Antibiotic Prophylaxis and Recurrent Urinary Tract Infection in Children

Antibiotic Prophylaxis and Recurrent
Urinary Tract Infection in Children
Craig et al. NEJM 361;18 October 29, 2009
Lindsey Yeats M.D., Keely Olmsted M.D.
November 20, 2009

• Today’s Lunch = mystery meat

Outline
• Introduction
• Methods
• Results
• Discussion
• Conclusion

Introduction
A brief history of antibiotics for UTI
Prophylaxis
• Why?
▫ 2% of boys, 8% of girls by age 7
▫ Between 8­30% experience recurrent UTI*
▫ Long­term morbidity with renal damage in 5% of kids
• The debate:
▫ Pro: Antibiotics have long been used to prevent
recurrent UTI – in VUR and in recurrent UTI
▫ Con: Doesn’t it just create multi­drug resistant
infections, and does it really prevent end organ
damage? And the side effects?

Sample of articles in past on ppx:
• Saux et al. CMAJ 2000
▫ Mini­meta (6 case and cohort studies of quality 0­2/5)
▫ Normal GU (Tx group: 0­4.0 per 10 patient­years vs. 4.0­16.7 for
control)
▫ Neurogenic bladders (tx group: 2.9 and 17.1 per 10 patient­years
vs 1.5 and 33.0 for the control groups)
▫ Concluded data severely lacking
• Williams et al. Cochrane Database Syst Rev. 2006
▫ Reviewed 8 studies comparing antibiotics, and comparing abx
with placebo
▫ One said nitrofurantoin better than TMP­SMX, but had worse
adherence from side effects
▫ Another said cefixime better than nitrofurantoin, but more
adverse effects
▫ Review of 5, gives RR 0.44 of recurrent positive urine culture with
abx
▫ more studies needed.

• Wheeler et al (2004)
▫ Meta­review of children with VUR
▫ No significant difference between abx ppx and none
▫ No difference in renal parenchymal damage
• Conrad et al (2007)
▫ Increased recurrent UTI with age 3­5, white, grade 4­5 VUR
▫ No significant difference with antibiotic ppx
▫ But increased risk of antimicrobial resistance (HR 7.5)
• NICE guidelines (UK)
▫ Interesting review of UTI setting UK policy
▫ Has extensive lit review
▫ Basis of our imaging guidelines for Valley

• Essentially, there are no RCT regarding subject
• Widely variable practice

Design
• Randomized, double blinded, control trial of
antibiotic versus placebo for 12 months.
• Computer randomization according to
▫ Center, referral source, frequency of prior UTIs,
reflux status, age and sex.

Methods
• Four centers in Australia
• Children 0­18 years
• One symptomatic UTI
• All grades of VUR
• Repeat UTIs

Definitions
• Symptomatic UTI
▫ Symptoms consistent with infection
▫ Positive urine culture
Pathogenic organism in suprapubic tap
10,000 colony forming units from catheter
100,000 CFUof a single organism via clean catch.

Inclusion Criteria
• Children who had
▫ completed short­term treatment
▫ Undergone renal tract imaging (if indicated)
▫ Clinically asymptomatic before recruitment

Study Arms
• Children received either
▫ Trimethoprim­sulfamethoxazole (Bactrim, Roche)
▫ Placebo (matched for color, taste and texture)

Patient enrollment

Patient Characteristics

Imaging
• Not required, performed according
to local protocol
• Renal US, VCUG, renal scintigraphy.
• 89% centrally reviewed
• VUR graded according to the international
reflux study.
• Renal damage graded according to Goldraich
criteria.

Study Medication
• All patients received TMP­SMX for 2weeks
during the run­in period.
• Dose: 2mg/kg TMP, 10mg/kg SMX daily
• Dispensed to study group at every 3month

Adherence
• Assessed at 3 month intervals
▫ Comparisons of drug levels in bottles
▫ Direct questioning
▫ Patient diaries

Follow‐up
• At three month intervals for 12 months
• Height, weight and blood pressure assessed
• Adherence assessed
• Primary and secondary outcomes assessed via
patient diaries and medical records.

Primary and Secondary outcomes
• Primary
▫ Symptomatic urinary tract infection within 12 months
of starting prophylaxis
If infected prophylaxis was stopped and treatment given
• Secondary
▫ UTI with fever
▫ Hospitalization for other causes
▫ Concomitant antibiotics for other causes
▫ Deterioration via scintigraphy of kidneys
▫ Resistance to Bactrim (added during editorial review)

Goals
• Recruit 780 children
• Reduce absolute risk by 10%
• 80% power
• Type 1 error of 5%
• Ongoing treatment risk of 20%

Statistical Analysis
• UTI
▫ Time to event analysis
▫ Log rank test
• Other outcomes
▫ Chi­square test

Statistical Analysis
• Cox proportional­hazards regression
▫ The effect of a treatment under study has a
multiplicative effect on the subject's hazard rate.
▫ Unadjusted hazard ratio
▫ Adjust for significant stratifying variables
▫ Effect modification in secondary analyses
• Kaplan­Meier
▫ Estimates of children with UTIs
• Number needed to treat

Statistical Analysis
• Cox model
▫ Pirori subgroup analysis of children according to
reflux grade.
• Post hoc subgroup analyses
▫ Antibiotic sensitivities
• Hazard ratio and absolute risk
▫ Treatment effects

Results

Patient Characteristics

Discontinuation of intervention
▫ 30% by 12 mo for reason other than UTI
Similar adverse reactions in both groups though not
specified
▫ No difference in non­adherence
▫ 2% dropped out for mild adverse drug reaction

Time to symptomatic UTI for all patients

Primary Outcome
• UTI diagnosed in 36 (13%) vs 55 (19%) patients
in treatment vs placebo groups (P=0.02)
• Hazard Ratio 0.61 (0.4­0.93) in antibiotic grp
• Number Needed to Treat is 14
• Abx group favored across age, sex, reflux status,
# of previous UTI, or h/o abx resistance
• EXCEPTION – h/o UTI caused by organism
resistant to TMP­SMX

Effect of antibiotics on risk for
symptomatic UTI

Secondary Outcomes

Time to symptomatic UTI

Discussion
• Long­term, low­dose trimethoprim­
sulfamethoxazole was associated with a modest
decrease in symptomatic UTI in predisposed
children.
• Absolute risk reduction of 6%
• Decreased risk of febrile UTI

Discussion
• The benefit of therapy is greatest during the first
6 months
• Over time the susceptibility patterns change
▫ Increased risk of pathogenic bacteria
▫ Increased risk of symptomatic UTI caused by
resistant organisms
• Likely long term antibiotic use does not
predispose to other infections

Previous Data
• Limited data from previous randomized,
controlled trials.
▫ Four trials tended to favor prophylaxis
▫ 171 children in all four studies
▫ 32 children with reflux
• Accepted as standard of care for 20 years

Recent changes
• Five randomized, controlled trials in children
with and without reflux
▫ Showed no benefit of prophylactic antibiotics
▫ None placebo controlled or assessed adherence
▫ Underpowered with 100­218 patients
• Different results
▫ Lack of adherence, lack of power, unbalanced co­
interventions.

Current research
• An ongoing placebo controlled randomized
intervention for children with vesicoureteral
reflux (RIVUR study)
▫ Data­linkage cohort study showed no benefit of
antibiotic prophylaxis

Limitations
• Study not powered to find risk of new kidney
damage
• Enrolled fewer patients than desired
• Low percentage of circumcised males
• Grouping of patients with VUR

Recommendations
• Use of TMP­SMX in children at high risk for
infection
▫ Females
▫ VUR
▫ Recurrent UTI
• Not routinely recommended in children with a
single symptomatic UTI
• Not recommended in children with congenital
hydronephrosis or siblings with reflux, but no
UTI

Conclusions
• Long term, low­dose antibiotic use was
associated with small but significant reduction
in the absolute risk of symptomatic UTI in
predisposed children.
• May reduce the likelihood that antibiotics will be
required for other infections.

References
• Conway et al. Recurrent urinary tract infections in children: risk factors and
association with prophylactic antimicrobials. JAMA. 2007 Jul
11;298(2):179­86.
• Saux et al. Evaluating the benefits of antimicrobial prophylaxis to prevent
urinary tract infections in children: a systematic review. CMAJ 2000 Sep
5;163(5):523­9.
• Shaikh et al. Long­term management and prevention of urinary tract
infections in children. Uptodate.com. Last update April 9, 2009.
• Urinary Tract Infection in Children. National Institute of Health and
Clinical Excellence guidelines. (2007) http://guidance.nice.org.uk/CG54.
Accessed 11/19/2009.
• Wheeler et al. Interventions for primary vesicoureteric reflux. (Cochrane
Review). Cochrane Database of Systematic Reviews, Issue 3, 2004.
• Williams et al. Long­term antibiotics for preventing recurrent urinary tract
infection in children. Cochrane Database Syst Rev. 2006 Jul
19;3:CD001534.