Journal of Antimicrobial Chemotherapy (1978) 4, 355-365

Methenamine hjppurate in urinary tract infections in children: prophylaxis, treatment and side effects

Jaakko Ho, Seppo Sarna, Katriina Ahava and Anja Lepo

Methenamine hjppurate was used as a prophylactic/suppressive agent after initial treatment of episodes of urinary tract infection in 116 children. The recurrence rate while on treatment was 12-2 and post-therapy was 31-4%. The recurrence rates for a group treated with sulfafurazolc were 2-0% during and 48-5% after therapy. For nitrofurantoin the respective rates WCTC 4-7 and 44-6%, and for alternating sulfafurazole and nitrofurantoin therapy 8-1 and 71-7%. Side effects and allergic reactions were encountered in M % of the cases given methenamine hippurate, 9-4% given sulfafurazole and 13-6% given nitrofurantoin. The incidence of Escherichia coli amongst organisms causing the recurrence during methenamine hippurate therapy increased, but decreased during sulfafurazole and nitrofurantoin therapy. In the post-therapy recurrences a higher incidence of E. coli was found only in the nitrofurantoin group. Introduction

Methenamine hippurate is absorbed rapidly from the gastrointestinal canal and when excreted in urine is dissociated into methenamine and hippuric acid. Methenamine is excreted by glomerular filtration, hippuric acid through the renal tubular transport system (Knoefel & Huang, 1959; Smith, Finkelstein, Aliminosa, Grawford & Graber, 1945). The use of methenamine is not recommended if renal function is severely impaired (Bennett, Singer & Coggins, 1970) or a reduced dosage is advisable (Gibson, 1970). Methenamine hippurate is contra-indicated in liver failure (Goodman & Gilman, 1975). The active agent of methenamine hippurate, formaldehyde, is formed only in the urinary tract and has not been demonstrated in blood or other tissues. Hippuric acid lowers the pH value of urine and has itself a bactericidal action (Bodel, 1959). The purpose of this study was to ascertain if methenamine hippurate was suitable for prophylaxis of urinary tract infections after previous treatment with conventional antimicrobial drugs. The results in the episodes treated with methenamine hippurate were compared with those treated by sulfafurazol and nitrofurantoin. Recurrence appearing during and after therapy, and the incidence of side effects caused by the drugs were compared. Materials and methods The children studied presented with urinary tract infections at Aurora Hospital, Helsinki, between 1960 and 1974. Aurora Hospital acts as the main consultation centre for schools 355 O3O5-7453/78/O7O1-O355 $01.00/0 © (1978) The British Society for Antimicrobial Chemotherapy

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Aurora Hospital and Department of Public Health Science, University of Helsinki, Helsinki, Finland

356

J. Eio, S. Sarna, K. Ahava and A. Lepo

Sulfafurazof - • ~ ~ NltrofuuiUuin Meihenamine hippurato

0 1 2 3 4 5 6

7 8 9 1 0

1 1 1 2 1 3 14

Figure 1. Age distribution of the children studied.

The sulfafurazol-treated group consisted of 492 cases, 79 boys and 413 girls. They had a total of 1268 episodes of urinary tract infection, 119 of them in boys and 1149 in girls. The nitrofurantoin-treated group consisted of 140 children, of which 13 were boys and 127 girls. There were 215 episodes of urinary tract infection, 17 in boys and 198 in girls. The methenamine hippurate-treated group comprised 91 children, of which 3 were boys and 88 girls. There were 116 episodes of urinary tract infection, 3 in boys and 113 in girls. Asymptomatic infections accounted for 14-9% of the sulfafurazol group, 23-7% of the nitrofurantoin group and 31-0% of the methenamine hippurate group. As all treated episodes of urinary tract infection since 1960 were included, the same child could appear in two or three of the groups under examination. Doses of sulfafurazol ranged up to 150 mg/kg/day and nitrofurantoin 2 to 6 mg/kg/day. Methenamine hippurate was given as 250 mg twice daily to children under 6 years old, 500 mg twice daily to the 6 to 12 year old and 1 g twice daily to children aged over 12, and usually given as a 3 month course. The duration of courses of sulfafurazole and nitrofurantoin were variable. A cure was defined as eradication of the organism from the urine. Recurrence was defined as the appearance of a different organism after the previous one had been eradicated. Sulfafurazole was administered mainly to small children and for methenamine hippurate medication there was a distinct age peak

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and is one of the two paediatric services for children from the city of Helsinki, having a population of 100,000 children. The episodes of infection occurred both in hospital and in the community. Midstream urine samples were examined on each visit to the hospital for the presence of white cells and a quantitative bacterial count was performed, also sedimentation rate, haemoglobin, leukocyte and blood urea were measured on alternate visits. The patients were followed up at 2- to 3-month intervals until they reached the age of 15 years. Infection was deemed to be present when a pathogen was cultured in numbers greater than 10s/ml. In some symptomatic episodes counts greater than 10*/ml were also considered to indicate infection. Seven hundred and thirty-five children under the age of 15 were studied. All patients who completed at least one course of treatment were used in the analysis. The age distribution is shown in Figure 1.

Paediatric use of meifamamfne

357

Results Episodes of infection associated with urological abnormalities accounted for 23-5 % of the sulfafurazole group, 340% of the nitrofurantoin and 37-1% of the methenamine hippurate group. Vesicoureteric reflux was seen in 33-5 % of the episodes in the sulfafurazole, 25-2% in the nitrofurantoin and 190% in the methenamine hippurate group. The other principal abnormalities are listed in Table I. Enuresis was recorded in children over 3 years. It was present in 12-2% of the sulfafurazole, 21-4% of the nitrofurantoin and 23-0% of the methenamine hippurate group. Table I. Prevalence of anatomical abnormalities in the treatment groups (Percentages in parentheses) Diagnosis ^^ Hydronephrosis Nephroptosis Ureterocele Urethra] stenosis Phimosis Hypoplastic kidney Megaureter Duplicity Urethral valves Neurogenic bladder Total episodes Total abnormalities

Sulfafurazole 13 24 8 5 12 10 23 46 4 2

(1-0) (1-9) (0-6) (0-4) (1) (0-8) (18) (3-6) (0-3) (0-2)

1268 147 01-6)

Nitrofurantoin 1 9 0 12 1 3 6 7 0 1

(0-5) (4-2) (0)

(56) (05) (1-4) (2-8) (33) (0)

(0-5)

215 40 (18-6)

, . enamme hippurate 0 4 0 2 1 2 1 7 1 1

(0)

(35) (0)

(1-7) (09) 0-7) (0-9) (6-0) (09) (0-9)

116 23 (19-8)

The distribution of the groups to be compared in respect to the number of infections at different ages is seen in Figure 2. The sulfafurazole group includes the larger number of acute episodes in small children, whereas the more refractory and most recurring episodes were treated both with nitrofurantoin and/or methenamine hippurate.

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between 9 and 10 years. Consequently, an age adjustment procedure was used for a part of the analysis of the results. Urography and urethrocystography was performed for boys after the first episode and for girls after the second or third episode. The statistical analysis was performed on the Burroughs 6700 computer of the Computing Centre of the University of Helsinki, using standard methods. The direct method was used for age standardization. For evaluation of the results three patient groups were selected for analysis. Group A: episodes of infection in which the sulfafurazole or nitrofurantoin were used alone. Group B: episodes of infection with analysis of the results of the last drug used for treatment. Group C: recurrent urinary infection in patients having their 4th, 5th or 6th episode of infection, the assessment of treatment being carried out on the last drug used.

J. E3o, S. Santa, K. Ahava and A. Lepo

358 30

U

hjppurots

0 Nitrofurantoin §j Sutfofurozol

20

10

IV

V

V

VII

VIII

IX

No. of episode Figure 2.

The distribution of the bacterial species causing the episodes in the methenamine hippurate group differs from that of the episodes treated with sulfafurazole and nitrofurantoin showing a greater preponderance of E. coli (See Table II). Bacteriological verification is absent for part of the cases as their diagnosis had been established elsewhere. Table III shows the results for group A. The recurrence rate during therapy was lowest (20%) with sulfafurazole and highest (12-1 %) with methenamine hippurate and when compared this is highly significant, P < 0-001 (?-test). The recurrence rate during nitrofurantoin therapy was 4-7 % (not statistically significant). The recurrence rate after the end of therapy was 58-2% with sulfafurazole, 46-9% with nitrofurantoin and 27-3% with methenamine hippurate. The difference between sulfafurazole and methenamine hippurate was highly significant (P< 0-001). The difference between nitrofurantoin and sulfafurazole and methenamine hippurate was statistically almost significant (P

Methenamine hippurate in urinary tract infections in children: prophylaxis, treatment and side effects.

Journal of Antimicrobial Chemotherapy (1978) 4, 355-365 Methenamine hjppurate in urinary tract infections in children: prophylaxis, treatment and sid...
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