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PREVENTION OF URINARY-TRACT INFECTION WITH LOW-DOSE NITROFURANTOIN
1112
PREVENTION OF URINARY-TRACT INFECTION WITH LOW-DOSE NITROFURANTOIN R. R. BAILEY* P. E. GOWER
A. P. ROBERTS H. E. DE WARDENER
Renal Infection Unit, Department of Medicine, Charing Cross Hospital Medical School, Fulham Hospital, London W.6
One hundred and two women with normal renal function having recurrent urinary-tract infections took part in trials of low-dose nitrofurantoin at night to prevent recurrence of infection. In the first trial, 50-100 mg. of nitrofurantoin was used and in the double-blind trial the dose was 50 mg. In the first trial the drug was given for periods up to 5 years and the double-blind trial lasted for up to 1 year. Fifteen of the fifty-two women in the first trial had an abnormal intravenous pyelogram. All the other patients had a normal intravenous pyelogram. Both trials demonstrated that such treatment is highly successful in reducing recurrences of infection, is acceptable to the patients, and almost free from side-effects.
Sum ary
Patients and Methods Initial Trial Women of any age referred to the urinary-infection clinic or seen in the casualty department with recurrent symptomatic urinary-tract infections were considered for inclusion in the trial. Only women who were not pregnant and had a serum-creatinine not exceeding 1-2 mg. per 100 ml. (estimated in anAutoAnalyzer ’) were included. Intravenous pyelography was done in all patients. Urinarytract infection was diagnosed if a specimen of urine obtained from the bladder by suprapubic aspiration was infected.4 The patient was then treated for 7-10 days with a standard dose of an antibacterial agent. Long-term treatment with nitrofurantoin was not started unless the urine obtained 7-14 days after completing the first treatment showed no significant growth. Fifty-two women were included in the trial. Each woman was instructed to take a single nitrofurantoin tablet each night after emptying her bladder immediately before going to bed. At first a 100 mg. dose was used, but later it was reduced to 50 mg. The women were seen at 4-14 weekly intervals for clinical assessment, and either a midstream urine or a urine sample collected by suprapubic aspiration was obtained for culture. The women were asked to contact the unit if they had symptoms referable to the urinary tract, at which time a specimen of bladder urine was obtained by suprapubic
aspiration. Double-blind Trial
Introduction
*
Present address: Renal Canada.
fifty women included in this trial all had a history of urinary-tract symptoms with bacteriuria. They pregnant and were premenopausal. They had a normal serum-creatinine and a radiologically normal urinary tract. The methods used for the diagnosis of The
WOMEN who have repeated attacks of frequency and dysuria are a difficult problem both in hospital and general practice. Only about one half of these women have bacteria multiplying within the urinary tract at the time that they are symptomatic, 1,2though many of those who are abacteriuric during one attack become bacteriuric subsequently.3 This has also been our own experience. Most women who get repeated attacks of lower-urinary-tract symptoms associated with bacteriuria have a radiologically normal urinary tract, and progressive impairment of renal function is rare. However, these episodes are very inconvenient and distressing for the patient and her family. Recurrent attacks of symptomatic urinary infection in women frequently follow sexual intercourse. Presumably, the urethral trauma that is induced makes it easier for an inoculum of bacteria to pass from the urethra into the bladder. The bacteria that have been introduced then multiply during the night. We considered that the presence of an antibacterial agent in the bladder urine overnight might eradicate any bacteria that have been introduced, and we describe here an initial trial and then a double-blind trial using low-dosage nitrofurantoin in an attempt to prevent recurrent urinary-tract infections. Unit, Victoria Hospital, London, Ontario,
recurrent were not
infection and its initial treatment were the same as in the previous trial. Later, when the urine showed no significant growth, the patient was admitted at random to the doubleblind trial. Each patient received either 50 mg. of nitrofurantoin each night or an identical placebo tablet. The women were seen every 4 weeks for the first 3 months and thereafter every 6-8 weeks for clinical assessment. A midstream urine was taken for culture, and if this specimen contained more than 10,000 pathogenic organisms per ml., the patient was recalled for a suprapubic aspiration of urine. Patients were also seen if urinary-tract symptoms developed, at which time a suprapubic sample of urine was obtained. If bacteriuria recurred, the treatment code was broken and the patient was withdrawn from the trial. Results
Initial Trial (table I) Women with a radiologically normal urinary
Thirty-seven
of the
fifty-two
women
trial had a normal intravenous pyelogram. They were treated with 50 or 100 mg. of nitrofurantoin each night for a mean period of almost a year. Only one woman developed bacteriuria. She presented with lower-urinary-tract symptoms 17 weeks after starting treatment (table i). The infecting organism was Klebsiella aerogenes localised to the upper urinary
TABLE I-WOMEN WITH RECURRENT SYMPTOMATIC URINARY-TRACT INFECTIONS AND NORMAL RENAL FUNCTION, TREATED WITH
5O-IOO mg.
tract.-
in the initial
NITROFURANTOIN EACH NIGHT
1113 tract
by the bladder-washout techniques Five of the
II-INITIAL INFECTING ORGANISMS OBTAINED BY SUPRAPUBIC ASPIRATION FROM PATIENTS SUBSEQUENTLY TREATED IN DOUBLE-BLIND TRIAL
TABLE
had side-effects from the treatthirty-seven ment. Three complained of nausea, which in two was eliminated by reducing the dose from 100 to 50 mg. daily; but in the third woman the treatment (50 mg.) had to be stopped after 11 weeks. The remaining two women with side-effects had a skin reaction after 26 weeks’ treatment. One, who was taking 50 mg. nitrofurantoin each night, had a widespread pruritic eruption of fine vesicles and pimples on the face, trunk, and extremities; the other, taking the 100 mg. dose, had an itchy generalised erythematous rash. Treatment was discontinued in both patients. Women with radiological abnormalities of urinary tract.-Fifteen women with recurrent symptomatic urinary-tract infection and a radiological abnormality of the urinary tract were treated in the same way for a mean period of 94 weeks. Five of these fifteen patients developed bacteriuria (table l). One woman who had obstructive atrophy of one kidney developed urinary infection after 56 weeks’ treatment. Another patient who had unilateral chronic childhood pyelonephritis became infected after 60 weeks. A further patient, with a complete duplex system who did not show vesicoureteric reflux, developed bacteriuria after 39 weeks of treatment. A fourth patient with a renal calculus became infected 19 weeks after the treatment commenced. The remaining woman developed asymptomatic bacteriuria after 9 weeks of nitrofurantoin and was subsequently shown to have an infected cyst in the upper pole of the left kidney. As far as could be ascertained these five patients were continuing to take the treatment. Of the ten women who did not develop bacteriuria, seven had the radiological appearance of chronic childhood pyelonephritis, two of phenacetin nephropathy, and one had a renal calculus. They all remained free of infection although they had previously suffered repeated attacks of urinary symptoms with bacteriuria. No patient with an abnormal intravenous pyelogram developed side-effects to women
acid. When the code of all fifty patients had been broken at the end of the double-blind trial, it was found that the initial infecting organism and the type of antibacterial agent used for its eradication were distributed similarly between the nitrofurantoin and the placebo group.
Nitrofurantoin group.-Twenty-five
treatment.
Double-blind Trial The organisms responsible for the last symptomatic episode of urinary-tract infection suffered by each patient before being included in the double-blind trial are shown in table 11. In 62 % (thirty-one patients) the infections were due to Escherichia coli, while in 26 % (thirteen patients) the infections were due to coagulasenegative staphylococci. The bacteriuria was eradicated from thirty-five women by nitrofurantoin, from twelve by co-trimoxazole (trimethoprim-sulphamethoxazole), and from the remaining three by nalidixic
*
1
stopped
were
(chi-squared 10-5, r<001). Discussion Nitrofurantoin has been used treatment
TABLE III-WOMEN WITH RECURRENT SYMPTOMATIC URINARY-TRACT AND NORMAL RENAL FUNCTION TREATED WITH
women
treated with 50 mg. of nitrofurantoin each night, and twenty-two of them remained free of infection throughOne patient had lowerout the period of study. urinary-tract symptoms 19 weeks after treatment The organism, obtained by suprapubic began. aspiration of urine, was a coagulase-negative staphylococcus. A second patient became infected asymptomatically with E. coli after 28 weeks’ treatment. The third patient also had an asymptomatic infection. She had stopped her tablets after 10 weeks. A suprapubic aspiration of urine 2 weeks later demonstrated the presence of E. coli (table ill). No patient receiving nitrofurantoin 50 mg. at night developed side-effects. The twenty-two women who did not develop bacteriuria were followed for a mean period of 34-9 weeks (range 5-53). Placebo group.-Twenty-five women were given the placebo. Only ten remained free of infection. Thirteen of the fifteen women who became infected had bacteriuria within 26 weeks of starting on the placebo (table III). In nine patients the infection presented with lower-urinary-tract symptoms and in one with acute pyelonephritis. The remaining five women were symptom-free. The ten women who did not develop bacteriuria were followed for a mean period of 19-3 weeks (range 4-39). The difference between the bacterial recurrence rate in patients receiving the placebo and those receiving nitrofurantoin was statistically significant
50 mg.
treatment 2
of
successfully in the urinary-tract infection for 20 years. It
INFECTIONS,
A NORMAL URINARY
TRACT,
NITROFURANTOIN OR PLACEBO EACH NIGHT
weeks before infection.
1114
has fallen from favour, however, because of the very high frequency of gastrointestinal side-effects associated with the manufacturer’s recommended dose of 100 mg. 6-hourly; this dose seems unnecessarily large. Nitrofurantoin is well absorbed and is rapidly excreted in the urine. The serum half-life of nitrofurantoin in patients with normal renal function is 20 minutes; plasma binding is 60% 6,7; a proportion of the drug is rapidly bound to red-blood-cell walls 8;the clearance of nitrofurantoin is 3-2 times that of inulin; and 25-50% of the orally administered dose is recovered in the urine. Nitrofurantoin has been shown by autoradiographic techniques to be present in the lumen of tubules in the medulla and in the interstitial spaces.10 Concentrations in the renal lymph are considerably higher than those in the blood. 1’Compared with the sulphonamides, nitrofurantoin has been shown not to cause any changes in the faecal flora of hospital or domiciliary patients,12while the development of resistant bacterial strains during its administration is virtually unknown.I3 The mode of action of nitrofurantoin is thought to be by inhibition of the formation of acetyl coenzyme A and thus a breakdown of the Krebs cycle. The drug is effective against a wide variety of gram-negative and grampositive organisms and is bactericidal in action.13, 14 A dosage of 50 mg. nitrofurantoin every 6 hours results in urinary concentrations that invariably exceed 5 mg. per 100 ml. throughout the day. On the basis of bacterial-sensitivity determinations this level has been found to be sufficient5 The recovery of nitrofurantoin in the urine is linearly related to the creatinine clearance. Below a clearance of 60 ml. per minute inadequate concentrations appear in the urine.9 The serum concentration of the drug increases in renal failure, but only to about 5-6 g. per ml., probably because of rapid extrarenal inactivation.9 Such levels, although low, are potentially toxic. In renal failure, therefore, the drug is valueless, and may be dangerous because such patients may develop
peripheral neuropathy.166 Nitrofurantoin in high dosage (50-100 mg. four times a day) has been shown to be highly effective in preventing recurrences of urinary-tract-infection over periods of 1 month to 3 years. 15 The first trials in the use of nitrofurantoin in small nocturnal doses were described by Little.17," Fiftysix pregnant bacteriuric women were treated with 100 mg. nitrofurantoin each night: in forty-four (79 %) the infection was eradicated and the urine remained uninfected, six patients did not take the drug, one had sideeffects and the treatment was discontinued, and the urinary infection persisted in five of those who continued to take the drug. These results in bacteriuric pregnant women have been confirmed. 19 There are two reports of the use of nitrofurantoin in small doses at night in women who were not pregnant..20,21. In one study, 2twenty women were treated with 100 mg. of nitrofurantoin each night for 6 months as part of a double-blind comparative trial of that drug with cycloserine and sulphadimidine in the treatment of urinary infection due to E. coli. During the 6 months’ treatment period only one of the twenty women treated with nitrofurantoin devel-
oped bacteriuria. From the bacteriological viewpoint nitrofurantoin proved the most successful of the three drugs used in this trial, but it caused slightly more troublesome side-effects. 20 In the other study,21 forty-four patients with recurrent urinary infections were allocated at random placebo, 100 mg. of nitrofurantoin at night, or 1 g. methanamine mandelate at night. Nightly nitro-
to
furantoin and methanamine were superior to the placebo in reducing the number of episodes of bacteriuria. Nitrofurantoin, but not methanamine, was superior to the placebo in reducing the number of episodes of renal symptoms requiring treatment. The results of our initial and double-blind trials in women with recurrent urinary infections clearly show that 50 mg. nitrofurantoin taken each night is highly successful in preventing bacteriuria. In these patients renal function was normal. The double-blind trial did not include women with radiological changes in the urinary tract. The initial trial, however, demonstrates that women with normal renal function and various pyelographic abnormalities can also be maintained for long periods without developing a further episode of bacteriuria. 50 and 100 mg. of nitrofurantoin at night were well tolerated. The frequency of side-effects, including nausea, was low. We suggest that most women who have recurrent attacks of urinary-tract symptoms with bacteriuria and who have normal renal function will benefit from treatment with 50 mg. nitrofurantoin each night. We wish to thank Nurse G. Stacey, Miss E. Tiverios, and Miss C. Fitzpatrick for technical assistance. The work was carried out in premises provided by Cerebos Ltd. and Ockley Bricks Ltd. Smith Kline and French Laboratories provided the placebo tablets. Requests for reprints should be addressed to P. E. G. REFERENCES 1. 2.
Gallagher, D. J. A., Montgomerie, J. Z., North, J. D. K. Br. med. J. 1965, i, 622. Mond, N. C., Percival, A., Williams, J. D., Brumfitt, W. Lancet,
1965, i, 514. O’Grady, F. W., Richards, B., McSherry, M. A., O’Farrell, S. M., Cattell, W. R. ibid. 1970, ii, 1208. 4. Monzon, O. T., Ory, E. M., Dobson, H. L., Carter, E., Yow, E. M. New Engl. J. Med. 1958, 259, 764. 5. Fairley, K. F., Bond, A. G., Brown, R. B., Habersberger, P. Lancet, 1967, ii, 427. 6. Reckendorf, H. K., Castringius, R. G., Spingler, H. K. in Antimicrobial Agents and Chemotherapy (edited by J. C. Sylvester); p. 531. Chicago, 1962. 7. Schirmeister, J., Stefani, F., Willmann, H., Hallauer, W. in Antimicrobial Agents and Chemotherapy (edited by G. L. Hobby); p. 233. Washington, 1965. 8. Little, P. J., Bailey, R. R. Australas. Ann. med. 1968, 17, 349. 9. Sachs, J., Geer, T., Noell, P., Kunin, C. M. New Engl. J. Med. 1968, 278, 1032. 10. Currie, G. A., Little, P. J., McDonald, S. J. Nephron, 1966, 3, 282. 11. Katz, Y. J., Cockett, A. T. K., Moore, R. S. Life Sci. 1964, 3, 1249. 12. Lincoln, K., Lidin-Janson, G., Winberg, J. in Renal Infection and Renal Scarring (edited by P. Kincaid-Smith and K. F. Fairley); p. 151. Melbourne, 1970. 13. Waisbren, B. A., Crowley, W. Archs intern. Med. 1955, 95, 653. 14. Jawetz, E., Hopper, J., Jr., Smith, D. R. ibid. 1957, 100, 549. 15. Lippmann, R. W., Wrobel, C. J., Rees, R., Hoyt, R. J. Urol. 1958, 80, 77. 16. Uesu, C. T. Ohio St. med. J. 1962, 58, 53. 17. Little, P. J. Lancet, 1966, ii, 925. 18. Little, P. J. in Symposium on Pyelonephritis; p. 17. Edinburgh, 3.
1967. 19. Bailey, R. R. N.Z. med. J. 1970, 71, 216. 20. Ormonde, N. W. H., Gray, J. A., Murdoch, J.
McC., Wallace,
E., Brumfitt, W., Pursell, R., Regan, J. W. J. infect. Dis. 1969, 120, 82. 21. Kincaid-Smith, P., Friedman, A., Nanra, R. S. in Renal Infection and Renal Scarring (edited by P. Kincaid-Smith and K. F. Fairley); p. 165. Melbourne, 1970.
PREVENTION OF URINARY-TRACT INFECTION WITH LOW-DOSE NITROFURANTOIN R. R. BAILEY* P. E. GOWER
A. P. ROBERTS H. E. DE WARDENER
Renal Infection Unit, Department of Medicine, Charing Cross Hospital Medical School, Fulham Hospital, London W.6
One hundred and two women with normal renal function having recurrent urinary-tract infections took part in trials of low-dose nitrofurantoin at night to prevent recurrence of infection. In the first trial, 50-100 mg. of nitrofurantoin was used and in the double-blind trial the dose was 50 mg. In the first trial the drug was given for periods up to 5 years and the double-blind trial lasted for up to 1 year. Fifteen of the fifty-two women in the first trial had an abnormal intravenous pyelogram. All the other patients had a normal intravenous pyelogram. Both trials demonstrated that such treatment is highly successful in reducing recurrences of infection, is acceptable to the patients, and almost free from side-effects.
Sum ary
Patients and Methods Initial Trial Women of any age referred to the urinary-infection clinic or seen in the casualty department with recurrent symptomatic urinary-tract infections were considered for inclusion in the trial. Only women who were not pregnant and had a serum-creatinine not exceeding 1-2 mg. per 100 ml. (estimated in anAutoAnalyzer ’) were included. Intravenous pyelography was done in all patients. Urinarytract infection was diagnosed if a specimen of urine obtained from the bladder by suprapubic aspiration was infected.4 The patient was then treated for 7-10 days with a standard dose of an antibacterial agent. Long-term treatment with nitrofurantoin was not started unless the urine obtained 7-14 days after completing the first treatment showed no significant growth. Fifty-two women were included in the trial. Each woman was instructed to take a single nitrofurantoin tablet each night after emptying her bladder immediately before going to bed. At first a 100 mg. dose was used, but later it was reduced to 50 mg. The women were seen at 4-14 weekly intervals for clinical assessment, and either a midstream urine or a urine sample collected by suprapubic aspiration was obtained for culture. The women were asked to contact the unit if they had symptoms referable to the urinary tract, at which time a specimen of bladder urine was obtained by suprapubic
aspiration. Double-blind Trial
Introduction
*
Present address: Renal Canada.
fifty women included in this trial all had a history of urinary-tract symptoms with bacteriuria. They pregnant and were premenopausal. They had a normal serum-creatinine and a radiologically normal urinary tract. The methods used for the diagnosis of The
WOMEN who have repeated attacks of frequency and dysuria are a difficult problem both in hospital and general practice. Only about one half of these women have bacteria multiplying within the urinary tract at the time that they are symptomatic, 1,2though many of those who are abacteriuric during one attack become bacteriuric subsequently.3 This has also been our own experience. Most women who get repeated attacks of lower-urinary-tract symptoms associated with bacteriuria have a radiologically normal urinary tract, and progressive impairment of renal function is rare. However, these episodes are very inconvenient and distressing for the patient and her family. Recurrent attacks of symptomatic urinary infection in women frequently follow sexual intercourse. Presumably, the urethral trauma that is induced makes it easier for an inoculum of bacteria to pass from the urethra into the bladder. The bacteria that have been introduced then multiply during the night. We considered that the presence of an antibacterial agent in the bladder urine overnight might eradicate any bacteria that have been introduced, and we describe here an initial trial and then a double-blind trial using low-dosage nitrofurantoin in an attempt to prevent recurrent urinary-tract infections. Unit, Victoria Hospital, London, Ontario,
recurrent were not
infection and its initial treatment were the same as in the previous trial. Later, when the urine showed no significant growth, the patient was admitted at random to the doubleblind trial. Each patient received either 50 mg. of nitrofurantoin each night or an identical placebo tablet. The women were seen every 4 weeks for the first 3 months and thereafter every 6-8 weeks for clinical assessment. A midstream urine was taken for culture, and if this specimen contained more than 10,000 pathogenic organisms per ml., the patient was recalled for a suprapubic aspiration of urine. Patients were also seen if urinary-tract symptoms developed, at which time a suprapubic sample of urine was obtained. If bacteriuria recurred, the treatment code was broken and the patient was withdrawn from the trial. Results
Initial Trial (table I) Women with a radiologically normal urinary
Thirty-seven
of the
fifty-two
women
trial had a normal intravenous pyelogram. They were treated with 50 or 100 mg. of nitrofurantoin each night for a mean period of almost a year. Only one woman developed bacteriuria. She presented with lower-urinary-tract symptoms 17 weeks after starting treatment (table i). The infecting organism was Klebsiella aerogenes localised to the upper urinary
TABLE I-WOMEN WITH RECURRENT SYMPTOMATIC URINARY-TRACT INFECTIONS AND NORMAL RENAL FUNCTION, TREATED WITH
5O-IOO mg.
tract.-
in the initial
NITROFURANTOIN EACH NIGHT
1113 tract
by the bladder-washout techniques Five of the
II-INITIAL INFECTING ORGANISMS OBTAINED BY SUPRAPUBIC ASPIRATION FROM PATIENTS SUBSEQUENTLY TREATED IN DOUBLE-BLIND TRIAL
TABLE
had side-effects from the treatthirty-seven ment. Three complained of nausea, which in two was eliminated by reducing the dose from 100 to 50 mg. daily; but in the third woman the treatment (50 mg.) had to be stopped after 11 weeks. The remaining two women with side-effects had a skin reaction after 26 weeks’ treatment. One, who was taking 50 mg. nitrofurantoin each night, had a widespread pruritic eruption of fine vesicles and pimples on the face, trunk, and extremities; the other, taking the 100 mg. dose, had an itchy generalised erythematous rash. Treatment was discontinued in both patients. Women with radiological abnormalities of urinary tract.-Fifteen women with recurrent symptomatic urinary-tract infection and a radiological abnormality of the urinary tract were treated in the same way for a mean period of 94 weeks. Five of these fifteen patients developed bacteriuria (table l). One woman who had obstructive atrophy of one kidney developed urinary infection after 56 weeks’ treatment. Another patient who had unilateral chronic childhood pyelonephritis became infected after 60 weeks. A further patient, with a complete duplex system who did not show vesicoureteric reflux, developed bacteriuria after 39 weeks of treatment. A fourth patient with a renal calculus became infected 19 weeks after the treatment commenced. The remaining woman developed asymptomatic bacteriuria after 9 weeks of nitrofurantoin and was subsequently shown to have an infected cyst in the upper pole of the left kidney. As far as could be ascertained these five patients were continuing to take the treatment. Of the ten women who did not develop bacteriuria, seven had the radiological appearance of chronic childhood pyelonephritis, two of phenacetin nephropathy, and one had a renal calculus. They all remained free of infection although they had previously suffered repeated attacks of urinary symptoms with bacteriuria. No patient with an abnormal intravenous pyelogram developed side-effects to women
acid. When the code of all fifty patients had been broken at the end of the double-blind trial, it was found that the initial infecting organism and the type of antibacterial agent used for its eradication were distributed similarly between the nitrofurantoin and the placebo group.
Nitrofurantoin group.-Twenty-five
treatment.
Double-blind Trial The organisms responsible for the last symptomatic episode of urinary-tract infection suffered by each patient before being included in the double-blind trial are shown in table 11. In 62 % (thirty-one patients) the infections were due to Escherichia coli, while in 26 % (thirteen patients) the infections were due to coagulasenegative staphylococci. The bacteriuria was eradicated from thirty-five women by nitrofurantoin, from twelve by co-trimoxazole (trimethoprim-sulphamethoxazole), and from the remaining three by nalidixic
*
1
stopped
were
(chi-squared 10-5, r<001). Discussion Nitrofurantoin has been used treatment
TABLE III-WOMEN WITH RECURRENT SYMPTOMATIC URINARY-TRACT AND NORMAL RENAL FUNCTION TREATED WITH
women
treated with 50 mg. of nitrofurantoin each night, and twenty-two of them remained free of infection throughOne patient had lowerout the period of study. urinary-tract symptoms 19 weeks after treatment The organism, obtained by suprapubic began. aspiration of urine, was a coagulase-negative staphylococcus. A second patient became infected asymptomatically with E. coli after 28 weeks’ treatment. The third patient also had an asymptomatic infection. She had stopped her tablets after 10 weeks. A suprapubic aspiration of urine 2 weeks later demonstrated the presence of E. coli (table ill). No patient receiving nitrofurantoin 50 mg. at night developed side-effects. The twenty-two women who did not develop bacteriuria were followed for a mean period of 34-9 weeks (range 5-53). Placebo group.-Twenty-five women were given the placebo. Only ten remained free of infection. Thirteen of the fifteen women who became infected had bacteriuria within 26 weeks of starting on the placebo (table III). In nine patients the infection presented with lower-urinary-tract symptoms and in one with acute pyelonephritis. The remaining five women were symptom-free. The ten women who did not develop bacteriuria were followed for a mean period of 19-3 weeks (range 4-39). The difference between the bacterial recurrence rate in patients receiving the placebo and those receiving nitrofurantoin was statistically significant
50 mg.
treatment 2
of
successfully in the urinary-tract infection for 20 years. It
INFECTIONS,
A NORMAL URINARY
TRACT,
NITROFURANTOIN OR PLACEBO EACH NIGHT
weeks before infection.
1114
has fallen from favour, however, because of the very high frequency of gastrointestinal side-effects associated with the manufacturer’s recommended dose of 100 mg. 6-hourly; this dose seems unnecessarily large. Nitrofurantoin is well absorbed and is rapidly excreted in the urine. The serum half-life of nitrofurantoin in patients with normal renal function is 20 minutes; plasma binding is 60% 6,7; a proportion of the drug is rapidly bound to red-blood-cell walls 8;the clearance of nitrofurantoin is 3-2 times that of inulin; and 25-50% of the orally administered dose is recovered in the urine. Nitrofurantoin has been shown by autoradiographic techniques to be present in the lumen of tubules in the medulla and in the interstitial spaces.10 Concentrations in the renal lymph are considerably higher than those in the blood. 1’Compared with the sulphonamides, nitrofurantoin has been shown not to cause any changes in the faecal flora of hospital or domiciliary patients,12while the development of resistant bacterial strains during its administration is virtually unknown.I3 The mode of action of nitrofurantoin is thought to be by inhibition of the formation of acetyl coenzyme A and thus a breakdown of the Krebs cycle. The drug is effective against a wide variety of gram-negative and grampositive organisms and is bactericidal in action.13, 14 A dosage of 50 mg. nitrofurantoin every 6 hours results in urinary concentrations that invariably exceed 5 mg. per 100 ml. throughout the day. On the basis of bacterial-sensitivity determinations this level has been found to be sufficient5 The recovery of nitrofurantoin in the urine is linearly related to the creatinine clearance. Below a clearance of 60 ml. per minute inadequate concentrations appear in the urine.9 The serum concentration of the drug increases in renal failure, but only to about 5-6 g. per ml., probably because of rapid extrarenal inactivation.9 Such levels, although low, are potentially toxic. In renal failure, therefore, the drug is valueless, and may be dangerous because such patients may develop
peripheral neuropathy.166 Nitrofurantoin in high dosage (50-100 mg. four times a day) has been shown to be highly effective in preventing recurrences of urinary-tract-infection over periods of 1 month to 3 years. 15 The first trials in the use of nitrofurantoin in small nocturnal doses were described by Little.17," Fiftysix pregnant bacteriuric women were treated with 100 mg. nitrofurantoin each night: in forty-four (79 %) the infection was eradicated and the urine remained uninfected, six patients did not take the drug, one had sideeffects and the treatment was discontinued, and the urinary infection persisted in five of those who continued to take the drug. These results in bacteriuric pregnant women have been confirmed. 19 There are two reports of the use of nitrofurantoin in small doses at night in women who were not pregnant..20,21. In one study, 2twenty women were treated with 100 mg. of nitrofurantoin each night for 6 months as part of a double-blind comparative trial of that drug with cycloserine and sulphadimidine in the treatment of urinary infection due to E. coli. During the 6 months’ treatment period only one of the twenty women treated with nitrofurantoin devel-
oped bacteriuria. From the bacteriological viewpoint nitrofurantoin proved the most successful of the three drugs used in this trial, but it caused slightly more troublesome side-effects. 20 In the other study,21 forty-four patients with recurrent urinary infections were allocated at random placebo, 100 mg. of nitrofurantoin at night, or 1 g. methanamine mandelate at night. Nightly nitro-
to
furantoin and methanamine were superior to the placebo in reducing the number of episodes of bacteriuria. Nitrofurantoin, but not methanamine, was superior to the placebo in reducing the number of episodes of renal symptoms requiring treatment. The results of our initial and double-blind trials in women with recurrent urinary infections clearly show that 50 mg. nitrofurantoin taken each night is highly successful in preventing bacteriuria. In these patients renal function was normal. The double-blind trial did not include women with radiological changes in the urinary tract. The initial trial, however, demonstrates that women with normal renal function and various pyelographic abnormalities can also be maintained for long periods without developing a further episode of bacteriuria. 50 and 100 mg. of nitrofurantoin at night were well tolerated. The frequency of side-effects, including nausea, was low. We suggest that most women who have recurrent attacks of urinary-tract symptoms with bacteriuria and who have normal renal function will benefit from treatment with 50 mg. nitrofurantoin each night. We wish to thank Nurse G. Stacey, Miss E. Tiverios, and Miss C. Fitzpatrick for technical assistance. The work was carried out in premises provided by Cerebos Ltd. and Ockley Bricks Ltd. Smith Kline and French Laboratories provided the placebo tablets. Requests for reprints should be addressed to P. E. G. REFERENCES 1. 2.
Gallagher, D. J. A., Montgomerie, J. Z., North, J. D. K. Br. med. J. 1965, i, 622. Mond, N. C., Percival, A., Williams, J. D., Brumfitt, W. Lancet,
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