Vol. 104, Oct. Printed in U.S.A.
THE JOURNAL OF UROLOGY
Copyright© 1970 by The Williams & Wilkins Co.
URINARY TRACT INFECTION AND RENAL HO~\!IOTRANSPLANTATION. IV. THE BLADDER DEFENSE MECHANISMS INVOLVED IN BACTERIURIA IN DONORS FRANK HINMAN, JR., FOLKERT 0. BELZER
AND
NOBUHIRO SUGINO
From the Division of Urology and the Departments of Surgery and Medicine, University of California School of Medicine, San Francisco, California
The bladder normally defends itself against introduced organisms. In a previous controlled study we observed only 6.6 per cent positive urine cultures from patients on open drainage with balloon catheters left indwelling for 18 to 24 hours, although the incidence rose to 45 per cent for the 36 to 72-hour period. 1 The invading bacteria are most often introduced into the bladder via the lumen of the catheter. 2 • 3 Once bacteria enter the bladder they can multiply in the 6 to 13 ml. of residual urine around the catheter, 4 • 5 aided by the poor exchange of urine on the surface of the catheter and its balloon 6 as well as by surface changes induced by pressure. 7 • 8 All of these factors would be amplified the longer the catheter was in place. Therefore, it was surprisAccepted for publication September 24, 1969. Read at annual meeting of Western Section, American Urological Association, Seattle, Washington, July 27-August 1, 1969. This work was supported in part by United States Public Health Services Grants AM-AI 11290, AM 10045 and AM-09181 from the National Institutes of Health. 1 Cox, C. E. and Hinman, F., Jr.: Incidence of bacteriuria with indwelling catheter in normal bladders. J.A.M.A., 178: 919, 1961. 2 Miller, A., Gillespie, W. A., Linton, K. B., Slade, N. and Mitchell, J. P.: Prevention of urinary infection after prostatectomy. Lancet, 2: 886, 1960. 3 Desautels, R. E., Walter, C. W., Graves, R. C. and Harrison, J. H.: Technical advances in the prevention of urinary tract infection. J. Urol., 87: 487, 1962. 4 Stfibrna, J. and Fabian, F.: The problem of residual urine after catheterization. Acta Univ. Carol. Med., 7: 931, 1961. 6 Hinman, F., Jr. and Cox, C. E.: Residual urine volume in normal male subjects. J. Urol., 97: 641, 1967. 6 Hinman, F., Jr. and Cox, C. E.: The voiding vesical defense mechanism: the mathematical effect of residual urine, voiding interval and volume on bacteriuria. J. Urol., 96: 491, 1966. 7 Mehrotra, R. M. L.: An experimental study of the vesical circulation during distention and in cystitis. J. Path. Bact., 66: 79, 1953. 8 Andriole, V. T. and Lytton, B.: The effect and critical duration of increased tissue pressure on susceptibility to bacterial infection. Brit. J. Exp. Path., 46: 308, 1965.
ing to see an incidence of bacteriuria much greater than 6.6 per cent in the present study of renal donors in whom the catheters were left for even shorter periods. Comparisons are not really justified, however, since all factors were not the same. The donors had each had a major operation and subsequent multiple samplings of urine for studies of renal function. The former would decrease vesical resistance and lead to residual urine after catheter removal and the latter would allow more opportunity for the introduction of bacteria into the system.• In addition 6.6 per cent represents the proportion of positive cultures at the moment of removal of the catheter, whereas in the donors, our clinical concern was the incidence of bacteriuria at any time before discharge from the hospital. Mere removal of the catheter after it has been indwelling allows the new urethral flora, cultivated by the presence of the catheter, to move back along the disturbed urethra and into the bladder, as was observed in transplant recipients. 10 Accordingly, 100 consecutive renal donors were studied for preoperative and postoperative bacteriuria. These observations were then correlated with other factors such as sex, duration of catheterization and treatment. MATERIALS AND METHODS
Two hours before operation catheters were inserted aseptically in the patient on the ward and connected to sterile drainage. No irrigations were used unless clots obstructed the catheter. Specimens for creatinine clearance and for other studies were obtained from the drainage bags. The design of the collection bags did not always insure closed drainage. 9 Hinman, F., Jr.: Bacterial elimination. J. Urol., 99: 811, 1968. 10 Hinman, F., Jr., Schmaelzle, J. F. and Belzer, F. 0.: Urinary tract infection and renal homotransplantation: II. Post-transplantation bacterial invasion. J. Urol., 101: 673, 1969.
518
URINARY TRACT INFECTION AND RENAL HOMOTRANSPLANTATION
Cultures were performed in the hospital laboratories by standard techniques. The tip of the catheter was cultured by cutting it off immediately after withdrawal and dropping it in a sterile test tube. In male subjects urine was obtained during midstream flow without preparation of the glans. In female subjects the vulva was washed by the nurse or aide and a midstream specimen was caught in a sterile container. The specimens were not refrigerated but were delivered to the laboratory without undue delay. Definitions of contamination and infection were strict. Contamination was defined as a maximum of 1,000 colonies per ml. of a single pathogen or 10,000 colonies per ml. of mixed organisms. Infection was defined as counts greater than that level. In general there were few borderline counts and, if they did occur, the previous or subsequent counts demonstrated whether a particular count was significant. The following data were obtained: 1) preoperative midstream urine cultures (30 or more days, 4 to 30 days and less than 4 days before operation), 2) culture of tip of catheter on withdrawal (when possible), 3) postoperative midstream urine cultures (first day, 2 to 4 days, after 4 days and on discharge from the hm,pital), 4) duration of catheterization (8 to 12 hours, 13 to 24 hours and more than 24 hours), 5) treatment (therapeutic or prophylactic) and 6) followup results. INCIDENCE 01=" AND IN\:"ECTED
RESULTS AND DISCUSSION
Incidence of infection and contamination. Of 100 patients, 30 were infected with organisms, either preoperatively, no,-,.,,110,rn,,, vc;, or both (fig. 1). Four patients (3 women) had urine infected with pathogenic organisms preoperatively only and 12 had infection postoperatively only. Eleven patients were infected both preoperatively and postoperatively (9 Nine patients had the same organism both times and 2 had different organisms (fig. 2). Three other patients had a contaminant in their cultures but had infection with the same nnm., ,,,n postoperatively. Twenty-eight patients had sterile urine mens throughout their preoperative studies and postoperative periods (18 men-65 per cent and 10 women-35 per cent). Another 42 patients had contaminated urine (15 men-36 per cent and 27 women-64 per cent). Comment: The occurrence of infection in a fourth of healthy renal donors demonstrates that vesical defenses are altered by operation, anesthesia, catheterization, bed rest and pain. Inadequately closed systems and the collect.ion of specimens for operative clearance studies made contamination possible. The influence of prior bacteriuria the organism responsible for subsequent infec11
CONTAMINATED URINE IN DONORS
STER.!LE
CONTAMINATED
L----,----,.-----,-----,-----1 10 20 40 30 50
0
NUMBER
OF
519
PATIENTS
Fm. l
520
HINMAN, BELZER AND SUGINO INCIDENCE AND
OF
PRE-OPERATIVE
POST-OPERATIVE 30
INl="ECTION
PATIENTS
1111111 MALE.S
E2:iJ FEMALES
PRE-OPERATIVE INl='ECTION
CONTAMINATED PRE-OPERATIVELY & INFECTED POST-OPERATIVELY SAME ORGAN/.SM
PRE-AND POST-OPERATIVE INl='ECTION BAME ORGANISM
POST-OPERATIVE INFECTION
10
PER
20 CENT
40
.30 INl='ECTED
50
PATIENTS
Fm. 2 tion is shown in 9 of 11 patients with infection both preoperatively and postoperatively. In these cases the same organism was involved both times, suggesting a urethral reservoir. Relation of sex to contamination and infection. As would be expected, there were proportionately more women with contaminated specimens (twothirds) and more men with sterile specimens. More women than men were infected both preoperatively and postoperatively (9 to 2) and also more women had postoperative infections even though they had sterile specimens preoperatively. However, 3 women who were infected preoperatively had no infection after operation; only 1 man was in this category. Comment: The difficulty of collecting sterile specimens undoubtedly accounts for the high incidence of contaminated specimens in women. The factors involved in the greater infection rate in women than in men both preoperatively and postoperatively have been well documented elsewhere.9 Ejfect of urethral bacteria on subsequent infection. The tip of the catheter was cultured for urethral bacteria on removal in 13 instances (fig. 3). In 7 patients (5 women) a subsequent infection in the bladder was by the same organism that had been cultured from the surface of the catheter. In the other 6 patients (4 men) no
infection developed despite positive cultures from the catheter. Comment: Short-term catheterization would not be expected to appreciably alter urethral defenses consistently, yet in more than half of our small series of patients, urethral bacteria subsequently entered the bladder. Since more women were affected than men, it is possible that movement of the catheter in the short female urethra distributed the bacteria widely and that the less efficiently emptying female bladder fostered their vesical establishment. Duration of catheterization. Of 39 patients in whom the duration of catheterization could be determined with accuracy, the catheter was left indwelling for 8 to 12 hours in 33, 13 to 24 hours in 5 and more than 24 hours in 1 patient. No relationship could be established between duration of catheterization and the occurrence of infection. One patient who had not been catheterized at all had an infection. Comment: Previous studies have shown a direct correlation between duration of catheterization and the incidence of infection. 1 In our study catheterization periods of 8 to 12 hours and up to 24 hours are too closely related to show a difference. In comparison with the longer 3-day period of the previous study in non-operative patients, the added factor of the abnormal postoperative state hastened the effect.
URINARY TRACT INFECTION AND RENAL HOMOTRANSPLANTATION
521
RELATION Of:' BACTERIA ON CATHETER TIP TO SUBSEQUENT BLADDER INF'ECTION Ill PATIENTS
SAME BACTERIAL ORGANISM
Dll='l='ERENT BACTERIAL ORGANISM
0
10
20
PER CENT
.30
40
BLADDER.
50
60
70
INFECTION
Fm. 3 Drugs used in patients with postoperative infection (26 cases) Prophylactic: None Gantrisin alone Furadantin alone Therapeutic: Gantrisin plus second antibiotic Other antibiotic
2
13 3
6 2
Prophylactic antibacterial therapy. Drugs were given prophylactically to almost all patients including all but 2 patients who were infected postoperatively (see table). Gantrisin (sulfisoxazole) and to a lesser extent furadantin (nitrofurantoin) were given to half the patients 2 days postoperatively, to a fourth on the first day and to the other fourth on the third day or later. When patients with infection were compared to those who did not have infection postoperatively, no differences in prophylactic drug therapy were detected. Specific antibacterial agents (penicillin derivatives) were used when clinical infection occurred. Comment: Prophylactic drugs are of little value in the prevention of infection when catheters are indwelling because resistant strains of bacteria are introduced. 11 In our present series oral agents were given after the catheter had been removed but, because patients had to refrain from eating 11 Osius, T. G., Tavel, F. R. and Hinman, F., Jr.: Tetracycline used prophylactically in transurethral procedures. Maryland Med. J., 14: 37,
1965.
or drinking for the first day or so after removal of the catheter, the oral agents were usually given 2 days postoperatively. Since the catheter had been removed 8 to 12 hours postoperatively, the intervening 1 to 1 ½ days were not covered by an antibacterial agent, thus allowing uninhibited establishment of bacteria. Followup cultures. Followup urine cultures were obtained from 24 of 30 patients with infection, 28 of whom had had sterile cultures on discharge from the hospital. Twenty-one remained sterile (5 were followed less than 1 month, 6 for 1 to 3 months and 10 for more than 3 months). Three patients subsequently had positive cultures: one was sterile at 3 months but an Escherichia coli infection developed at 10 months, another had an E. coli infection at 6 months but the culture was sterile at 12 months and the third was infected with E. coli at 8 months. Comparative preoperative data from these patients revealed that among the 100 donors, 6 (4 women) had previous infection-2 were associated with pregnancy and in 4 cases the causative factors were unknown. Three of the 6 patients had postoperative infections and none had infection during followup. Comment: The normal lower urinary tract rids itself of bacteria once the catheter is removed.1 This was true in all cases in our series, although the mechanisms were aided by semispecific antibacterial therapy in 8 patients and continuation of prophylactic (suppressive) drugs up to 2 weeks after hospitalization in the remainder.
522
HINMAN, BELZER AND SUGINO SUMMARY AND CONCLUSIONS
Of 100 renal donors, 26 had bacteriuria postoperatively. Nine of the 11 who had infection both preoperatively and postoperatively were infected with the same organism at both times, suggesting a urethral reservoir. The high incidence of infection is ascribed to decreased intrinsic urethral and vesical defenses12· 13 due to the operation, pressure from the catheter, diminished washout around the catheter and incomplete voiding while in bed after the kidney has been removed. Possibly, breaks in closed drainage techniques were added factors. 12 Cabot, H.: The doctrine of the prepared soil: a neglected factor in surgical infections. Canad. Med. Ass. J., 11: 610, 1921. 18 Cox, C. E. and Hinman, F., Jr.: Experiments with induced bacteriuria, vesical emptying and bacterial growth on the mechanism of bladder defense to infection. J. Urol., 86: 739, 1961.
Urethral bacteria cultured from the catheter tips were subsequently found in the bladders in 7 of 13 patients, indicating derangement of the urethral washout mechanism. Since catheters were indwelling for such short periods, no difference was found between periods of less than 12 hours and those up to 24 hours. Prophylactic antibacterial drugs had no demonstrable effect but, since they were not started immediately because of the patient's inabilitv to take them orally, in effect they were given only after bacteriuria was (or was not) initiated. Followup cultures were uniformly sterile, although 3 patients later had apparently unrelated urinary tract infections. It is concluded that retention catheterization by routine techniques is followed by a higher incidence of bacteriuria in postoperative renal donors than in normal individuals due to the several factors inherent in the postoperative state.