Macrodantin

* EVIDENCE-BASED ANSWER

Evidence is insufficient to recommend for or against antibiotic prophylaxis to prevent recurrent urinary tract infections (UTI) in children with anatomic abnormalities. Guidelines acknowledge this lack of evidence, but still recommend using prophylactic antibiotics in children with vesiculoureteral reflux (strength of recommendation: B, based on poor-quality or inconclusive cohort and randomized controlled studies). (1-3) No controlled, prospective studies have examined the effectiveness of prophylactic antibiotics to prevent UTI recurrence or renal scarring.

* EVIDENCE SUMMARY

Recommendations about antibiotic prophylaxis are based on several premises. Reflux predisposes children to acute pyelonephritis; reflux plus infection leads to reflux nephropathy and ultimately to renal scarring. In theory, if antibiotics could be initiated at the appropriate time and be maintained until reflux resolves, we could successfully prevent infection and scarring. (4)

A recent systematic review evaluated the use of antibiotics to prevent UTI in children. (5) This review of 5 randomized controlled trials included a total of 463 children between the ages of 2 months to 16 years. Three out of 5 trials evaluated the effectiveness of antibiotic treatment for 2 to 6 months to prevent subsequent off-treatment recurrence. The 2 smaller trials (n=71) evaluated the use of low-dose long-term antibiotics to prevent UTI.

There was a clinically, but not statistically, significant trend towards reduced risk of UTI during long-term antibiotic treatment (risk reduction [RR]=0.31; 95% confidence interval [CI]=0.10-1.00); however, no sustained benefit was seen once antibiotics were stopped (RR=0.79; 95% CI, 0.61-1.02). There were many problems with the methodological quality of these trials, including significant heterogeneity. The researchers concluded that well-designed randomized controlled trails are still needed to evaluate this commonly used intervention in the pediatric population. (4) Benefits for long-term prophylaxis are even less clear in children with low-grade reflux (I-II). (5) Furthermore, no randomized controlled trials assess whether prophylaxis prevents the development of new renal scars in children. (6)

In addition, a recent systematic review of studies done in children with normal urinary tracts, as well in children with neurogenic bladders, found that the available evidence is of low quality. Only 6 out of 31 potential studies fulfilled the inclusion criteria. These were small (mean sample size was 28), and the quality scores of all 6 trials were low, indicating that the evidence may be unreliable. (7)

Two of 3 studies done in children with normal urinary tracts demonstrated statistically significant higher rates of UTI recurrence in control groups compared with treatment groups receiving 6 to 10 months of either nitrofurantoin or cotrimoxazole (RR=24-31). The third study showed no difference between groups.

One of 2 trials in children with neurogenic bladder demonstrated higher recurrence rates of 2.9 per 10 patient years for patients receiving antibiotics compared with 1.5 in the untreated group. The other study showed lower recurrence rates of 17.1 for patients receiving antibiotics, compared with 33 in the untreated group. (7) Neither of these findings were statistically significant.

A different meta-analysis of 15 controlled clinical trials in children with neurogenic bladder due to spinal cord dysfunction. This analysis showed that antibiotic prophylaxis was associated with a reduction in asymptomatic bacteruria among children with acute spinal cord injury (P<.05), but there was no significant reduction in symptomatic infections. Prophylaxis resulted in an approximately twofold increase in antimicrobial-resistant bacteria. The researchers concluded that although a clinically important effect has not been excluded, the regular use of antimicrobial prophylaxis for most patients who have neurogenic bladder caused by spinal cord dysfunction is not supported at this time. (8)

Poor compliance may be an issue with long-term prophylaxis and may represent patient or parent practice. (9) One study found that in children taking low-dose trimethoprim, 97% of the parents reported giving antibiotics on daily basis, but in 31% of subjects, trimethoprim was not detectable in the urine. (6) Risk of prophylaxis includes nausea, vomiting, and rash in 8% to 10% of patients; development of resistant organisms; and change in indigenous microflora. (6) One study of resistance found that children who received antibiotics for more than 4 weeks in the previous 6 months were more likely to have resistant Escherichia coli isolates than children who had not received prolonged antibiotic treatment (odds ratio [OR]=13.9; 95% CI, 8.2-23.5). Children with abnormalities of the genitourinary tract were approximately 4 times more likely to have resistant isolates of E coli than children without abnormalities of the genitourinary tract (OR=3.9; 95% CI, 2.7-5.7). (11)

* RECOMMENDATIONS FROM OTHERS

The American Academy of Pediatrics, American Urological Association, and the Swedish Medical Research Council guidelines recommend prophylaxis for children with reflux (Table), but they all acknowledge that the recommendations are not supported by well-designed randomized controlled trials. (1-3) No guidelines are available for children with neurogenic bladder and recurrent urinary tract infections. (7)

Amer Shakil, MD, Lane Reed, MD, Department of Family Practice and Community Medicine, University of Texas Southwestern, Dallas; Laura Wilder, MLS, University of Texas Southwestern Medical Center Library, Dallas

* CLINICAL COMMENTARY:

UTI prevention most successful when the child exhibits efficiency of voiding

The relative benefit of antibiotic prophylaxis in prevention of UTI in children with anatomic abnormalities like vesicoureteral reflux could best be determined if all other risk factors for UTI were controlled. Unfortunately, these other factors are often more significant in promoting UTI than is reflux, and they are also more difficult to quantify. Voiding dysfunction and constipation can both increase bladder storage pressures and postvoid residual urine volumes, and as such greatly predispose children for UTI. Furthermore, a distended colon provides an abundant reservoir of pathogens with an array of uropathogenic virulence factors.

Published reports have failed to detect significant benefit for antibiotic prophylaxis in part because the children studied possess varying risks for UTI. Prevention of UTI is most successful when the child exhibits efficiency of voiding and elimination. Clinical practice in pediatric urology advocates use of antibiotic prophylaxis in children with vesicoureteral reflux. Reflux should be suspected in children with hydroureter, multicystic renal dysplasia, ureteral duplication, and ureterocele.

William R. Strand, MD, Division of Pediatric Urology, University of Texas Southwestern Medical Center, Dallas

REFERENCES

(1.) Jodal U, Lindberg U. Guidelines for management of children with urinary tract infection and vesico-ureteric reflux. Recommendations from a Swedish state-of-the-art conference. Swedish Medical Research Council. Acta Paediatr Suppl 1999; 88:87-89.

(2.) Elder JS, Peters CA, Arant BS Jr, et al. Pediatric Vesicoureteral Reflux Guidelines Panel summary report on the management of primary vesicoureteral reflux in children. J Urol 1997; 157:1846-1851.

(3.) Practice parameter: the diagnosis, treatment, and evaluation of the initial urinary tract infection in febrile infants and young children. American Academy of Pediatrics. Committee on Quality Improvement. Subcommittee on Urinary Tract Infection. Pediatrics 1999; 103:843-852.

(4.) Hoberman A, Charron M, Hickey RW, Baskin M, Kearney DH, Wald ER. Imaging studies after a first febrile urinary tract infection in young children. N Engl J Med 2003; 348:195-202.

(5.) Williams G, Lee A, Craig J. Antibiotics for the prevention of urinary tract infection in children. A systematic review of randomized controlled trials. J Pediatr 2001; 138:868-874.

(6.) Bollgren I. Antibacterial prophylaxis in children with urinary tract infection. Acta Paediatr Suppl 1999; 88:48-52.

(7.) Le Saux N, Pham B, Moher D. Evaluating the benefits of antimicrobial prophylaxis to prevent urinary tract infections in children: a systematic review. CMAJ 2000; 163:523-529.

(8.) Morton SC, Shekelle PG, Adams JL, et al. Antimicrobial prophylaxis for urinary tract infection in persons with spinal cord dysfunction. Arch Phys Med Rehabil 2002; 83:129-138.

(9.) Ghiro L, Cracco AT, Sartor M, Comacchio S, Zacchello G, Dall'Amico R; Veneto Urinary Tract Infection Study Group. Retrospective study of children with acute pyelonephritis. Evaluation of bacterial etiology, antimicrobial susceptibility, drug management and imaging studies. Nephron 2002; 90:8-15.

(10.) Evidence based clinical guideline for children with first UTI, Health Policy and Clinical Effectiveness Program. Cincinnati, Ohio: Cincinnati Children's Hospital Medical Center; 1999. Available at: www.cincinnatichildrens.org/ svc/dept-div/health-policy/ev-based/uti.htm. Accessed on May 5, 2004.

(11.) Allen UD, MacDonald N, Fiute L, Chan F, Stephen D. Risk factors for resistance to "first-line" antimicrobials among urinary tract isolates of Escherichia coli in children. CMAJ 1999; 160:1436-1440.

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