Suppression and Treatment of Urinary Tract Infection in Patients with an Intermittently Catheterized Neurogenic Bladder

0022-534 7/87 /1382-0336$02.00/0 Vol. 138, August

THE JOURNAL OF UROLOGY

Copyright© 1987 by The Williams & Wilkins Co.

Printed in U.S.A.

SUPPRESSION AND TREATMENT OF URINARY TRACT INFECTION IN PATIENTS WITH AN INTERMITTENTLY CATHETERIZED NEUROGENIC BLADDER JAMES L. MOHLER,* DAVID L. COWEN

AND

ROBERT C. FLANIGANt

From the Department of Surgery, Division of Urology and Department of Rehabilitation Medicine, University of Kentucky Medical Center, Lexington, Kentucky

ABSTRACT

We evaluated the optimal means of prevention and treatment of urinary tract infections in 46 patients with an intermittently catheterized neurogenic bladder. Suppression with nightly 160 mg. trimethoprim and 800 mg. sulfamethoxazole compared to placebo showed no difference in the rate of symptomatic or total urinary tract infections. Symptomatic urinary tract infections occurred at the same rate whether routine asymptomatic infections were treated or not. Three-day antibiotic treatment of urinary tract infections showed no decrease in the frequency of symptomatic or total urinary tract infections compared to 10-day therapy. The frequency of post-treatment urinary tract infection persistence, relapse and cure was identical in both groups. Suppressive antibiotics, treatment of asymptomatic urinary tract infections and full course antibiotic therapy offered no advantage over placebo, treatment of symptomatic urinary tract infection only and short course therapy in the management of urinary tract infection in patients with an intermittently catheterized neurogenic bladder. J. Ural., 138: 336-340, 1987 Intermittent catheterization has revolutionized the care of patients with spinal cord injury or disease and neurogenic bladders. 1• 2 The risk of urinary tract infection is reduced by the absence of a chronic indwelling catheter and the periodic elim ination of residual urine, However, with each catheterization bacteria may be introduced into the urinary tract. In the noninstitutional setting clean intermittent catheterization constitutes a minimal risk, since introduction of bacteria of the normal flora from the skin and distal urethra rarely produces serious infection. 3 In an institutional setting the more pathogenic and antibiotic resistant members of the skin flora of staff and patients may be eliminated by the maintenance of sterility during catheterization. Breaks in sterile technique as well as the inability to prevent introduction of distal urethral bacteria during catheterization subject the patient with a neurogenic bladder to a high risk of urinary tract infection. In fact, acute and chronic urinary tract infection occurs in the majority of spinal cord injured patients treated with intermittent catheterization during initial institutionalization for rehabilitation. 4 ' 5 The frequency of urinary tract infection warrants the selection of optimal methods of suppression and treatment. The use of suppressive antibiotics, long-term therapy for urinary tract infection and treatment of asymptomatic urinary tract infection increase antibiotic exposure without demonstrated benefit in the reduction of symptomatic urinary tract infection or treatment expense. Short-term therapy of urinary tract infection, omission of antimicrobial suppression and nontreatment of asymptomatic urinary tract infections decrease initial antibiotic exposure but may result in an increased incidence of serious urinary tract infections. We report a prospectively randomized study of the prophylaxis and treatment of urinary tract infections in patients with a neurogenic bladder Accepted for publication February 12, 1987. Read at annual meeting of American Urological Association, New York, New York, May 18-22, 1986. * Requests for reprints: Division of Urology, University of North Carolina, Burnett-Womack Clinical Sciences Bldg.-229 H, Chapel Hill, North Carolina 27514. t Current address: Department of Urology, Loyola University Medical Center, 2160 S. First Ave., Maywood, Illinois 60153. 336

managed by intermittent catheterization. In addition, prophylaxis was evaluated in a double-blinded fashion. The 3 principal questions of investigation were: 1) did prophylactic antibiotics affect the incidence of asymptomatic and/or complicated urinary tract infections, 2) did treatment of asymptomatic urinary tract infections affect the frequency of complicated urinary tract infections and 3) was a 10-day course of antibiotics more efficacious than a 3-day course. MATERIALS AND METHODS

All adult patients admitted to the spinal cord injury service of the Cardinal Hill Hospital, a private rehabilitation facility affiliated with the University of Kentucky Medical Center, were considered for evaluation. Patients with anticipated stays of greater than 30 days who were managed at admission to the facility by intermittent catheterization or in whom intermittent catheterization appeared to be the management of choice were approached by a research nurse clinician and a principal investigator. Informed consents were obtained from 4 7 of 58 patients admitted to the facility from November 1, 1982 to February 1, 1985. All patients had a complete history and physical examination, instruction in the technique of intermittent catheterization, education regarding the importance of urinary tract management in the prevention of chronic renal failure, and a radiographic and laboratory baseline evaluation. Particularly noteworthy were patient age, type of injury or disease, interval since onset, functional cord level, method of urinary tract management at admission to the facility and any urological history. Each patient was questioned carefully in regard to sensation of bladder fullness, sensation during voiding, hesitancy, urgency, incontinence, enuresis, decreased stream, incomplete voiding, dysuria, hematuria, nocturia, frequency, dysreflexia, erections, ejaculation and bowel function. Physical examination assessed anal tone and sensation, bulbocavernosus reflex, and muscular tone, sensation and deep tendon reflexes in the upper and lower extremities. A post-void residual and urine culture were obtained. Laboratory evaluation consisted of blood urea nitrogen (BUN), creatinine and 24-hour urine collection for creatinine clearance measurement. When indi-

URINARY TRACT INFECTION MANAGEMENT IN INTERMITTENTLY CATHETERIZED PATIENTS

cated cystoscopy, excretory urography, voiding cystourethrography, cystometry and electromyography were performed. Patients were assigned through use of a random number table to treatment groups for antimicrobial suppression. They received nightly either a tablet containing 160 mg. trimethoprim and 800 mg. sulfamethoxazole or an identical placebo.* Patients then were randomized into 2 urinary tract infection treatment groups: group 1-urinary tract infections treated whether they were asymptomatic or complicated and group 2only complicated urinary tract infections treated. A complicated urinary tract infection consisted of a positive urine culture in a patient with temperature greater than 38C, white blood count greater than 10,000, symptoms or signs of urinary tract infection and no other apparent source of infection. An asymptomatic urinary tract infection consisted of a positive urine culture in a patient without any of the aforementioned findings. Urine culture was considered positive when 10,000 organisms of a single or predominant species per cc of urine were found in a catheterized specimen, when 10,000 organisms , of a single or predominant species per cc of urine were found in a clean-catch specimen obtained in a male patient with suspected complicated urinary tract infection or when 100,000 organisms of a single or predominant species per cc of urine were found in a clean -catch urine specimen in an asymptomatic male patient. All cultures in female patients, whether symptomatic or not, were obtained by sterile catheterization. All urine cultures were performed by the dip slide technique 6 and if positive, antibiotic susceptibility testing was performed by the Vitekt system. 7 Organism identification was limited to genus and often species. More sophisticated typing by subgroups, antibiograms and biochemical markers was not performed. The third and final random group assignment defined the length of treatment for urinary tract infection. Patients were randomized to receive either 3 or 10 days of antibiotic. When symptoms or signs of urinary tract infection were recognized or if a patient had been assigned previously to the asymptomatic infection treated group 160 mg. trimethoprim and 800 mg. sulfamethoxazole were given twice daily (when a urine culture was positive). If the infecting organism was sensitive to trimethoprim-sulfamethoxazole the 3 or 10-day course was completed. If the organism was resistant, the most appropriate antibiotic was chosen by the attending physician, approved by a principal investigator and administered for 3 or 10 days. If the urine culture failed to reveal infection when performed for symptoms or signs of infection, antibiotics were discontinued. All patients had a urine culture obtained on admission to Cardinal Hill Hospital. Entrance into the study was delayed until urinary tract sterility was achieved. At that point suppression with antibiotic or placebo was initiated and urine cultures were obtained routinely every 14 days. Urine culture was performed 4 and 14 days after completion of a course of antibiotic therapy. If both cultures were negative the patient was returned to routine monitoring. If a urine culture was positive 4 days after completion of therapy with the same organism, a persistent infection had occurred and was attributed to failure of the antibiotic to eradicate the initial infection. Regardless of the randomized duration of treatment, a 10-day course of antibiotic was administered and cultures were repeated. If 4 days after treatment the urine culture yielded a different organism, rein fection had occurred. The reinfection then was treated with an additional course of antibiotics according to the group of ran domization. If the 4-day followup urine culture was negative the initial infection was considered to be eradicated. A positive urine culture at 14 days represented relapse if the infecting organism was the same as the initial urinary pathogen and a reinfection if the infecting organism was different. Again, relapse infections resulted in a 10-day course of antibiotic regard* Burroughs

Wellcome, Research Triangle Park, North Carolina.

t Vitek, St. Louis, Missouri.

337

less of the randomization group. Reinfection was treated according to the initial randomization. When a patient suffered symptoms or signs of urinary tract infection a urinary tract infection report was completed. The temperature and white blood count, if obtained, were recorded. The nurse recorded any observed changes in the color, odor and solid content of the urine, and increases in frequency of urination or leakage of urine. If the patient complained .of frequency, dysuria, urgency or a change in the color, odor or solid content of the urine, urine culture was obtained and the observations were recorded. All febrile patients were evaluated by physicians for nonurinary sources of infection. All urine culture results were reviewed and antibiotic treatments were approved by a principal investigator. The urological management of the neurogenic bladder was supervised by a principal investigator. Adherence to the treatment protocol was assured by biweekly review of patient care and all report forms by a nurse clinician. One patient was eliminated from the study owing to a protocol violation (extended antibiotic administration) that was not prevented by our safeguards and, thus, 46 patients were evaluable. Foley catheters were removed, if present, at hospitalization and all patients were managed by sterile intermittent catheterization. Intermittent catheterization was initiated at a frequency of every 4 hours and the urinary tract was sterilized. All patients received 1 or 2 gm. ascorbic acid 4 times daily as required to maintain a urinary pH of less than or equal to 6.0. The frequency of intermittent catheterization was reduced to 4 times daily and fluid intake was adjusted to achieve a catheterized volume of 1,600 to 2,000 cc per day. Anticholinergic medications were used as required to eliminate leakage between catheterizations. The characteristics of the 46 patients studied were described by means. Standard deviations were not reported owing to nonnormal distribution. The predictive value and incidence of fever, leukocytosis, and symptoms and signs of urinary tract infection were assessed by chi-square analysis. The outcome of asymptomatic urinary tract infections that were treated was compared to those that were not treated. The relative merits of antimicrobial suppression and alternative forms of treatment of urinary tract infection were compared by examining infection rates. For each patient the period of risk terminated when he was discharged from the Cardinal Hill Hospital, at which time urine was cultured. Risk began at different times for each of the randomly assigned groups. For evaluation of antibiotic suppression risk began at initiation of suppression after sterile urine was obtained. For consideration of the value of treatment of all versus only complicated urinary tract infections risk began as soon as a positive urine culture was obtained regardless of whether the culture was routine or initiated owing to signs or symptoms of infection. Finally, the period of risk for urinary tract infection when evaluating 3 versus 10-day courses of antibiotic therapy began with the initiation of antibiotic treatment. Therefore, patients randomized to group 2 may have had 1 or more asymptomatic infections before receiving antibiotics for a complicated infection, which began the risk period for consideration of the relative merits of different durations of antibiotic treatment. For each patient the number of days at risk for each of the 3 random group assignments, and the number of asymptomatic and complicated infections that occurred during each of these periods were computed and treated as a Poisson variable. 8 The infection rates per 100 risk days were summed across the patients assigned to the same treatments of each of these categories and combination of treatments and categories. The maximum likelihood approach9 was used to construct a likelihood ratio test of the null hypothesis that the infection rates between competing treatments or competing combinations of treatments were equal versus the research hypothesis that at least 2 of the infection rates being compared were

338

MOHLER, COWEN AND FLANIGAN

unequal. This test statistic considers the fact that different patients on the same treatment have different periods of risk for that treatment. A large sample approximation to the critical region of the likelihood ratio test statistic was given by chisquare distribution, and the degrees of freedom for the chisquare were 1 less than the number of infection rates compared. For each comparison the chi-square value was calculated and its corresponding p value was reported. In addition, a power analysis evaluated the sample size required to prevent concluding that no difference existed between infection rates when, in fact, there was a true difference (type II error). The characteristics of the patients with regard to age, injury type, history of urinary tract infection, disease, surgery, functional cord level and bladder management at hospitalization were compared by chi-square analysis. The BUN, creatinine, creatinine clearance and duration of neurogenic bladder were compared by Mann-Whitney or Wilcoxon rank sum analysis. All comparisons were performed to ensure that groups established by randomization did not differ significantly by age, sex, injury type or duration, urological history or renal function. RESULTS

There were 36 men and 10 women (mean patient age 35. 7 years) who completed the study. At hospitalization 35 patients were managed by intermittent catheterization. Of the remaining patients 3 voided on their own but they were incontinent and required condom catheter drainage, 5 had an indwelling Foley catheter placed at injury 7, 15, 28, 42 and 56 days before removal and initiation of intermittent catheterization, and 3 voided freely, were incontinent and had no urological bladder management. There were 37 patients with no history of urinary tract infection, 6 had 1 infection and 2 had 2 prior uncomplicated urinary tract infections. A 50-year-old woman with multiple sclerosis had had recurrent simple urinary tract infections since marriage. A 39-year-old man with multiple sclerosis had been followed for stable asymptomatic bilateral urolithiasis without urinary tract infection for 10 years by a urologist. No other patients had a history of urological disease or urological operations. Four patients had received chronic suppressive antibiotics and 3 had received pharmacological manipulation of the bladder detrusor (cholinergic agents 2 and anticholinergic agent 1). In 14 patients functional cord levels were cervical, including 12 complete quadriplegics and 1 incomplete quadriplegic owing to traumatic injury. The remaining patient had nearly complete idiopathic cervical myelopathy. There were 5 patients with high thoracic (Tl to T6), 13 with low thoracic (T6 to T12) and 9 with lumbar cord functional levels. These patients suffered traumatic injury resulting in complete paraplegia in 18 and incomplete paraplegia in 5, or degenerative cord diseases owing to multiple sclerosis in 4, Guillain-Barre syndrome in 1 and cauda equina lesions in 4. Mean BUN was 13. 7 mg./100 cc, creatinine 0.94 mg./100 cc and creatinine clearance 89.6 cc. per minute. These 46 patients completed an average of 56.1 days of hospitalization and 36 were hospitalized for greater than 30 days. For suppression 25 patients were randomized to receive placebo and 21 patients received trimethoprim-sulfamethoxazole. For urinary tract infection treatment 27 patients were randomized to receive treatment only for complicated urinary tract infection, whereas 19 patients received treatment for asymptomatic as well as complicated urinary tract infection. Lastly, 28 patients received 3-day courses of antibiotic therapy for urinary tract infection, while 18 patients received 10-day courses. The distribution of patients between groups was the same by type and duration of spinal cord injury or disease, functional cord level, renal function, history and frequency of urinary tract infection before study entry, sex and age (chisquare, Mann-Whitney or Wilcoxon rank sum p >0.05). In addition, the distribution of patients within each suppression

group is identical with regard to treatment and antibiotic duration groups (chi-square p >0.05). The same is true of the intergroup distributions with regard to treatment and antibiotic duration groups. Table 1 summarizes the days at risk, number of infections and infection rates (urinary tract infection per 100 days) for each treatment considered alone. Although there is no significant difference between competing treatments, the possibility that statistically significant but opposing effects could occur between treatment groups at the second or third treatment level cannot be excluded. Therefore, table 2 summarizes the days at risk and infection rates for all 3 treatment factors considered simultaneously and compares the infection rates among competing treatment combinations. When compared to placebo, 800 mg. sulfamethoxazole and 160 mg. trimethoprim showed no statistically significant difference in the rate of symptomatic, asymptomatic or total urinary tract infections in 2,173 days at risk. In the placebo group symptomatic infections occurred with a frequency of 1.86 per 100 patient days in the placebo group. This rate exceeded the 1.11 infections per 100 patient days in those who received suppressive antibiotics but it was not statistically significant (chi-square p = 0.15). Treatment of asymptomatic urinary tract infections failed to reduce the rate of symptomatic or asymptomatic infection when compared to treatment of complicated infections alone. To evaluate further treatment of asymptomatic infections, the outcome of treated and untreated asymptomatic infections was compared. Of 29 patients with antibiotic-treated asymptomatic urinary tract infections symptomatic urinary tract infection developed in 10 (34 per cent) after a mean interval of 29.8 days. If the asymptomatic infection was not treated symptomatic urinary tract infection developed in 6 of 12 cases (50 per cent) after a mean of 17.7 days. Of the untreated infections 5 of 12 resolved spontaneously. In fact, among the patients with TABLE 1. Days at risk, infections and infection rates for each treatment and statistical comparison of the infection rates between competing treatments

Treatment

Days at Risk

No. Pts.

Placebo Antibiotics P value Complicated infections All infections P value 3-day therapy 10-day therapy Pvalue

25 21

1,180 993

21 15

886 672

21 14

814 584

No. Infections of Each Type (infection rate) Symptomatic

Asymptomatic

Totals

22 (1.86) 11(1.11) 0.15 13 (1.47) 9 (1.34) 0.83 11 (1.35) 8 (1.37) 0.98

26 (2.20) 25 (2.52) 0.63 12 (1.35) 14 (2.08) 0.27 18 (2.21) 7 (1.20) 0.15

48 (4.06) 36 (3.02) 0.60 25 (2.82) 23 (3.42) 0.50 29 (3.56) 15 (2.57) 0.30

P values for chi-square statistic were based on 1 degree of freedom. TABLE 2. Days at risk, infections and infection rates for all 6 treatments considered simultaneously and statistical comparison of the infection rates among competing treatment combinations

Treatment

Placebo/complicated 3-day Placebo/complicated 10-day Placebo/all 3-day Placebo/all 10-day Antibiotics/complicated 3-day Antibiotics/complicated 10-day Antibiotics/all 3-day Antibiotics/all 10-day P value (based on 6 degrees of freedom)

No. Pts.

Days at Risk

No. Infections of Each Type (infection rate) Sympto- Asymptomatic matic

Totals

6 7 5 3 4

218 335 210 85 99

3 (1.38) 6 (1.79) 4 (1.90) 1(1.18) 1 (1.01)

4 4 5 0 1

(1.83) (1.19) (2.38) (0.00) (1.01)

7 (3.21) 10 (2.99) 9 (4.29) 1(1.18) 2 (2.02)

4

164

1 (0.60)

3 (1.82)

4 (2.44)

6 0

287 0

3 (1.05) 0(-) 0.92

8 (2.79) 0(-) 0.55

11 (3.83) 0(-) 0.77

URINARY TRACT INFECTION tliANAGEMENT IN INTERMITTENTLY CATHETERIZED PATIENTS

urinary tract infections who received neither treatment nor antibiotic suppression 4 of 7 urinary tract infections resolved spontaneously with no antibiotic therapy of any kind. Among the 7 µ"""'""o in whom asymptomatic untreated urinary tract infections failed to resolve spontaneously 6 progressed to symptomatic urinary tract infection. The remaining patient was discharged from the hospital 12 days after initial culture with asymptomatic but persistent urinary tract infection as indicated by discharge culture. There was no difference in the infection rates between patients who received 3 or 10-day antibiotic treatment for urinary tract infections. Although the infection rates subsequent to 3 or 10-day treatment of urinary tract infections were equivalent, the incidence of development of antibiotic resistance and infection persistence or relapse and reinfection may have differed. Antibiotic courses were delivered to 58 patients with urinary tract infection, including 3-day courses in 29 and 10-day courses in 29. The distribution of complicated and asymptomatic infections was statistically the same between both groups (table 3). All patients were treated preferentially with trimethoprimsulfamethoxazole. In each group 15 patients received this agent, while 14 required different antibiotics owing to resistance to trimethoprim-sulfamethoxazole or infection with an organism not commonly susceptible to that agent. Among the 3-day treatment group 3 microorganisms developed antibiotic resistance. In 1 case each Escherichia coli and Klebsiella pneumoniae became resistant during therapy with trimethoprim-sulfamethoxazole. Cultures obtained 4 days after completion of therapy demonstrated persistent infection that had become resistant to trimethoprim-sulfamethoxazole. In 1 patient with a coagulasenegative staphylococcal infection penicillin resistance developed upon infection relapse 14 days after completion of treatment. No patient in the 10-day treatment group had antibiotic resistance. Urinary tract infection cure defined by sterile cultures at 4 and 14 days occurred in a similar proportion of treatments. The incidence of persistent and relapse infection as well as urinary tract reinfection also was similar. The similarity of outcome of 3 and 10-day antibiotic treatment groups was not biased by an unequal distribution of urinary tract pathogens. Of the 3-day treatment cases infection was owing to E. coli in 9, Klebsiella in 9, coagulase-negative staphylococci in 4, Proteus in 3, Enterobacter in 3, gammastreptococci in 2, Pseudomonas in 1 and Serratia in 1. Of the 10-day treatment cases infection was owing to Klebsiella in 14, E. coli in 9, gamma-streptococci in 3, enterococci in 2, Enterobacter in 2, Pseudomonas in Serratia in 1 and coagulasenegative staphylococci in l. In groups recurrent infections were dominated E. coli and Klebsiella. The difference in the infection rates in the versus trimethoprim-sulfamethoxazole suppression groups most closely ownw,~'''°''·" statistical significance, The chance of detecting a true difference as as 1.86 infections per 100 days for placebo and l.lJ infections per 100 days for trimethoprimsulfamethoxazole with the size of our study was approximately 33 per cent. To obtain an 80 per cent chance of detecting a true p,c,~~~~

TABLE

3. Outcome of 3 versus JO-day treatment of urinary tract

infection Urinary tract infections treated: Complicated Asymptomatic Totals Antibiotic: Trimethoprim-sulfamethoxazole Other Antibiotic resistance developed Treated urinary tract infections followed by: Cure Persistence Relapse Reinfection

3-Day

10-Day

12

16

17

13

29

29

15 14 3

lo 14

20

18 5 3 8

5 2 11

0

339

difference of this uw, 5 u,,c,,uc, would require a study of 3.5 times the number of patients with similar hospital stays. Recognition of significant differences in infection rates from other single treatment comparisons as well as simultaneous treatments would require even larger studies to prevent type II statistical errors. During our study 175 routine urine cultures were performed, of which 56 (32 per cent) were positive. Of 40 cultures performed for signs or symptoms that suggested complicated urinary tract infection 32 (80 per cent) were positive, which is significantly greater than the rate of positivity when routine cultures are performed (chi-square p <0.001). Of these 40 suspected complicated infections urinary tract infection report forms were completed in 31 cases. Whether the urine culture was obtained at the instigation of the patient or caretaker, the culture positivity was the same (85 versus 83 per cent). In only 2 instances were actual symptoms of infection reported by the patient. Owing to the sensory denervation associated with spinal cord injury and diseases in this population, the patients were sensitive to the same signs as the caretaker. Changes in urine color, odor and solid content were responsible for 92 per cent of the urine cultures obtained. Owing to the high prevalence of infection among patients with signs of urinary tract infection, no single sign had a statistically significant predictive value of urine culture positivity or negativity. DISCUSSION

The use of intermittent catheterization for management of the low pressure and incompletely emptying neurogenic bladder has been well established. However, the optimal means of prevention and treatment of urinary tract infection in this patient population are unclear. Methods of urinary tract infection prevention may be grouped into 2 categories. The oral administration of antimicrobials includes antibiotics and agents that become bactericidal when excreted into acid urine. Alternatively, bactericidal substances may be introduced directly into the bladder at the termination of catheterization. Duffy and Smith compared 200 mg. nitrofurantoin macrocrystals to placebo in a double-blind cross-over study in an outpatient setting. 10 The incidence of bacteriuria was lower during antibiotic prophylaxis. However, during the 6-month study period complicated urinary tract infections were too rare to draw any conclusions regarding the relative merit of suppressive antibiotics in diminishing the frequency of complicated urinary tract infections. Only 4 urinary tract infections occurred in the antibiotic suppression group and, therefore, no conclusions should have been drawn concerning the emergence of antimicrobial resistance. When urine was acidified properly, oral methenamine mandelate achieved bactericidal levels in the urine in patients with a noninstrnmented neurogenic bladder.n The m~intenance of a uniformly acidic urine is difficult even in an inpatient setting thus, the usefulness of methenamine mandelate in suppressing or preventing bacteriuria has been questioned. 12 The efficacy of catheter instillation of neomycin polymyxin irrigant was reported in an uncontrolled study, which stimulated an evaluation of the combination of oral methenamine and catheter instilled hemiacidrin. 13 In a randomized prospective study patients who received methenamine and hemiacidrin treatment had lower rates of bacteriuria as well as clinical urinary tract infection. 14 Our over-all infection rate of 3.8 infections per 100 patient days compares with the study of Maynard and Diokno. 15 They found a significant reduction in the over-all infection rate but no difference in the clinical infection rate between patients receiving 80 mg. trimethoprim and 400 mg. sulfamethoxazole versus controls in a prospectively randomized but unblinded study. In our study there was no difference in the incidence of asymptomatic, complicated or total urinary tract infections in patients receiving 160 mg. trimethoprim and 800 mg. sulfa-

340

MOHLER, COWEN AND FLANIGAN

methoxazole daily versus placebo. We sought to establish whether treatment of asymptomatic urinary tract infections altered the frequency of complicated urinary tract infections. Again, we found no difference in the rate of symptomatic, asymptomatic or total urinary tract infections in the 2 treatment groups. Maynard and Diokno also found that the infection rates did not differ when asymptomatic urinary tract infections were treated or observed. 15 Additionally, we evaluated the outcome of asymptomatic urinary tract infections and half of all untreated asymptomatic infections resolved spontaneously. Unfortunately, all untreated infections that failed to resolve during a followup of more than 2 weeks progressed to symptomatic urinary tract infections. Thus, if asymptomatic infections are treated the over-all incidence of infection in a large population will be unaltered. The development of symptomatic urinary tract infections will be prevented 50 per cent of the time at a cost of unnecessary antibiotic exposure to the remaining 50 per cent of the patients. The morbidity of allowing complicated urinary tract infection to develop by withholding antibiotic therapy of asymptomatic infection is unclear. In our study morbidity from complicated urinary tract infection was minimal. No patient required emergency care for pyelonephritis or urinary sepsis. To our knowledge no one has evaluated the efficacy of short course antibiotic therapy in patients with an intermittently catheterized neurogenic bladder. The efficacy of short-term antibiotic therapy in women with uncomplicated urinary tract infection has been well established. 16 Extension of short course antibiotic therapy to patients with an intermittently catheterized neurogenic bladder seems warranted owing to the relative frequency of urinary tract infection and the relative paucity of complicated urinary tract infection. We found no difference in the rate of asymptomatic, complicated or total urinary tract infections in patients who received 3 or 10-day courses of antibiotics. In fact, the incidence of cure, infection persistence and relapse virtually was identical in both groups. Surprisingly, among persistent and relapse infections antibiotic resistance developed only in the 3-day treatment group. The institution of our study had several effects upon the care of patients with a neurogenic bladder at Cardinal Hill Hospital. Adoption of an inexpensive oral antimicrobial as first line therapy in all cases of suspected or treated documented urinary tract infection decreased pharmaceutical costs (data not shown). The antimicrobial flora of the institution as a whole changed from a pattern of frequent and multiple antibiotic resistance to one of more uniform susceptibility. This occurred at the expense of a slightly increased resistance to trimethoprim-sulfamethoxazole. However, antimicrobial susceptibility remained relatively constant during the latter 1½ years of the study (data not shown). In addition, the value of patient or caretaker signs of urinary tract infection was recognized. The 80 per cent positivity of urine cultures obtained upon clinical suspicion of infection contrasted with the 32 per cent incidence of infection in routinely collected urine specimens. Confidence in the predictive value of signs of infection resulted in earlier administration of antimicrobials without awaiting results of urine culture and sensitivity. Thus, in the institution as a whole antibiotic use changed to permit more frequent use of a single

agent and earlier institution of therapy. In summary, suppressive antibiotics, treatment of asymptomatic urinary tract infection and full course antibiotic therapy offer no advantage over placebo, treatment of only symptomatic urinary tract infection and short course therapy in the management of urinary tract infection in patients with an intermittently catheterized neurogenic bladder. In an institutional setting decreased antibiotic use should reduce expense as well as prevent the development of polymicrobial resistance. The staff and Ms. Janet C. Schwartz of Cardinal Hill Hospital assisted in the performance of this complicated protocol, and Dr. Richard J. Kryscio, Department of Statistics, University of Kentucky, provided statistical expertise. REFERENCES 1. Guttmann, L.: Initial treatment of traumatic paraplegia. Proc. Roy. Soc. Med., 47: 1103, 1954. 2. Guttmann, L. and Frankel, H.: The value of intermittent catheterization in the early management of traumatic paraplegia and tetraplegia. Paraplegia, 4: 63, 1966. , 3. Lapides, J., Diokno, A. C., Silber, S. J. and L