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Three Part Question

In [infants who have had UTI], does [the administration of oral antibiotic prophylaxis] [decrease the rate of recurrence of UTI or sequelae thereof]?

Clinical Scenario

A nine-month-old boy comes to clinic two weeks after being diagnosed on the ward with a urinary tract infection (UTI), having presented febrile and with a pure growth of greater than 100000 cfu/ml E. Coli on a clean catch specimen of urine. The infection has been appropriately treated according to sensitivities and the SHO who saw the baby has organised an ultrasound scan, cystogram and dimercaptosuccinic acid (DMSA) scan. The SHO has also started the patient on prophylactic antibiotics to prevent any further UTI until the results of investigations are known. You wonder whether there is any evidence for the efficacy of these prophylactic antibiotics.

Search Strategy

Dialog Datastar was used to search Medline 1950-February 2007.
The Cochrane database was searched
Additional searching was made of the citations used in the references of the papers found in the initial search.
(((RECURRENT ADJ INFECTION) OR (RECURRENCE)) AND ((PROPHYLACTIC ADJ ANTIBIOTICS) OR (ANTIBIOTIC-PROPHYLAXIS.DE.)) AND (((INFANT) OR (INFANT#)) AND (((URINARY ADJ TRACT ADJ INFECTION) OR (URINARY-TRACT-INFECTIONS.DE.)) OR (URINARY-TRACT-INFECTIONS.DE. OR BACTERIURIA.W..DE.)))) AND (PT=RANDOMIZED-CONTROLLED-TRIAL)

Search Outcome

The search of Medline produced one recent RCT. From the reference list of this article two recent systematic reviews were found. Search of the Cochrane database found a further review on the subject. There is some overlap between these three systematic reviews and, in all, a further 10 other RCTs were found (making 11 RCTs in total).
Of these only one further trial was found to be a placebo controlled RCT with data including infants less than 2 years of age5. Four RCTs were trials comparing two different antibiotics. One compared antibiotics with immunotherapy. One trial was a crossover trial with only 18 patients and no washout period. One trial was an RCT of prophylaxis in girls with asymptomatic bacteriuria. One trial included only patients over age 3. The last trial compared short and long-term treatment rather than prophylaxis and outcomes were measured after the treatment.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Williams GJ, Wei L, Lee A, Craig JC 2006 Australia	Systematic review of trials on the subject. There is a lot of heterogeneity in the study design. Patients often older than infancy. Also inclusion criteria vary from true UTI to asymtomatic bacteriuria.	Only one RCT in the Cochrane review compared prophylactic antibiotics to placebo and used recurrent symtomatic UTI as the outcome (n=61)	Recurrent symptomatic UTI	RR (95% C.I.) = 1.97 (0.63 to 5.92	This RCT had small numbers and inclusion criteria were asymtomatic bacteriuira in children up to 14 years.
Smellie JM, Katz G, Gruneberg RN 1978	45 patients with 47 episodes of UTI	Patients were randomised to 6 months treatment with septrin or nitrofurantoin compared vs. no treatment. Outcome used was recurrence of UTI.	Recurrence of UTI	No recurrence in the treatment group. 50% recurrence in the control group. No statistics done	This influential paper has some methodological flaws. It is not blinded and the control group was untreated rather than placebo controlled. There was no standardisation of diagnostic criteria or follow up procedure. In addition the results are so strikingly in favour of prophylaxis as to seem too good to have come about without a follow up bias of some sort.
Garin EH, Olavarrio F, Nieto VG, Valenciano B, Campos A, Young L	236 patients with Pyelonephritis.	Divided into groups with and without VUR (grade I – III). Each group randomised to receive 1 year prophylaxis vs no treatment. Outcomes measured were: overall recurrence rate of UTI; sub-type of UTI; occurence of renal scarring on DMSA	Recurrence of pyelonephritis in prophylaxis vs control groups with VUR	7 recurrences in the treatment group vs. 1 in the control group (p=0.0291)	Within the study population there are too many subdivisions into groups. The researchers did not recruit enough subjects to attain sufficient power. Dropouts excluded from analysis. Not placebo controlled. No use of relative risks with CI. In general the study is confused by the researchers comparing results in those with and without VUR. The intervention they have trialled is prophylactic antibiotics and the key question of their overall efficacy is not addressed.

Comment(s)

The use of prophylactic antibiotics in childhood UTI has a very poor evidence base. There have been a surprisingly small number of trials to address this question and attempts to collate the results are confounded by heterogeneity of inclusion and intervention. The results of these studies are also often contradictory. Indeed in the present search of the literature, the most recent RCT seemed to find a significant detrimental effect, with increased recuurent pyelonephritis in the treatment group, caused by organisms resistant to the prophylactic antibiotics. The group of patients that this BET attempts to focus on is infants with proven UTI who are putatively at risk of renal scarring. The evidence base is confounded by other groups, including older children with symtomatic UTi and also older childen with assymtomatic bacteriuria. The other confounding factor is the presence or absence of vesicoureteric reflux. In practice it is the infants who are prescribed prophylactic antibiotics as they are felt to be the group vulnerable to scarring and also are unable to report their symptoms to allow for brisk urine collection and appropriate treatment. The hypothesis of infection plus reflux leading to renal scarring is based upon animal models. Currently, an increasing body of evidence is calling into question the validity of this model in humans. Prophylactic antibiotics are very commonly prescribed in general padiatric practice but adherence levels are extremely low and their efficacy cannot be supported by what evidence is available.

Clinical Bottom Line

The current accepted practice is informed by expert opinion and consensus views. Large, well designed randomised trials with inclusion only of infants (as the group vulnerable to scars) will be needed to properly address the question of efficacy of prophylactic antibiotics.

References

1. Williams GJ, Wei L, Lee A, Craig JC Long-term antibiotics for preventing recurrent urinary tract infection in children Cochrane Database of Systematic Reviews 2006, Issue 3. Art. No.: CD001534. DOI: 10.1002/14651858.CD001534.pub2.
2. Smellie JM, Katz G, Gruneberg RN Controlled trial of prophylactic treatment in childhood urinary tract infection Lancet 1978;2(80820:175-8
3. Garin EH, Olavarrio F, Nieto VG, Valenciano B, Campos A, Young L Clinical significance of Primary Vesicoureteral Reflux and Urinary Antibiotic Prophylaxis After Acute Pyelonephritis: A Multicenter, Randomised Controlled Study Pediatrics 2006;117(3):626-32