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Short-course aminoglycoside therapy in patients with spinal cord injury Standard dose versus low dose
SHORT-COURSE
AMINOGLYCOSIDE
THERAPY IN
PATIENTS WITH SPINAL CORD INJURY* Standard Dose Versus Low Dose FRANCISCO
L. SAPICO,
LEE B. LINDQUIST,
ENES M. JIMENEZ,
M.D.
JAMES W. MORROW,
M.D.
JOHN Z. MONTGOMERIE,
R.N. M.D.
M.B., CH.B.
From the Departments of Medicine and Surgery, Ranch0 Los Amigos Hospital, Downey, and the University of Southern California School of Medicine, Los Angeles, California
ABSTRACT - Twenty-nine patients with spinal cord injury and asymptomatic urinary tract infection were treated with standard or reduced doses of tobramycin and amikacin. The patients received jive days of intramuscular antibiotics. Most of the patients in the tobramycin groups had Pseudomonas aeruginosa infection and most of those in the amikacin group had either Proteus rettgeri or Providencia stuartii infections. Only 1 patient had a positive urine antibody coating test. High antibiotic concentrations were demonstrated in the urine of all patients during therapy. Urine cultures were obtained two and seven days after completion of therapy. Forty-eight per cent of the patients were cured, while 31 per cent showed persistence or relapse, and 21 per cent had reinfection with other bacteria. No signijcant differences in results were observed between the standard-dose and low-dose regimens and between the amikacin and tobramycin groups. The low success rate of the regimens used may indicate the need to evaluate alternative therapeutic regimens to treat urinary tract infections in this special group of patients.
Tobramycin and amikacin are aminoglycoside antibiotics which have been shown to be effective in the therapy of Gram-negative infections, including urinary tract infections. These agents are particularly useful for infections where multiple prior courses of therapy with different antibiotics have resulted in the emergence of resistant organisms. Since aminoglycosides are concentrated in urine, some studies have suggested that reduction in accepted therapeutic doses or time courses may eradicate infections localized to the urinary bladder. l-5 These alternative therapeutic modalities potentially could reduce the toxicity of these aminoglycosides. Ranch0 Los Amigos Hospital has a large population of patients with spinal cord injury who are subject to recurrent urinary tract infec*This study was supported pany, Indianapolis, Indiana.
UROLOGY
/
in part by Eli Lilly and Com-
MAY1980 / VOLUMEXV,NUMBERS
tions. The presence of neurogenic bladder with significant urine residual volumes as well as the use of intermittent urethral catheterization are believed to be responsible for these infections. Bacteria with multiple drug resistance are common pathogens in this population group, including Pseudomonas aeruginosa, Proteus rettgeri, and Providencia species. We have studied the therapeutic efficacy of five-day courses of tobramycin and amikacin for urinary tract infections caused by these pathogens in spinal cord injury patients and compared the results of low-dose against standard-dose regimens. Material and Methods Twenty-nine patients with spinal cord injury and urinary tract infections due to bacteria resistant tocommonly used antibiotics were ineluded in the study. Informed consents were obtained from all the patients. Twenty-five of
457
these patients were voiding by reflex at the time of the infection, and 4 were receiving intermittent catheterization (2 patients twice daily and 2 four times daily). Most patients, however, were receiving urethral catheterizations at irregular intervals, primarily for residual volume determinations. The patients were randomized into four therapeutic groups: group I, standard-dose tobramycin; group II, low-dose tobramycin; group III, standard-dose amikacin; and group IV, low-dose amikacin. The tobramycin standarddose group received 1 mg./Kg. body weight given intramuscularly (IM) every eight hours, and the low-dose group received 0.5 mg./Kg. body weight IM every eight hours. The standard-dose amikacin group received 500 mg. IM every twelve hours, and the low-dose amikacin group received 250 mg. IM every twelve hours. The duration of therapy was five days for both antibiotics. In general, patients with Ps. aeruginosa infections received tobramycin and those with either P. rettgeri or Providencia sp. infections received amikacin. All the patients had urine cultures obtained by urethral catheterization and had at least two consecutive positive urine cultures prior to therapy (the last positive urine culture was obtained within twenty-four hours before institution of therapy). Urine cultures were repeated two and four days after completion of therapy. Urine cultures with 3 lo4 bacteria/ml. urine were considered positive. Antibiotic sensitivity testing was performed using the FDA standardized techniques. Tubedilution sensitivity studies using trypticase soy broth with an inoculation of 1OYml. were also done for the particular antibiotic employed. Pretherapy urines were saved and immediately frozen at -20” C. Immunofluorescent testing for urine antibacterial antibody coating was later performed according to methods described previouslys-’ within three months of urine storage. Pretherapy tests also included an audiogram, intravenous pyelography, urinary bladder residual volume determination, complete blood cell count and differential, serum creatinine, The audiogram and serum and urinalysis. creatinine level determination were repeated after completion of therapy. Peak (one hour after IM dose) and trough (< one hour before the next dose) serum antibiotic levels were determined by the agar-diffusion method using Bacillus subtilis as the indicator organism.* A timed, six-hour urine collection
458
UROLOGY
/ MAY 1980 / VOLUME
XV, NUMBER5
Response to therapy according to infecting pathogen
TABLE II.
Bacterial Isolate (No.) Ps. aeruginosa (15)
Therapy Group I II III IV
TOTALS
Persistence or Relapse
Cures 3 2
2 3 1 0
; 5 (33%)
P. rettgeri (5)
III IV
TOTALS
L3
III IV
10
TOTALS
2 2
1 (20%)
:
4 (60%)
1
2 0 L
6 (40%)
4 (80%)
Providencia sp. (6)
Reinfection
4 (27%)
: 0
::
2 (33%)
0
III Iv*
!:
0 1
TOTALS E. coli (1)
II
0 1
:
1 0
Unidentified nonlactose fermenter (1)
I
0
0
1
P. mirabilis (2)
;
*Isolated concomitantly withPs. aeruginosa in 1 patient.
after antibiotic administration was also studied for urine antibiotic concentrations. Response to therapy was categorized into three groups: (1) cure = urine cultures sterile two days and seven days after completion of therapy; (2) persistence or relapse = original infecting organism present in the urine after completion of therapy; and (3) reinfection = bacteria other than original infecting organism isolated in post-therapy cultures. The clinical features of the patients in each group are shown in Table I. Seven patients each were included in therapy groups I, II, and IV (Table I). Therapy group III had 8 patients. Ages ranged from sixteen to fifty years, with a mean age of twenty-eight years. Twenty-seven patients were male and 2 female, a reflection of the general sex distribution of patients with spinal cord injury. Twenty-two patients were evaluated as having upper motor neuron urinary bladders, and 7 had lower motor neuron involvement. The latter group of patients was fairly evenly distributed among the four therapy groups. None of the patients had elevated temperatures or elevated white blood cell counts prior to institution of therapy. Twenty-six patients had pretherapy intravenous urograms, and abnormalities were detected in 5 (unilateral ureterovesical reflux in 3, unilateral calyceal dilatation in 1, and bladder diverticula in another patient). Three of these patients were in group I, 1 in group II, 2 in group III, and none in group IV.
UROLOGY /
MAY 1980 /
VOLUME XV, NUMBER5
Significant pyuria (> 5/HPF) was detected in 18 of 28 patients. Twelve of these patients showed resolution of pyuria after therapy. Pretherapy serum creatinine was normal in each patient and showed no significant change after therapy. Pre- and post-therapy audiograms were done in 26 patients and showed no change in all but 1 patient. The patient that showed some decrease in high-frequency hearing post-therapy showed a normal audiogram one week later. No antibody coating was detected in any of the urine specimens except for 1 patient. Fourteen of the 29 therapy courses (48 per cent) resulted in cures, 9 (31 per cent) in persistence or relapse, and 6 (21 per cent) in reinfections. Ps. aeruginosa accounted for 15 of the isolates (Table II). Six patients with this pathogen were in group I, 7 in group II, and 1 each in groups III and IV. P. rettgeri comprised 5 of the isolates (3 in group III and 2 in group IV). Providencia stuartii accounted for 6 isolates (2 in group III and 4 in group IV). Other bacteria isolated included: P. mirabilis (2, 1 concomitantly with P. aeruginosa), Escherichia coli (l), and unidentified nonlactose fermenting aerobic Gram-negative bacillus (1). Therapy of Ps. aeruginosa infections appeared less successful than that of other infecting organisms (Table II), but the rate of cures, relapses, or reinfections was not statistically significant (p > 0.05 by Chi-square test). In addition, no significant differences were observed
459
between low-dose and standard-dose antibiotic therapy and between amikacin therapy and tobramycin therapy (p > 0.05 by Chi-square test). Comment The potential toxicity of aminoglycosides has led to several therapeutic regimens using lowdose and/or shortened time courses for therapy of lower urinary tract infection.‘” High concentration of these antibiotics achieved in the urine has been believed to eradicate the bacteriuria. The presence of neurogenic bladders with significant urinary residual volume coupled with the necessity for frequent urethral catheterizations makes the spinal cord-injury patient particulary susceptible to recurrent urinary tract infections. Intermittent urethral catheterization, with an aim at achieving a “balanced bladder” having ability to empty periodically by reflex, has been shown to reduce significantly the incidence of urinary tract infections and other urologic complications in this unique population group. ‘-11 These patients frequently become colonized with drug-resistant bacteria, and these organisms are frequently isolated from these patients when urinary tract infections develop.i2 The necessity for the use of aminoglycosides such as tobramycin and amikacin, therefore, often arises. These patients, however, stand to benefit greatly from low-dose or abbreviatedcourse aminoglycoside regimens. All the patients in our study were asymptomatic and afebrile, and none of them had signficant peripheral leukocytosis. It was believed that these infections were confined to the lower urinary tract. The results of the tests for antibody coating of our urine bacteria appeared to confirm this belief. A recent study, however, has suggested that mucoidity of some Ps. aeruginosa isolates may inhibit antibody coating in kidney infections.13 We did not examine this particular property of our Ps. aeruginosa isolates. Although we cannot rule out totally the possibility of upper urinary tract infections in a significant percentage of our cases, we nevertheless believe, based on the over-all clinical and laboratory picture, that most of the infections were localized to the urinary bladder. The high incidence of therapeutic failures with persisting and relapsing infections in our patient population was disturbing. We discontinued the study when it became apparent that there was a high incidence of failure even with standard doses of aminoglycosides given for five days. The existence of neurogenic bladders and
460
significant urine residuals may have resulted in the difficulty eradicating the bacteriuria in our patients using the therapeutic regimens chosen. Inhibition of aminoglycoside activity in urine has also been described by some investigators.14 The inhibitory activity was shown to be dependent on the urinary acidity, osmolality, and the presence of individual solutes, We did not study these factors. Based on the results of this study, alternative regimens, such as extended courses of therapy or antibiotic combinations (aminoglycosides plus oral carbenicillin) should be evaluated in the management of urinary tract infections in the patient with spinal cord injury. Downey, California 90242 (DR. SAPICO) ACKNOWLEDGMENT. To M. Nancy Young, R.N., and the Intermittent Catheterization Team for their assistance in obtaining specimens, Donna Gilmore, R.N., and Gloria Aeilts, R.N. for assisting in the collection of data, and Jong T. Huang, M.D. for doing the urine antibody coating test.
References 1. Harrison LH: Treatment of complicated urinary tract infections with amikacin, Urology 10: 110 (1977). 2. Prat V, Bohuslav V, Hatala M, and Lisko M: Twice-daily sisomycin therapy in complicated upper urinary tract infections, in Current Chemotherapy, Washington, D.C., American Society ibr Microbiology, 1978, p. 922. 3. Prat V, Bohuslav V, and Hatala M: Treatment with a single daily dose of gentamicin in urinary tract infection in relation to the site of infection, Infection 6: 29 (1978). 4. Landes RR: Single daily doses of tobramycin in therapy of urinary tract infections, J. Infect. Dis. (Suppl.) 134: 142 (1976). 5. Ronald AR, Boutros P, and Mourtade H: Bacteriuria localization and response to single-dose therapy in women, JAMA 235: 1854 (1976). 6. Johnson GD, and Holbomw EJ: Immunofluorescence, in: Handbook of Experimental Immunology, Oxford, London, Blackwell Scientific Publications, 1973, p. 18. 7. Thomas V, Shelokov A, and Forland M: Antibody-coated bacteria in the urine and the site of urinary tract infection, N. Engl. J. Med. 290: 588 (1974). 8. Sabath LD, and Matsen JM: Assay of antimicrobial agents, in Jennett E, Spaulding EH, and Truant JP, Eds: Manual of Clinical Microbiology, Washington, D.C., American Society for Microbiology, 1974, chap. 47, p. 428. 9. Pearman JW: The catheter team: an essential service for rehabilitating neumgenic bladders, Aust. N. 2. J. Surg. 47: 339 (1977). 10. Lindan It, and Bellomy V: Effect of delayed intermittent catheterisation on kidney function in spinal cord injury patients a long-term follow-up study, Paraplegia 13: 49 (1975). 11. Pearman JW: Urological follow-up of 99 spinal cord injured patients initially managed by intermittent catheterisation, Br. J. Urol. 48: 297 (1976). 12. Montgomerie JZ, and Morrow JW: Pseudomonas colonimtion in patients with spinal cord injury, Am. J. Epidemiol. 108: 328 (1978). 13. Marrie TJ, et al: Influence of mucoidity on antibody coating, J. Infect. Dis. 139: 357 (1979). 14. Minuth JN, Musher DM, and Thorsteinsson SB: Inhibition of antibacterial activity of gentamicin by urine, ibid. 133: 14 (1976).
UROLOGY
/
MAY 1986
/
VOLUME XV, NUMBER 5
AMINOGLYCOSIDE
THERAPY IN
PATIENTS WITH SPINAL CORD INJURY* Standard Dose Versus Low Dose FRANCISCO
L. SAPICO,
LEE B. LINDQUIST,
ENES M. JIMENEZ,
M.D.
JAMES W. MORROW,
M.D.
JOHN Z. MONTGOMERIE,
R.N. M.D.
M.B., CH.B.
From the Departments of Medicine and Surgery, Ranch0 Los Amigos Hospital, Downey, and the University of Southern California School of Medicine, Los Angeles, California
ABSTRACT - Twenty-nine patients with spinal cord injury and asymptomatic urinary tract infection were treated with standard or reduced doses of tobramycin and amikacin. The patients received jive days of intramuscular antibiotics. Most of the patients in the tobramycin groups had Pseudomonas aeruginosa infection and most of those in the amikacin group had either Proteus rettgeri or Providencia stuartii infections. Only 1 patient had a positive urine antibody coating test. High antibiotic concentrations were demonstrated in the urine of all patients during therapy. Urine cultures were obtained two and seven days after completion of therapy. Forty-eight per cent of the patients were cured, while 31 per cent showed persistence or relapse, and 21 per cent had reinfection with other bacteria. No signijcant differences in results were observed between the standard-dose and low-dose regimens and between the amikacin and tobramycin groups. The low success rate of the regimens used may indicate the need to evaluate alternative therapeutic regimens to treat urinary tract infections in this special group of patients.
Tobramycin and amikacin are aminoglycoside antibiotics which have been shown to be effective in the therapy of Gram-negative infections, including urinary tract infections. These agents are particularly useful for infections where multiple prior courses of therapy with different antibiotics have resulted in the emergence of resistant organisms. Since aminoglycosides are concentrated in urine, some studies have suggested that reduction in accepted therapeutic doses or time courses may eradicate infections localized to the urinary bladder. l-5 These alternative therapeutic modalities potentially could reduce the toxicity of these aminoglycosides. Ranch0 Los Amigos Hospital has a large population of patients with spinal cord injury who are subject to recurrent urinary tract infec*This study was supported pany, Indianapolis, Indiana.
UROLOGY
/
in part by Eli Lilly and Com-
MAY1980 / VOLUMEXV,NUMBERS
tions. The presence of neurogenic bladder with significant urine residual volumes as well as the use of intermittent urethral catheterization are believed to be responsible for these infections. Bacteria with multiple drug resistance are common pathogens in this population group, including Pseudomonas aeruginosa, Proteus rettgeri, and Providencia species. We have studied the therapeutic efficacy of five-day courses of tobramycin and amikacin for urinary tract infections caused by these pathogens in spinal cord injury patients and compared the results of low-dose against standard-dose regimens. Material and Methods Twenty-nine patients with spinal cord injury and urinary tract infections due to bacteria resistant tocommonly used antibiotics were ineluded in the study. Informed consents were obtained from all the patients. Twenty-five of
457
these patients were voiding by reflex at the time of the infection, and 4 were receiving intermittent catheterization (2 patients twice daily and 2 four times daily). Most patients, however, were receiving urethral catheterizations at irregular intervals, primarily for residual volume determinations. The patients were randomized into four therapeutic groups: group I, standard-dose tobramycin; group II, low-dose tobramycin; group III, standard-dose amikacin; and group IV, low-dose amikacin. The tobramycin standarddose group received 1 mg./Kg. body weight given intramuscularly (IM) every eight hours, and the low-dose group received 0.5 mg./Kg. body weight IM every eight hours. The standard-dose amikacin group received 500 mg. IM every twelve hours, and the low-dose amikacin group received 250 mg. IM every twelve hours. The duration of therapy was five days for both antibiotics. In general, patients with Ps. aeruginosa infections received tobramycin and those with either P. rettgeri or Providencia sp. infections received amikacin. All the patients had urine cultures obtained by urethral catheterization and had at least two consecutive positive urine cultures prior to therapy (the last positive urine culture was obtained within twenty-four hours before institution of therapy). Urine cultures were repeated two and four days after completion of therapy. Urine cultures with 3 lo4 bacteria/ml. urine were considered positive. Antibiotic sensitivity testing was performed using the FDA standardized techniques. Tubedilution sensitivity studies using trypticase soy broth with an inoculation of 1OYml. were also done for the particular antibiotic employed. Pretherapy urines were saved and immediately frozen at -20” C. Immunofluorescent testing for urine antibacterial antibody coating was later performed according to methods described previouslys-’ within three months of urine storage. Pretherapy tests also included an audiogram, intravenous pyelography, urinary bladder residual volume determination, complete blood cell count and differential, serum creatinine, The audiogram and serum and urinalysis. creatinine level determination were repeated after completion of therapy. Peak (one hour after IM dose) and trough (< one hour before the next dose) serum antibiotic levels were determined by the agar-diffusion method using Bacillus subtilis as the indicator organism.* A timed, six-hour urine collection
458
UROLOGY
/ MAY 1980 / VOLUME
XV, NUMBER5
Response to therapy according to infecting pathogen
TABLE II.
Bacterial Isolate (No.) Ps. aeruginosa (15)
Therapy Group I II III IV
TOTALS
Persistence or Relapse
Cures 3 2
2 3 1 0
; 5 (33%)
P. rettgeri (5)
III IV
TOTALS
L3
III IV
10
TOTALS
2 2
1 (20%)
:
4 (60%)
1
2 0 L
6 (40%)
4 (80%)
Providencia sp. (6)
Reinfection
4 (27%)
: 0
::
2 (33%)
0
III Iv*
!:
0 1
TOTALS E. coli (1)
II
0 1
:
1 0
Unidentified nonlactose fermenter (1)
I
0
0
1
P. mirabilis (2)
;
*Isolated concomitantly withPs. aeruginosa in 1 patient.
after antibiotic administration was also studied for urine antibiotic concentrations. Response to therapy was categorized into three groups: (1) cure = urine cultures sterile two days and seven days after completion of therapy; (2) persistence or relapse = original infecting organism present in the urine after completion of therapy; and (3) reinfection = bacteria other than original infecting organism isolated in post-therapy cultures. The clinical features of the patients in each group are shown in Table I. Seven patients each were included in therapy groups I, II, and IV (Table I). Therapy group III had 8 patients. Ages ranged from sixteen to fifty years, with a mean age of twenty-eight years. Twenty-seven patients were male and 2 female, a reflection of the general sex distribution of patients with spinal cord injury. Twenty-two patients were evaluated as having upper motor neuron urinary bladders, and 7 had lower motor neuron involvement. The latter group of patients was fairly evenly distributed among the four therapy groups. None of the patients had elevated temperatures or elevated white blood cell counts prior to institution of therapy. Twenty-six patients had pretherapy intravenous urograms, and abnormalities were detected in 5 (unilateral ureterovesical reflux in 3, unilateral calyceal dilatation in 1, and bladder diverticula in another patient). Three of these patients were in group I, 1 in group II, 2 in group III, and none in group IV.
UROLOGY /
MAY 1980 /
VOLUME XV, NUMBER5
Significant pyuria (> 5/HPF) was detected in 18 of 28 patients. Twelve of these patients showed resolution of pyuria after therapy. Pretherapy serum creatinine was normal in each patient and showed no significant change after therapy. Pre- and post-therapy audiograms were done in 26 patients and showed no change in all but 1 patient. The patient that showed some decrease in high-frequency hearing post-therapy showed a normal audiogram one week later. No antibody coating was detected in any of the urine specimens except for 1 patient. Fourteen of the 29 therapy courses (48 per cent) resulted in cures, 9 (31 per cent) in persistence or relapse, and 6 (21 per cent) in reinfections. Ps. aeruginosa accounted for 15 of the isolates (Table II). Six patients with this pathogen were in group I, 7 in group II, and 1 each in groups III and IV. P. rettgeri comprised 5 of the isolates (3 in group III and 2 in group IV). Providencia stuartii accounted for 6 isolates (2 in group III and 4 in group IV). Other bacteria isolated included: P. mirabilis (2, 1 concomitantly with P. aeruginosa), Escherichia coli (l), and unidentified nonlactose fermenting aerobic Gram-negative bacillus (1). Therapy of Ps. aeruginosa infections appeared less successful than that of other infecting organisms (Table II), but the rate of cures, relapses, or reinfections was not statistically significant (p > 0.05 by Chi-square test). In addition, no significant differences were observed
459
between low-dose and standard-dose antibiotic therapy and between amikacin therapy and tobramycin therapy (p > 0.05 by Chi-square test). Comment The potential toxicity of aminoglycosides has led to several therapeutic regimens using lowdose and/or shortened time courses for therapy of lower urinary tract infection.‘” High concentration of these antibiotics achieved in the urine has been believed to eradicate the bacteriuria. The presence of neurogenic bladders with significant urinary residual volume coupled with the necessity for frequent urethral catheterizations makes the spinal cord-injury patient particulary susceptible to recurrent urinary tract infections. Intermittent urethral catheterization, with an aim at achieving a “balanced bladder” having ability to empty periodically by reflex, has been shown to reduce significantly the incidence of urinary tract infections and other urologic complications in this unique population group. ‘-11 These patients frequently become colonized with drug-resistant bacteria, and these organisms are frequently isolated from these patients when urinary tract infections develop.i2 The necessity for the use of aminoglycosides such as tobramycin and amikacin, therefore, often arises. These patients, however, stand to benefit greatly from low-dose or abbreviatedcourse aminoglycoside regimens. All the patients in our study were asymptomatic and afebrile, and none of them had signficant peripheral leukocytosis. It was believed that these infections were confined to the lower urinary tract. The results of the tests for antibody coating of our urine bacteria appeared to confirm this belief. A recent study, however, has suggested that mucoidity of some Ps. aeruginosa isolates may inhibit antibody coating in kidney infections.13 We did not examine this particular property of our Ps. aeruginosa isolates. Although we cannot rule out totally the possibility of upper urinary tract infections in a significant percentage of our cases, we nevertheless believe, based on the over-all clinical and laboratory picture, that most of the infections were localized to the urinary bladder. The high incidence of therapeutic failures with persisting and relapsing infections in our patient population was disturbing. We discontinued the study when it became apparent that there was a high incidence of failure even with standard doses of aminoglycosides given for five days. The existence of neurogenic bladders and
460
significant urine residuals may have resulted in the difficulty eradicating the bacteriuria in our patients using the therapeutic regimens chosen. Inhibition of aminoglycoside activity in urine has also been described by some investigators.14 The inhibitory activity was shown to be dependent on the urinary acidity, osmolality, and the presence of individual solutes, We did not study these factors. Based on the results of this study, alternative regimens, such as extended courses of therapy or antibiotic combinations (aminoglycosides plus oral carbenicillin) should be evaluated in the management of urinary tract infections in the patient with spinal cord injury. Downey, California 90242 (DR. SAPICO) ACKNOWLEDGMENT. To M. Nancy Young, R.N., and the Intermittent Catheterization Team for their assistance in obtaining specimens, Donna Gilmore, R.N., and Gloria Aeilts, R.N. for assisting in the collection of data, and Jong T. Huang, M.D. for doing the urine antibody coating test.
References 1. Harrison LH: Treatment of complicated urinary tract infections with amikacin, Urology 10: 110 (1977). 2. Prat V, Bohuslav V, Hatala M, and Lisko M: Twice-daily sisomycin therapy in complicated upper urinary tract infections, in Current Chemotherapy, Washington, D.C., American Society ibr Microbiology, 1978, p. 922. 3. Prat V, Bohuslav V, and Hatala M: Treatment with a single daily dose of gentamicin in urinary tract infection in relation to the site of infection, Infection 6: 29 (1978). 4. Landes RR: Single daily doses of tobramycin in therapy of urinary tract infections, J. Infect. Dis. (Suppl.) 134: 142 (1976). 5. Ronald AR, Boutros P, and Mourtade H: Bacteriuria localization and response to single-dose therapy in women, JAMA 235: 1854 (1976). 6. Johnson GD, and Holbomw EJ: Immunofluorescence, in: Handbook of Experimental Immunology, Oxford, London, Blackwell Scientific Publications, 1973, p. 18. 7. Thomas V, Shelokov A, and Forland M: Antibody-coated bacteria in the urine and the site of urinary tract infection, N. Engl. J. Med. 290: 588 (1974). 8. Sabath LD, and Matsen JM: Assay of antimicrobial agents, in Jennett E, Spaulding EH, and Truant JP, Eds: Manual of Clinical Microbiology, Washington, D.C., American Society for Microbiology, 1974, chap. 47, p. 428. 9. Pearman JW: The catheter team: an essential service for rehabilitating neumgenic bladders, Aust. N. 2. J. Surg. 47: 339 (1977). 10. Lindan It, and Bellomy V: Effect of delayed intermittent catheterisation on kidney function in spinal cord injury patients a long-term follow-up study, Paraplegia 13: 49 (1975). 11. Pearman JW: Urological follow-up of 99 spinal cord injured patients initially managed by intermittent catheterisation, Br. J. Urol. 48: 297 (1976). 12. Montgomerie JZ, and Morrow JW: Pseudomonas colonimtion in patients with spinal cord injury, Am. J. Epidemiol. 108: 328 (1978). 13. Marrie TJ, et al: Influence of mucoidity on antibody coating, J. Infect. Dis. 139: 357 (1979). 14. Minuth JN, Musher DM, and Thorsteinsson SB: Inhibition of antibacterial activity of gentamicin by urine, ibid. 133: 14 (1976).
UROLOGY
/
MAY 1986
/
VOLUME XV, NUMBER 5