Prophylactic antibiotics in vesicoureteric reflux: Evidence-based analysis.

OBJECTIVES: The aim of this review was to systematically examine the available evidence for the effectiveness of prophylactic antibiotics in cases of vesicoureteric reflux (VUR).
MATERIALS AND METHODS: We searched the relevant data on medical management of VUR and the date of last search was June 2008. The search included both randomized controlled trials as well as the nonrandomized trials and the data sources were; MEDLINE, online peer reviewed journals, Cochrane database and abstracts from conference proceedings.
RESULTS: Barring few most of the studies published on medical management were nonrandomized. Besides being small in number many of these studies were of poor-quality and poorly designed eventually failing in giving a reliable answer in this regard. Few of the studies suggest that the children with low grade VUR might do well even without antibiotic prophylaxis.
CONCLUSIONS: In the absence of properly designed, randomized controlled trials and long-term follow-up the question of antibiotic prophylaxis in cases of VUR remains unanswered in large part of it. Whether to give prophylactic antibiotics or not would ultimately need a shared decision-making involving both the treating physician and the parents assessing both the risks and the benefits.

INTRODUCTION

In 1997, The American Urological Association (AUA) Pediatric Vesicoureteral Reflux Guidelines Panel recommended an antibiotic prophylaxis as an appropriate or a reasonable initial therapy for all children up to 5 years of age who have primary reflux grade I-IV.[1] Prophylactic antibiotics have traditionally been used with a presumption that they prevent new scarring. The main concerns were that the infection and the reflux, even if it is low grade, can lead to renal injury.[2-6] Recently, this concept of presumed benefit of antibiotic prophylaxis has been challenged and its efficacy been questioned.[27-9] Further, the matter has been debated on the ground that; it not only incurs cost but also carries the inherent risk of adverse effect of the antibiotics. It may also increase the risk of antibiotic resistance.[2] The aim of this review was to systematically examine the available evidence of the effectiveness of prophylactic antibiotic.

DISCUSSION

After the first symptomatic urinary tract infection (UTI), nearly 6-10% of the children develop renal scarring. The renal scars may even develop in 10-15% of the patients with low-grade reflux. The main concern remains the risk of development of chronic kidney disease (CKD) and hypertension (HT) in adulthood in many of these children, which have been reported up to 10 and 23%, respectively. This association between UTI, renal scarring, and HT has given birth to the concept of prophylactic antibiotics and surveillance in cases of vesicoureteric reflux (VUR).[3-5]

Saux et al. (2000) in a meta-analysis of six randomized studies reported a higher rate of infection in control group as compared to the children who received antibiotic prophylaxis. The rate of infections for patients with normal urinary tracts ranged from 0 to 4.0 per 10 patient-years in the treatment groups (i.e. on antibiotic prophylaxis) and from 4.0 to 16.7 in the control groups.[2] In another recent meta-analysis, Williams et al. (2006) compared the efficacy of antibiotics with placebo/no treatment in 406 children. The duration of antibiotic prophylaxis treatment in these studies varied from 10 weeks to 12 months. When compared to placebo or no treatment, antibiotics reduced the risk of repeat positive urine culture and no side effects were reported.[3] Similarly, Hellerstein et al. (2002) reported the outcome of 66 children considered at risk for UTI during the period of suppressive antibiotics. The follow-up period was 3.7 ± 2.2 years (range 0.92-9.83 years). It was inferred that most of the children with low-grade VUR did well. However, there was an increased risk of infection among those with voiding dysfunction and VUR of grade 3 or greater. These observations highlight that the higher grades are at definitive risk of developing UTI or febrile UTI and need to be addressed differently as compared to lower grades.[4] Interestingly, in another recent multicenter prospective study by Edmondson et al. (2006), the occult VUR was detected by positioned instillation of contrast and not by the conventional voiding cystourethrogram (VCU) after febrile UTI. The overall incidence of febrile UTI was reported to be reduced significantly from 0.16 per patient per month to 0.008 after the antibiotic prophylaxis.[5]

Contrary to this, some of the studies, although nonrandomized, have shown the incidence of UTI between 20 and 30% in spite of prophylactic antibiotics. Moreover, some of the randomized studies have also raised doubts regarding the preventive role of prophylactic antibiotics.[6-9] Kesler et al. (2008) in a multicenter, prospective, randomized study of the children under 3 years of age with grade I-III did not find any significant difference in the recurrence of UTIs as well as febrile UTIs (P = 0.2) in both the groups. However, the incidence of UTI was significantly higher in boys with grade III VUR (P = 0.042).[6] Likewise, Garin et al. (2006) in another multicenter, randomized, controlled study of children with mild-to-moderate VUR reported similar rate of UTIs, pyelonephritis, and new scars in both the groups (23 vs 22) after one-year follow-up.[7] Wheeler et al. (2004) performed a meta-analysis of 10 randomized controlled trials (964 children) to evaluate whether any intervention for VUR is better than no treatment. They also highlighted that no significant differences in risk for UTI or renal damage were found between antibiotic prophylaxis and no treatment in one small study.[8]

Interestingly, in some of these studies analysed, the authors tried to document that the antibiotic prophylaxis may not be useful in low-grade VUR; however, one should not undermine the malicious sequealae of VUR that may be associated with even the first UTI and any grade of reflux. Hansson et al. (2004) reported that after an episode of UTI, 51% of the children had an abnormal dimercapto-succinic acid scintigraphy (DMSA) scan and 46% with a positive DMSA scan had no evidence of VUR on VCUG. There was a significant association between grade III or higher VUR and DMSA positive renal lesions.[9] Moreover, one should be careful in interpreting these studies, both for and against, due to low quality, duration of antibiotic prophylaxis treatment not being uniform, short follow-up besides many not being double-blind, and lacking a placebo arm. Currently, the National Institute of Diabetes and Digestive and Kidney (NIDDK) is running a prospectively randomized trial to study the long-term effect of antibiotic prophylaxis on VUR. Once the data are mature we may be able to answer many of the unsolved mysteries associated with VUR.[10]

CONCLUSIONS

Despite the suggestions made through some of the recent studies that the children with low-grade VUR might do well even without antibiotic prophylaxis, the question remains unanswered in larger part of it. Whether to give prophylactic antibiotics or not would ultimately need a shared decision-making involving both the treating physician and the parents assessing both the risks and the benefits. Lastly, until proven otherwise by a prospective, randomized, and double-blind placebo-controlled study, it looks sensible to err on the side of caution.