Catheter associated urinary tract infection and encrustation

Transcription

1 International Journal of Antimicrobial Agents 17 (2001) Catheter associated urinary tract infection and encrustation S. Choong *, S. Wood, C. Fry, H. Whitfield Institute of Urology and Nephrology, London, UK Abstract This paper examines the relationship between urinary ph, infection and urinary catheter encrustation and discusses the current management and problems of catheter associated urinary infection and encrustation Elsevier Science B.V. and International Society of Chemotherapy. All rights reserved. Keywords: UTI; Catheter encrustation; ph 1. Introduction The risk of catheter-associated infection increases by 5 8% per day [1] and over 90% of patients undergoing long-term catheterization will develop bacteriuria within 4 weeks, despite closed drainage systems [2]. The association between urinary infection and stone formation was first recognized by Horton Smith in 1897 and Brown in During the last decade, there has been significant advancement in the understanding of the association between urinary infection, biofilm formation on biomaterials and encrustation. Fifty percent of patients with long-term indwelling catheters suffer regular encrustation and catheter blockage [3]. The majority of them are elderly and cause 4% of the community nursing caseload [4] and 28% of patients in chronic care facilities require indwelling urinary catheters [5]. District nursing commitment in a district with a total population of has been estimated at 500 h per month and 1000 visits per year [6]. Urinary tract infection and encrustation are two major complications of indwelling urinary devices and the cost of managing these complications amount to 1 billion per year in Western Europe and a similar amount in North America. Catheter encrustation may develop with or without urinary infection but it is widely recognized that a raised urinary ph is associated * Corresponding author. Tel.: ; fax: address: simon@choong.demon.co.uk (S. Choong). with urinary infection and encrustation. The aim of this study was to determine the relationship between urinary ph, UTI and catheter encrustation. A large component of catheter encrustation is composed of calcium salts and this study focused on the relationship between urinary ph and ionic calcium concentration in patients with long-term catheters. 2. Patients and methods Urine samples were collected from 64 patients with long-term indwelling urinary catheters. Patients who had suffered acute spinal injury within the last 6 months were excluded as they might have been hypercalciuric. The patients were subdivided into two groups; catheter blockers were those whose catheters regularly became blocked by encrustation within a 6 week period requiring replacement; and non-catheter blockers were those whose catheters could be changed at intervals longer than 6 weeks. No change to the food or liquid consumption of patients in the study was made which might alter urinary composition. Experiments were performed on freshly voided urine within 4 h of collection. The total [Ca], [Mg], [Na], [K], osmolality, phosphate, oxalate, citrate, creatinine, urate, and glycosaminoglycans were measured. The voided ph was measured in a urine sample drawn into a glass syringe within 45 s of micturition, to minimize CO 2 loss. Urine was sent for bacteriological culture and testing for urease activity. Experiments were performed in a 5 ml water-jacketed chamber, maintained at 37 C. To generate Ca 2+ /ph /01/$ - $ Elsevier Science B.V. and International Society of Chemotherapy. All rights reserved. PII: S (00)

2 306 S. Choong et al. / International Journal of Antimicrobial Agents 17 (2001) relationships, urinary ph was reduced to 4.75 by adding 1 mol/l HCl to the sample, and subsequently alkalinised in steps of 0.25 ph units by adding 1 mol/l NaOH. The potential difference of the Ca 2+ electrode as shown on the voltmeter was recorded at each ph increment. The free [Ca 2+ ] was calculated from the calibration curve in which Ca 2+ titration experiments were carried out at constant ph by adding CaCl 2 samples from a 1 mol/l stock solution of CaCl 2 and the ph corrected by adding NaOH. All experimental data were expressed as the mean value and one standard deviation (mean S.D.) of at least four individual measurements. The data were displayed as X Y plots or frequency histograms using graph-plotting programmes on an Apple Macintosh computer (Kaleidagraph, StatView II and Statworks; Apple Computer, Cupertino, CA). In current practice, patients who are non-blockers have their catheters changed every 6 12 weeks whereas patients who are blockers are managed by crisis management, when catheters are changed before the 6- week period when they became blocked acutely. Getliffe [7] found that patients with recurrent problems associated with catheter blockage usually required catheter changes in less than 6 weeks. Patients with infrequent, or no problems usually retained their catheters for up to 12 weeks. Based on these findings of Getliffe [7] and the current clinical management de- 3. Results The ph values at which crystals precipitated (ph n ) and voided ph values (ph v ) of urine from catheter blockers and non-blockers were measured. The catheter-blocking group was subdivided into those with and without urease-producing organisms. There were no statistical differences seen in the urinary variables (total calcium, magnesium, sodium, potassium, oxalate, phosphate, urate, citrate, creatinine, proteins, glycosaminoglycans and osmolality) measured between the three groups. The relationship between the voided urinary ph and the ph at which crystallization occurred among the three different groups is seen in Fig. 1. The thick vertical lines represent the voided urinary ph (ph v ). The ph values at which crystals precipitate out of solution, crystallization ph (ph n ) are shown in dotted lines, above which crystallization would continue (shaded area). The non-blocker group shows that there is a wide safety margin between the ph in the bladder, ph v and the crystallization ph, ph n. The blocker with urease producing organisms group shows that this margin of safety has been significantly reduced and therefore, crystallization and precipitation are more likely to occur in this group. The blocker and urease negative group shows that the voided ph of the blockers without urease-producing organisms lies within the crystallization zone, which favours encrustation and blockage of the urinary catheters. 4. Discussion Fig. 1. The relationship between the voided urinary ph and ph n,the ph at which crystallization occurred among catheter non-blockers and blockers with and without urease activity.

3 S. Choong et al. / International Journal of Antimicrobial Agents 17 (2001) Table 1 Urinary differences between catheter blockers and non-blockers Non-blockers (n=23) Blockers (Urease +ve; n=33) Blockers (Urease ve; n=8) ph v 6.26 (0.93) 7.85 (0.66)** 6.90 (0.32)* ph n 7.66 (0.63) 7.58 (0.75) (n=29) 6.49 (0.65)* ph n ph v 1.40 (0.98) 0.19 (0.98)** (n=29) 0.42 (0.75)** * P ** P blockers vs. non-blockers; P 0.05, P ph n vs. ph v Mann Whitney U-test. scribed, we chose the same criteria to differentiate patients into catheter non-blockers and blockers. The limited population of long-term catheterized patients, and the frailness of many elderly patients (who were therefore unwilling or unable to be recruited) precluded the design of a randomized population sample. The relationship between urinary ph and Ca 2+ concentration was markedly different in catheter blockers and non-blockers. Non-blockers had a significantly more acidic voided urine ph as compared to blockers and did not have a urinary infection. Catheter nonblockers had a wide safety margin between the voided ph and the ph value above which crystallization occurred, ph n, which was absent in catheter blockers. Catheter blockers were subdivided into those associated with and without urease producing organisms. Many catheter blockers had urease producing urinary infection (80%, n=33/41). Blockers with urease producing organisms had nucleation ph values similar to those of non-blockers; the main difference being the value of the voided urine ph, which was significantly more alkaline (Table 1). Hence, the safety margin between the voided ph (ph v ), and ph n was abolished, thus increasing the tendency for crystal precipitation to occur. Catheter blockers with no evidence of urease producing (20%, n=8/41) had a voided urine ph significantly more alkaline, and a nucleation ph significantly more acidic when compared to non-blockers. The voided urine ph then came within the nucleation zone thus promoting crystallization and encrustation. The reasons which could account for the differences in the nucleation ph between catheter blockers and non-blockers need to be sought as no significant difference could be found in the total concentrations of Ca, Mg, Na, K, phosphate, oxalate, citrate, creatinine, urate, glycosaminoglycans and osmolality. Langley and Fry [8] studied the nucleation ph in urine collected from stone-formers and normal subjects and found that the nucleation ph value was strongly dependent on the [Ca 2+ ] at a standardized ph. However, in catheter blockers and non-blockers, other factors must be responsible for the nucleation ph value as there was no difference in the [Ca] in catheter blockers and non-blockers. Since calcium phosphate crystals were the predominant type of crystals found in the urine of catheter blockers, the ratio of the different types of phosphates and their interactions with other urinary constituents might have a role in determining the nucleation ph value. Several factors remain to be determined to gain more insight into the particular conditions which initiate the formation of urinary tract crystals and their deposition on urinary catheters. Further work is required in the measurement of the actual values of urinary ph and their variation in the upper and lower urinary tract, in the evaluation of the effect of known promoters and inhibitors of crystallization on the Ca 2+ /ph relationship and in detailed investigation of those urinary components which determine the particular value of ph n. The long-term goal is to manipulate the nucleation ph of catheter blockers to render it more alkaline and re-establish the margin of safety Urinary infection and biofilm Urinary infection leads to biofilm formation on urological devices in the urinary tract. The processes involved in the formation of biofilm and encrustation are as follows: 1. Protein adsorption on the biomaterial. 2. The formation of an organic conditioning film on the surface. 3. The adherence of the urease-producing bacteria to the biofilm. 4. The development of a bacterial biofilm community within a matrix of bacterial exopolysaccharide. 5. The elevation of the ph of urine and biofilm matrix by the action of urease on urea. 6. The attraction of calcium and magnesium ions into the gel of the matrix. 7. Stabilization of the calcium and magnesium ammonium phosphates crystals by the biofilm matrix. 8. Crystal formation in the alkaline urine and bacteria attaching to the surfaces of the biofilm promoting aggregation and growth of the biofilm. It is known that proteins can adhere to polymer surfaces. Adsorption of protein onto polymer surfaces is the net result of various interactions involving the surface, the protein and the solvent. The factors influ-

4 308 S. Choong et al. / International Journal of Antimicrobial Agents 17 (2001) encing the binding of proteins include the electrostatic and polarity forces between the molecules and the surface, and temperature and solute composition of the fluid environment. The kinetics of adsorption in biological fluids depends on the amount and type of proteins present. Initially, the interface will mainly accommodate those protein molecules that are most abundantly present in solution. Later, the adsorbed molecules may be displaced by other molecules that have a stronger tendency to adsorb (sequential adsorption). This adsorbed layer may initiate the process of encrustation by attracting certain molecules. The prevention of encrustation and biofilm formation requires a detailed and systematic examination in the processes of these mutifactorial phenomena. It is also necessary to identify the adsorbing proteins and elucidate the interaction of urinary solutes and bacteria to this layer. Micro-organisms have a strong tendency to grow on available surfaces in preference to remaining suspended in an aqueous environment such as urine [9]. The production of exopolysaccharides and the formation of a glycocalyx by the proliferating micro-organisms chemically bind this living and constantly changing layer to the polymer surface, which is known as a biofilm. The ability of uropathogens to adhere to the surface of a prosthetic material is an important factor in the development of infection. Electron micrographs of catheter surfaces have shown that the internal surface topography varies between catheters composed of different materials, and those of similar materials produced by different manufacturers [10]. Adherence may be influenced by factors such as cell surface properties, biomaterial surface characteristics, bacterial species and the clinical conditions present. Gram-negative bacilli adhere differentially to catheter materials [11]. Furthermore, pre-adherence by one species may enhance the adherence of another, as demonstrated by the enhanced adherence of Proteus mirabilis by Staphylococcus epidermidis on a variety of urinary catheter materials [12]. A raised urinary ph, as a result of urinary infection with urease-producing micro-organisms, is an important mechanism of encrustation in an infected urinary environment. Localized urease production from within a biofilm has been demonstrated experimentally [13] and the ph of urine within blocked catheters was more alkaline than the ph of urine flowing from a newly changed catheter which suggested a localized production of urease by micro-organisms colonizing the blocked catheter. A different microbial flora was identified on 11/33 catheter surfaces compared to that of urine from the bladder [14] and catheterized patients were found to have a different distribution of micro-organisms, in particular a higher proportion of gram-negative bacilli as compared to non-catheterized patients [15]. Prolonged catheterization is associated with mixed growths of micro-organisms which are frequently unresponsive to antibacterial therapy [16] or antiseptic bladder washouts [17]. These bacterial colonies within a biofilm form a functional consortium in which a microenvironment is maintained and together with encrustation protect the micro-organisms from therapeutic agents and lead to a reservoir of viable organisms which can continue to cause infection and encrustation. A physical barrier is not the only mechanism of biofilm resistance. Micro-organisms deep within the biofilm are characterized by a slow and variable growth rate which is influenced by the availability of nutrients, and as growth rate is a primary modulator of antibiotic action, may account for the resistance to anti-microbial therapy Catheter encrustation A variety of methods are currently used in the management of catheter encrustation and blockage. Catheter replacement and altering the type or size of the catheter, increasing fluid intake, dietary modification of the urine with cranberry juice or acidification with vitamin C, bladder washouts with saline, acidic or antiseptic solutions, and antibacterial treatment of the associated urinary tract infection have all been investigated. The high incidence of recurrent catheter blockage and the variety of management methods suggest that the solution to the problem had not been found. Indeed, surveys of nursing staff responsible for catheter management have revealed diverse opinions and uncertainties about the most appropriate method for the management of the blocked catheter as a result of the unsatisfactory clinical experience with the current methods of management. The length of time catheters can safely remain in situ prior to removal for blockage is variable, not only between patients who are blockers, but also between catheter episodes for the same patient. In over 60% of blockers a pattern was identifiable and Norberg et al. [18] have recommended monitoring three to five catheter episodes to identify a characteristic pattern of catheter life in order that re-catheterization can be planned to precede the predicted development of blockage. However, the underlying cause has not been resolved and catheter replacement is only a short-term solution to relieve the obstructed system as rapid encrustation usually occurs. A high fluid intake is frequently recommended for catheterized patients [5] but, in practice, it is difficult to maintain a high diuresis over a prolonged period by increasing water intake and urinary solute concentration is not correlated with the degree of encrustation [19]. Oral intake of cranberry juice or vitamin C have been recommended [19] but prevention of struvite precipita-

5 S. Choong et al. / International Journal of Antimicrobial Agents 17 (2001) tion by maintaining a low urinary ph is difficult in the presence of urease-producing micro-organisms. Furthermore, the addition of hydrogen ions in the presence of urease causes more urea to be converted into ammonia and restores the alkaline conditions. Inhibitors of urease were found to be more effective in lowering the ph in P. mirabilis infected urine but the side effects were unacceptable to the patients receiving them [20]. A variety of bladder washouts are currently available on the market containing saline, antiseptic or a weak acidic solution. The daily instillation of the acidic Suby G solution was shown to be effective in controlling encrustation in vitro [21] and dissolved struvite crystals in suspension but was ineffective in removing crystals entrapped within the biofilm [22] and in vivo [23]. Dilute acid solutions can remove the protective surface layer of mucus in the bladder [24] and increase exfoliation of bladder mucosal cells [25]. An antiseptic bladder washout containing chlorhexidine produced only minor and temporary effects on P. mirabilis infections in vitro [17]. A prospective, randomized controlled trial showed that chlorhexidine washouts produced no significant reduction in bacteriuria and resulted in an alteration in the microbial flora, with the tendency for P. mirabilis to become the predominant organism, which is counterproductive. An increased risk of infection accompanies frequent breaking of the closed drainage system and bacteraemia may be facilitated by bacterial invasion as a result of chemical cystitis or mechanical damage [26]. The use of antimicrobial agents to prevent urinary infection in the presence of a urethral catheter is controversial. Even when long-term low-dose antimicrobials were administered, bacterial growth could be identified in 76% of patients. The bacterial biofilm protects the organism from antimicrobial agents, and thus treatment of patients with indwelling catheters can be very difficult. Long-term anti-microbial treatment of patients with indwelling catheters should be avoided in order to prevent antibiotic resistance acquired by the permeation of a low dose of an anti-microbial across the bacterial biofilm [27]. Pre-catheterization anti-microbial prophylaxis is useful but only provides protection for 3 4 days. To reduce the incidence of infection, aseptic insertion and maintenance of a closed urinary drainage system play a significant role but do not eliminate the risk, which increases with each additional day of urethral catheterization. Ideally, infected patients should be separated from uninfected patients to prevent cross-contamination, and patients who can perform clean intermittent self-catheterization should be taught the technique instead of having a long-term indwelling catheter. Further scientific research is required to prevent crisis management, which has been the current practice, and to move on to well-informed, planned strategies derived from improved knowledge of this multifactorial phenomenon. More work is required in this field, which has received little attention in the past and together with a co-ordinated multidisciplinary approach and adequate resources, the problem, which is responsible for reducing the quality of life in the affected patients and an unacceptably high complication rate with spiralling management costs, may yet be solved. References [1] Mulhall AB, Chapman RG, Crow RA. Bacteriuria during indwelling urethral catheterisation. J Hosp Infect 1988;11: [2] Slade N, Gillespie WA. The urinary tract and the catheter: infection and other problems. Chichester: Wiley, 1985: [3] Kohler-Ockmore J, Feneley RCL. Long-term catheterisation of the bladder: prevalence and morbidity. Br J Urol 1996;77: [4] Getliffe K. Catheter blockage in community patients. Nurs times 1990;5:33 6. [5] Kunin CM. Care of the urinary catheter. In: Detection, prevention and management of urinary tract infections, 4th ed. Philadelphia: Lea and Ferbiger, 1987:5 6. [6] Sassoon E, Abercrombie F, Goodrum P. The permanent indwelling catheter: a domiciliary survey. Health trends 1991;23: [7] Getliffe KA. The characteristics and management of patients with recurrent blockage of long-term urinary catheters. J Adv Nurs 1994;20: [8] Langley SEM, Fry CH. The influence of ph on urinary ionized [Ca 2+ ]: differences between urinary tract stone formers and normal subjects. Br J Urol 1997;79:8 14. [9] Costerton JW, Lappin-Scott HM. Behaviour of bacteria in biofilms. ASM News 1989;55: [10] Cox AJ. Comparison of catheter surface morphologies. Br J Urol 1990;65: [11] Sugarman B. Adherence of bacteria to urinary catheters. Urol Res 1982;10: [12] Merritt K, Chang CC. Factors influencing bacterial adherence to biomaterials. J Biomater Appl 1991;5: [13] Nickel JC, Oslen M, McLean RJC, Grant SK, Costerton JW. An ecological study of infected stone genesis in an animal model. Br J Urol 1987;59: [14] Ramsay JWA, Garnham AJ, Mulhall AB, Crow RA, Bryan JM, Eardley I, et al. Biofilms, bacteria and bladder catheters. A clinical study. Br J Urol 1989;64: [15] Cools HJM, Van Der Meer JWM. Restriction of long-term urethral catheterization in the elderly. Br J Urol 1986;58: [16] MacFarlane DE. Prevention and treatment of urinary tract infections. J Infect 1985;10: [17] Stickler DJ, Clayton CL, Chawla JC. The resistance of urinary tract pathogens to chlorhexidine bladder washouts. J Hosp Infect 1987;10:2838. [18] Norberg B, Norberg A, Parkhede U. The spontaneous variation in catheter life in long stay geriatric patients with indwelling catheters. Gerontology 1983;29: [19] Kunin CM. Blockage of urinary catheters. The role of micro-organisms and constituents of urine on the formation of encrustations. J Clin Epidemiol 1989;42: [20]Griffith DP, Gleeson MJ, Lee H, Longuet R, Deman E, Earle N. Randomized double-blind trial of Lithostat (acetohydramic acid) in the palliative treatment of infection-induced urinary calculi. Eur Urol 1991;20:243 7.

6 310 S. Choong et al. / International Journal of Antimicrobial Agents 17 (2001) [21] Hesse A, Nolde A, Klump B, Marklein G, Tuschewitzki GJ. In vitro investigations into the formation and dissolution of infection-induced catheter encrustations. Br J Urol 1992;70: [22] McLean RJC, Lawrence J, Korber D, Caldwell DE. Proteus mirabilis protection against struvite dissolution and its implications in struvite urolithiasis. J Urol 1991;146: [23] Kennedy AP, Brocklehurst JC, Robinson JM, Faraghar EB. Assessment of the use of bladder washouts/instillations in patients with long-term indwelling catheters. Br J Urol 1992;70: [24] Parsons CL, Mulholland SG, Anwar H. Antibacterial activity of bladder surface mucin duplicated by exogenous glycosaminoglycan (Heparin). Infect Immunol 1979;25: [25] Elliott TSJ, Reid L, Gopal Rao G, Rigby RC, Woodhouse K. Bladder irrigation or irritation. Br J Urol 1989;64: [26] Getliffe KA, Mulhall AB. The encrustation of indwelling catheters. Br J Urol 1991;67: [27] Schaeffer AJ. Urinary tract infections and sexually transmitted diseases. Editorial review. Curr Opin Urol 1993;3: Questions and answers Dr. Reid. What is the ph at the interface of the material and the urine? We do not know the effect of different materials on the ph of urine. Could you use a functional food, such as cranberry juice, vitamin C, etc., that might acidify the urine more in these patients, and reduce the chances of encrustation? Dr. Choong. There are two approaches to this problem. One is to shift the ph to a more acidic level with vitamin C and cranberry juice. The other is to determine what are the factors that would promote precipitation in the urine. Dr. Smith. Do you have any idea why ammonia, phosphate or other chemicals that may be in the individuals, tend to precipitate at lower ph? Dr. Choong. We collected urine samples for all these patients, catheter blockers and non-blockers, and looked at the various constituents: sodium, potassium, citrate, proteins, calcium phosphate. There were no significant differences between the groups, which was surprising. It is disturbing that we do not know the composition of urine and the various mediators or modifiers of crystallization and those that inhibit and enhance crystal formation. Until we know this basic problem, we will not be able to modify the situation. We could modify the biomaterial factors. We could re-design devices, such as catheters. The urethral catheter leads to a significant amount of residual urine, and pooling of urine in the bladder enhances bacterial growth in the bladder. We can attack the biofilm formation, that we now understand how it is formed, by preventing the adhesion of the protein layer on the biomaterial layer the first step to bacterial adhesion. We can also look for ways to inhibit bacterial adhesion on the protein layer..