Antibiotic Prophylaxis and Recurrent Urinary Tract Infection in Children

Article: Jonathan C. Craig, Judy M. Simpson, Gabrielle J. Williams, et al. Antibiotic Prophylaxis and Recurrent Urinary Tract Infection in Children. N Engl J Med 2009;361:1748-59.

Journal Club Author: Mohammed-Nafi’u, Ramatu. Bsc, MBBS, FWACP, FMCP, Consultant Paediatrician, DSSMC, Abuja, Nigeria.

Reviewer: Sanjeev Swami, MD Division of Infectious Diseases, Children’s Hospital of Philadelphia.

Background:

Urinary tract infection (UTI) is a very common illness in children associated with long-term morbidity. It affects 2% of boys and 8% of girls by the age of 7 years with renal damage reported in about 5% of affected children. The associated renal damage noted in children who had urinary tract infection has necessitated the use of radio-imaging technique such as voiding cystourethrography to detect the presence of vesicoureteral reflux (VUR) in these children. Over the years, the administration of daily low-dose antibiotics for prevention of further urinary tract infections and renal damage in these children was warranted due to lack of preventive therapy. This manuscript recognized that other children without reflux are also at risk for recurrent urinary tract infection and sequelae, and, therefore, recommend the use of long-term antibiotics in such children. The aim of the study was to determine whether the long-term use of low-dose antibiotics prevents recurrent urinary tract infection in children.

Methodology

The study was conducted from December 1998 through March 2007 infourAustralian cities (Sydney, Canberra, Brisbane and Melbourne). It was a double blind, placebo – controlled randomized clinical study. The randomization sequence was computer-generated and stratified.A total of 576 children underwent randomization, 288 were assigned to receive trimethoprim- sulfamethoxazole (TMX) and 288 to receive placebo. The primary outcome was symptomatic urinary tract infection within 12 months.

Children from birth to 18 years, who had had at least 1 symptomatic and recurrent microbiologically proven urinary tract infections (UTI) or those with all grades of vesicoureteral reflux were recruited while children with known skeletal, neurologic or urologic anomalies and those with known contraindication to trimethoprim–sulfamethoxazole therapy were excluded from the study.

All children received either TMP-SMX after consent but before randomization for 2 weeks, at (2mg trimethoprim and 10mg sulfamethoxazole (per kg body weight)). The administration of the study drug ceased when a symptomatic urinary tract infection occurred. TMP-SMX was chosen as the study drug because it is consistently recommended as the first-line agent for the prevention of urinary tract infection worldwide. After randomization and at 3 –month visit, one study group received the drug daily while the other group received placebo daily. Children were seen at 3-month interval during a 12 -month follow up.

Results

Urinary tract infection was diagnosed in 36 of 288 patients (13%) in the antibiotic group and in 55 of 288 (19%) in the placebo group (hazard ratio was 0.61; 95% confidence interval [CI], 0.40 to 0.93; P = 0.02.  In the two groups (antibiotics and placebo), approximately 87% of the index infections were caused by Escherichia coli, and 15% of the infecting bacteria were resistant to TMP-SMX. The effect of TMP-SMX on the prevention of symptomatic urinary tract infection did not vary significantly according to any stratifying variable: age, sex, reflux status, history of more than one urinary tract infection, or susceptibility of the causative organism for the index infection to TMP-SMX. 

Discussion:

This study highlights modest reduction in the risk of symptomatic UTI with long term low dose TMP-SMX in predisposed children.  There are changes in the bacteria susceptibility pattern and increased risk following prolonged administration of antibiotics. The need to treat at least 14 children in order to prevent one case of UTI and the absolute treatment effect is consistent across a wide range of risk factors. The pattern of recurrence suggests that the benefit of antibiotic therapy was greatest during the first 6 months of treatment with reduced risk of febrile UTI in those children treated with antibiotic. The study showed that an index infection resistant to TMP-SMX was unlikely to benefit from antibiotics prophylaxis. Mild adverse drug reaction accounted for reasons of discontinuation of drug in fourteen children (4%) in the antibiotic group and 10(2%) in the placebo group. It was concluded that long-term, low-dose trimethoprim-sulfamethoxazole was associated with a decreased number of urinary tract infections in predisposed children, regardless of; age, sex, frequency of previous UTI and concomitant reflux.

Comment:

Patient recruitment and randomization was clearly and comprehensively described. Administration of trimethoprim–sulfamethoxazole treatment to all patients before randomization would ensure that no patients had and existing undiagnosed UTI that could have affected the primary outcome. Although this study calculated sample size was 780 only 576 were eventually analysed and this would have affected the final result.