Is antibiotic prophylaxis of any use in nephro-urology?

Giovanni Montini

Pediatric Nephrology and Dialysis Unit University of Milan

Italy

UTI_VUR

Bacteria and Humans: diverse behaviours!!

Bacteria

• Extremely numerous

• Memorise generational experiences within a few hours

• Capacity to transfer vast quantities of information in seconds

• Extraordinary ability to adapt under the selective pressure of antibiotics

• Outstanding collaboration

Humans

• Often few and isolated

• Endless discussions!!

• Difficulty in confronting and resolving issues

• Tendency to maintain the same diagnostic and therapeutic approaches

• Scarce collaboration for the most part

Causes of CKD (n=1197)

Hypodysplasia and VUR

24.7%

PUV

10.2%

Glomerulopathies

6.8% Other uropathies

12.2% Hypodysplasia

13.9%

Others

13.2%

Heredithary

nephropathies

15.4%

HUS

3.6%

ItalKid 2003

0

10

20

30

40

50

60

70

80

90

100

0 1 2 3 4 5 6 7 8 9 10 11 12

months

Cumulative

%

2 3 3,5 4 5 6 6,5 7 8 8,5 9,5 10 11 12

years

males

females

Age at diagnosis of VUR

Age at diagnosis of vesicoureteral reflux (as cumulative percent) by sex in children with CRF (n:187)

ItalKid 2002

Gonzalez Celedon PN 2007 176 CAKUT children

6.7%

5.7%

8%

27.5%

42.8%

n = 516

The old concept

G. Montini, I. Hewitt and K Tullus

J De Bessa, J Urol 2015

May 4, 2014

Hoberman, NEJM 2014

71/126 toilet-

trained children

VUR GRADE II-III = 80%

RESULTS: primary endpoint

The treatment proved statistically significant, but of doubtful clinical value: requiring 16 or 22 patient years of antibiotics to prevent 1 UTI or 1 febrile UTI, respectively

RESULTS

p. NS

p < 0,001

The treatment group had in excess of 600 years of prophylaxis without a

demonstrable effect on scar formation but a much higher propensity to induce

bacterial resistance

Guidelines Antibiotic prophylaxis Others interventions

NICE

Not for routine use

Treat dysfunctional elimination syndromes and constipation

Drink an adequate amount of fluid Do not delay voiding

AAP

Not for routine use Not considered

ISPN

For reflux III-V Recurrent febrile UTI*

Not considered

* ≥3 febrile UTIs within 12 months

Reflux grades of all RCTs of antibiotic prophylaxis

VUR grade n

0 549

I-II 777

III 577

IV 172

V 5

Total 2080

Previous studies

THE PREDICT TRIAL

Antibiotic Prophylaxis and REnal Damage In Congenital abnormalities of the kidney and urinary Tract

Giovanni Montini Nefrologia e Dialisi Pediatrica Policlinico Sant’Orsola-Malpighi Bologna

PREDICT Trial: INCLUSION/EXCLUSION CRITERIA

INCLUSION CRITERIA

• Age 1 - 4 months (until the 20th week of post-natal age!)

• Gestational age > 35 weeks

• GFR (according to Schwartz) > 15 ml/min/1.73 m2

• Grade III to V vesico-ureteral reflux

• No previous symptomatic UTI

EXCLUSION CRITERIA

- Neurogenic bladder - Myelomeningocele - Uretero-pelvic junction and/or uretero-vescico junction obstruction - Malformations leading to potential voiding disturbances

- Urethral valves

326 ( 436 )PATIENTS with VUR III-V

36 months FOLLOW-UP

STRATIFICATION Renal damage

CAKUT (prenatal or postnatal US screening)

PRE-RANDOMIZATION renal function, US, VCUG and DMSA

GROUP B Antibiotic

prophylaxis

GROUP A Follow-up

RANDOMIZATION

24 months (renal function, US + DMSA +/- VCUG+ BMI)

60 months (renal function, US + DMSA + VCUG+ BMI)

END-POINTS

Primary end point: first symptomatic urinary tract infection during the 24-

month observation period.

Secondary end point: febrile UTIs, number of new renal scars at the 2 years

follow-up DMSA scan, development of renal function, hypertension and/or

proteinuria, anatomical growth of the kidneys at 2 and 5 years follow-up,

evaluation of the natural course of renal function for hypo-dysplastic kidneys

during the first 5 years of life and evaluation of BMI at 2 and 5 years of age.

Nitrofurantoin (1.5-2 mg/kg/day) Co-amoxiclav (15 mg/kg/day) Cefixime (2 mg/kg/day) Trimetropim/sulfametoxazole (2.5 mg/kg/day)

ANTIBIOTIC PROPHYLAXIS

ONCE DAILY AT EVENING

According to the local antibiotic resistance pattern of E. coli

Each single patient may switch from one antibiotic to another.

Alberici I et al EUR J Ped 2015

Inpatients UC: resistance to E.coli

STATE OF THE ART: COUNTRIES

14 EUROPEAN COUNTRIES

Aims: - explore the modification in gut microbiota induced by antibiotic exposure in early infancy - Modifications in the pattern of resistance genes coded by gut microbiota (gut resistome profile).

GUT MICROBIOTA

collect and freeze a STOOL SAMPLE from every patient

8 time points:

(0, 4, 8, 12, 24, 36, 48, 60 months)

Current Understanding of Febrile Urinary Tract Infections and Renal Scarring.

Montini G et al. N Engl J Med 2011;365:239-250

Cystitis: antibiotic prophylaxis

- If frequently recurrent but > antibiotic resistance

- Short periods (1-3 months)

- Main aim is to remove symptoms secondary to

cystitis and then to evaluate bladder function

with no concomitant infection

- Cranberry ??

Results

Mean duration of follow-up was 47±30 months (12 to 78 months). The mean age of diagnosis in the cases that were not discovered prenatally was 10±19 months (1 week–77 months).

24%

During follow-up, a high rate of spontaneous regression

was observed.

At 7 years of follow-up, 70% of POM had

regressed spontaneously

What about prophylaxis? • In the first year of life, 30/44 received antibiotic prophylaxis.

–7 UTIs occurred during 199 patient months with prophylaxis

– 19 UTIs during 244 patient months without prophylaxis

– Prophylaxis appeared particularly effective in the first 6 months of life, where an 83% reduction of UTI rate was found.

• In the second year of life 38% received antibiotic prophylaxis

• In the third year of life 21% received antibiotic prophylaxis

reduction of UTI incidence on proph by 55% (0.94 vs. 0.42 UTIs per year, p<0.05)

0.46 UTIs/year without prophylaxis

0.14 UTIs/year without prophylaxis

NO Prophylaxis

• Hydronephrosis

• Neurogenic bladder and CIC

• Non dilating Refux

YES Prophylaxis

• Dilating Reflux

• Non Refluxing Megaureter

• Recurrent cystitis

• Urethral valves

Is antibiotic prophylaxis of any use in nephro-urology?

Giovanni Montini

Pediatric Nephrology and Dialysis Unit University of Milan

Italy