Treatment of Urinary Tract Infections in Persons with Spinal Cord Injury: A Review John Z. Montgomerie, MB, ChB, FRACP University of California School of Medicine, Los Angeles, CA, and Department of Medicine, Infectious Disease Division, Rancho Los Amigos Medical Center, Downey, CA Despite improvements in the techniques to drain the urinary bladder in patients with spinal cord injury (SCI), urinary tract infection (UTI) remains one of the most common complications of SCI. Despite many studies of the management of UTIs, differences of opinion remain. This has resulted from the use of different definitions of UTI, including the definitions of ''significant'' bacteriuria, "asymptomatic" bacteriuria, the inclusion (or exclusion) of ''soft'' symptoms, evidence of few complications from the infection and other risks of infection. The need to treat patients with high fever who may have bacteremia and patients with symptoms is clear. Broad coverage may be necessary until the results of culture are available because of the frequent presence of resistant bacteria colonizing the perineum or bowel. Eradication of bacteriuria is not a reasonable goal in many patients with indwelling catheters. The treatment of patients with asymptomatic bacteriuria (those patients without symptoms or pyuria) remains controversial. Asymptomatic bacteriuria is often treated in recently injured inpatients and those that have their first infection and is not treated in persons in whom asymptomatic bacteriuria is detected more than one year following the injury. Selection of the antibiotics depends on the symptoms of UTI, but at the risk of developing colonization of the urinary tract, perineum, or bowel with resistant gram-negative bacilli. Keywords: Urinary tract infection (UTI); treatment; spinal cord injury (SCI); antibiotics and
prophylaxis
Urinary tract infections (UTIs) are well established as a common complication responsible for morbidity and some mortality in spinal cord injury (SCI) patients. 1-3 This complication may retard the rehabilitation process and increase the cost of medical care. UrIs are a recurrent problem for most individuals with SCI throughout their lives and may also lead to serious complications, such as pyelonephritis, bacteremia, calculi, and renal failure.
GENERAL PRINCIPLES Definitions The definition of bacteriuria and UTI outlined in the NIDRR Consensus Statement (see Table 1) are used in this review. 4 The significance oflow counts
of bacteria in the urine ( < 105/mL) was discussed by Dr. Gribble in Chapter 1. 4 More controversial is the use of "soft" symptoms-increased spasticity, autonomic hyperreflexia, cloudy urine or increased odor, malaise or lethargy-as symptoms of infection in the absence offever or other significant symptoms and signs of infection. This will be discussed later.
Host Reduced bladder emptying and increased residual urine are the important host factors leading to UTIs. 5 Improved techniques of bladder emptying resulted in decreased UTI and their complications. In 1966, Guttman and Frankel showed sterile intermittent catheterization was a major improvement over indwelling urethral catheters NeuroRehabil1994; 4(4):214-221 Copyright © 1994 by Butterworth-Heinemann
UTI in Persons with Spinal Cord Injury
in the management of patients with SCI. 6 The use of drugs and surgical procedures to aid bladder emptying have also been important in the control of UTIs. Intermittent catheterization, however, still has its problems because there is a risk of introduction of bacteria through the process of catheterization. Other host factors that influence the treatment ofUTIs in SCI involve the method of drainage of the bladder in these patients.
1. Indwelling, urethral, and suprapubic catheters are associated with calculi and multiple organisms. Antimicrobial agents rarely eradicate microorganisms in the presence of the catheter or other foreign bodies. 2. Intermittent catheterization is associated with an increased incidence of bacteriuria and is influenced by the frequency of catheterization. As the time interval between catheterization increases, the incidence of bacteriuria increases. 3. Urinary diversion, such as ileal conduits and Koch pouches, are also associated with bactenuna. 4. Patients with SCI who void reflexly without catheterization often have residual urine volumes greater than that of normal subjects. 5. The presence of external or condom catheters alters colonization of urethra and perineal skin.
MICROORGANISMS Many different microorganisms have been isolated from patients with SCI and UTIs. Studies of UTIs from different SCI centers have suggested a Table 1.
Definitions.
• Urinary tract infection is bacteriuria with tissue invasion and resultant tissue response with signs and/or symptoms. • Asymptomatic bacteriuria represents colonization of the urinary tract with no references to symptoms or signs. Source: National Institute on Disability and Rehabilitation Research (NIDRR) Consensus Statement: The prevention and management of urinary tract infections. January, 1992.
215
wide range of microorganisms with different bacteria predominating at different centers. The reason for this is unclear. Research in recent years examined colonization of the patient for specific organisms which may be responsible for the infections. 7- 11 Organisms causing UTI probably reflect bacteria colonizing the perineal skin of these patients. A series of studies examined colonization of the body with two bacteria frequendy isolated from UTIs in the SCI Unit at Rancho Los Amigos Medical Center. A high colonization rate with PseudortWnas aeruginosa and Klebsklla pneumoniae, which reside in the perineum, urethra, and bowel flora has been demonstrated. This colonization has been associated with the use of external urinary catheter systems. We have been unable to alter this colonization with the use of increased bathing, antiperspirants, or antiseptics to clean the skin. 12 ,13 In a study of colonization of the patients at Casa Colina, another spinal cord injury unit in Los Angeles County, we were unable to demonstrate any differences in the colonization rates. 14 The predominant microorganisms causing UTIs in patients with SCI have been E. coli, Pseudomonas, Klebsiella, and Enterococcus sp. Vaziri et al. (1982) who examined bacterial infections in SCI patients with chronic renal failure 15 found a high prevalence of Proteus sp. that may relate to the frequent use of indwelling catheters. Klebsiella, Pseudomonas, and Proteus sp. tend to be more resistant than E. coli to commonly used antibiotics-ampicillin and trimethoprim-sulfamethoxazole (SXT). Outbreaks of infection with multiresistant gram-negative bacilli have been described relatively infrequendy in SCI units. 16 Some centers have used oral prophylactic antimicrobial therapy to prevent infections 17 ,18 or antibiotic solutions, such as neomycin, placed in the bladder after intermittent catheterization. Both prophylactic antibiotics and instillation of antibiotics into the bladder at the time ofintermittent catheterization have reduced the number of incidents of significant bacteriuria and seem to have changed the type of bacteria isolated from these patients, so gram-negative bacilli may be replaced with gram-positive organisms, such as Enterococcus sp. and Staphylococcus epidermidis. 19- 21
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NEUROREHABILI11\TION / OCTOBER 1994
Are some microorganisms more or less virulent for patients with SCI? The presence of bacteria that are urease producers has raised concerns about calculus formation or alkaline encrusting cystitis. The possibility that some E. coli strains are more or less virulent than other strains has not been established for patients with SCI. Antibiotic susceptibility testing is important. Continued treatment of microorganisms that are resistant to the agent used has not been shown to be of benefit.
GOALS The main goals of treatment are to eradicate the infection and prevent complications of infection. The main complications of infection have been pyelonephritis and renal calculi in the upperurinary tract and bladder calculi, chronic cystitis, bladder mucosal changes, fibrosis with loss of bladder function 22 and epididymitis in the lowerurinary tract. Possible effects at the ureteral vesical junction may also occur. Bacteremia may result from infections in the upper- and lower-urinary tract. In some patients, for example, those with indwelling catheters and patients with calculi, eradication of the infecting organism is not a reasonable goal and these patients should be treated to relieve symptoms.
DIAGNOSIS During rehabilitation and at the time of routine visits to clinics, the urine cultures are usually monitored. Because of the lack of sensation in most persons with SCI, the presence of symptoms, urgency, abdominal and loin pain are usually absent. UTI may be associated with soft symptoms (headache, increased spasms, autonomic hyperreflexia), but the significance of these symptoms has not been established. If symptoms of UTI develop, verification of the diagnosis by urine culture is important. Blood cultures should be obtained if patients have a high fever. Localization of the
infection and exclusion of obstruction and other factors that might influence response to treatment is important.
INDICATIONS FOR TREATMENT Treatment of asymptomatic bacteriuria has been controversial. 23-25 Mohler et al. 24 suggested that treatment of asymptomatic UTIs offered no advantage over placebo. When asymptomatic bacteriuria was treated, symptomatic infections developed in 10 out of29 (34%) patients after a mean interval of 29.8 days. When asymptomatic infections were observed, 6 out of 12 cases (50%) developed symptomatic infection after a mean of 17.7 days. These results were similar to an earlier study23 and the policy of many spinal units has been to treat patients only when symptoms appear-this usually means the presence of fever. Others have used pyuria or C-reactive protein 26 as an indication for treatment in patients with asymptomatic bacteriuria. Symptoms are limited in patients with SCI because of the lack of sensation. Pyuria is variable and a poor indication of tissue invasion in this group of patients. 27 Some studies have raised concerns about the presence of urea splitting bacteria such as Proteus sp., which may be used as an indication for treatment. 28 Renal localization has been a criterion for the treatment of urinary tract infection in some groups of patients, but localization has been difficult in SCI. 29 Although some studies have shown no advantage to the treatment of asymptomatic bacteriuria in patients with SCI over the short term, there have been no adequate studies over the long term. A low frequency of upper-tract problems has been reported in long-term follow-up studies of patients managed with intermittent catheterization 23 ,30-32 or voiding reflexly without catheterization. 33 Complications have been more frequent in the lower urinary tracts than the upper tract. 30 These complications included cystolithiasis (18%) and hospitalization for symptomatic UTIs (30%). In the hope of preventing these complications, many units (including our own at Rancho Los Amigos Medical Center) routinely treat
UTI in Persons with Spinal Cord Injury
inpatients on the basis of bacteriuria in significant numbers (> I05/m L urine) or lesser number of bacteria in successive cultures. 19 Treatment of asymptomatic bacteriuria may have prevented these complications over three years in one study. 34 Many SCI units differentiate asymptomatic bacteriuria in recently injured inpatients and those who have their first infection 35 from patients in whom asymptomatic bacteriuria is detected more than one year following injury-treating the former, not the latter. The rate of persistent infection or relapse after treatment is high in patients who are seen more than one year after their injury and retreatment may lead to the development of resistant pathogens. This may happen in the absence of obvious cause, such as calculi or an indwelling catheter. Thus, the failure of therapy of asymptomatic bacteriuria in this group of patients may be used as a contraindication to further treatment.
SELECTION OF AGENT Because the bacteria causing UTI in SCI patients tend to be resistant to antibiotics, in vitro testing of the bacteria is important before starting therapy. If the patient has a high fever and leucocytosis, broad coverage with antibiotics is important until antibiotic susceptibility testing is known. For the patient who may have bacteremia, treatment has frequently been aminoglycosides and ampicillin. If there is concern about renal function, aminoglycosides may be replaced by a third generation cephalosporin or quinoline.
Chemotherapeutic Agents Although a wide variety of drugs are available for the treatment of UTIs, the effectiveness of the agent will depend on the susceptibility of the microorganisms and concentrations of this agent at the infected site. Oral beta lactams, ampicillin, amoxicillin, amoxicillinlclavulanate, carbenicillin, oral cephalosporins and SXT are effective agents, but patients with SCI are colonized and infected with many bacteria resistant to these agents. The
217
quinolines are effective against many bacteria resistant to other antibiotics including aminoglycosides, however, there can also be resistance to these agents. Parenteral therapy with third generation cephalosporins has been useful because of their broad activity against gram-negative bacilli, but these agents are not active against Enterococcus sp. The parenteral penicillin agents (carbenicillin, ticarcillin, and piperacillin) may be more useful than third generation cephalosporins because they are effective against enterococci with or without the beta-Iactamase inhibitors. Although aminoglycosides have been the gold standard in the treatment ofUTIs, there has been an increasing reluctance to use these agents in patients with SCI because of potential nephrotoxicity. There is also evidence oflack of effectiveness when used alone in patients with pseudomonas UTIs in patients Witll SCI. In a clinical study of patients with SCI, we found that UTIs responded poorly to aminoglycosides when used alone. 36 Further studies have supported this observation, particularly for infections with Pseudomonas aeruginosa. 37 This is surprising because aminoglycosides have been well accepted as one of the most effective therapies for UTI with gram negative bacilli. The reason for the failure of SCI patients to respond to aminoglycosides despite in vitro susceptibility is not clear. The patients in these studies did not have significant structural abnormalities other than increased residual volume, which should not selectively influence the effectiveness of aminoglycosides. Other concerns have been raised about the use of aminoglycosides with SCI. The volume of distribution is decreased 38 in patients with SCI which may result in low blood levels. An oral agent to which the bacteria has been susceptible (usually carbenicillin) for ten days, combined with aminoglycosides for the first five days, has been an effective therapy for Pseudomonas infectionsY In recent years, ciprofloxacin has been advocated for bacteriuria in patients with SCI. In a study of 11 patients (6 months to 28 years after injury) treated with 250 mg twice a day for six days, there was a 50% relapse rate at four weeks. 39 Unfortunately, resistance of enterococci, pseudomonas, E. coli
218
NEUROREHABILITATION / OCTOBER 1994
to ciprofloxacin and other quinolines has been observed with increased use of this agent.
RESPONSE TO TREATMENT The improvement in clinical symptoms (fever, etc.) and clearing of pyuria, if present, may be used as an indication of improvement in the infection if they were present at the onset. If there is concern about the response of a patient to treatment, a repeat culture of the urine at 1-3 days should be negative if the patient is responding to treatment. Bacteriologic response to treatment is usually described as a cure ifbacteria are cleared from the urine and the urine remains free of bacteria after a specified time. Reinfection has been defined as the development of bacteriuria with a new organism. Persistent infection or relapse has been defined as the persistence or relapse of the bacteriuria with the same microorganism cultured before treatment. Persistence or relapse has been the main indication of failure of a particular antibiotic. Relapse may be a reinfection with the same bacteria and this may be a particular problem in patients with SCI because the skin of the perineum and urethra may be heavily colonized.
DURATION OF THERAPY Short courses of antibiotics (5-14 days) have usually been recommended for patients with UTIs and SCI. 25,34,40 Duration of therapy may be determined by the type of infection. Infections with abscess formation-intrarenal, perinephric, or scrotal-will require surgical drainage and longer courses of antibiotics. Prostatitis is usually treated for four weeks. Infections with persistence of an organism in the urine (failure of 10 days of treatment) may be associated with other urinary tract abnormalities. In a number of studies of recently injured patients using a range of different antibiotics, treatment for 5-10 days resulted in cures in
44-78%, persistence or relapse in 8-31 % and reinfection in 14-35% when examined 5-9 days after discontinuing treatment. 37 Even shorter courses of antibiotics may be adequate. Mohler et al. 24 compared a three- and ten-day course of antibiotics in the treatment of UTI in SCI (symptomatic and asymptomatic combined). Cures (sterile urine at 14 days after treatment) occurred in 20 out of29 (69%) patients after three days and 18 out of29 (62%) of patients after ten days of treatment. Persistence or relapse was seen in 7 out of 29 (24%) and 8 out of 29 (28%) of patients, respectively. The treatment of patients who are seen more than one year after SCI has not been well studied. Even in patients without catheters or intermittent catheters, persistent infections and relapse are more frequent than in the recently injured. Whether courses of treatment longer than 14 days would benefit this group of patients is unclear.
PROPHYLAXIS Because of the high rate of reinfection in patients with SCI, studies have examined the use of chemoprophylaxis to prevent urine infections. 24,41.42 The use of chemotherapy in the prevention of UTIs has been difficult because UTIs may be caused by a large number of organisms with a wide range of antibiotic susceptibilities. There have also been problems with the urine acidifying agents. Krebs et al. studied the effectiveness of oral methenamine and intravesicular acidifying agent for prevention of UTIs and bladder calculus formation during intermittent catheterization. 43 Although the incidence of bacteriuria was halved, there was a 25% incidence of gross hematuria, a complication known also to occur with methenamine alone. The possibility has also been raised that ascorbic acid, an agent frequently used to acidify the urine, may predispose to UTIs in patients with SCI.40 Although, in 1982, Merritt et al. suggested that the use of SXT was an effective, preventive antibiotic for UTIs, there are risks
UTI in Persons with Spinal Cord Injury
in patients in hospital taking this agent. 18 Klebsiella resistant to SXT and multiple antibiotics has been seen following administration of SXT in patients with SCI. 44,45 Nitrofurantoin in SCI patients has not been impressive in the hospital probably because the bacteria colonizing the patients and introduced into the bladder in the hospital are resistant to nitrofurantoin. 19 The existing data are not conclusive. Most studies indicate that prophylaxis reduces the rate of bacteriuria. However, there has been little effect on morbidity or symptomatology and there are always concerns about the development of resistance and side effects from the agents used.
TREATMENT OF INFECTION IN THE PRESENCE OF AN INDWELLING URETHRAL OR SUPRAPUBIC CATHETER Bacteriuria is expected with an indwelling urethral or suprapubic catheters and should be treated only when the patient is symptomatic. The complication of indwelling urethral catheters includes penoscrotal fistula, abscesses, bladder diverticula, acute epididymitis, and bladder calculi. It is important to examine the patient to exclude these complications. The most frequent concern in the patient with an indwelling urethral catheter and fever is associated bacteremia. Because of the risk of bacteremia with high fevers, initial treatment should be with parenteral antibiotics with doses that achieve serum concentrations that are adequate to treat bacteremia. The appropriate duration for parenteral or oral therapy has not been established. Treatment beyond 5-14 days would not seem to be warranted. Because long-term patients with indwelling urethral catheters have been found to have frequently changing urinary flora, routinely culturing the urine from the catheter to predict the bacteria that may be present when bacteremia occurs has not been of benefit.
219
TREATMENT OF PATIENTS WITH INFECTIOUS STONES Infectious stones are commonly associated with urea-splitting bacteria. 46 Treatment of stones with surgery or lithotripsy, urease inhibitors and chemical dissolution with irrigation fluids may control infection. 47 Attention in recent years has focused on acetohydroxamic acid which may prevent the recurrence of stones. 48 Antibiotics with activity against the bacteria isolated from the urine at the time of lithotripsy are recommended to prevent bacteremia and efforts should be made to clear the urine of that organism with a course of antibiotics. There are no studies of antibiotic use after lithotripsy to remove renal calculi or removal of bladder calculi.
SUMMARY In summary, many questions remain in the management of UTIs in patients with SCI. Improved methods are needed to determine the presence of infection, that is, the invasion of tissues. Are some bacteria more virulent than others for patients with SCI? What is the significance of asymptomatic bacteriuria and "soft" symptoms? Further studies are needed to resolve these questions.
REFERENCES l. Anderson JM, Schutt AH. Spinal injury in chil-
dren: A review of 156 cases seen from 1950 through 1978. Mayo Clin Proc 1980; 55:499-504. 2. Khella L, Stoner EK. 101 cases of spinal cord injury: 15-year follow-up study in a large city hospital. Am] Phys Med 1977; 56:21-32. 3. Wilcox NE, Stauffer ES. Follow-up of 423 consecutive patients admitted to the Spinal Cord Center, Rancho Los Amigos Hospital, 1 January to 31 December 1967. Paraplegia 1972; 10:115122. 4. National Institute on Disability and Rehabilitation Research (NIDRR) Consensus Statement. The prevention and management of urinary tract infections among people with spinal cord injuries.] Am Paraplegia Soc 1992; 15(3):194207.
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5. Merritt JL. Residual urine volume: Correlate of urinary tract infection in patients with spinal cord injury. Arch Phys Med Rehabi11981; 62:558-561. 6. Guttmann L, Frankel H. Value of intermittent catheterization in early management of traumatic paraplegia and tetraplegia. Paraplegia 1966; 4:63-84. 7. Fawcett C, ChawlaJC, QuoraishiA, Stickler DJ. A study of the skin flora of spinal cord injured patients.] Hasp Infect 1986; 8:149-158. 8. Gilmore DS, Bruce SK, Jimenez EM, et a!. Pseudomonas aeruginosa colonization in patients with spinal cord injuries.] Clin Microbial 1982; 16:856-860. 9. Montgomerie JZ, Morrow JW Pseudomonas colonization in patients with spinal cord injury. Am ] Epidemiol1978; 108:326-335. 10. Montgomerie JZ, Morrow JW Long-term Pseudomonas colonization in spinal cord injury patients. Am] Epidemiol 1980; 112:508-517. 11. Stickler DJ, 1110mas B, Chawla Je. Antiseptic and antibiotic resistance in gram-negative bacteria causing urinary tract infection in spinal cord injured patients. Paraplegia 1981; 19:50-58. 12. Gilmore DS,Jimenez EM, Aeilts GD, eta!' Effects of bathing on colonization of spinal cord injury patients with Pseudomonas and Klebsiella.] Clin Microbial 1982; 14:404. 13. Gilmore DS, MontgomerieJZ, Graham IE, et a!. Effect of antiseptic agents on skin flora of the perineum of men with spinal cord injury. Infect Control 1984; 5:431-434. 14. Montgomerie .JZ, Madorsky JGB, Gilmore DS, Graham IE. Colonization of patients with spinal cord injury with Pseudomonas aeruginosa and Klebsiella pneumoniae at different institutions. ] Hasp Infect 1987; 10:198-203. 15. Vaziri ND, Cesario T, Mootoo K, et a!. Bacterial infections in patients with chronic renal failure. Arch Intern Med 1982; 142:1273-1276. 16. Simor AE, Ramage L, Wilcox L, et a!. Molecular and epidemiologic study of multiresistant Serratia marcescens infections in a spinal cord i~ury rehabilitation unit. Infect Control Hasp Epidemiol 1988; 9(1):20-27. 17. Lindan R, Joiner E. A prospective study of the efficacy oflow dose nitrofurantoin in preventing urinary tract infections in spinal cord injury patients with comments on the role of pseudomonads. Paraplegia 1984; 22:61-65. 18. Merritt JL, Erickson RP, Opitz JL. Bacteriuria during follow-up in patients with spinal cord injury: I1. Efficacy of antimicrobial suppressants. Arch Phys Med Rehabi11982; 63:413-415. 19. Anderson RU. Prophylaxis of bacteriuria during intermittent catheterization of the acute neurogenic bladder.] Ural 1980; 123:364-366.
20. Pearman JW The value of kanamycin-colistin bladder instillations in reducing bacteriuria during intermittent catheterization of patients with acute spinal cord injury.] Ural 1979; 51:367-374. 21. Rhame FS, Perkash 1. Urinary tract infections occurring in recent spinal cord injury patients on intermittent catheterization. ] Ural 1979; 122:669-673. 22. Tribe CR, Silver JR, eds. Renal failure in paraplegia. London: Pitman Medical Publishing Company,1969. 23. Maynard FM, Diokno Ae. Urinary infection and complications during clean intermittent catheterization following spinal cord injury. ] Ural 1984; 132:943-946. 24. Mohler JL, Cowen DL, Flanigan RC. Suppression and treatment of urinary tract infection in patients with intermittently catheterized neurogenic bladder.] Ural 1987; 138:336-340. 25. Stickler DJ, Chawla.Je. An appraisal of antibiotic policies for urinary tract infections in patients with spinal cord injuries undergoing long-term intermittent catheterization. Paraplegia 1988; 26:215-225. 26. Galloway A, Green HT, Windsor J.J, et a!. Serial concentrations of C-reactive protein as an indicator of urinary tract infection in patients with spinal injury.] Clin Pathol 1986; 39:851-855. 27. Gribble MJ, Puterman ML, McCallum NM. Pyuria: Its relationship to bacteriuria in spinal cord injured patients on intermittent catheterization. Arch Phys Med Rehabill989; 70:376-379. 28. Perkash I, Giroux J. Prevention, treatment and management of urinary tract infection in neuropathic bladders.] Am Paraplegia Soc 1985; 8:1517. 29. Merritt JL, Keys TE Limitations of the antibody coated bacteria test in patients with neurogenic bladders.]AMA 1982; 247:1723-1725. 30. Maynard FM, Glass J. Management of the neuropathic bladder by clean intermittent catheterization: 5 year outcomes. Paraplegia 1987; 25:106-110. 31. McGuire E, Savastano JA Long-term follow-up of spinal cord injured patients managed by intermittent catheterization.] Ural 1983; 123:775-776. 32. Timoney AG, Shaw PJR. Urological outcome in female patients with spinal cord injury: The effectiveness of intermittent catheterization. Paraplegia 1990; 28:556-563. 33. Sotolongo Jr JR, Koleilat N. Significance of asymptomatic bacteriuria in spinal cord injury patients on condom catheter.] Ural 1990; 143:979-980. 34. Pearman JW Urological follow-up of 99 spinal cord injured patients initially managed by intermittent catheterization. Br] Urol 1976; 48:297310.
UTI in Persons with Spinal Cord Injury
35. Stover SL, Lloyd LK, Waites KB, Jackson AB. Urinary tract infection in spinal cord injury. Arch Phys Med Rehabi11989; 70:47-54. 36. Sapico FL, Lindquist LB, Montgomerie JZ, et al. Short-course aminoglycoside therapy in patients with spinal cord injury. Urology 1980; 15:457460. 37. Montgomerie jZ. Advances in the treatment of urinary tract infections with cephalosporins. In: Loose H, Asscher AW, Lison AE, Andriole V'C eds. Pyelonephritis, Vol. V. New York: ThiemeStratton, 1984; 131-135. 38. Segal jL, Gray DR, Gordon SK, et al. Gentamicin disposition kinetics in humans with spinal cord injury: Preliminary report.] Am Paraplegia Soc 1983; 6:41-42. 39. Pedersen SS, Horbov S, Biering-Sorensen F, Hoiby N. Peroral treatment with ciproftoxacin of patients with spinal cord lesion and bacteriuria caused by multiply resistant bacteria. Paraplegia 1990; 28:41-47. 40. Stover SL, Fleming We. Recurrent bacteriuria in complete spinal cord injury patients on external condom drainage. Arch Phys Med Rehabil 1980; 61:178-181. 41. Kevorkian G, Merritt JL, Ilstrup DM. Methenamine mandelate with acidification: An effective urinary antiseptic in patients with neurogenic bladder. Mayo Clin Proc 1984; 59:523-529.
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42. Kuhlemeier KV, Lloyd LK, Stover SL. Prophylactic antibacterial therapy for preventing urinary tract infections in spinal cord i~jury patients.] Ural 1985; 134:514-517. 43. Krebs M, Halvorsen RB, Fishman Ij, SantoMendoza N. Prevention of urinary tract infection during intermittent catheterization.] Urol 1984; 131:82-85. 44. jimenez EM, Schick DG, Canawati HN, Montgomerie jZ. Klebsiella pneumoniae colonization of the bowel associated with the use of trimethoprim-sulfamethoxazole. Eur] Clin Microbial 1982; 1:253-254. 45. Gribble MJ, Puterman ML. Prophylaxis of urinary tract infection in persons with recent spinal cord injury: A prospective, randomized, doubleblind, placebo-controlled study of trimethoprim-sulfamethoxazole.Am] Med 1993; 95:141152. 46. DeVivo MJ, Fine PR, Cutter GR, Maetz HM. The risk of bladder calculi in patients with spinal cord injuries. Arch Intern Med 1985; 145:428-430. 47. Nemoy NJ, Stamey TA. Surgical, bacteriological, and biochemical management of "Infection Stones."]AMA 1971; 215(9):1470. 48. Griffith DP, Moskowitz PA, Carlton CEo Adjuncof infection-induced tive chemotherapy staghorn calculi.] Uro11979; 121:711-715.
prophylaxis
Urinary tract infections (UTIs) are well established as a common complication responsible for morbidity and some mortality in spinal cord injury (SCI) patients. 1-3 This complication may retard the rehabilitation process and increase the cost of medical care. UrIs are a recurrent problem for most individuals with SCI throughout their lives and may also lead to serious complications, such as pyelonephritis, bacteremia, calculi, and renal failure.
GENERAL PRINCIPLES Definitions The definition of bacteriuria and UTI outlined in the NIDRR Consensus Statement (see Table 1) are used in this review. 4 The significance oflow counts
of bacteria in the urine ( < 105/mL) was discussed by Dr. Gribble in Chapter 1. 4 More controversial is the use of "soft" symptoms-increased spasticity, autonomic hyperreflexia, cloudy urine or increased odor, malaise or lethargy-as symptoms of infection in the absence offever or other significant symptoms and signs of infection. This will be discussed later.
Host Reduced bladder emptying and increased residual urine are the important host factors leading to UTIs. 5 Improved techniques of bladder emptying resulted in decreased UTI and their complications. In 1966, Guttman and Frankel showed sterile intermittent catheterization was a major improvement over indwelling urethral catheters NeuroRehabil1994; 4(4):214-221 Copyright © 1994 by Butterworth-Heinemann
UTI in Persons with Spinal Cord Injury
in the management of patients with SCI. 6 The use of drugs and surgical procedures to aid bladder emptying have also been important in the control of UTIs. Intermittent catheterization, however, still has its problems because there is a risk of introduction of bacteria through the process of catheterization. Other host factors that influence the treatment ofUTIs in SCI involve the method of drainage of the bladder in these patients.
1. Indwelling, urethral, and suprapubic catheters are associated with calculi and multiple organisms. Antimicrobial agents rarely eradicate microorganisms in the presence of the catheter or other foreign bodies. 2. Intermittent catheterization is associated with an increased incidence of bacteriuria and is influenced by the frequency of catheterization. As the time interval between catheterization increases, the incidence of bacteriuria increases. 3. Urinary diversion, such as ileal conduits and Koch pouches, are also associated with bactenuna. 4. Patients with SCI who void reflexly without catheterization often have residual urine volumes greater than that of normal subjects. 5. The presence of external or condom catheters alters colonization of urethra and perineal skin.
MICROORGANISMS Many different microorganisms have been isolated from patients with SCI and UTIs. Studies of UTIs from different SCI centers have suggested a Table 1.
Definitions.
• Urinary tract infection is bacteriuria with tissue invasion and resultant tissue response with signs and/or symptoms. • Asymptomatic bacteriuria represents colonization of the urinary tract with no references to symptoms or signs. Source: National Institute on Disability and Rehabilitation Research (NIDRR) Consensus Statement: The prevention and management of urinary tract infections. January, 1992.
215
wide range of microorganisms with different bacteria predominating at different centers. The reason for this is unclear. Research in recent years examined colonization of the patient for specific organisms which may be responsible for the infections. 7- 11 Organisms causing UTI probably reflect bacteria colonizing the perineal skin of these patients. A series of studies examined colonization of the body with two bacteria frequendy isolated from UTIs in the SCI Unit at Rancho Los Amigos Medical Center. A high colonization rate with PseudortWnas aeruginosa and Klebsklla pneumoniae, which reside in the perineum, urethra, and bowel flora has been demonstrated. This colonization has been associated with the use of external urinary catheter systems. We have been unable to alter this colonization with the use of increased bathing, antiperspirants, or antiseptics to clean the skin. 12 ,13 In a study of colonization of the patients at Casa Colina, another spinal cord injury unit in Los Angeles County, we were unable to demonstrate any differences in the colonization rates. 14 The predominant microorganisms causing UTIs in patients with SCI have been E. coli, Pseudomonas, Klebsiella, and Enterococcus sp. Vaziri et al. (1982) who examined bacterial infections in SCI patients with chronic renal failure 15 found a high prevalence of Proteus sp. that may relate to the frequent use of indwelling catheters. Klebsiella, Pseudomonas, and Proteus sp. tend to be more resistant than E. coli to commonly used antibiotics-ampicillin and trimethoprim-sulfamethoxazole (SXT). Outbreaks of infection with multiresistant gram-negative bacilli have been described relatively infrequendy in SCI units. 16 Some centers have used oral prophylactic antimicrobial therapy to prevent infections 17 ,18 or antibiotic solutions, such as neomycin, placed in the bladder after intermittent catheterization. Both prophylactic antibiotics and instillation of antibiotics into the bladder at the time ofintermittent catheterization have reduced the number of incidents of significant bacteriuria and seem to have changed the type of bacteria isolated from these patients, so gram-negative bacilli may be replaced with gram-positive organisms, such as Enterococcus sp. and Staphylococcus epidermidis. 19- 21
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NEUROREHABILI11\TION / OCTOBER 1994
Are some microorganisms more or less virulent for patients with SCI? The presence of bacteria that are urease producers has raised concerns about calculus formation or alkaline encrusting cystitis. The possibility that some E. coli strains are more or less virulent than other strains has not been established for patients with SCI. Antibiotic susceptibility testing is important. Continued treatment of microorganisms that are resistant to the agent used has not been shown to be of benefit.
GOALS The main goals of treatment are to eradicate the infection and prevent complications of infection. The main complications of infection have been pyelonephritis and renal calculi in the upperurinary tract and bladder calculi, chronic cystitis, bladder mucosal changes, fibrosis with loss of bladder function 22 and epididymitis in the lowerurinary tract. Possible effects at the ureteral vesical junction may also occur. Bacteremia may result from infections in the upper- and lower-urinary tract. In some patients, for example, those with indwelling catheters and patients with calculi, eradication of the infecting organism is not a reasonable goal and these patients should be treated to relieve symptoms.
DIAGNOSIS During rehabilitation and at the time of routine visits to clinics, the urine cultures are usually monitored. Because of the lack of sensation in most persons with SCI, the presence of symptoms, urgency, abdominal and loin pain are usually absent. UTI may be associated with soft symptoms (headache, increased spasms, autonomic hyperreflexia), but the significance of these symptoms has not been established. If symptoms of UTI develop, verification of the diagnosis by urine culture is important. Blood cultures should be obtained if patients have a high fever. Localization of the
infection and exclusion of obstruction and other factors that might influence response to treatment is important.
INDICATIONS FOR TREATMENT Treatment of asymptomatic bacteriuria has been controversial. 23-25 Mohler et al. 24 suggested that treatment of asymptomatic UTIs offered no advantage over placebo. When asymptomatic bacteriuria was treated, symptomatic infections developed in 10 out of29 (34%) patients after a mean interval of 29.8 days. When asymptomatic infections were observed, 6 out of 12 cases (50%) developed symptomatic infection after a mean of 17.7 days. These results were similar to an earlier study23 and the policy of many spinal units has been to treat patients only when symptoms appear-this usually means the presence of fever. Others have used pyuria or C-reactive protein 26 as an indication for treatment in patients with asymptomatic bacteriuria. Symptoms are limited in patients with SCI because of the lack of sensation. Pyuria is variable and a poor indication of tissue invasion in this group of patients. 27 Some studies have raised concerns about the presence of urea splitting bacteria such as Proteus sp., which may be used as an indication for treatment. 28 Renal localization has been a criterion for the treatment of urinary tract infection in some groups of patients, but localization has been difficult in SCI. 29 Although some studies have shown no advantage to the treatment of asymptomatic bacteriuria in patients with SCI over the short term, there have been no adequate studies over the long term. A low frequency of upper-tract problems has been reported in long-term follow-up studies of patients managed with intermittent catheterization 23 ,30-32 or voiding reflexly without catheterization. 33 Complications have been more frequent in the lower urinary tracts than the upper tract. 30 These complications included cystolithiasis (18%) and hospitalization for symptomatic UTIs (30%). In the hope of preventing these complications, many units (including our own at Rancho Los Amigos Medical Center) routinely treat
UTI in Persons with Spinal Cord Injury
inpatients on the basis of bacteriuria in significant numbers (> I05/m L urine) or lesser number of bacteria in successive cultures. 19 Treatment of asymptomatic bacteriuria may have prevented these complications over three years in one study. 34 Many SCI units differentiate asymptomatic bacteriuria in recently injured inpatients and those who have their first infection 35 from patients in whom asymptomatic bacteriuria is detected more than one year following injury-treating the former, not the latter. The rate of persistent infection or relapse after treatment is high in patients who are seen more than one year after their injury and retreatment may lead to the development of resistant pathogens. This may happen in the absence of obvious cause, such as calculi or an indwelling catheter. Thus, the failure of therapy of asymptomatic bacteriuria in this group of patients may be used as a contraindication to further treatment.
SELECTION OF AGENT Because the bacteria causing UTI in SCI patients tend to be resistant to antibiotics, in vitro testing of the bacteria is important before starting therapy. If the patient has a high fever and leucocytosis, broad coverage with antibiotics is important until antibiotic susceptibility testing is known. For the patient who may have bacteremia, treatment has frequently been aminoglycosides and ampicillin. If there is concern about renal function, aminoglycosides may be replaced by a third generation cephalosporin or quinoline.
Chemotherapeutic Agents Although a wide variety of drugs are available for the treatment of UTIs, the effectiveness of the agent will depend on the susceptibility of the microorganisms and concentrations of this agent at the infected site. Oral beta lactams, ampicillin, amoxicillin, amoxicillinlclavulanate, carbenicillin, oral cephalosporins and SXT are effective agents, but patients with SCI are colonized and infected with many bacteria resistant to these agents. The
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quinolines are effective against many bacteria resistant to other antibiotics including aminoglycosides, however, there can also be resistance to these agents. Parenteral therapy with third generation cephalosporins has been useful because of their broad activity against gram-negative bacilli, but these agents are not active against Enterococcus sp. The parenteral penicillin agents (carbenicillin, ticarcillin, and piperacillin) may be more useful than third generation cephalosporins because they are effective against enterococci with or without the beta-Iactamase inhibitors. Although aminoglycosides have been the gold standard in the treatment ofUTIs, there has been an increasing reluctance to use these agents in patients with SCI because of potential nephrotoxicity. There is also evidence oflack of effectiveness when used alone in patients with pseudomonas UTIs in patients Witll SCI. In a clinical study of patients with SCI, we found that UTIs responded poorly to aminoglycosides when used alone. 36 Further studies have supported this observation, particularly for infections with Pseudomonas aeruginosa. 37 This is surprising because aminoglycosides have been well accepted as one of the most effective therapies for UTI with gram negative bacilli. The reason for the failure of SCI patients to respond to aminoglycosides despite in vitro susceptibility is not clear. The patients in these studies did not have significant structural abnormalities other than increased residual volume, which should not selectively influence the effectiveness of aminoglycosides. Other concerns have been raised about the use of aminoglycosides with SCI. The volume of distribution is decreased 38 in patients with SCI which may result in low blood levels. An oral agent to which the bacteria has been susceptible (usually carbenicillin) for ten days, combined with aminoglycosides for the first five days, has been an effective therapy for Pseudomonas infectionsY In recent years, ciprofloxacin has been advocated for bacteriuria in patients with SCI. In a study of 11 patients (6 months to 28 years after injury) treated with 250 mg twice a day for six days, there was a 50% relapse rate at four weeks. 39 Unfortunately, resistance of enterococci, pseudomonas, E. coli
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NEUROREHABILITATION / OCTOBER 1994
to ciprofloxacin and other quinolines has been observed with increased use of this agent.
RESPONSE TO TREATMENT The improvement in clinical symptoms (fever, etc.) and clearing of pyuria, if present, may be used as an indication of improvement in the infection if they were present at the onset. If there is concern about the response of a patient to treatment, a repeat culture of the urine at 1-3 days should be negative if the patient is responding to treatment. Bacteriologic response to treatment is usually described as a cure ifbacteria are cleared from the urine and the urine remains free of bacteria after a specified time. Reinfection has been defined as the development of bacteriuria with a new organism. Persistent infection or relapse has been defined as the persistence or relapse of the bacteriuria with the same microorganism cultured before treatment. Persistence or relapse has been the main indication of failure of a particular antibiotic. Relapse may be a reinfection with the same bacteria and this may be a particular problem in patients with SCI because the skin of the perineum and urethra may be heavily colonized.
DURATION OF THERAPY Short courses of antibiotics (5-14 days) have usually been recommended for patients with UTIs and SCI. 25,34,40 Duration of therapy may be determined by the type of infection. Infections with abscess formation-intrarenal, perinephric, or scrotal-will require surgical drainage and longer courses of antibiotics. Prostatitis is usually treated for four weeks. Infections with persistence of an organism in the urine (failure of 10 days of treatment) may be associated with other urinary tract abnormalities. In a number of studies of recently injured patients using a range of different antibiotics, treatment for 5-10 days resulted in cures in
44-78%, persistence or relapse in 8-31 % and reinfection in 14-35% when examined 5-9 days after discontinuing treatment. 37 Even shorter courses of antibiotics may be adequate. Mohler et al. 24 compared a three- and ten-day course of antibiotics in the treatment of UTI in SCI (symptomatic and asymptomatic combined). Cures (sterile urine at 14 days after treatment) occurred in 20 out of29 (69%) patients after three days and 18 out of29 (62%) of patients after ten days of treatment. Persistence or relapse was seen in 7 out of 29 (24%) and 8 out of 29 (28%) of patients, respectively. The treatment of patients who are seen more than one year after SCI has not been well studied. Even in patients without catheters or intermittent catheters, persistent infections and relapse are more frequent than in the recently injured. Whether courses of treatment longer than 14 days would benefit this group of patients is unclear.
PROPHYLAXIS Because of the high rate of reinfection in patients with SCI, studies have examined the use of chemoprophylaxis to prevent urine infections. 24,41.42 The use of chemotherapy in the prevention of UTIs has been difficult because UTIs may be caused by a large number of organisms with a wide range of antibiotic susceptibilities. There have also been problems with the urine acidifying agents. Krebs et al. studied the effectiveness of oral methenamine and intravesicular acidifying agent for prevention of UTIs and bladder calculus formation during intermittent catheterization. 43 Although the incidence of bacteriuria was halved, there was a 25% incidence of gross hematuria, a complication known also to occur with methenamine alone. The possibility has also been raised that ascorbic acid, an agent frequently used to acidify the urine, may predispose to UTIs in patients with SCI.40 Although, in 1982, Merritt et al. suggested that the use of SXT was an effective, preventive antibiotic for UTIs, there are risks
UTI in Persons with Spinal Cord Injury
in patients in hospital taking this agent. 18 Klebsiella resistant to SXT and multiple antibiotics has been seen following administration of SXT in patients with SCI. 44,45 Nitrofurantoin in SCI patients has not been impressive in the hospital probably because the bacteria colonizing the patients and introduced into the bladder in the hospital are resistant to nitrofurantoin. 19 The existing data are not conclusive. Most studies indicate that prophylaxis reduces the rate of bacteriuria. However, there has been little effect on morbidity or symptomatology and there are always concerns about the development of resistance and side effects from the agents used.
TREATMENT OF INFECTION IN THE PRESENCE OF AN INDWELLING URETHRAL OR SUPRAPUBIC CATHETER Bacteriuria is expected with an indwelling urethral or suprapubic catheters and should be treated only when the patient is symptomatic. The complication of indwelling urethral catheters includes penoscrotal fistula, abscesses, bladder diverticula, acute epididymitis, and bladder calculi. It is important to examine the patient to exclude these complications. The most frequent concern in the patient with an indwelling urethral catheter and fever is associated bacteremia. Because of the risk of bacteremia with high fevers, initial treatment should be with parenteral antibiotics with doses that achieve serum concentrations that are adequate to treat bacteremia. The appropriate duration for parenteral or oral therapy has not been established. Treatment beyond 5-14 days would not seem to be warranted. Because long-term patients with indwelling urethral catheters have been found to have frequently changing urinary flora, routinely culturing the urine from the catheter to predict the bacteria that may be present when bacteremia occurs has not been of benefit.
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TREATMENT OF PATIENTS WITH INFECTIOUS STONES Infectious stones are commonly associated with urea-splitting bacteria. 46 Treatment of stones with surgery or lithotripsy, urease inhibitors and chemical dissolution with irrigation fluids may control infection. 47 Attention in recent years has focused on acetohydroxamic acid which may prevent the recurrence of stones. 48 Antibiotics with activity against the bacteria isolated from the urine at the time of lithotripsy are recommended to prevent bacteremia and efforts should be made to clear the urine of that organism with a course of antibiotics. There are no studies of antibiotic use after lithotripsy to remove renal calculi or removal of bladder calculi.
SUMMARY In summary, many questions remain in the management of UTIs in patients with SCI. Improved methods are needed to determine the presence of infection, that is, the invasion of tissues. Are some bacteria more virulent than others for patients with SCI? What is the significance of asymptomatic bacteriuria and "soft" symptoms? Further studies are needed to resolve these questions.
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UTI in Persons with Spinal Cord Injury
35. Stover SL, Lloyd LK, Waites KB, Jackson AB. Urinary tract infection in spinal cord injury. Arch Phys Med Rehabi11989; 70:47-54. 36. Sapico FL, Lindquist LB, Montgomerie JZ, et al. Short-course aminoglycoside therapy in patients with spinal cord injury. Urology 1980; 15:457460. 37. Montgomerie jZ. Advances in the treatment of urinary tract infections with cephalosporins. In: Loose H, Asscher AW, Lison AE, Andriole V'C eds. Pyelonephritis, Vol. V. New York: ThiemeStratton, 1984; 131-135. 38. Segal jL, Gray DR, Gordon SK, et al. Gentamicin disposition kinetics in humans with spinal cord injury: Preliminary report.] Am Paraplegia Soc 1983; 6:41-42. 39. Pedersen SS, Horbov S, Biering-Sorensen F, Hoiby N. Peroral treatment with ciproftoxacin of patients with spinal cord lesion and bacteriuria caused by multiply resistant bacteria. Paraplegia 1990; 28:41-47. 40. Stover SL, Fleming We. Recurrent bacteriuria in complete spinal cord injury patients on external condom drainage. Arch Phys Med Rehabil 1980; 61:178-181. 41. Kevorkian G, Merritt JL, Ilstrup DM. Methenamine mandelate with acidification: An effective urinary antiseptic in patients with neurogenic bladder. Mayo Clin Proc 1984; 59:523-529.
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42. Kuhlemeier KV, Lloyd LK, Stover SL. Prophylactic antibacterial therapy for preventing urinary tract infections in spinal cord i~jury patients.] Ural 1985; 134:514-517. 43. Krebs M, Halvorsen RB, Fishman Ij, SantoMendoza N. Prevention of urinary tract infection during intermittent catheterization.] Urol 1984; 131:82-85. 44. jimenez EM, Schick DG, Canawati HN, Montgomerie jZ. Klebsiella pneumoniae colonization of the bowel associated with the use of trimethoprim-sulfamethoxazole. Eur] Clin Microbial 1982; 1:253-254. 45. Gribble MJ, Puterman ML. Prophylaxis of urinary tract infection in persons with recent spinal cord injury: A prospective, randomized, doubleblind, placebo-controlled study of trimethoprim-sulfamethoxazole.Am] Med 1993; 95:141152. 46. DeVivo MJ, Fine PR, Cutter GR, Maetz HM. The risk of bladder calculi in patients with spinal cord injuries. Arch Intern Med 1985; 145:428-430. 47. Nemoy NJ, Stamey TA. Surgical, bacteriological, and biochemical management of "Infection Stones."]AMA 1971; 215(9):1470. 48. Griffith DP, Moskowitz PA, Carlton CEo Adjuncof infection-induced tive chemotherapy staghorn calculi.] Uro11979; 121:711-715.
