Scandinavian Journal of Infectious Diseases
ISSN: 0036-5548 (Print) 1651-1980 (Online) Journal homepage: http://www.tandfonline.com/loi/infd19
Short-term treatment of acute urinary tract infection in girls K. E. Petersen To cite this article: K. E. Petersen (1991) Short-term treatment of acute urinary tract infection in girls, Scandinavian Journal of Infectious Diseases, 23:2, 213-220 To link to this article: http://dx.doi.org/10.3109/00365549109023403
Published online: 08 Jul 2009.
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Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=infd19 Download by: [McMaster University]
Date: 27 September 2015, At: 20:55
Scand J Infect Dis 23: 213-220, 1991
Short-term Treatment of Acute Urinary Tract Infection in Girls COPENHAGEN STUDY GROUP OF URINARY TRACT INFECTIONS IN CHILDREN*
Downloaded by [McMaster University] at 20:55 27 September 2015
From the Departments of Paediatrics, Gentofte Hospital. Glostrup Hospital. Hvidovre Hospital, Rigshospitalet, University of Copenhagen, the Departments of Paediatrics, Hiller& Hospital, Holbek Hospital, Nnstved Hospitul, Roskilde Hospital, Sundby Hospital, and the Department of Clinical Microbiology, Herlev Hospital, University of Copenhagen, Denmark
The efficiency of treatment of acute urinary tract infections with sulfamethizole for 3 days, sulfamethizole for 10 days, and pivmecillinam for 3 days was compared in a randomized multicentre study comprising 264 girls aged 1-15 years. For ethical reasons children with complicated diseases were not included. In these treatment groups no significant growth after treatment was , 77 I , and 74 %, respectively (NS).New bacteria after treatment were found less found in 81I frequently after sulfamethizole for 3 days (4%) when compared to sulfamethizole for 10 days (14%) and pivmecillinam for 3 days (13%) (p=0.048). After pivmecillinam treatment 75% of new bacteria were Streptococcus faecalis versus 25% after sulfamethizole for 3 days and 18% after sulfamethizole for 10 days (p=0.016). In the subgroup with nephro-urological abnormalities no significant growth after treatment was found in 68% of the sulfamethizole 3-day treated group, 54% of the sulfamethizole 10-day treated group, and 67% of the pivmecillinam 3-day treated group (NS).All treatments resulted in a change in the bacterial sensitivity pattern when bacteria isolated 1-10 days after treatment was compared to those found before treatment. This was more pronounced after the 10-day treatment when compared to the 3-day treatment. The sensitivity patterns of the bacteria isolated from recurrences were similar to those seen before treatment. After treatment there was no difference in the actuarial percentage recurrence-free curves of the 3 treatment groups. Side effects were rare in the sulfamethizole treated groups, and seen more often in the pivmecillinam treated group. 3-day treatment with sulfamethizole or alternatively pivmecilh a m i s recommended as first choice for treatment of uncomplicated acute urinary tract infections in girls.
K. E. Petersen, M D , Department of Paediatrics, Kolding Hospital, DK-6000 Kolding, Denmark
INTRODUCTION The traditional 10-14 days duration of antimicrobial therapy for urinary tract infection (UTI) in children is empirically chosen and not based upon clinical trials. Most antimicrobial agents are excreted in high concentration in the urine and a satisfactory outcome of a shorter therapeutic regimen could thus be expected. The advantages would be convenience, improved compliance, diminished cost, decreased side effects, and a reduced likelihood of emergence of resistant strains in the bacterial flora of the gut and perineum. Our traditional first choice in treatment of UTI in children has been a short acting sulfonamide for 10 days. This is a cheap, effective, and safe treatment for uncomplicated UTI (I). The aim of the present study was to evaluate the efficiency of 3-day treatment with sulfamethizole or pivmecillinam compared to 10-day treatment with sulfamethizole.
*
Copenhagen Study Group of Urinary Tract Infections in Children: Managing committee: Sten Petersen, Lisbeth Brendstrup, Knud E. Petersen, Anita Hansen, Vibeke Hvorslev, Vagn Braendholt Jensen, Birger Pagh, Anders Paerregaard, Geert Schou (biostatistician), Rene Vejlsgaard, Carsten Vrang. Other participants: Peder Daugbjerg, Karsten Hjelt, Ole Nielsen, Jes Reinholdt Petersen, Henrik Sardemann, Bent Stagegaard, Torben Serensen, Klaus Tobiasen, Inge Winslev.
2 14 Copenhagen Study Group
Scand 3 Infect Dis 23 (1991)
Downloaded by [McMaster University] at 20:55 27 September 2015
PATIENTS AND METHODS Study design A prospective, open, randomized, multicentre study was designed to include children aged 1-15 years with significant bacteriuria treated at 10 paediatric departments in and around Copenhagen. Treatment was initiated if the following criteria were met: ( I ) clinical symptoms demanding immediate treatment, or (2) significant bacteriuria, i.e. > lo5 colony forming units (CFU) of a single bacterium per ml in a clean-catch mid-stream urine specimen. Bag samples of urine were not accepted. The associated clinical symptoms were not registered. Children included with clinical symptoms in whom significant bacteriuria was not found were subsequently excluded from effect evaluation. Exclusion criteria were (1) antibiotic treatment within 1 week prior to inclusion, (2) suspicion of allergy to penicillin or sulfonamides, (3) need of parenteral antibiotic treatment, (4) temperature > 39°C or impaired general condition, (5) serum creatinine level exceeding 120 pmolll, ( 6 ) knowledge of severe urinary tract malformations, (7) immunosuppressive treatment or known immunodeficiency, and (8) previous participation in the study. The children included in the study were either cases without previous UTI (n=45; 17%), new referred cases with a history ofUTI (n=82;31 %), or well-known outpatients with recurrent UTI (n= 137; 52%). For ethical reasons we did not find it justifiable to include children with severe or complicated diseases in this randomized study. Irrespective of the sensitivity test the children were randomly allocated to one of the following treatment groups: (1) sulfamethizole 40-80 mg/kg/24 h in 2 doses for 3 days, (2) sulfamethizole 40-80 mg/kg/24 h in 2 doses for 10 days, or (3) pivmecillinam 20-40 mg/kg/24 h in 2 doses for 3 days. Sulfarnethizole was administered as tablets or mixture and pivmecillinam as tablets or single-dose powders. Allocation was performed by drawing consecutively numbered sealed envelopes. These were prepared by the manufacturer by randomization i n blocks of 6 within each of the participating departments. Microbiology Urine cultures were performed 1-10 days after treatment. The result was recorded as (1) no growth or insignificant growth, i.e. < lo5 CFU/ml-in the following referred to as ‘no growth’, (2) growth of original bacteria with the same sensitivity pattern, or (3) growth of new bacteria or same species with changed sensitivity pattern. A second urine culture was scheduled to be collected 1 month after treatment or at the time symptoms of UTI reappeared. Routine in vitro sensitivity test (Roscoe or Biodisce) toward ampicillin, sulfamethizole, nitrofurantoin, pivmecillinam and trimethoprim was carried out in all cultures with a significant growth and the result was expressed using a semiquantitative score. Statistics In children with no growth after treatment and observed without long-term prophylaxis, the results and the time to next urine culture were recorded, and the actuarial percentage recurrence-free curves for each treatment group were compared by log-rank test. Chi-square test or Fisher’s exact test was used for evaluation of differences between groups. With 90 patients in each of 2 groups it is possible with a power of 80% to detect a difference in the probability for no growth after treatment in the order of 20% (e.g. from 60% to 80%).The study was dimensioned accordingly. Ethics Parental consent following verbal and written information was obtained in all children before inclusion and the protocol was approved by the scientific ethics committee.
RESULTS Treatment was given to 359 children. 26 children with symptoms suggesting UTI but without significant bacteriuria in the initial urine culture were excluded. Six were excluded because their treatment was discontinued before scheduled. In 32 children evaluation of effect was not possible as urine cultures after treatment were not obtained within 10 days after treatment. In 10 children culture samples were collected in urine bags, and in 2 evaluation was not possible for other reasons. 19 boys were excluded from the effect evaluation because of the small number and an uneven distribution among the treatment groups. In total 95 children were excluded from evaluation of effect, but as they had received treatment side effects were registered. These 95 children were equally distributed in the 3 treatment groups.
Short-term treatment oj'urinury tract infection 2 I5
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Scand J Infect Dis 23 (1991)
Clinical evaluation Evaluation of the efficiency of treatment was possible in 264 girls of whom 96 were treated with sulfamethizole for 3 days, 78 with sulfamethizole for 10 days, and 90 with pivmecillinam for 3 days. In these 3 treatment groups the mean and SD of the patients ages were 7.552.7, 7.9? 3.4, and 7.7 t 2.8 years, respectively. The mean and SD of drug dosage in the treatment groups were 50 -+ 8, 50 2 7, and 25 2 3 mg/kg/day, respectively. Intravenous pyelography (IVP) andlor micturition cystourethrography (MCU) was registered when performed within 6 months after the study. IVP was normal in 194, abnormal in 53 (2 1 YO),and not performed in 17 girls. The abnormalities found on IVP are presented in Table 1. MCU was normal in 125, and abnormal (i.e. showed vesicoureteral reflux) in 63 (34Oh). MCU was not performed in 76 girls. In the sulfamethizole 3-day group 78/96 girls (81 Yo) had no growth after treatment compared t o 60/78 (77%) in the sulfamethizole 10-day group, and 67/90 (749/0) in the pivmecillinam 3-day group. These differences are not statistically significant (Table 11). New bacteria after treatment were found significantly less frequently in the sulfamethizole 3-day group (4 Yo) versus 14% and 13% in the other 2 groups (chi-square=6.06, p=0.048). The new bacterium after treatment was Streptococcus faecalis in 1/4 in the sulfamethizole 3-day group and 2/11 in the sulfamethizole 10-day group versus 9/12 in the pivmecillinam 3-day treated group (chisquare=8.22, p=0.016). The s. faecalis strains were insensitive to sulfamethizole as well as pivmecillinam. Efficiency of the 3 treatment regimens in relation to abnormalities demonstrated on IVP or MCU are presented in Table 111. No statistically significant differences were found between the treatment groups in the numbers of girls with no growth after treatment in girls with abnormalities and in girls with normal investigations, respectively. No growth after treatment was found in 57/89 (64%) of girls with abnormalities versus 86/105 (82%) with normal investigations (p=0.004). Among the smaller number of patients in each treatment group this difference only attained statistical significance in the sulfamethizole 3-day group (p=O.OI 5).
Table I. Abnormalities on IVP in 531247 girls investigated Finding
n
Pyelonephritis Hydronephrosis Double kidney Diverticulum of the bladder Heminephrectomy Horseshoe kidney Combinations and other diagnoses
16 13 10 4 3
I 6
Table 11. Results of urine cultures 1-10 days afer treatment
No growth Growth of original bacteria Growth of new bacteria
Sulfamethizole 3 days (n=96)
Sulfamethizole 10 days (n=78)
Pivmecillinam 3 days (t1=90)
78 (81 %) 14 (15%)
60 (7 7 O/a) 7 (9 %)
67 (74%) I 1 (12%)
4 (4O/o)
1 1 (14%)
12 (13%)
2 16 Copenhagen Study Group
Scand J Infect Dis 23 (1991)
Fig. 1. Actuarial percentage recurrence-free curves after treatment with sulfamethizole for 3 days in 68 girls (-), sulfamethizole for 10 days in 53 girls (. . . .), and pivmecillinam for 3 days in 5 1 girls (---).
-0
20
40
Downloaded by [McMaster University] at 20:55 27 September 2015
Days after treatment
Actuarial percentage recurrence-free curves after treatment in 172 girls followed without prophylaxis (Fig. 1) showed no statistically significant differences between the treatment groups (log-rank=0.68, p=0.71).
Bacteriological evaluation Before treatment Escherichia coli was found in 246 urine samples from 264 girls (93 Yo). Other bacteria found were Klebsiella species (3 %), and S. faecalis (1 %). In vitro sensitivity to the treatment drug was found in 83% in the sulfamethizole 3-day group, 74%in the sulfamethizole 10-day group, and 95Yo in the pivmecillinam treated group (pcO.001). No growth after treatment was found in 81 % of girls infected with bacteria which were sensitive in vitro to the antibiotic given and in 60% of girls with bacteria that were insensitive (p=0.005)(Table IV). 48 (20%) of 246 E. coli strains were in vitro insensitive to sulfonamides and 5 (2%) to pivmecillinam (29 were not tested towards pivmecillinam). All E. coli infections treated with pivmecillinam and examined for in vitro sensitivity were caused by strains sensitive to pivmecillinam. In non-coli strains, in vitro insensitivity to sulfonamides and pivmecillinam was found in 33 Yo and 44 %, respectively. The bacterial sensitivity patterns are presented in Table V. The bacteria found 1-10 days after treatment with sulfamethizole for 3 days were sensitive to sulfamethizole in 56% of the cases compared to 83 Yo before treatment (p=O.Ol). Sensitivity to other antibiotics were not significantly changed. After treatment with sulfamethizole for 10 days sensitivity towards sulfamethizole occurred in 22% of the bacteria versus 74% of the bacteria found before treatment (p 1 year old, if the clinical condition is not suggestive of pyelonephritis. If this treatment fails the bacterium found before treatment is usually still present and easily treatable. Pivmecillinam for 3 days is an effective alternative, but has more side effects (25) and if this treatment fails a resistant strain of S. faecalis is usually present. ACKNOWLEDGEMENTS We thank Leo Pharmaceutical Products for preparing and randomising the trial. The study was supported by grants from the Danish Medical Research Council (5.52.1 1.10 and 5.52.14.86).
REFERENCES 1. Winberg J, Andersen HJ, Bergstrom T, Jacobson B, Larson H, Lincoln K. Epidemiology of symptom-
atic urinary tract infection in childhood. Acta Paediatr Scand, Suppl 252, 1974. 2. Tolkoff-Rubin NE, Wilson ME, Zuromskis P, Jacoby I, Martin AR, Rubin RH. Single-dose amoxicillin therapy of acute uncomplicated urinary tract infection in women. Antimicrob Agents Chemother 25: 626-629, 1984. 3. Gossius G. Single-dose nitrofurantoin therapy for urinary tract infections in women. Curr Ther Res 35: 925-931, 1984. 4. Schultz HJ, McCaffrey LA, Keys TF, Norbrega FT. Acute cystitis. A prospective study of laboratory tests and duration of therapy. Mayo Clin Proc 59: 391-397, 1984. 5. McCracken GH, Ginsburg CM, Namasonthi V, Petruska M. Evaluation of short-term antibiotic therapy in children with uncomplicated urinary tract infections. Pediatrics 67: 796-801, 1981. 6. Avner ED, Ingelfinger JR, Herrin JT, Link DA. Marcus E, Tolkoff-Rubin NE, Russell-Getz L. Rubin RH. Single-dose arnoxicillin therapy of uncomplicated pediatric urinary tract infections. J Pediatr 102: 623-627, 1983. 7. Fine JS, Jacobson MS. Single-dose versus conventional therapy of urinary tract infections in female adolescents. Pediatrics 75: 916-920, 1985. 8. Wallen L, Zeller WP, Goessler M, Connor E, Yogev R. Single-dose amikacin treatment of first childhood E. coli lower urinary tract infections. J Pediatr 103: 3 16-31 9, 1983. 9. Vigano A, dalla Villa A, Bianchi C, Gandini G, Gaboardi F, Principi N. Single-dose netilmycin therapy of complicated and uncomplicated lower urinary tract infections in children. Acta Paediatr Scand 74: 584-588, 1985. 10. Kallenius G, Winberg J . Urinary tract infections treated with single dose of short-acting sulfonamide. B r M e d J 1 : 1175-1176, 1979. 1 1 . Philbrick JT, Bracikowski JP. Single-dose antibiotic treatment for uncomplicated urinary tract infections. Arch Intern Med 145: 1672-1678, 1985. 12. Charlton CAC. Crowther A, Davies JG, Dynes J . Haward MWA, Mann PG, Kye S. Three-day and tenday chemotherapy for urinary tract infections in general practice. Br Med J I : 124-126. 1974. 13. Hansen PH, Kristensen KH, Eriksen HAL, Pagh J, Ostergaard JE. Pivmecillinam in acute cystitis. A comparison of three and seven days treatment. J Drug Res 5: 758-761, 1980. 14. Richards HH. Comparative efficacy of 3-day and 7-day chemotherapy with twice-daily pivmecillinam in urinary tract infections seen in general practice. Curr Med Res Opin 9: 197-203, 1984. 15. Bitsch M, Hansen PH, Pagh J. Treatment of acute cystitis. A comparison of a three day course of pivmecillinarn and a six day course of sulfamethizole. J Drug Ther Res 9: 26-28, 1984. 16. Navrbjerg P, Johansen H, Thomsen OH. Diagnosis and treatment of acute urinary tract infection in general practice. J Drug Ther Res 1 0 938-941, 1985.
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Scand J Infect Dis 23 (1991)
17. Norrby SR, Short-term treatment of uncomplicated lower urinary tract infections in women. Rev Infect Dis 12: 458-467, 1990. 18. Godard C, Girardet P,Frutiger P, Hynek R,Delarue C, Christen J-P. Short treatment of urinary tract infections in children. Pediatrician 9: 309-321, 1980. 19. Lohr JA, Hayden GF, Kesler RW, Gleason CH, Wood JB, Ford RF, Perriello VA, Benjamin JT, Dickens MD. Three-day therapy of lower urinary tract infections with nitrofurantoin macrocrystals: A randomized clinical trial. J Pediatr 99: 980-983, 1981. 20. Khan AJ, Kumar K, Evans HE. Three-day antimicrobial therapy of urinary tract infection. J Pediatr 99: 992-994, 1981. 21. Ruberto U, DEufemia P, Ferretti L, Giardini 0. Effect of 3- vs 10-day treatment of urinary tract infections. J Pediatr 104: 483434, 1984. 22. Helin I, Lindberg U. Korttidsbehandling med pivmecillinam vid okomplicerad UVI hos barn. Lakartidningen 81: 3800-3801, 1984. (In Swedish.) 23. Madrigal G, Odio CM, Mohs E, Guevara J, McCracken GH. Single dose antibiotic therapy is not as effective as conventional regimens for management of acute urinary tract infection in children. Pediatr Infect Dis J 7: 316-319, 1988. 24. Shapiro ED. Short course antimicrobial treatment of urinary tract infections in children: a critical analysis. Pediatr Infect Dis I: 294-297, 1982. 25. Holme E,Jacobson C-E, Nordin I, Greter J, Lindstedt S, Kristiansson B, Jodal U.Carnitine deficiency induced by pivampicillin and pivmecillinam therapy. Lancet 2: 469-472, 1989.
ISSN: 0036-5548 (Print) 1651-1980 (Online) Journal homepage: http://www.tandfonline.com/loi/infd19
Short-term treatment of acute urinary tract infection in girls K. E. Petersen To cite this article: K. E. Petersen (1991) Short-term treatment of acute urinary tract infection in girls, Scandinavian Journal of Infectious Diseases, 23:2, 213-220 To link to this article: http://dx.doi.org/10.3109/00365549109023403
Published online: 08 Jul 2009.
Submit your article to this journal
Article views: 12
View related articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=infd19 Download by: [McMaster University]
Date: 27 September 2015, At: 20:55
Scand J Infect Dis 23: 213-220, 1991
Short-term Treatment of Acute Urinary Tract Infection in Girls COPENHAGEN STUDY GROUP OF URINARY TRACT INFECTIONS IN CHILDREN*
Downloaded by [McMaster University] at 20:55 27 September 2015
From the Departments of Paediatrics, Gentofte Hospital. Glostrup Hospital. Hvidovre Hospital, Rigshospitalet, University of Copenhagen, the Departments of Paediatrics, Hiller& Hospital, Holbek Hospital, Nnstved Hospitul, Roskilde Hospital, Sundby Hospital, and the Department of Clinical Microbiology, Herlev Hospital, University of Copenhagen, Denmark
The efficiency of treatment of acute urinary tract infections with sulfamethizole for 3 days, sulfamethizole for 10 days, and pivmecillinam for 3 days was compared in a randomized multicentre study comprising 264 girls aged 1-15 years. For ethical reasons children with complicated diseases were not included. In these treatment groups no significant growth after treatment was , 77 I , and 74 %, respectively (NS).New bacteria after treatment were found less found in 81I frequently after sulfamethizole for 3 days (4%) when compared to sulfamethizole for 10 days (14%) and pivmecillinam for 3 days (13%) (p=0.048). After pivmecillinam treatment 75% of new bacteria were Streptococcus faecalis versus 25% after sulfamethizole for 3 days and 18% after sulfamethizole for 10 days (p=0.016). In the subgroup with nephro-urological abnormalities no significant growth after treatment was found in 68% of the sulfamethizole 3-day treated group, 54% of the sulfamethizole 10-day treated group, and 67% of the pivmecillinam 3-day treated group (NS).All treatments resulted in a change in the bacterial sensitivity pattern when bacteria isolated 1-10 days after treatment was compared to those found before treatment. This was more pronounced after the 10-day treatment when compared to the 3-day treatment. The sensitivity patterns of the bacteria isolated from recurrences were similar to those seen before treatment. After treatment there was no difference in the actuarial percentage recurrence-free curves of the 3 treatment groups. Side effects were rare in the sulfamethizole treated groups, and seen more often in the pivmecillinam treated group. 3-day treatment with sulfamethizole or alternatively pivmecilh a m i s recommended as first choice for treatment of uncomplicated acute urinary tract infections in girls.
K. E. Petersen, M D , Department of Paediatrics, Kolding Hospital, DK-6000 Kolding, Denmark
INTRODUCTION The traditional 10-14 days duration of antimicrobial therapy for urinary tract infection (UTI) in children is empirically chosen and not based upon clinical trials. Most antimicrobial agents are excreted in high concentration in the urine and a satisfactory outcome of a shorter therapeutic regimen could thus be expected. The advantages would be convenience, improved compliance, diminished cost, decreased side effects, and a reduced likelihood of emergence of resistant strains in the bacterial flora of the gut and perineum. Our traditional first choice in treatment of UTI in children has been a short acting sulfonamide for 10 days. This is a cheap, effective, and safe treatment for uncomplicated UTI (I). The aim of the present study was to evaluate the efficiency of 3-day treatment with sulfamethizole or pivmecillinam compared to 10-day treatment with sulfamethizole.
*
Copenhagen Study Group of Urinary Tract Infections in Children: Managing committee: Sten Petersen, Lisbeth Brendstrup, Knud E. Petersen, Anita Hansen, Vibeke Hvorslev, Vagn Braendholt Jensen, Birger Pagh, Anders Paerregaard, Geert Schou (biostatistician), Rene Vejlsgaard, Carsten Vrang. Other participants: Peder Daugbjerg, Karsten Hjelt, Ole Nielsen, Jes Reinholdt Petersen, Henrik Sardemann, Bent Stagegaard, Torben Serensen, Klaus Tobiasen, Inge Winslev.
2 14 Copenhagen Study Group
Scand 3 Infect Dis 23 (1991)
Downloaded by [McMaster University] at 20:55 27 September 2015
PATIENTS AND METHODS Study design A prospective, open, randomized, multicentre study was designed to include children aged 1-15 years with significant bacteriuria treated at 10 paediatric departments in and around Copenhagen. Treatment was initiated if the following criteria were met: ( I ) clinical symptoms demanding immediate treatment, or (2) significant bacteriuria, i.e. > lo5 colony forming units (CFU) of a single bacterium per ml in a clean-catch mid-stream urine specimen. Bag samples of urine were not accepted. The associated clinical symptoms were not registered. Children included with clinical symptoms in whom significant bacteriuria was not found were subsequently excluded from effect evaluation. Exclusion criteria were (1) antibiotic treatment within 1 week prior to inclusion, (2) suspicion of allergy to penicillin or sulfonamides, (3) need of parenteral antibiotic treatment, (4) temperature > 39°C or impaired general condition, (5) serum creatinine level exceeding 120 pmolll, ( 6 ) knowledge of severe urinary tract malformations, (7) immunosuppressive treatment or known immunodeficiency, and (8) previous participation in the study. The children included in the study were either cases without previous UTI (n=45; 17%), new referred cases with a history ofUTI (n=82;31 %), or well-known outpatients with recurrent UTI (n= 137; 52%). For ethical reasons we did not find it justifiable to include children with severe or complicated diseases in this randomized study. Irrespective of the sensitivity test the children were randomly allocated to one of the following treatment groups: (1) sulfamethizole 40-80 mg/kg/24 h in 2 doses for 3 days, (2) sulfamethizole 40-80 mg/kg/24 h in 2 doses for 10 days, or (3) pivmecillinam 20-40 mg/kg/24 h in 2 doses for 3 days. Sulfarnethizole was administered as tablets or mixture and pivmecillinam as tablets or single-dose powders. Allocation was performed by drawing consecutively numbered sealed envelopes. These were prepared by the manufacturer by randomization i n blocks of 6 within each of the participating departments. Microbiology Urine cultures were performed 1-10 days after treatment. The result was recorded as (1) no growth or insignificant growth, i.e. < lo5 CFU/ml-in the following referred to as ‘no growth’, (2) growth of original bacteria with the same sensitivity pattern, or (3) growth of new bacteria or same species with changed sensitivity pattern. A second urine culture was scheduled to be collected 1 month after treatment or at the time symptoms of UTI reappeared. Routine in vitro sensitivity test (Roscoe or Biodisce) toward ampicillin, sulfamethizole, nitrofurantoin, pivmecillinam and trimethoprim was carried out in all cultures with a significant growth and the result was expressed using a semiquantitative score. Statistics In children with no growth after treatment and observed without long-term prophylaxis, the results and the time to next urine culture were recorded, and the actuarial percentage recurrence-free curves for each treatment group were compared by log-rank test. Chi-square test or Fisher’s exact test was used for evaluation of differences between groups. With 90 patients in each of 2 groups it is possible with a power of 80% to detect a difference in the probability for no growth after treatment in the order of 20% (e.g. from 60% to 80%).The study was dimensioned accordingly. Ethics Parental consent following verbal and written information was obtained in all children before inclusion and the protocol was approved by the scientific ethics committee.
RESULTS Treatment was given to 359 children. 26 children with symptoms suggesting UTI but without significant bacteriuria in the initial urine culture were excluded. Six were excluded because their treatment was discontinued before scheduled. In 32 children evaluation of effect was not possible as urine cultures after treatment were not obtained within 10 days after treatment. In 10 children culture samples were collected in urine bags, and in 2 evaluation was not possible for other reasons. 19 boys were excluded from the effect evaluation because of the small number and an uneven distribution among the treatment groups. In total 95 children were excluded from evaluation of effect, but as they had received treatment side effects were registered. These 95 children were equally distributed in the 3 treatment groups.
Short-term treatment oj'urinury tract infection 2 I5
Downloaded by [McMaster University] at 20:55 27 September 2015
Scand J Infect Dis 23 (1991)
Clinical evaluation Evaluation of the efficiency of treatment was possible in 264 girls of whom 96 were treated with sulfamethizole for 3 days, 78 with sulfamethizole for 10 days, and 90 with pivmecillinam for 3 days. In these 3 treatment groups the mean and SD of the patients ages were 7.552.7, 7.9? 3.4, and 7.7 t 2.8 years, respectively. The mean and SD of drug dosage in the treatment groups were 50 -+ 8, 50 2 7, and 25 2 3 mg/kg/day, respectively. Intravenous pyelography (IVP) andlor micturition cystourethrography (MCU) was registered when performed within 6 months after the study. IVP was normal in 194, abnormal in 53 (2 1 YO),and not performed in 17 girls. The abnormalities found on IVP are presented in Table 1. MCU was normal in 125, and abnormal (i.e. showed vesicoureteral reflux) in 63 (34Oh). MCU was not performed in 76 girls. In the sulfamethizole 3-day group 78/96 girls (81 Yo) had no growth after treatment compared t o 60/78 (77%) in the sulfamethizole 10-day group, and 67/90 (749/0) in the pivmecillinam 3-day group. These differences are not statistically significant (Table 11). New bacteria after treatment were found significantly less frequently in the sulfamethizole 3-day group (4 Yo) versus 14% and 13% in the other 2 groups (chi-square=6.06, p=0.048). The new bacterium after treatment was Streptococcus faecalis in 1/4 in the sulfamethizole 3-day group and 2/11 in the sulfamethizole 10-day group versus 9/12 in the pivmecillinam 3-day treated group (chisquare=8.22, p=0.016). The s. faecalis strains were insensitive to sulfamethizole as well as pivmecillinam. Efficiency of the 3 treatment regimens in relation to abnormalities demonstrated on IVP or MCU are presented in Table 111. No statistically significant differences were found between the treatment groups in the numbers of girls with no growth after treatment in girls with abnormalities and in girls with normal investigations, respectively. No growth after treatment was found in 57/89 (64%) of girls with abnormalities versus 86/105 (82%) with normal investigations (p=0.004). Among the smaller number of patients in each treatment group this difference only attained statistical significance in the sulfamethizole 3-day group (p=O.OI 5).
Table I. Abnormalities on IVP in 531247 girls investigated Finding
n
Pyelonephritis Hydronephrosis Double kidney Diverticulum of the bladder Heminephrectomy Horseshoe kidney Combinations and other diagnoses
16 13 10 4 3
I 6
Table 11. Results of urine cultures 1-10 days afer treatment
No growth Growth of original bacteria Growth of new bacteria
Sulfamethizole 3 days (n=96)
Sulfamethizole 10 days (n=78)
Pivmecillinam 3 days (t1=90)
78 (81 %) 14 (15%)
60 (7 7 O/a) 7 (9 %)
67 (74%) I 1 (12%)
4 (4O/o)
1 1 (14%)
12 (13%)
2 16 Copenhagen Study Group
Scand J Infect Dis 23 (1991)
Fig. 1. Actuarial percentage recurrence-free curves after treatment with sulfamethizole for 3 days in 68 girls (-), sulfamethizole for 10 days in 53 girls (. . . .), and pivmecillinam for 3 days in 5 1 girls (---).
-0
20
40
Downloaded by [McMaster University] at 20:55 27 September 2015
Days after treatment
Actuarial percentage recurrence-free curves after treatment in 172 girls followed without prophylaxis (Fig. 1) showed no statistically significant differences between the treatment groups (log-rank=0.68, p=0.71).
Bacteriological evaluation Before treatment Escherichia coli was found in 246 urine samples from 264 girls (93 Yo). Other bacteria found were Klebsiella species (3 %), and S. faecalis (1 %). In vitro sensitivity to the treatment drug was found in 83% in the sulfamethizole 3-day group, 74%in the sulfamethizole 10-day group, and 95Yo in the pivmecillinam treated group (pcO.001). No growth after treatment was found in 81 % of girls infected with bacteria which were sensitive in vitro to the antibiotic given and in 60% of girls with bacteria that were insensitive (p=0.005)(Table IV). 48 (20%) of 246 E. coli strains were in vitro insensitive to sulfonamides and 5 (2%) to pivmecillinam (29 were not tested towards pivmecillinam). All E. coli infections treated with pivmecillinam and examined for in vitro sensitivity were caused by strains sensitive to pivmecillinam. In non-coli strains, in vitro insensitivity to sulfonamides and pivmecillinam was found in 33 Yo and 44 %, respectively. The bacterial sensitivity patterns are presented in Table V. The bacteria found 1-10 days after treatment with sulfamethizole for 3 days were sensitive to sulfamethizole in 56% of the cases compared to 83 Yo before treatment (p=O.Ol). Sensitivity to other antibiotics were not significantly changed. After treatment with sulfamethizole for 10 days sensitivity towards sulfamethizole occurred in 22% of the bacteria versus 74% of the bacteria found before treatment (p 1 year old, if the clinical condition is not suggestive of pyelonephritis. If this treatment fails the bacterium found before treatment is usually still present and easily treatable. Pivmecillinam for 3 days is an effective alternative, but has more side effects (25) and if this treatment fails a resistant strain of S. faecalis is usually present. ACKNOWLEDGEMENTS We thank Leo Pharmaceutical Products for preparing and randomising the trial. The study was supported by grants from the Danish Medical Research Council (5.52.1 1.10 and 5.52.14.86).
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