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

bacteria to various antibacterial agents using the "wash-out" Translating this into clinical terms, O'Grady and his coworkmethod, showed that by giving a single dose of trimethoprim, ers have treated 83 patients with a history of persistent urinary tract infection for 6 months or more, and following initial 100 mg, followed by a drink of 300 ml of fluid there was a dramatic fall in the bacterial count in the urine from over 108 ampicillin, tetracycline and nitrofurantoin the patients were maintained on trimethoprim therapy.5 When the urine became colonies/ml to fewer than 103 colonies/ml.4 This effect took place within a few hours and the urine remained sterile for up to sterile the dosage was gradually reduced to once daily and 4 to 5 days. The authors conclude that "Of all the drugs tested finally to twice weekly. Confronted by these facts, we believed that these results it would seem that trimethoprim may have the most prolonged should be confirmed when TMP-SMX was released for use in effect in maintaining the urine free of organisms following a Canada. Accordingly, 10 children with acute or recurrent single dose." Table I.Children treated with a combination of sulfisoxazole, mandelamine, nitrofurantoin, ampicillin and trimethoprim-sulfamethoxazole

Sulf. sulfisoxazole; nit. nitrofurantoin; amp. ampicillin; mand. mandelamine IVP intravenous pyelogram; VCU voiding cystourethrogram =

=

=

=

=

=

Table II.Children treated with trimethoprim-sulfamethoxazole only Dominant

organism in urine Patient

Age

>

10:7ml

Sympt;

IVP VCU

S. faecalis

Twice

mo

Results of urinary culture

5

mo

6

mo

Twice daily, then twice weekly

E. coli

6

weekly

Neg.

mo

10

treatment

Neg.

urine cult. neg.

21

Duration of Treatment

E. coli

Neg.

Twice daily for 1 week, then twice weekly

5

mo

E. coli

Neg.

Twice daily for 7 days, then twice weekly

7

mo

E. coli S. faecalis

Neg.

Twice daily for 5 days, then twice weekly

6

mo

IVP intravenous pyelogram; VCU voiding cystourethrogram. =

=

CMA JOURNAL/JUNE

14, 1975/VOL. 112 17S

urinary tract infection were given a trial with low dosage trimethoprim-sulfamethoxazole when the drug became available. The first five patients had already been on maintenance therapy with sulfisoxazole, ampicillin, nitrofurantoin or mandelamine, with varying success due to "breakthrough" infections. Three of these had yarying degrees of vesicoureteral reflux and one had had a reimplantation. The youngest patient in this group was 7 weeks old when first seen and the oldest was 9 years. The TMP.SMX* was given twice weekly and the medication was usually administered at the time of a specific recurrent event in the week in order that the parent or child should not forget the day of treatment. The parents were instructed to encourage the drinking of 100 to 150 ml of fluid after the medication was given. This treatment has been administered for approximately 4 months in the youngest infant and for 19 months in the 9-year-old child. A second group of 5 children were treated with TNfP-SMX from the time of the initial diagnosis of acute infection of the urinary tract. The medication was given twice or three times daily for 1 week or until the urinary bacterial count was less than l0. colonies/mI. Then the same dosage was administered twice weekly, as in the first group. The youngest infant in this group was aged 6 months and the oldest child was 9 years. The treatment has now been given for at least 3 months and up to 7 months. The dosage has been trimethoprim, 40 mg and sulfamethoxazole, 200 mg in children over 2 years of age and half these amounts for those under 2 years. A midstream specimen of urine was obtained by the laboratory technician (not by the mother) after cleansing the genitalia with sterile water, by catching the urine in a sterile bottle. If the patient was too young for this method the infant was admitted to hospital, where a clean specimen was obtained in a plastic bag and immediately transported to the laboratory. Our results are shown in Tables I and II.

Discussion The urine from both groups of patients became sterile shortly after commencing treatment with TMP-SMX. Infection recur*Kindly supplied as Septra by the Burroughs Weilcome Company.

18S CMA JOURNAL/JUNE 14, 1975/VOL. 112

red in patient 2 after treatment was discontinued, but when treatment was recommenced no further positive cultures were obtained. This child has had a reimplantation for gross reflux and is still on treatment. In the group in whom treatment with TMP-SMX was initiated from the onset of the infection, not a single recurrence of positive urinary culture has been noted. Admittedly, the two groups are not entirely comparable since in cases 6 to 10 no renal pathology could be demonstrated and, as expected, the infection was symptomatically less severe than in the first five cases. Nevertheless, the results are encouraging. The medication was well accepted by all the children. The parents were favourably impressed and maintained that the twice weekly dosage was much to be preferred to the previous treatment, which had to be given thrice daily for a prolonged period. This led to a lessening of domestic tension when giving the medication to a difficult child. None of the children taking the doses as described showed any untoward effect such as diarrhea, unexplained fever or rash. The serum folic acid concentration was measured in all patients after 3 and again after 6 months of treatment and no reduction was noted. It is hoped that the ease with which the twice weekly regimen of TMP/SMX can be continued in children will help to reduce the relapse rate and prevent the development of permanent renal damage. In addition, it appears from this small series that it would be preferable, in children at any rate, to begin the treatment of acute urinary tract infection with TMP-SMX, provided the organism is sensitive to this agent. My thanks are due to Dr. C.P. Rance, chief of nephrology, The Hospital for Sick Children, Toronto for his kind criticisms. References I. STEELE RE, LEADBETTER GW, CRAWFORD JD: Prognosis of childhood urinary tract infection. Current status of patients hospitalized between 1940.1950. N Engi J Med 269: 883, 1963 2. GOWER PE: Long.tcrm therapy in chronic renal infections, in Urinary Tract Infection, edited by O'GRADY F, BRUMFITT W, London, Oxford U Pr, 1968 3. FORBES PA, DRUMMOND KN: Trimethoprim.sulfamethoxazole in recurrent urinary tract infection in children. J Infect Dis 128 (suppl): 626, 1973 4. CATTELL WR, SARDESON JM, et al: Kinetics of urinary bacterial response to antibacterial agents, in Urinary Tract Infection, op cit 5. O'GRADY F, CHAMBERLAIN DA, et al: Long.term low-dosage trimethoprim-sulphonamide in the control of chronic bacteriuria. Postgrad Med J45 (suppl): 61, 1969