Prophylaxis After First UTI May Not Be Necessary

Source: Montini G, Rigon L, Zucchetta P, et al. Prophylaxis after first febrile urinary tract infection in children? a multicenter, randomized, controlled, noninferiority trial. Pediatrics. 2008;122(5):1064–1071; doi:10.1542/peds.2007-3770Italian investigators conducted a multicenter, randomized, placebo-controlled trial to determine if antibiotic prophylaxis helps prevent recurrence of urinary tract infection (UTI) or renal scarring in the first 12 months after beginning prophylaxis for the first episode of febrile UTI. Between July 2000 and September 2005, children two months to seven years of age were recruited.Inclusion criteria included normal renal function, no or grades I to III vesicoureteral reflux (VUR), two consecutive urine specimens with pyuria, elevated acute phase reactants and peripheral leukocyte counts, and urine culture yielding one organism ≥100,000 colony-forming units/mL. Children with complex urologic malformation or poor renal function in at least one kidney were excluded.The initial UTI was treated for a total of 10 days with either a combination of intravenous ceftriaxone (three days) and oral amoxicillin-clavulanic acid (seven days) or 10 days of amoxicillin-clavulanic acid. All children were given antibiotic prophylaxis after completion of treatment for UTI until voiding cystourethrography (VCUG) was performed. All children underwent ultrasonography and dimercaptosuccinic acid (DMSA) scan within 10 days of starting antibiotic treatment for UTI.After the results of the initial VCUG were known, subjects were randomized to either receive no prophylaxis or receive antibiotic prophylaxis with either amoxicillin-clavulanic acid or trimethoprim-sulfamethoxazole. A second DMSA scan was performed 12 months after randomization or if a new episode of UTI occurred at least six months after the initial UTI.In the 338 enrolled subjects the mean age was approximately 10 months and 70% were girls. The no prophylaxis group totaled 127 and the antibiotic prophylaxis group 211. Approximately 62%, 9%, 17%, and 12% of the population had no reflux or grade I, II, or III reflux, respectively. Adherence to the protocol was between 71% and 86%.Repeat episodes of febrile UTI were not significantly different between the two groups: 12 (9.45%) without prophylaxis and 15 (7.11%) with prophylaxis. These results did not change when stratified by degree of VUR. In bivariate analysis younger age (7.1 vs 14.6 months, P=.02) and higher VUR grade (increasing from no VUR to each grade, I-III, P<.01) were independently associated with recurrence of febrile UTI. The study showed that 41.7 children would have to receive antibiotic prophylaxis for 12 months to prevent one febrile recurrence.A total of 295 (87%) of the subjects had a repeat DMSA scan at 12 months. A new renal scar was found in two (1.9%) of 108 subjects with no prophylaxis and two (1.1%) of 187 subjects who received prophylaxis (risk difference 0.8%; 95% CI, −2.1% to 3.7%). Twenty-five (7.3%) children, all in the prophylaxis group, experienced minor adverse events (mainly gastrointestinal) during the 12-month period.The authors conclude that in children with no or mild to moderate reflux (grades I-III), antibiotic prophylaxis does not reduce the rate of recurrent febrile UTIs after the first episode.Dr. Rathore has disclosed no financial relationship relevant to this commentary. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device.The data accrued by Montini, et al, provide a strong argument against antibiotic prophylaxis after the first episode of UTI in children without underlying urologic malformations, abnormal renal function, or grade >III VUR.The study shows that there is no increased risk of UTI recurrence and no risk of renal damage if antibiotic prophylaxis is not used. UTI prophylaxis has been discussed in these pages at least six times since 2000; most recently a retrospective study questioning the use of antibiotic prophylaxis was reported (see AAP Grand Rounds, September 2007;18:25–261).In Montini’s study, VCUG was performed after an average of 40 (range 33–50) days during which time antibiotic prophylaxis was continued. Both the need for a VCUG and its timing have been debated. VCUG can be performed as early as one week after diagnosis of UTI,2–5 further significantly reducing the duration of antibiotic prophylaxis. Decreased and prudent use of antibiotics is a goal to prevent the emergence of resistant organisms. The current investigation certainly supports a no prophylaxis policy in the patient population defined by the study.The principal argument for administering prophylactic antibiotics to children with VUR is to prevent renal damage from subsequent UTIs. This approach stems from work performed in the 1970s by Smelie.6 Recent observations, however, have led many to question this recommendation. First, the widespread use of prenatal ultrasound has demonstrated that the renal damage seen in many children with VUR is a part of congenital renal dysplasia.7 Second, epidemiologic studies have not documented a decrease in chronic renal failure due to reflux nephropathy over the last 30 years.8 Third, some studies demonstrate an increased risk of infection with resistant organisms in children taking prophylactic antibiotics.1 Fourth, three recent randomized studies, including this study by Montini, failed to demonstrate that prophylactic antibiotics prevent UTIs or renal scarring in children with VUR.9–10Caution is required when weighing the results of Montini, et al’s study because the majority of the children did not have VUR, thus severely limiting the power to detect differences in the subset with VUR. There were only 40 children (12%) with grade III VUR, and this group had the highest rate of febrile UTI recurrence. Finally, the study used VUR results, ultrasonography, and DMSA scan to exclude children with the most severe reflux, complex urologic malformations, or a significant unilateral decrease in renal function.Careful follow-up coupled with individualized therapy seem to us essential components of optimal management of UTI as we move from universal prophylaxis in children with VUR to a more selective strategy.