of recurring urinary tract infection Prophylaxis in females: a comparison of nitrofurantoin with trimethoprim-sulfamethoxazole A.R. RONALD, MD, FRCP[C]; G.K.M. HARDING, MD, FRCP[C]; R. MATHIAS, MD; C.K. WONG, MD; P. MUIR, RN
Summary: Twenty-eight females with recurrent urinary tract infection were treated to eradicate their existing infections and then observed for recurrences while receiving one of the three following prophylactic regimens for 6 to 12 months: nitrofurantoin, 50 mg daily; one half tablet of trimethoprim-sulfamethoxazole (TMP-SMX) twice weekly; or one tablet of TMP-SMX once weekly. Preadolescent girls received half the adult doses. After completion of the course of the prophylactic agent the patients were followed up at bimonthly intervals until infection recurred. After eradication of this new infection they were started on another prophylactic regimen. Six infections (1.0 / patient-year) recurred in patients on nitrofurantoin, four infections (0.4 / patient-year) recurred in those receiving twice weekly TMP-SMX, and 12 infections (1.3 / patient-year) in those receiving once weekly TMP-SMX. The mean interval between discontinuation of prophylaxis and recurrence of infection was 2.6 months. TMP-SMX in the doses used eliminated aerobic gram-negative rods from swabs from the anal canal in many patients. Gram-negative organisms resistant to trimethoprim did not cause infection either during or after therapy. Resume: Prophylaxis de Yinfection urinaire rScidivante chez la femme: comparaison de la nitrofurantoine avec le
trimethoprime-sulfamSthoxazole Nous avons traite 28 femmes souffrant d'infection recidivante des voies urinaires en vue d'eliminer I'infection existante et avons ensuite note les rechutes quand elles recevaient une des trois medications prophylactiques suivantes pendant une periode variant de 6 a 12 mois: nitrofurantoine, 50 mg par jour; un demi comprime de trimethoprime-sulfamethoxazole (TMP-SMX) deux fois par semaine; ou un comprime de TMP-SMX une fois par semaine. Les filles preadolescentes recevaient la moitie de la dose adulte. Une fois terminee le cours prophylactique, les malades etaient revues aux intervalles bimensuels jusqu'a reapparition de I'infection. Une fois cette nouvelle infection eliminee, on soumettait les malades a un nouveau traitement prophylactique. Les resultats ont ete les suivants: 6 infections ont recidive (1.0 / malade-an) chez les malades recevant la
nitrofurantoine, 4 infections (0.4 / malade-an) ont recidive chez les malades recevant le TMP-SMX deux fois par semaine et 12 infections (1.3 / malade-an) ont eu une rechute avec la posologie de TMP-SMX une fois par semaine. L'intervalle moyen entre la cessation du traitement prophylactique et la resurgence de I'infection etait de 2.6 mois. Aux posologies utilisees, le TMP-SMX eliminait les bdtonnets gram-negatifs aerobies preleves sur des frottis du conduit anal chez de nombreux malades. Les organismes gram-negatifs resistants au trimethoprime n'ont pas provoque d'infection, ni durant ni apres le traitement.
Females with multiple closely spaced episodes of urinary tract infection are benefited by continuous prophylaxis to prevent recurrences following eradication of existing infections.1'3 In a previous report from this institution prophylaxis with trimetho¬ prim, 40 mg combined with sulfamethoxazole, 200 mg daily hs was compared with methenamine mandelate, 2 g daily, and with sulfamethoxazole, 500 mg hs and with no prophylaxis.l Trime¬ thoprim-sulfamethoxazole (TMP-SMX) was the most effective of the three regimens, preventing both periurethral colonization with Enterobacteriaceae and infections with gram-negative rods during 9.2 years of cumulative experience. The present study is an interim report on the use of continuous prophylaxis in 28 females with documented evidence of frequent reinfections. The investigation was designed to study prophylaxis with nitrofurantoin, to determine the effectiveness of less frequent administration of TMP-SMX, to study alterations in aerobic bacterial flora of the periurethral area and anal canal, and to evaluate the frequency of bacterial resistance to nitrofurantoin, trimethoprim and sulfamethoxazole during pro¬
phylaxis.
Methods Patient selection
subjects were 18 nonpregnant women and 10 preadoles¬ girls who met the following conditions: at least two documented reinfections in the year before entry into the study, occurring despite effective therapy for each episode and instructions concerning postcoital micturition in sexually active wom¬ en; maintenance of bimonthly outpatient visits to the urinary clinic; immediate consultation at the first symptoms of infec¬ tion; no antimicrobial medication during the study period without permission; serum creatinine concentration of 1.5 mg/dl The
cent
From the departments of medical microbiology and medicine, University of Manitoba and the Health Sciences Centre, Winnipeg
or
Supported in part by a grant from Burroughs Wellcome Ltd. Reprint requests to: Dr. A.R. Ronald, Infectious diseases, Health Sciences Centre, 700 William Ave., Winnipeg, Man. R3E 0Z3
Regimens Prophylactic regimens were not started until existing urinary CMA JOURNAL/JUNE 14, 1975/VOL. 112 13S
less; and no instrumentation or catheterization.
tract infections had been eradicated. Once started, they were continued in most cases for 6 months but in a few patients for as long as 12 months. Specific appropriate antibacterial therapy was given concurrently for infections as they were detected. The three regimens were: nitrofurantoin, 50 mg daily at bedtime; trimethoprim, 40 mg with sulfamethoxazole, 200 mg (half a tablet) every Sunday and Wednesday at bedtime; and trimetho¬ prim, 80 mg in combination with sulfamethoxazole, 400 mg (one tablet) once weekly, each Wednesday, at bedtime. The 10 girls each received half the adult dose taken according to the same schedule. After completion of each period of prophylactic therapy the patients were followed up at bimonthly intervals on no medication until infection recurred. Once the new infection was eradicated they were started on a different prophylactic
regimen.
Collection of specimens
bimonthly
intervals and whenever an anal canal swab and a clean-voided midstream urine specimen were obtained. Patients were questioned in regard to urinary symp¬ toms, drug compliance and intolerance during the preceding month. Specimens were collected with the patient in the lithotomy position. After spreading the labia to expose the urethral meatus, a sterile, cotton-tipped applicator was swept with a circular motion around the entire urethra. Then a swab was inserted into the anal canal a distance of 2 cm. The swabs were inserted into sterile screw-capped glass tubes containing 5 ml of sterile physiologic saline. Finally a clean-voided midstream urine specimen was obtained. Patients
were seen at
symptoms occurred. At each visit a periurethral swab,
Bacteriologic techniques The tubes containing the swabs were vortexed at high speed for 1 minute and then amounts of 0.001 and 0.01 ml were inoculated onto sheep-blood agar, MacConkey agar and chocolate agar. After 24 hours of incubation, colony counts of all organisms were made. Sensitivity tests were performed on all urinary pathogens, using a single-disc diffusion method with an inoculum of approximately 10** organisms/ml on Mueller-Hinton agar.
Results This report concerns itself with 47 courses of prophylaxis, consisting of 12 courses of daily nitrofurantoin (cumulative experience of 5.8 years), 19 courses of twice weekly TMP-SMX (cumulative experience, 11.5 years) and 16 courses of weekly TMP-SMX (cumulative experience, 9.0 years). Fig. 1 depicts the course of a patient during two prophylactic regimens. In April 1973, after eradication of a symptomatic
Escherichia coli infection with a curative course of TMP-SMX in a conventional dose, she was started on a continuous course of TMP-SMX, one half tablet weekly, and remained free of recurrences and symptoms. Towards the end of this course both the periurethral and anal canal cultures were negative for E. coli and other aerobic gram-negative rods. After medication was discontinued in October 1973, anal canal cultures again grew E. coli and within 10 weeks the patient had a symptomatic recurrence of E. coli infection. Again the infection was eradicat¬ ed and the patient began a second course of TMP-SMX, one quarter tablet twice weekly, for 7 months. When prophylactic therapy was stopped she became reinfected with another strain of E. coli within 3 months. Six infections have occurred during 5.8 years of continuous nitrofurantoin therapy, an incidence of 1.0 infections per year. In four of these the etiologie agent was E. coli, one of which 14S CMA JOURNAL/JUNE 14, 1975/VOL. 112
resistant to nitrofurantoin. Two were caused by Klebsiella with intermediate sensitivity to nitrofurantoin. Four infections have developed during 11.3 years of twice weekly TMP-SMX prophylaxis, an incidence of 0.4 infections per year. Sulfonamide-resistant E. coli were responsible for two infec¬ tions, a Citrobacter freundii for one and Staphylococcus years of weekly epidermidis for one. During 9 cumulative TMP-SMX, 12 infections occurred, an annual incidence of 1.3. Seven of these infections were due to E. coli, all sulfonamideresistant. One infection caused by Klebsiella species, one by Enterobacter species and one by Streptococcus faecalis also infection developed. Two further patients in whom symptomatic without treated were on were while therapy they developed having a urine culture performed so that the causative organism is unknown. All the organisms responsible for infection, except two that were gram-positive, were sensitive to trimethoprim, whatever the type of prophylaxis employed. Follow-up of 6 months' duration or longer has been obtained subsequent to 32 courses of therapy. Four of the 11 patients on nitrofurantoin, 1 of the 18 on twice weekly TMP-SMX, and 3 of the 16 on once weekly TMP-SMX were infected at the Two pa¬ completion of their course of prophylactic therapy.with twice tients, one treated with nitrofurantoin and one weekly TMP-SMX, have not had a recurrence during 12 months of follow-up and have been discharged from the study as no longer subject to frequent recurrent urinary tract infections. All other patients have had a recurrence caused by E. coli. The mean interval before recurrence in 4 patients treated with nitrofurantoin was 3.7 months, in 11 treated with twice weekly TMP-SMX 2.1 months and in 7 treated with once weekly TMP-SMX 2.9 months. Twenty-one of the 22 recurrences were due to E. coli that were sensitive to nitrofurantoin, sulfonamides and trimethoprim. One patient on twice weekly TMP-SMX had a recurrence due to a sulfonamide-resistant strain of E. coli. Table I summarizes the results of periurethral and anal canal cultures during prophylaxis with each of the three regimens. In spite of the reduced frequency of administration of TMP-SMX, 33 of 95 anal canal swabs failed to grow any aerobic gramnegative rods. In contrast, all anal canal cultures from patients on daily nitrofurantoin, with only one exception, grew E. coli or other aerobic gram-negative rods. There was no significant difference between the three regimens in regard to periurethral colonization with E. coli, other Enterobacteriaceae or Pseudo¬ monas species. Although there appeared to be a tendency for TMP-SMX to select out group D streptococci in the periurethr¬ al flora, this was not significant. Trimethoprim-sulfamethox¬ azole prophylaxis was frequently associated with the isolation of sulfonamide-resistant' E. coli from the anal canal swab but again this was not significantly more common than with daily nitrofurantoin therapy. Periurethral and anal canal cultures grew trimethoprim-resistant Enterobacteriaceae in only one patient in the course of the study. This organism, a Klebsiella species, required a level of trimethoprim of 12.5 /ng/ml to was
species
'.lip^L.,.
..:iiiiiBii3i
||||§|
FIG. 1.Course of 12-year-old girl with urinary tract infection treated by two different prophylactic regimens.
inhibit growth. However, the patient did not develop a urinary tract infection during TMP-SMX prophylaxis and the organism disappeared spontaneously. None of the patients experienced untoward effects from low-dose trimethoprim-sulfamethoxazole. Six of the 28 patients had a history of intolerance to nitrofurantoin and could not follow this therapeutic regimen. Discussion Continuous daily long-term low-dose chemotherapy with a number of antimicrobial agents, including nitrofurantoin3'4 sulfonamides,1'4 trimethoprim-sulfamethoxazole,1'3 methanamine salts1 and cephalexin,5 has been shown to prevent recurrences of urinary tract infection. At present a major problem in the management of urinary tract infection in females is the high rate of recurrence, usually due to reinfection by bowel and perineal flora.6 Physicians treating urinary tract infection must clearly differentiate between eradication, suppression and prophylaxis. The present study only pertains to prophylaxis in females with closely spaced reinfections and a relatively normal urinary tract. Initial management, after excluding remediable abnormalities, should include an adequate daily fluid load, meticulous perineal hygiene, postcoital micturition if recurrences are related to sexual activity and double voiding if the patient has vesicoureteral reflux or a significant amount of residual urine. If these measures fail, chemoprophylaxis should be considered. At present there is no evidence that prophylactic treatment forestalls renal scarring or the development of renal failure in the minority who may run this course. However, recurrent morbidity can be prevented. The antimicrobial agent chosen for continuous prophylaxis depends on patient tolerance, efficacy in preventing recurrences, cost, effect on bacterial ecology and the potential harm to the individual or the community from the emergence of drug resistance. The optimal duration of prophylactic therapy is not known and probably should be individualized. O'Grady et a17 noted that patients maintained on continuous prophylaxis for 6 months or less seemed usually to become reinfected, whereas this was less likely in those maintained on therapy for longer periods. Brumfitt et al reported that only 36% of their series of 78 females had a recurrence within 6 months following a 6-month. course of low-dose prophylaxis.8 In school girls, Kunin noted that even some with repeated infections tended to stop having recurrences if each episode was effectively treated with a short course of chemotherapy.9 On the other hand, in the present highly selected series there is little evidence that prophylaxis prolonged for 6 to 12 months prevented later Table l-Periurethral and anal canal culturee during three prophylactic regimena
No.teken No aerobic gramnegative rods E. cciii sulfa-sensitive
Nitrofurantoin 50 mg daily
TMP-SMX 40/200 twice weekly
TMP-SMX 80/400 once weekly
.u
Ac
PU
AC
PU
AC
35
33
68
67
56
51
24
1
55
23
40
10
5
27
6
26
9
22
3
5
6
11
6
16
Refereuces
E. cciii
sulfa-resistant Other Enterobacterieceae Pseudomonessp. Group D Streptococcus sp.
recurrences. Following 22 courses of prophylaxis in patients with negative urine cultures at the completion of therapy, in only two was there no recurrence in 12 months; in the others the mean interval before recurrence was only 2.6 months. Fortunately all 20 recurrences were due to E. coil susceptible to both nitrofurantoin and trimethoprim and only 1 was resistant to sulfonamides. These infections were readily eradicated and afterwards the patient was started on an alternative prophylactic regimen. Once-daily sulfonamide prophylaxis with either sulfamethoxazole or sulfadimidine has been shown in controlled studies to reduce reinfections significantly."4 However, the selective pressure of sulfonamides on gastrointestinal aerobic gram-negative flora results within a few days in the replacement of susceptible by resistant strains, and subsequently infection with resistant strains is common.10 Nitrofurantoin is effective,2'4 as we have shown, and has little or no effect on either periurethral or stool flora.10 Although E. coil seldom emerges resistant, many other Enterobacteriaceae are naturally resistant and these may be responsible for reinfections.1 1 Also, a significant number of patients are not able to tolerate even low doses of nitrofurantom.4 Cattell et al showed that TMP-SMX was effective in preventing recurrent urinary tract infection.3 In a few patients they noted that recurrences could be prevented with thrice weekly therapy. Other studies have since confirmed the usefulness of TMP-SMX in prophylaxis of urinary tract infection."8"2 The efficacy of less frequent administration of this combination may be related to the kinetics of the trimethoprim component and its prolonged activity in the urine following a single dose.13 The reservoir for urinary pathogens is the normal colonic microflora. Trimethoprim-sulfamethoxazole in its usual therapeutic dose can have a marked effect on the aerobic gramnegative stool flora.14 In a previous study it was noted that daily low dose therapy with TMP-SMX prevented colonization of the periurethral area by Enterobacteriaceae.1 In the present series less frequent TMP-SMX administration and daily nitrofurantoin appeared to have little effect on aerobic periurethral bacterial ecology. However, TMP-SMX, even in a total dose of one tablet a week or less, eliminated aerobic gram-negative rods from anal canal swabs in many patients. It is not known if the effectiveness of this form of prophylaxis is due to intermittent urinary antimicrobial activity preventing the establishment of bacteria in the urinary tract or to a reduction in the bacterial reservoir with interruption of the sequence of events leading to infection. A major concern of prophylactic therapy is that resistant organisms may come to dominate the patient's flora and make subsequent infections more difficult to treat. This does occur with sulfonamide therapy.'0 Gram-negative organisms resistant to trimethoprim did not cause infection either during or after therapy in this study or in the earlier investigation.1 However, in one patient the perineum was colonized with a trimethoprimresistant Kiebsiella species and it is only logical to assume that urinary tract infections with resistant organisms will develop during prophylaxis. Long-term epidemiologic studies are needed to determine the significance of this potential risk of prophylaxis.
2 1
6 1
3 2
14 1
3 2
5 3
3
7
16
20
8
11
1. HARDING GKM, RONALD AR: A controlled study of antimicrobial
prophylaxis of recurrent urinary infection in women. N Engi J Med 291: 597, 1974
2. BAILEY RR, ROBERTS AP, GOWER PE, Ct al: Prevention of urinary tract infection with low-dose nitrofurantoin. Lance: 2:1112, 1971 3. CATTELL WR, CHAMBERLAIN DA, FRY 1K, Ct at: Long-term
control of bacteriuria. Br Med J 1: 377, 1971 4. ORMONDE NWH, GRAY JA, MURDOCH J McC, et al: Chronic bacteriuria due to Escherschia coIl. 1. Assessment of the value of combined short- and long-term treatment with cycloserine, nitrofurantoin and sulphadimidine. J Infect Dis 120: 82, 1969 5. FAIRLEY KF, HUBBARD M, WHITWORTH JA: Prophylactic longterm cephalexin in recurrent urinary infection. Med J Aust 1: 318, 1974
CMA JOURNAL/JUNE 14, 1975/VOL. 112
15S
6. STAMEY TA, TIMOTHY M, MILLAR M, et al: Recurrent urinary infections in adult women: the role of introital enterobacteria. Calif Med 115:1,1971 7. O'GRADY F, FRY 1K, MCSHERRY A, Ct al: Long-term treatment of
persistent or recurrent urinary infection with trimethoprim-sulfamethox-
azole. J Infect Dis 128 (suppl): 652, 1973 8. BRUMFITT W, PURSELL R, ORMONDE NWH, et al: Chronic
bacteruria due to Escherichia coil. II. Correlation of microbiological, radiological, and biochemical finding with the clinical results. J Infect Dis 120: 87, 1969 9. KUNIN CM: The natural history of recurrent bacteriuria in school girls. NEnglJ Med 282: 1443, 1970 10. WINBERO J, BERGSTROM T, LINCOLN K, et al: Treatment trials in urinary-tract infection (UTI) with special reference to the effect of
antimicrobials on the fecal and periurethral flora. Clin Nephrol 1: 142, 1973 11. TURCK M, RONALD AR, PETERSDORF RG: Susceptibility of Enterobacteriaceae to nitrofurantoin correlated with eradication of bacteriuria. Antimicrob Agents Chemother 6: 446, 1966 12. KINcAID- SMITH P. KALOWSKI 5, NANRA RS: Co-trimoxazole in urinary tract infection. Med J Aust 1: S49, 1973 13. CATTELL WR, SARDESON IM, SUTCLJFFE MB, et al: Kinetics of urinary bacterial response to antibacterial agents, in Urinary Tract Infection, edited by O'GRADY F, BRUMFITT W, London, Oxford U
Pr, 1968, p 227
14. MOORHOUSE EC, FARRELL W: Effect of co-trimoxazole on faecal enterobacteria: no emergence of resistant strains. J Med Microbiol 6: 249, 1973
Prophylactic chemotherapy with low-dosage trimethoprim-sulfamethoxazole following acute urinary tract infections in children NATHAN SHER,* MD, MRCPE, FRCP[C]
Summary: The cases of 10 children with acute and recurrent infection of the urinary tract are presented. Their ages were between 7 weeks and 9 years. Five of the children had been previously treated with a combination of sulfisoxazole, ampicillin. mandelamine and nitrofurantoin and four of these children had "breakthrough" infections. When trimethoprim-sulfamethoxazole was administered twice weekly no further infections were noted in four of these five patients. The second group of five children were started on trimethoprim-sulfamethoxazole from the start of their infection and treatment was continued twice weekly for 5 to 7 months. No recurrence of infection of the urine has been detected up to the present time. It is concluded that treatment with trimethoprim-sulfamethoxazole initiated at the outset of urinary tract infection and continued twice weekly is a valuable drug in children, provided the organism responsible for the infection is sensitive to this agent. RAsumA: Chimioth6rapie prophylactique avec une faible posologie de trim6thoprime-sulfam6thoxazole apr.s une infection aigue des voles urinaires chez I'enfant Nous prAsentons les cas de 10 enfants souffrant d'infection aigul et rAcidivante des voies urinaires. L'Age de ces enfants variait de 7 semaines A 9 ans. Cinq enfants avaient dejA etA traitAs avec une association de sulfisoxazole, d'ampicilline, de mandAlamine et de nitrofurantosne et quatre d'entre eux avalent subi des ricidives infectieuses. Par contre. A partir du moment oA on administra l'association jtrimAthoprime-sulfambthoxazole (TMP-SMX) deux fois par $*maine, aucune nouvelle pouss6e infectieuse ne put Atre observ6e chez quatre des cinq malades. Chez le second *.p.j.t.Cfl. of pediatrics, North York General Hospital, and lODE Children's Centre, Willowdale, Ont. Reprint requests to: Dr. Nathan Sher, North York Medical Arts Bldg., 1333 Sheppard Ave. E, Willowdale, Ont.
16S CMA JOURNAL/JUNE 14,1975/VOL. 112
groupo do cinq onfants le traitomont au TMP-SMX a AtA commoncA dis le dAbut do l'infection, A Ia posologie do doux doses par somaino, ot ii a AtA poursuivi pendant uno pAriodo variant do 5 A 7 mois. Jusqu'A prAsont, aucune rAcidivo do I'infoction urinairo n'a AtA notAo. Nous croyons donc pouvoir concluro quo le traitemont au TMP-SMX, amorce dAs lo dAbut do I'infoction urinairo A raison do doux doses par somaino ost uno mAdication prAciouso choz l'onfant. A condition evidemmont quo I'organismo responsablo do l'infoction soit sensible A co mAdicament.
It is generally agreed that long-term treatment of urinary tract infection in children will prevent progressive renal damage. Of 72 children investigated by Steele, Leadbetter and Crawford in 1963, 13 (18%) died in the 20-year period 1940 to 1961 and in only 2 was the cause of death not related to their renal disease; of the remainder, 37% gave evidence of persistent or recurrent disease.1 Consequently, most physicians will treat children with acute infection of the urinary tract for at least 3 to 6 months and in many cases much longer. Gower showed that continuous therapy was more effective than intermittent treatment in controlling symptomatic relapses.2 Forbes and Drummond have treated 51 children with recurrent urinary tract infection with trimethoprim-sulfamethoxazole for up to 22 months and all were free from infection during the course of therapy.3 There are many problems in treating a child for a lengthy period. Not the least of these is the failure of the patient to take the medication because of unpleasantness or other reason. Consequently, any treatment that is readily acceptable to both child and mother will improve the chances of rendering the urinary tract sterile and prevent relapse and the complications of renal damage. Another and perhaps even more difficult problem is to determine whether the urinary tract is truly free from infection, because of the difficulty of obtaining a clean specimen of urine from an infant or young child. Cattell and his colleagues from St. Bartholomew's Hospital, London, England, in their studies of the kinetics of urinary
Summary: Twenty-eight females with recurrent urinary tract infection were treated to eradicate their existing infections and then observed for recurrences while receiving one of the three following prophylactic regimens for 6 to 12 months: nitrofurantoin, 50 mg daily; one half tablet of trimethoprim-sulfamethoxazole (TMP-SMX) twice weekly; or one tablet of TMP-SMX once weekly. Preadolescent girls received half the adult doses. After completion of the course of the prophylactic agent the patients were followed up at bimonthly intervals until infection recurred. After eradication of this new infection they were started on another prophylactic regimen. Six infections (1.0 / patient-year) recurred in patients on nitrofurantoin, four infections (0.4 / patient-year) recurred in those receiving twice weekly TMP-SMX, and 12 infections (1.3 / patient-year) in those receiving once weekly TMP-SMX. The mean interval between discontinuation of prophylaxis and recurrence of infection was 2.6 months. TMP-SMX in the doses used eliminated aerobic gram-negative rods from swabs from the anal canal in many patients. Gram-negative organisms resistant to trimethoprim did not cause infection either during or after therapy. Resume: Prophylaxis de Yinfection urinaire rScidivante chez la femme: comparaison de la nitrofurantoine avec le
trimethoprime-sulfamSthoxazole Nous avons traite 28 femmes souffrant d'infection recidivante des voies urinaires en vue d'eliminer I'infection existante et avons ensuite note les rechutes quand elles recevaient une des trois medications prophylactiques suivantes pendant une periode variant de 6 a 12 mois: nitrofurantoine, 50 mg par jour; un demi comprime de trimethoprime-sulfamethoxazole (TMP-SMX) deux fois par semaine; ou un comprime de TMP-SMX une fois par semaine. Les filles preadolescentes recevaient la moitie de la dose adulte. Une fois terminee le cours prophylactique, les malades etaient revues aux intervalles bimensuels jusqu'a reapparition de I'infection. Une fois cette nouvelle infection eliminee, on soumettait les malades a un nouveau traitement prophylactique. Les resultats ont ete les suivants: 6 infections ont recidive (1.0 / malade-an) chez les malades recevant la
nitrofurantoine, 4 infections (0.4 / malade-an) ont recidive chez les malades recevant le TMP-SMX deux fois par semaine et 12 infections (1.3 / malade-an) ont eu une rechute avec la posologie de TMP-SMX une fois par semaine. L'intervalle moyen entre la cessation du traitement prophylactique et la resurgence de I'infection etait de 2.6 mois. Aux posologies utilisees, le TMP-SMX eliminait les bdtonnets gram-negatifs aerobies preleves sur des frottis du conduit anal chez de nombreux malades. Les organismes gram-negatifs resistants au trimethoprime n'ont pas provoque d'infection, ni durant ni apres le traitement.
Females with multiple closely spaced episodes of urinary tract infection are benefited by continuous prophylaxis to prevent recurrences following eradication of existing infections.1'3 In a previous report from this institution prophylaxis with trimetho¬ prim, 40 mg combined with sulfamethoxazole, 200 mg daily hs was compared with methenamine mandelate, 2 g daily, and with sulfamethoxazole, 500 mg hs and with no prophylaxis.l Trime¬ thoprim-sulfamethoxazole (TMP-SMX) was the most effective of the three regimens, preventing both periurethral colonization with Enterobacteriaceae and infections with gram-negative rods during 9.2 years of cumulative experience. The present study is an interim report on the use of continuous prophylaxis in 28 females with documented evidence of frequent reinfections. The investigation was designed to study prophylaxis with nitrofurantoin, to determine the effectiveness of less frequent administration of TMP-SMX, to study alterations in aerobic bacterial flora of the periurethral area and anal canal, and to evaluate the frequency of bacterial resistance to nitrofurantoin, trimethoprim and sulfamethoxazole during pro¬
phylaxis.
Methods Patient selection
subjects were 18 nonpregnant women and 10 preadoles¬ girls who met the following conditions: at least two documented reinfections in the year before entry into the study, occurring despite effective therapy for each episode and instructions concerning postcoital micturition in sexually active wom¬ en; maintenance of bimonthly outpatient visits to the urinary clinic; immediate consultation at the first symptoms of infec¬ tion; no antimicrobial medication during the study period without permission; serum creatinine concentration of 1.5 mg/dl The
cent
From the departments of medical microbiology and medicine, University of Manitoba and the Health Sciences Centre, Winnipeg
or
Supported in part by a grant from Burroughs Wellcome Ltd. Reprint requests to: Dr. A.R. Ronald, Infectious diseases, Health Sciences Centre, 700 William Ave., Winnipeg, Man. R3E 0Z3
Regimens Prophylactic regimens were not started until existing urinary CMA JOURNAL/JUNE 14, 1975/VOL. 112 13S
less; and no instrumentation or catheterization.
tract infections had been eradicated. Once started, they were continued in most cases for 6 months but in a few patients for as long as 12 months. Specific appropriate antibacterial therapy was given concurrently for infections as they were detected. The three regimens were: nitrofurantoin, 50 mg daily at bedtime; trimethoprim, 40 mg with sulfamethoxazole, 200 mg (half a tablet) every Sunday and Wednesday at bedtime; and trimetho¬ prim, 80 mg in combination with sulfamethoxazole, 400 mg (one tablet) once weekly, each Wednesday, at bedtime. The 10 girls each received half the adult dose taken according to the same schedule. After completion of each period of prophylactic therapy the patients were followed up at bimonthly intervals on no medication until infection recurred. Once the new infection was eradicated they were started on a different prophylactic
regimen.
Collection of specimens
bimonthly
intervals and whenever an anal canal swab and a clean-voided midstream urine specimen were obtained. Patients were questioned in regard to urinary symp¬ toms, drug compliance and intolerance during the preceding month. Specimens were collected with the patient in the lithotomy position. After spreading the labia to expose the urethral meatus, a sterile, cotton-tipped applicator was swept with a circular motion around the entire urethra. Then a swab was inserted into the anal canal a distance of 2 cm. The swabs were inserted into sterile screw-capped glass tubes containing 5 ml of sterile physiologic saline. Finally a clean-voided midstream urine specimen was obtained. Patients
were seen at
symptoms occurred. At each visit a periurethral swab,
Bacteriologic techniques The tubes containing the swabs were vortexed at high speed for 1 minute and then amounts of 0.001 and 0.01 ml were inoculated onto sheep-blood agar, MacConkey agar and chocolate agar. After 24 hours of incubation, colony counts of all organisms were made. Sensitivity tests were performed on all urinary pathogens, using a single-disc diffusion method with an inoculum of approximately 10** organisms/ml on Mueller-Hinton agar.
Results This report concerns itself with 47 courses of prophylaxis, consisting of 12 courses of daily nitrofurantoin (cumulative experience of 5.8 years), 19 courses of twice weekly TMP-SMX (cumulative experience, 11.5 years) and 16 courses of weekly TMP-SMX (cumulative experience, 9.0 years). Fig. 1 depicts the course of a patient during two prophylactic regimens. In April 1973, after eradication of a symptomatic
Escherichia coli infection with a curative course of TMP-SMX in a conventional dose, she was started on a continuous course of TMP-SMX, one half tablet weekly, and remained free of recurrences and symptoms. Towards the end of this course both the periurethral and anal canal cultures were negative for E. coli and other aerobic gram-negative rods. After medication was discontinued in October 1973, anal canal cultures again grew E. coli and within 10 weeks the patient had a symptomatic recurrence of E. coli infection. Again the infection was eradicat¬ ed and the patient began a second course of TMP-SMX, one quarter tablet twice weekly, for 7 months. When prophylactic therapy was stopped she became reinfected with another strain of E. coli within 3 months. Six infections have occurred during 5.8 years of continuous nitrofurantoin therapy, an incidence of 1.0 infections per year. In four of these the etiologie agent was E. coli, one of which 14S CMA JOURNAL/JUNE 14, 1975/VOL. 112
resistant to nitrofurantoin. Two were caused by Klebsiella with intermediate sensitivity to nitrofurantoin. Four infections have developed during 11.3 years of twice weekly TMP-SMX prophylaxis, an incidence of 0.4 infections per year. Sulfonamide-resistant E. coli were responsible for two infec¬ tions, a Citrobacter freundii for one and Staphylococcus years of weekly epidermidis for one. During 9 cumulative TMP-SMX, 12 infections occurred, an annual incidence of 1.3. Seven of these infections were due to E. coli, all sulfonamideresistant. One infection caused by Klebsiella species, one by Enterobacter species and one by Streptococcus faecalis also infection developed. Two further patients in whom symptomatic without treated were on were while therapy they developed having a urine culture performed so that the causative organism is unknown. All the organisms responsible for infection, except two that were gram-positive, were sensitive to trimethoprim, whatever the type of prophylaxis employed. Follow-up of 6 months' duration or longer has been obtained subsequent to 32 courses of therapy. Four of the 11 patients on nitrofurantoin, 1 of the 18 on twice weekly TMP-SMX, and 3 of the 16 on once weekly TMP-SMX were infected at the Two pa¬ completion of their course of prophylactic therapy.with twice tients, one treated with nitrofurantoin and one weekly TMP-SMX, have not had a recurrence during 12 months of follow-up and have been discharged from the study as no longer subject to frequent recurrent urinary tract infections. All other patients have had a recurrence caused by E. coli. The mean interval before recurrence in 4 patients treated with nitrofurantoin was 3.7 months, in 11 treated with twice weekly TMP-SMX 2.1 months and in 7 treated with once weekly TMP-SMX 2.9 months. Twenty-one of the 22 recurrences were due to E. coli that were sensitive to nitrofurantoin, sulfonamides and trimethoprim. One patient on twice weekly TMP-SMX had a recurrence due to a sulfonamide-resistant strain of E. coli. Table I summarizes the results of periurethral and anal canal cultures during prophylaxis with each of the three regimens. In spite of the reduced frequency of administration of TMP-SMX, 33 of 95 anal canal swabs failed to grow any aerobic gramnegative rods. In contrast, all anal canal cultures from patients on daily nitrofurantoin, with only one exception, grew E. coli or other aerobic gram-negative rods. There was no significant difference between the three regimens in regard to periurethral colonization with E. coli, other Enterobacteriaceae or Pseudo¬ monas species. Although there appeared to be a tendency for TMP-SMX to select out group D streptococci in the periurethr¬ al flora, this was not significant. Trimethoprim-sulfamethox¬ azole prophylaxis was frequently associated with the isolation of sulfonamide-resistant' E. coli from the anal canal swab but again this was not significantly more common than with daily nitrofurantoin therapy. Periurethral and anal canal cultures grew trimethoprim-resistant Enterobacteriaceae in only one patient in the course of the study. This organism, a Klebsiella species, required a level of trimethoprim of 12.5 /ng/ml to was
species
'.lip^L.,.
..:iiiiiBii3i
||||§|
FIG. 1.Course of 12-year-old girl with urinary tract infection treated by two different prophylactic regimens.
inhibit growth. However, the patient did not develop a urinary tract infection during TMP-SMX prophylaxis and the organism disappeared spontaneously. None of the patients experienced untoward effects from low-dose trimethoprim-sulfamethoxazole. Six of the 28 patients had a history of intolerance to nitrofurantoin and could not follow this therapeutic regimen. Discussion Continuous daily long-term low-dose chemotherapy with a number of antimicrobial agents, including nitrofurantoin3'4 sulfonamides,1'4 trimethoprim-sulfamethoxazole,1'3 methanamine salts1 and cephalexin,5 has been shown to prevent recurrences of urinary tract infection. At present a major problem in the management of urinary tract infection in females is the high rate of recurrence, usually due to reinfection by bowel and perineal flora.6 Physicians treating urinary tract infection must clearly differentiate between eradication, suppression and prophylaxis. The present study only pertains to prophylaxis in females with closely spaced reinfections and a relatively normal urinary tract. Initial management, after excluding remediable abnormalities, should include an adequate daily fluid load, meticulous perineal hygiene, postcoital micturition if recurrences are related to sexual activity and double voiding if the patient has vesicoureteral reflux or a significant amount of residual urine. If these measures fail, chemoprophylaxis should be considered. At present there is no evidence that prophylactic treatment forestalls renal scarring or the development of renal failure in the minority who may run this course. However, recurrent morbidity can be prevented. The antimicrobial agent chosen for continuous prophylaxis depends on patient tolerance, efficacy in preventing recurrences, cost, effect on bacterial ecology and the potential harm to the individual or the community from the emergence of drug resistance. The optimal duration of prophylactic therapy is not known and probably should be individualized. O'Grady et a17 noted that patients maintained on continuous prophylaxis for 6 months or less seemed usually to become reinfected, whereas this was less likely in those maintained on therapy for longer periods. Brumfitt et al reported that only 36% of their series of 78 females had a recurrence within 6 months following a 6-month. course of low-dose prophylaxis.8 In school girls, Kunin noted that even some with repeated infections tended to stop having recurrences if each episode was effectively treated with a short course of chemotherapy.9 On the other hand, in the present highly selected series there is little evidence that prophylaxis prolonged for 6 to 12 months prevented later Table l-Periurethral and anal canal culturee during three prophylactic regimena
No.teken No aerobic gramnegative rods E. cciii sulfa-sensitive
Nitrofurantoin 50 mg daily
TMP-SMX 40/200 twice weekly
TMP-SMX 80/400 once weekly
.u
Ac
PU
AC
PU
AC
35
33
68
67
56
51
24
1
55
23
40
10
5
27
6
26
9
22
3
5
6
11
6
16
Refereuces
E. cciii
sulfa-resistant Other Enterobacterieceae Pseudomonessp. Group D Streptococcus sp.
recurrences. Following 22 courses of prophylaxis in patients with negative urine cultures at the completion of therapy, in only two was there no recurrence in 12 months; in the others the mean interval before recurrence was only 2.6 months. Fortunately all 20 recurrences were due to E. coil susceptible to both nitrofurantoin and trimethoprim and only 1 was resistant to sulfonamides. These infections were readily eradicated and afterwards the patient was started on an alternative prophylactic regimen. Once-daily sulfonamide prophylaxis with either sulfamethoxazole or sulfadimidine has been shown in controlled studies to reduce reinfections significantly."4 However, the selective pressure of sulfonamides on gastrointestinal aerobic gram-negative flora results within a few days in the replacement of susceptible by resistant strains, and subsequently infection with resistant strains is common.10 Nitrofurantoin is effective,2'4 as we have shown, and has little or no effect on either periurethral or stool flora.10 Although E. coil seldom emerges resistant, many other Enterobacteriaceae are naturally resistant and these may be responsible for reinfections.1 1 Also, a significant number of patients are not able to tolerate even low doses of nitrofurantom.4 Cattell et al showed that TMP-SMX was effective in preventing recurrent urinary tract infection.3 In a few patients they noted that recurrences could be prevented with thrice weekly therapy. Other studies have since confirmed the usefulness of TMP-SMX in prophylaxis of urinary tract infection."8"2 The efficacy of less frequent administration of this combination may be related to the kinetics of the trimethoprim component and its prolonged activity in the urine following a single dose.13 The reservoir for urinary pathogens is the normal colonic microflora. Trimethoprim-sulfamethoxazole in its usual therapeutic dose can have a marked effect on the aerobic gramnegative stool flora.14 In a previous study it was noted that daily low dose therapy with TMP-SMX prevented colonization of the periurethral area by Enterobacteriaceae.1 In the present series less frequent TMP-SMX administration and daily nitrofurantoin appeared to have little effect on aerobic periurethral bacterial ecology. However, TMP-SMX, even in a total dose of one tablet a week or less, eliminated aerobic gram-negative rods from anal canal swabs in many patients. It is not known if the effectiveness of this form of prophylaxis is due to intermittent urinary antimicrobial activity preventing the establishment of bacteria in the urinary tract or to a reduction in the bacterial reservoir with interruption of the sequence of events leading to infection. A major concern of prophylactic therapy is that resistant organisms may come to dominate the patient's flora and make subsequent infections more difficult to treat. This does occur with sulfonamide therapy.'0 Gram-negative organisms resistant to trimethoprim did not cause infection either during or after therapy in this study or in the earlier investigation.1 However, in one patient the perineum was colonized with a trimethoprimresistant Kiebsiella species and it is only logical to assume that urinary tract infections with resistant organisms will develop during prophylaxis. Long-term epidemiologic studies are needed to determine the significance of this potential risk of prophylaxis.
2 1
6 1
3 2
14 1
3 2
5 3
3
7
16
20
8
11
1. HARDING GKM, RONALD AR: A controlled study of antimicrobial
prophylaxis of recurrent urinary infection in women. N Engi J Med 291: 597, 1974
2. BAILEY RR, ROBERTS AP, GOWER PE, Ct al: Prevention of urinary tract infection with low-dose nitrofurantoin. Lance: 2:1112, 1971 3. CATTELL WR, CHAMBERLAIN DA, FRY 1K, Ct at: Long-term
control of bacteriuria. Br Med J 1: 377, 1971 4. ORMONDE NWH, GRAY JA, MURDOCH J McC, et al: Chronic bacteriuria due to Escherschia coIl. 1. Assessment of the value of combined short- and long-term treatment with cycloserine, nitrofurantoin and sulphadimidine. J Infect Dis 120: 82, 1969 5. FAIRLEY KF, HUBBARD M, WHITWORTH JA: Prophylactic longterm cephalexin in recurrent urinary infection. Med J Aust 1: 318, 1974
CMA JOURNAL/JUNE 14, 1975/VOL. 112
15S
6. STAMEY TA, TIMOTHY M, MILLAR M, et al: Recurrent urinary infections in adult women: the role of introital enterobacteria. Calif Med 115:1,1971 7. O'GRADY F, FRY 1K, MCSHERRY A, Ct al: Long-term treatment of
persistent or recurrent urinary infection with trimethoprim-sulfamethox-
azole. J Infect Dis 128 (suppl): 652, 1973 8. BRUMFITT W, PURSELL R, ORMONDE NWH, et al: Chronic
bacteruria due to Escherichia coil. II. Correlation of microbiological, radiological, and biochemical finding with the clinical results. J Infect Dis 120: 87, 1969 9. KUNIN CM: The natural history of recurrent bacteriuria in school girls. NEnglJ Med 282: 1443, 1970 10. WINBERO J, BERGSTROM T, LINCOLN K, et al: Treatment trials in urinary-tract infection (UTI) with special reference to the effect of
antimicrobials on the fecal and periurethral flora. Clin Nephrol 1: 142, 1973 11. TURCK M, RONALD AR, PETERSDORF RG: Susceptibility of Enterobacteriaceae to nitrofurantoin correlated with eradication of bacteriuria. Antimicrob Agents Chemother 6: 446, 1966 12. KINcAID- SMITH P. KALOWSKI 5, NANRA RS: Co-trimoxazole in urinary tract infection. Med J Aust 1: S49, 1973 13. CATTELL WR, SARDESON IM, SUTCLJFFE MB, et al: Kinetics of urinary bacterial response to antibacterial agents, in Urinary Tract Infection, edited by O'GRADY F, BRUMFITT W, London, Oxford U
Pr, 1968, p 227
14. MOORHOUSE EC, FARRELL W: Effect of co-trimoxazole on faecal enterobacteria: no emergence of resistant strains. J Med Microbiol 6: 249, 1973
Prophylactic chemotherapy with low-dosage trimethoprim-sulfamethoxazole following acute urinary tract infections in children NATHAN SHER,* MD, MRCPE, FRCP[C]
Summary: The cases of 10 children with acute and recurrent infection of the urinary tract are presented. Their ages were between 7 weeks and 9 years. Five of the children had been previously treated with a combination of sulfisoxazole, ampicillin. mandelamine and nitrofurantoin and four of these children had "breakthrough" infections. When trimethoprim-sulfamethoxazole was administered twice weekly no further infections were noted in four of these five patients. The second group of five children were started on trimethoprim-sulfamethoxazole from the start of their infection and treatment was continued twice weekly for 5 to 7 months. No recurrence of infection of the urine has been detected up to the present time. It is concluded that treatment with trimethoprim-sulfamethoxazole initiated at the outset of urinary tract infection and continued twice weekly is a valuable drug in children, provided the organism responsible for the infection is sensitive to this agent. RAsumA: Chimioth6rapie prophylactique avec une faible posologie de trim6thoprime-sulfam6thoxazole apr.s une infection aigue des voles urinaires chez I'enfant Nous prAsentons les cas de 10 enfants souffrant d'infection aigul et rAcidivante des voies urinaires. L'Age de ces enfants variait de 7 semaines A 9 ans. Cinq enfants avaient dejA etA traitAs avec une association de sulfisoxazole, d'ampicilline, de mandAlamine et de nitrofurantosne et quatre d'entre eux avalent subi des ricidives infectieuses. Par contre. A partir du moment oA on administra l'association jtrimAthoprime-sulfambthoxazole (TMP-SMX) deux fois par $*maine, aucune nouvelle pouss6e infectieuse ne put Atre observ6e chez quatre des cinq malades. Chez le second *.p.j.t.Cfl. of pediatrics, North York General Hospital, and lODE Children's Centre, Willowdale, Ont. Reprint requests to: Dr. Nathan Sher, North York Medical Arts Bldg., 1333 Sheppard Ave. E, Willowdale, Ont.
16S CMA JOURNAL/JUNE 14,1975/VOL. 112
groupo do cinq onfants le traitomont au TMP-SMX a AtA commoncA dis le dAbut do l'infection, A Ia posologie do doux doses par somaino, ot ii a AtA poursuivi pendant uno pAriodo variant do 5 A 7 mois. Jusqu'A prAsont, aucune rAcidivo do I'infoction urinairo n'a AtA notAo. Nous croyons donc pouvoir concluro quo le traitemont au TMP-SMX, amorce dAs lo dAbut do I'infoction urinairo A raison do doux doses par somaino ost uno mAdication prAciouso choz l'onfant. A condition evidemmont quo I'organismo responsablo do l'infoction soit sensible A co mAdicament.
It is generally agreed that long-term treatment of urinary tract infection in children will prevent progressive renal damage. Of 72 children investigated by Steele, Leadbetter and Crawford in 1963, 13 (18%) died in the 20-year period 1940 to 1961 and in only 2 was the cause of death not related to their renal disease; of the remainder, 37% gave evidence of persistent or recurrent disease.1 Consequently, most physicians will treat children with acute infection of the urinary tract for at least 3 to 6 months and in many cases much longer. Gower showed that continuous therapy was more effective than intermittent treatment in controlling symptomatic relapses.2 Forbes and Drummond have treated 51 children with recurrent urinary tract infection with trimethoprim-sulfamethoxazole for up to 22 months and all were free from infection during the course of therapy.3 There are many problems in treating a child for a lengthy period. Not the least of these is the failure of the patient to take the medication because of unpleasantness or other reason. Consequently, any treatment that is readily acceptable to both child and mother will improve the chances of rendering the urinary tract sterile and prevent relapse and the complications of renal damage. Another and perhaps even more difficult problem is to determine whether the urinary tract is truly free from infection, because of the difficulty of obtaining a clean specimen of urine from an infant or young child. Cattell and his colleagues from St. Bartholomew's Hospital, London, England, in their studies of the kinetics of urinary
