dealt with separately.
The clinical presentations of the three UTI entities are shown in Table 1. PN is always more severe than CY, and US is always more severe than the former two; however, in clinical practice it can be difficult to differentiate between even CY and US. In addition, PN can present as a mild and moderate infection, which can usually be treated by oral antimicrobials in an outpatient setting, or as a severe infection with systemic reactions like nausea and vomiting, which usually needs initial parenteral therapy and hospitalization. For US, fortunately rare in patients performing CIC , the severity grading is: sepsis, severe sepsis and septic shock . The EAU/ESIU suggests ascribing each of the clinical presentations a severity grade in Arabic letters. The clinical situation is always the most important prognostic criterion.
Table 1. Clinical presentation of CY, PN and US and grading of severity
|CY-1||CY||Dysuria, frequency, urgency, suprapubic pain; sometimes unspecific symptoms||1|
|PN-2||Mild and moderate PN||Fever, flank pain, costovertebral angle tenderness; sometimes unspecific symptoms with or without symptoms of CY||2|
|PN-3||Severe PN||As PN-2, but in addition nausea and vomiting with or without symptoms of CY||3|
|US-4||US (simple)*||Temperature >38 °C or <36 °C||4|
|Heart rate >90 beats min|
|Respiratory rate >20 breaths/min or|
|PaCO2 <32 mmHg (<4.3 kPa)|
|White blood cell count >12 000 cells/mm3 or <4000 cells/mm3 or ≥10% immature (band) forms|
|With or without symptoms of CY or PN|
|US-5||Severe US*||As US-4, but with associated organ dysfunction, hypoperfusion or hypotension†.||5|
|Hypoperfusion and perfusion abnormalities may include but are not limited to lactic acidosis, oliguria or an acute alteration of mental status|
|US-6||Uroseptic shock||As US-4 or US-5, but in addition 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.||6|
RISK FACTORS FOR UTI WHEN PERFORMING CIC
Many types of risk factors are described, e.g. risk factors for contracting UTI, recurrences, serious complications and kidney failure. Long and often overlapping lists of risk factors have been presented for either uncomplicated or complicated UTI based on possible anatomical disorders and catheter use [8,9]. The ESIU introduced the new concept of phenotyping to describe the different groups of risk factors of UTI, assessing prognosis by considering what can happen if treatment is not initiated. Risk factors related to UTI will modify the patient's prognosis. In the diagnostic evaluation of patients with UTI it is important to detect risk factors that need to be considered or eliminated to achieve treatment aims. The ESIU uses the ‘ORENUC’ system of six categories, each referred to by a letter (Table 2). The use of CIC is considered to be a ‘urological risk factor’. Non-resolvable urinary obstruction and badly controlled neurogenic bladder disturbances are considered risk factors of a separate phenotype. Likewise, the use of a permanent catheter is regarded as a risk factor for a more severe outcome of the infectious episode.
Table 2. Host risk factors in UTIs, categorized according to the ORENUC system
| O ||NO known risk factor||Otherwise healthy premenopausal women|
| R ||Risk factors for Recurrent UTI, but no risk of more severe outcome||Sexual behaviour (frequency, spermicide),|
|Hormonal deficiency in postmenopause|
|Secretor type of certain blood groups|
|Well controlled diabetes mellitus|
| E || Extra-urogenital risk factors with risk of more severe outcome||Prematurity, newborn|
|Badly controlled diabetes mellitus|
|Relevant immunosuppression (not well defined)|
| N || Nephropathic diseases with risk of more severe outcome||Relevant renal insufficiency (not well defined)|
|Interstitial nephritis, e.g. owing to analgesics|
| U || Urological risk factors with risk of more severe outcome, which can be resolved during therapy||Ureteric obstruction resulting from a ureteric stone|
|Well controlled neurogenic bladder disturbances|
|Transient short-term external urinary catheter|
| C ||Permanent urinary Catheter and non-resolvable urological risk factors with risk of more severe outcome||Long-term external urinary catheter|
|Non-resolvable urinary obstruction|
|Badly controlled neurogenic bladder disturbances|
A literature review of risk factors for UTI in adults with spinal cord dysfunction, found some evidence supporting increased bladder residual volume as a risk factor, conflicting evidence over the value of sterile or ‘non-touch’ catheter techniques compared with CIC, and insufficient evidence to assess the risk attributable to psychological, behavioural and hygiene factors, sex, level of function and time since injury . Previous treatment with an indwelling catheter is a special risk for developing sepsis, especially during the period of 24 h to 3 days after changing CIC drainage when UTI was present . If catheterization is begun by patients with recurrent or chronic UTI and urinary retention, the incidence of infection decreases and patients may become totally free of infection. If symptomatic infections occur, improper practice of CIC or misuse can often be found. Chronic infection persists after CIC has been started, if the underlying cause of the chronicity remains .
IMPORTANCE OF BIOFILM
Traditionally UTI has been regarded as caused by free-floating, planktonic bacteria; however, bacteria easily attach to the catheter surface and form multicellular communities or bacterial biofilm. When a urinary catheter is introduced into the bladder the host almost immediately deposits a conditioning film on the surface which neutralizes the anti-adhesive cover . This conditioning film is formed from urinary components such as Tamm–Horsfall glycoproteins, electrolytes and organic molecules . This transformation of the catheter is vital for biofilm formation since it provides receptor sites for bacteria and thereby allows free-floating bacteria to attach to the surface . The first step of biofilm formation occurs mainly through hydrophobic and electrostatic interactions but also through the ionic strength, osmolality and pH . Micro-organisms, however, not only adhere to the underlying substrates but also to each other  and once they have attached, they start multiplying and recruiting new bacteria. Next, bacteria undergo a change in gene expression leading to a phenotype different from when they grew in a planktonic state. Lastly, extracellular matrix is produced . An established biofilm consists of an accumulation of bacteria immobilized on a surface. In the majority of biofilms micro-organisms only account for <10%, while the extracellular matrix accounts for >90% . Most of the matrix is produced by the micro-organisms themselves and the formation of biofilm allows a life style that differs from planktonic bacteria. Within the biofilm, micro-organisms show coordinated behaviour with the formation of a complex three-dimensional structure containing fluid channels permitting exchange of nutrients and waste and functionally heterogeneous bacterial communities . Such a mode of growth allows the bacteria to survive in a hostile environment and conveys several survival strategies to the micro-organisms. The major advantages for the bacteria are that: antimicrobial agents often fail to penetrate the full depth of the biofilm (extrinsic resistance); the microorganisms within the biofilm grow more slowly and therefore are more resistant to antimicrobial agents that require active growth; the antimicrobial binding proteins are poorly expressed in these bacteria; many genes that alter cell envelope, molecular targets and susceptibility to antimicrobial agents are activated (intrinsic resistance); and bacteria within a biofilm can survive in the presence of antimicrobial agents at concentrations 1000–1500 times higher than those needed to kill bacteria of the same species in the planktonic state . In addition, micro-organisms are resistant to phagocytosis and they are not swept away by simple shear forces .
A practical consequence of biofilm growth is that the results of microbiological analysis can be misleading, both regarding bacterial species and susceptibility pattern, since the results reflect the micro-organisms free-floating at the time of sampling and not those encapsulated in the biofilm . Biofilm is considered a problem mainly for patients with long-term indwelling catheters as these allow the biofilm to be formed during a longer period of time; however, it was recently shown that the biofilm-promoting components curli fimbriae and cellulose were expressed on uropathogenic Escherichia coli of individuals with uncomplicated UTIs . Established curli induced immune response and promoted resistance to the antimicrobial peptide LL-37, a key factor in the mucosal immunity of the urinary tract . LL-37 prevented the formation of new curli fimbriae, thus interacting with biofilm formation, while cellulose reduced immune induction thereby delaying bacterial elimination .
Although UTIs were previously considered to be extracellular infections, it has recently been shown that E. coli can invade and replicate themselves in mouse bladder cells. Within the cells E. coli can form biofilm-like intracellular bacterial communities (IBCs). These IBCs use a multistep pathogenic cycle with changes in morphology. Late IBCs dissociate from and filamentous bacteria flux out of the superficial facet cells. Through the morphology change into a filamentous form, they avoid engulfment by neutrophils, thus allowing them to re-invade the uroepithelium . The findings of exfoliated cells with filamentous bacteria in the urine of women with CY support the occurrence of an intracellular niche that may be of importance for recurrent UTIs in humans , and it has been argued that a greater number of IBCs formed during the acute stages of infection precedes chronic CY . Based on these findings, biofilm-forming components and IBCs may also have implications in patients performing CIC. This is highly clinically relevant and needs further research.
To diagnose UTIs in patients performing CIC, it is recommended that the urine is obtained by catheterization . The frequency of examining urine samples differs greatly between studies. Several investigators advocate daily use of a dipslide technique during the acute phase of a UTI after spinal cord injury, once a week during the subacute phase and monthly or a few times a year in long-term care, although this is not recommended by all . Because catheter urine specimens are not as likely to be contaminated by peri-urethral flora as are voided urine specimens, low colony counts more easily represent true bladder bacteriuria in patients performing CIC . Unfortunately, there is no standard definition for significant bacteriuria in such patients. A colony count of 102 cfu/mL specimen had optimum sensitivity and specificity, compared with paired suprapubic aspirates [27,29]. But, most patients have colony counts of 105 cfu/mL. The international guidelines on catheter-associated UTI suggest a quantitative count of at least103 cfu/mL as a reasonable compromise between sensitivity in detecting UTI and feasibility for the microbiology laboratory in quantifying organisms . The bacterial species must also be taken into consideration. E. coli and other Gram-negative enteric rods are more virulent and are most likely to be the causative agent, even in low bacterial concentrations, while other bacteria, e.g. coagulase-negative staphylococci and some streptococci are doubtful pathogens even in high concentrations.
Escherichia coli is considered to be the dominant species in several studies . The detection of E. coli on the peri-urethra is associated with bacteriuria at a much higher rate (93%) than other bacteria on the peri-urethra (≤80%) . E. coli isolates from patients who develop symptomatic UTI may be distinguished from bacteria recovered from patients who remain asymptomatic and possibly also from normal faecal E. coli. The local flora in particular hospitals and regions and their susceptibilities should also be taken into account. Pyuria is evidence of inflammation in the genitourinary tract, but is not helpful in establishing a diagnosis in patients with neurogenic bladders . The absence of pyuria in a symptomatic catheterized patient suggests a diagnosis other than UTI .
SYMPTOMS AND SIGNS SUGGESTIVE OF UTI
Patients performing CIC who have a UTI usually do not present with the classic symptoms of dysuria, frequent and urgent urination, although such symptoms may occur. In addition, patients with neurogenic bladders frequently have an absence of sensation in the pelvis, and ascertainment of potential symptoms of UTI is often difficult . Different guidelines recommend thorough evaluation to identify the source of signs and symptoms before attributing them to the urinary tract . Symptoms that should indicate obtaining a culture and initiating antimicrobial therapy include new costovertebral angle tenderness, rigors or new onset of delirium . The National Institute on Disability and Rehabilitation Research Consensus Statement  listed the following as suggestive of UTI in patients with spinal cord injury: discomfort or pain over the kidney or bladder or during urination, onset of urinary incontinence, fever, increased spasticity, autonomic dysreflexia, malaise, lethargy, or sense of unease. When no alternative source of symptoms is identified in patients with bacteriuria, it is reasonable to monitor symptoms and treat only if the symptoms do not resolve . In the guidelines for the evaluation of fever and infection in residents of long-term care facilities, it has been recommended that evaluation is undertaken if there is suspected US (i.e. fever, shaking chills, hypotension or delirium), especially in the context of recent catheter obstruction or change .
The strong smell of urine around patients with urinary incontinence is thought to be attributable mainly to the production of ammonia from urea by bacterial ureases , but not all individuals with UTI have an unpleasant odour to their urine, and not all urine with an unpleasant odour is indicative of infection . Thus, odorous or cloudy urine should not be used alone to determine the presence of bacteria or, in particular, to distinguish it from UTI .
Different techniques have been described to prevent, or at least postpone, bacteriuria and symptomatic UTI in patients performing CIC. A correct catheterization technique is necessary, therefore education is important for patients, carers, nurses and physicians. Educational intervention by a clinic nurse is a simple, cost-effective means of decreasing the risk . Anderson  found a fivefold incidence of UTI when CIC was performed three times a day compared with six times a day, reflecting the importance of balancing evacuation and speed of bacterial growth. Prevention of bladder overdistention is important . Cross-infection is less prevalent if CIC during hospitalization is done by specialized members of a catheter team  or by the patients themselves . Attention must be paid to emptying the bladder completely .
A 2007 Cochrane review evaluated the available studies comparing sterile vs clean techniques, coated vs uncoated catheters, single- or multiple-use catheters and self-catheterization vs catheterization by others with regard to the incidence of symptomatic UTIs in individuals with incomplete emptying, who are otherwise unable to void adequately to protect bladder and renal health . It concluded that there was no difference in the risk of catheter-related bacteriuria or UTI, and owing to the lack of evidence it is not possible to state that one catheter type, technique or strategy was better than another. Meanwhile some studies have suggested that hydrophilic catheters are superior to non-hydrophilic ones in UTI prevention [45,46]. There is no evidence that the re-use of catheters would increase the risk of infection, but this may be inconvenient for many patients . Different procedures have been described to reduce bacterial colonization of reusable catheters, but there are no published trials evaluating the effectiveness of any of these cleaning methods in preventing bacteriuria or symptomatic infection among patients performing CIC . E. coli 83972-coated urinary catheters were shown as a viable means of achieving bladder colonization with this potentially protective strain in patients performing CIC and of lowering the UTI rate . The use of silver-coated alloy indwelling catheters reduced UTI in adult patients hospitalized for the short term , but the effect of such catheters used for CIC is unknown as yet.
In another 2007 Cochrane review, the effectiveness of cranberry products in patients performing CIC was not clearly demonstrated , and their routine use in patients with neurogenic bladder is not advocated .
Benefits from antiseptic substances, such as oral methenamine or bladder instillation of povidone–iodine and chlorhexidine, have never been established in CIC . The question of whether antibacterial prophylaxis decreases the infection rate has been the subject of different studies, but randomized controlled trials are scarce. According to a Cochrane review by Niel-Weise and van den Broeck , there are, for patients performing CIC for >14 days, inconsistent findings about the effect of antibiotic prophylaxis on symptomatic UTI, limited evidence that receiving antibiotics reduced the rate of bacteriuria (asymptomatic and symptomatic) and weak evidence that prophylactic antibiotics were better in terms of fewer symptomatic bacteriuria. Antimicrobial prophylaxis can result in resistant micro-organisms, and therefore is not recommended .
Instillations of antibacterial solutions in the bladder after catheterization had conflicting outcomes: Kanamycin-colistin decreased the incidence of bacteriuria , but this was not found with neomycin or polymixin . Studies with gentamicin instillations show a reduction in bacteriuria and UTI in patients with resistant E coli. Studies show contradictory results about ascorbic acid prophylaxis alone, or as adjuvant therapy together with other antibacterial drugs [56,57]. Several studies highlight the risk of developing dangerous resistance as side effects of the antibiotics, and at the expense of the risk to other patients from cross-infection with resistant organisms .
Treatment of bacteriuria remains uncertain, but treatment of UTI is necessary and assessment of the prognosis and severity of UTI is valuable for deciding the optimum antimicrobial treatment . A EAU/ESIU grading with small letters a-c describes the susceptibility of the causative pathogen(s) and the availability of effective antimicrobials at the same time (Table 3). Based on clinical presentation, risk phenotype and therapeutic options, all episodes of UTI may be given a UTI severity score .
Table 3. Susceptibility of the causative pathogen(s) and the availability of effective antimicrobials
|Situation||Pathogen(s) is (are) susceptible against commonly used antibiotics, which are available||Pathogen(s) has (have) reduced susceptibility against commonly used antibiotics, but alternative antimicrobials are available||Pathogen(s) is (are) multiresistant and/or appropriate antimicrobials are not available|
In conclusion, UTI is a major complication of CIC. The incidence of UTI in patients performing CIC varies widely in the literature due to differences in methodology, but uniform guidelines on definitions are available and it is recommended they are followed. There are several risk factors for UTI and phenotyping them helps to assess prognosis by considering what can happen if treatment is not initiated. The role of biofilms deserves more attention in CIC. Diagnosis can be made on urine sample obtained with catheterization. Because of neurological or other deficiencies in patients performing CIC, symptoms are less reliable. Thorough evaluation for the source of signs and symptoms should be made before attributing them to the urinary tract. Treatment in those who perform CIC for a long time is only necessary for symptomatic infections.
Many different proposals for prevention of UTI in CIC patients exist, but more research is warranted. The role of the type of catheter is unclear but further exploration of special catheter types might be worthwhile. Other specific items for future research could include the role of frequency of catheterization, prophylactic antibiotics and preservation of natural defence mechanisms in the lower urinary tract.