Urinary tract infection in patients with neurogenic bladder dysfunction

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1 International Journal of Antimicrobial Agents 19 (2002) 592/597 Urinary tract infection in patients with neurogenic bladder dysfunction D. Sauerwein * Department of Neuro/Urology, Werner Wicker Klinik, Im Kreuzfeld 4, D Bad Wildungen, Germany Abstract Recurrent urinary tract infections (UTI) are a significant problem in all patients with neurogenic bladder leading to high morbidity, poor quality of life and a limited life expectancy. For the diagnosis of UTI, a urine specimen taken by bladder puncture or catheterization is required. In patients with neurogenic bladders, clinical symptoms and leukocyturia must be present together with bacteriuria in order to qualify as UTI. The spectrum of pathogens differs significantly from that in patients with normal bladder function. Culture and antimicrobial susceptibility testing must, therefore, be performed prior to the initiation of antibiotic therapy. This is also important in the prevention of the emergence of antimicrobial resistance. The main way to prevent recurrent UTI in the neurogenic bladder is by restoring the normal low-pressure reservoir function of the bladder and is the aim of neuro/ urological management. # 2002 Elsevier Science B.V. and International Society of Chemotherapy. All rights reserved. Keywords: UTI in neurogenic bladder; Spinal injury 1. Introduction Chronic or recurrent urinary tract infections (UTI) pose a significant risk to all patients with neurogenic bladder. The high morbidity of these patients means frequent hospitalization which lead to significant costs. Furthermore, the higher average length of hospital stay of these patients compared with other urological patients, in itself creates an additional risk of nosocomial urinary tract infection [1]. Recurrent UTI increase the risk for the development of renal insufficiency, especially in patients with high bladder pressure in the storage phase. Before 1945, 80% of patients with acquired paraplegia died of renal failure secondary to urological problems. After the introduction of antibiotics, the life expectancy increased. In 1967, patients with traumatic paraplegia who survived the first year lived for an average of 7.8 years post accident. These days, these patients have a much increased life expectancy and better quality of life partly due to improved diagnostic tools such as video-urodynamics and the knowledge of the control mechanisms of the * Corresponding author. Tel.: / ; fax: / address: sauerwein@uni-greifswald.de (D. Sauerwein). urinary tract. On empirical grounds, the restoration of a normal bladder storage function directly reduces the frequency of recurrent UTIs. Microbiological diagnostics are used to select the appropriate antibiotic therapy or prophylaxis in patients with neurogenic bladder and recurrent UTIs. 2. Neuro/urological causes of the recurrent UTI in patients with neurogenic bladder dysfunction The unstable storage function and uncoordinated emptying are a high risk for infection. Most patients with neurogenic voiding dysfunction are not able to empty their bladder via the urethra in one or two streams. Therefore, the physiological cleansing of the urethra by bladder emptying does not take place. Even in normal subjects without bladder dysfunction, the outer parts of the distal urethra are colonized with bacterial species of the skin of the perineum, labia or penis. Hamamci et al. [2] studied the bacterial colonization in 50 paraplegic patients (27 males, 23 females). They compared the microbiological findings in urine specimens with specimens taken from the skin of the perineum, the labia, and the penis. Identical coloniza /02/$ - see front matter # 2002 Elsevier Science B.V. and International Society of Chemotherapy. All rights reserved. PII: S ( 0 2 )

2 D. Sauerwein / International Journal of Antimicrobial Agents 19 (2002) 592/ tion was found significantly more frequently in females compared with males. The study revealed no relationship between the level of the neurological injury or the mode of bladder management and the presence or the distribution of the bacterial species. In a study involving 151 spinal cord injury patients, Moser et al. [3] detected a significant relationship between the time after injury and the presence of antibodies against urinary tract pathogens, such as Escherichia coli, Proteus mirabilis and Pseudomonas aeruginosa. 3. Symptoms indicative for UTI in patients with neurogenic bladder dysfunction In patients without bladder function disorders, the symptoms that correlated with UTI have been well defined. Frequency and dysuria suggest the presence of UTI. In many patients with neurogenic bladder dysfunction, the classic symptoms of UTI are absent due to the underlying neurological changes, which includes sensory deficits. Bakke and Malt [4] followed patients who performed intermittent self-catheterization over a period of 7 years and found that the typical symptoms of UTI correlate to psycho /social conditions rather than bacteriuria. Therefore, the telltale pain during micturition is frequently not present. Specific symptoms like frequency and worsened incontinence are caused by autonomic factors. Sweating, fatigue or restlessness, increased somatomotor spasticity, decreased heart rate and increased blood pressure (the latter only in paralysed patients) should initiate a leukocyte count of the urine. If leukocyturia of greater than /ml is found, a microbiological investigation of the catheterized or bladder puncture urine is indicated. 4. Urine sampling in patients with neurogenic bladder dysfunction In patients with bladder function disorders, a specimen collected by catching a mid-stream urine in males or by straight catheterization in females usually allows identification of the pathogen. Typically, a mid-stream urine cannot be obtained since there is no normal voiding of large quantities of urine in these patients. Consequently, in a urine specimen obtained by spontaneous voiding, 2 /4 different bacterial species are frequently isolated. Bladder puncture urine or urine collected by (self) catheterization must, therefore, be used for diagnosis. 5. Leukocyturia and bacteriuria Sauerwein et al. [5 /7] showed that bacteriuria is only indicative for UTI in combination with leukocyturia. Consequently, the following criteria for the presence of UTI were established: i) Leukocyturia of B/ /ml without clinical symptoms is not indicative for UTI. Action: no antibiotic therapy; watchful waiting; urine culture not necessary. ii) Leukocyturia of / /ml without clinical symptoms justifies the suspicion of UTI. A bladder aspirate (bladder puncture urine sample) or catheterized urine should be obtained for culture. Action: no blind antibiotic therapy; urine culture indicated. iii) Leukocyturia of B/ /ml and bacteriuria of B/ /ml in bladder puncture urine without clinical symptoms excludes the presence of UTI. Action: no antibiotic therapy; watchful waiting. iv) Leukocyturia of / /ml and bacteriuria of / /ml in bladder puncture urine even without clinical symptoms proves the presence of UTI. Action: antibiotic therapy according to culture and antimicrobial susceptibility testing; empiric antibiotic therapy only if clinically necessary. v) Leukocyturia of / /ml and and bacteriuria of B/ /ml in bladder puncture urine without clinical symptoms. Action: watchful waiting; repeat urinalysis and urine culture. 6. Number of pathogens per UTI-episode Between 1983 and 1988, uropathogens cultured from the urine of paraplegic patients with bacteriuria and leukocyturia of more than /ml were analysed. On average, 1.3 pathogens per urine specimen were found (Table 1). Bacteriuria and leukocyturia above /ml are the basis for the diagnosis of a UTI requiring therapy. Table 1 Number of UTI episodes and strains isolated from urine of patients with bladder dysfunction 1983/1988 Year UTI */ Episodes Number of pathogens Pathogens per urine sample

3 594 D. Sauerwein / International Journal of Antimicrobial Agents 19 (2002) 592/597 Considering the high number of false-positive findings, if based on bacteriuria alone, the rationale of combining the criteria of significant bacteriuria with pyuria, helps to avoid unnecessary use of antibiotics. This rationale also has important consequences in preventing the development of resistance. If, however, clinical symptoms are present or in cases of increased autonomic dysreflexia, antibiotic therapy is indicated despite the definitions above. 7. The spectrum of uropathogens in patients with neurogenic bladder dysfunction American as well as European Guidelines [8,9] recognize predisposing factors such as use of indwelling catheters, intermittent catheterization, post-void residual urine above 100 ml, obstructive uropathy, vesico / ureteral reflux, ileum or colon augmentation or renal transplantation for the differentiation between complicated and uncomplicated UTI. Kumazawa et al. [10] reported a different spectrum of uropathogens involved in complicated and uncomplicated UTI including cystitis and pyelonephritis. The authors also noted that the spectrum of pathogens found in patients with neurogenic bladder dysfunction differs considerably from that of patients with UTI with other urological conditions. For 10 years (1988 /1997) the spectrum and antimicrobial resistance of various pathogens cultured from the urine of patients with neurogenic bladder were recorded in our institution. Thirty-seven thousand bacterial strains were isolated from catheterized urine specimens or from bladder aspirates. Fig. 1 shows the distribution of the uropathogens. E. coli and enterococci are the most frequently cultured species. Only a marginal fluctuation is detected in the distribution over the years. A change is seen in E. coli from 20 to 25% and in Klebsiella spp. from 7 to 12%. The presence of Staphylococcus epidermidis seemed to coincide with suprapubic drainage. Obviously, it is not possible to predict the bacterial species causing UTI associated with neurogenic bladder. 8. Susceptibility pattern of uropathogens We also continuously monitored the bacterial resistance pattern. Over the 10 year period, 8339 isolates of E. coli were studied. In 1988, nearly all isolates of E. coli were susceptible to ciprofloxacin. The effectiveness of the quinolones, especially in infections caused by Gramnegative species has generally led to their widespread use and this has promoted a steady development of resistance. In 1997, only 77% of the E. coli isolates were susceptible to ciprofloxacin (Fig. 2). Nitrofurantoin was frequently used for the prophylaxis of recurrent UTI caused by E. coli. Subsequently, the rate of susceptibility decreased from 92% in 1988, at the beginning of our study, to 72% in Nitrofurantoin should, therefore, not be considered for therapy any more, but can still be used for prophylaxis against E. coli infections. We analyzed 5011 strains of P. aeruginosa. During the study the susceptibility of the isolates for ciprofloxacin decreased to 50%. The susceptibility of 2877 isolates of Enterobacter spp. to ciprofloxacin was similar to P. aeruginosa. The susceptibility has reduced to below 50%. During the period, cefmenoxime, ceftazidime, amikacin and imipenem were kept as reserve antibiotics and the physician requesting culture and susceptibility was not informed of the results of susceptibility of these compounds. The information was given only when there were no other antibiotics suitable for treatment. This restrictive policy translated into maintaining the susceptibility of E. coli for these antibiotics, as can be seen in Fig. 2. There was also no change of the resistance pattern observed for the reserve antibiotics (data not shown) with Pseudomonas spp. (ceftazidime, imipenem), Kleb- Fig. 1. Distribution of uropathogens from patients with neurogenic bladder dysfunction during 1988/1997. Fig. 2. Resistance pattern of 8339 E. coli isolates from patients with neurogenic bladder dysfunction during 1988/1997.

4 D. Sauerwein / International Journal of Antimicrobial Agents 19 (2002) 592/ siella spp. (imipenem, amikacin) and Enterobacter spp. (imipenem, amikacin). 9. Antibiotic policy in patients with UTI secondary to neurogenic bladder dysfunction In patients with neurogenic bladder dysfunction the predisposition for UTI cannot be relieved completely. Therefore, one has always to suspect a UTI. On the other hand, the susceptibility pattern of uropathogens is dependent on the antibiotic policy. In order to counteract the emergence of resistance and to have treatment options available, it is helpful to restrict the use of certain antibiotics for specific pathogens. These reserve antibiotics would then be available for the treatment of serious infections only. The results of this long-term study with uropathogens of patients with neurogenic bladder dysfunction show that the identity of the causative organism cannot easily be assumed. Species-specific therapy is also difficult if the result of susceptibility testing of the individual isolate is not known. Therefore, any empirical antibacterial therapy may fail and could eventually lead to the emergence of resistant pathogens. On the other hand, these epidemiological data may be helpful for anticipating the resistance pattern if antibiotic therapy must be initiated before the results of susceptibility testing are available. 10. Results of the treatment of the recurrent UTI by the restoration of the reservoir function of the lower urinary tract During childhood, the neurologically normal lower urinary tract matures to provide a low pressure reservoir system for more than 90% of the time. Fig. 3 shows the functional elements of the lower urinary tract with the parasympathic and somatomotor control centre at the lowest part of the spinal cord, the reflex connections to the sympathic system at the levels of T11 to L2, the micturition centre in the diencephalon and the supratentorial centres of the cortex. In a urodynamic study, the normal control of the reservoir function is termed stable bladder. If the complex control system of the lower urinary tract is impaired by trauma or diseases, incontinence and recurrent UTI are the typical result. The so-called high pressure bladder poses the highest risk. If untreated, and combined with recurrent UTI, it will lead to the destruction of the urinary tract. Therefore, predisposing factors of this condition must be identified and treated accordingly. The following two clinical examples demonstrate that normalization of the low pressure storage function of the bladder will lead to lower rates of urinary tract infection. 11. Surgical treatment of the spastic bladder by intervention at the level of the control system In the spinal cord injury above the level of the conus medullari, the cessation of the pontine inhibition leads to the development of the spastic bladder. Clinically, high pressures exist in the bladder both during the storage and the emptying phases. In the urodynamic study, a detrusor-sphincter-dys-synergy is diagnosed. In surgical intervention, the sensory part of the spinal reflex loop is interrupted by means of sacral deafferentation (SDAF). In the same setting, the motor part of the reflex loop is connected to a sacral anterior root stimulator (SARS) enabling the activation of the detrusor muscle. For the storage phase of the bladder, the low-pressure reservoir is restored, while the emptying is re-subjugated to the patient and occurs without autonomic dysreflexia such as in sweating and hypertensive crisis. In successfully treated patients the rate of recurrent UTI episodes decreased significantly (Table 2). Table 2 Effect of SDAF in 352 patients with neurogenic bladder dysfunction (follow up period 1986/1999) on UTI episodes, continence, bladder capacity and renal function Clinical findings before and after SDAF Preoperative Postoperative Fig. 3. Neurological control centres of the lower urinary tract. Continence (% of patients) 0% 87% UTI per year (n) Bladder capacity (ml) Renal function (% of normal) 65% 78%

5 596 D. Sauerwein / International Journal of Antimicrobial Agents 19 (2002) 592/ Surgical treatment of the structurally fixed low compliance bladder If left untreated or insufficiently treated, the highpressure bladder may be destroyed by fibrotic changes of the musculature. Consequently, surgical intervention at the level of the control system of the bladder is ineffective in this case. In order to obtain a low-pressure storage reservoir, the bladder is resected above the trigone and substituted with an ileum and/or colon graft. The augmented bladder is emptied by intermittent catheterization. In successfully treated patients the rate of recurrent UTI episodes decreased significantly (Table 3). 13. Prophylaxis in patients with neurogenic bladder dysfunction Even with optimal management, the neurogenic bladder dysfunction poses an increased risk for the development of UTI. The type of disorder and degree of the damage to the urinary tract determine whether an antibiotic prophylaxis is indicated or not. The type of prophylaxis is determined by the pathogen that causes the UTI in the individual patient. If found suitable, nitrofurantoin may be used at a low dose (50/100 mg per day). In addition, acidification of the urine must be achieved [11]. This is possible with l-methionine, or methenaminohippurate. If by means of medical therapy or operation the physiological bladder capacity reaches 500 ml, antibiotic prophylaxis is not necessary. Up to 30% of the patients with neurogenic bladder dysfunction must resort to intermittent self-catheterization. As a rule, at the initial management, antibiotic prophylaxis is indicated. After 1 year and with a UTI rate of no more than 1 per year, prophylaxis may be discontinued. An increase in the UTI rate makes it necessary to re-evaluate the type of neuro-urological condition. Table 3 Effect of bladder augmentation in 71 patients with neurogenic bladder dysfunction (follow up period 1989/2000) on UTI episodes, continence, bladder capacity and renal function Clinical findings before and after bladder augmentation Preoperative Continence (% of patients) 0% 85% UTI per year (n) 6 2 Capacity (ml) Renal function (% of normal) 61% 71% Postoperative 14. Conclusions Recurrent UTI in conjunction with unbalanced urodynamics leads to high morbidity, poor quality of life and reduced life expectancy. The diagnosis of UTI in patients with neurogenic bladder dysfunction is reliable only if catheterized urine or bladder aspirate is used. Bacteriuria, even at CFU/ml or more but without clinical symptoms is not indicative for the presence of a UTI in patients with neurogenic bladder dysfunction. Only bacteriuria concurrent with leukocyturia of / /ml are reliable signs. Antibiotic therapy is indicated in these cases. The spectrum of uropathogens in patients with neurogenic bladder disorders differs from that in other patient groups and therefore, blind antibiotic therapy is not warranted. The knowledge of the susceptibility of the causative organism is important for effective treatment of the individual patient. Restrictive management of antibiotic therapy contributes to controlling the emergence of resistant pathogens. The presence of recurrent UTI makes reconsideration of the neuro /urological management necessary. The restoration of a normal reservoir function of the bladder is the prime requisite for the lasting treatment of recurrent UTIs in patients with neurogenic bladder dysfunction. References [1] Pittet D, Harbarth S, Ruef C, et al. Prevalence and risk factors for nosocomial infections in four university hospitals in Switzerland. Infect Control Hosp Epidemiol 1999;20:37 /42. [2] Hamamci N, Dursun E, Akbas E, Aktepe OC, Cake A. 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