URINARY TRACT INFECTIONS IN CHILDREN

Moises Auron, MD, FAAP, FACPMoises Auron, MD, FAAP, FACPAssistant Professor of Medicine and Assistant Professor of Medicine and

PediatricsPediatricsCleveland Clinic, Cleveland OHCleveland Clinic, Cleveland OH

04/08/23

EpidemiologyChildren < 2 years old Prevalence - 7 % percent in febrile infants and

young children Caucasian have a 2-4 fold higher prevalence

compared with African Americans Girls have a 2-4 fold higher prevalence compared

with circumcised boys. Caucasian girls with fever ≥39ºC - 16% prevalence Shorter female urethra

Children > 2 years old Prevalence is underestimated : 8 – 9 % UTI are associated with urinary symptoms but in less

frequency than adults Higher frequency of non-specific vulvovaginitis in children Adults have better ability to recognize UTI symptoms

Pediatr Infect Dis J 2008; 27:302-308 04/08/23

Epidemiology

Age Boys < 1 year Girls < 4 years

Circumcision Febrile uncircumcised infant: 4-8 fold

prevalence of UTI vs. circumcised infant

Pediatr Infect Dis J 2008; 27:302-308 04/08/23

Pathogenesis

Almost all UTIs are ascending in origin (except in neonates)

Begins with colonization of the periurethral area by a pathogenic bacteria and then entry of pathogenic bacteria into the urinary bladder

04/08/23

Microbiology

Escherichia coli cause 80-90% of UTIs in children

Proteus species cause about 30% of cases of uncomplicated cystitis in boys

S. saprophyticus cause about 30% of UTIs in adolescents

04/08/23

MicrobiologyNon-E.coli organisms: Urinary tract

malformations Voiding dysfunction Previous antibiotic

treatment Enterococci Pseudomonas Staphylococcus aureus Staphylococcus

epidermidis Group A or B

streptococcus Haemophylus

influenzae

Fungal infections Immunosuppression Long-term

antibiotics Indwelling Foley

Arch Dis Child. 2006 Oct;91(10):845-6Clin Infect Dis 2000 Jan;30(1):14-8.

04/08/23

Uropathogenic E. Coli Virulence factors

Enhance multiplication and inflammation

Adherence Pili or bacterial fimbriae that bind to

uroepithelial cells making possible contact between tissues and toxins

Lipopolysaccharides (O antigens or endotoxin)

Capsular or K antigens Provide resistance to serum bactericidal

effect and phagocytosis

04/08/23

Bacterial AdhesionBacterial Adhesion

Transmission of a P-fimbriated E. coli adhering to a uroepithelial cell

Winberg J. Arch Dis Child (1984);59:18004/08/23

Host Defense Mechanisms Anti-adhesive molecules Secretory IgA, Tamm-Horsfall protein Organic acids

Bladder washout

04/08/23

Breast Feeding and UTI

Anti-adhesive capacity of secretory IgA

Receptor analogues against bacterial adhesion

Promotion of a stable intestinal flora with fewer potentially pathogenic strains

Acta Paediatr. 2004 Feb;93(2):164-8.04/08/23

Circumcision and UTI

Mucosal surface of the uncircumcised foreskin – moist surface that promotes adhesion and replication of uropathogenic bacterial Circumcised penis – keratinized skin Decreased meatal contamination and

bacterial ascent into the bladder Partial obstruction of the urethral

meatus by a tight foreskin NNT = 111 circumcisions to prevent

one UTI J Urol 1988 Nov;140(5):997-1001.Arch Dis Child 2005 Aug;90(8):853-8.

04/08/23

Circumcision and UTIAmerican Academy of Pediatrics: UTI risk: 7-14/1000 uncircumcised

male < 1 y/o vs. 1-2/1000 circumcised Risk in uncircumcised increased 4-10

fold Data are not sufficient to recommend

routine neonatal circumcision

Pediatrics. 1999; 103:686-93

04/08/23

Circumcision and STD

3 randomized trials HIV decreases by 53% to 60% HSV 2 by 28% to 34% HPV by 32% to 35% Female partners:

Bacterial vaginosis decreases 40% Trichomonas vaginalis decreases 48%

Arch Pediatr Adolesc Med. 2010 Jan;164(1):78-84. 04/08/23

Urinary obstruction

Anatomical: PUV, UPJ obstruction), Neurogenic (myelomeningocele) Functional Suspected when the patient has

voiding problems – enuresis, abnormal stream, abnormal genital examination.

04/08/23

Voiding dysfunction

Abnormal elimination pattern (frequent or infrequent voids, urgency, constipation)

Bladder and or bowel incontinence

Withholding maneuvers Contraction of the perineal muscles

and external sphincter to prevent incontinence results in spreading of the contents of the distal urethra into the bladder

Pediatrics 2003 Nov;112(5):1134-7.Urology 1991 Oct;38(4):341-4.04/08/23

Pathogenesis Perineal Hygiene:

No data associates that having girls wipe from front to back prevents vaginal and perineal colonization by enterobacteria

If fecal soiling were important in the pathogenesis of UTIs, female infants should have a very high incidence prior to bowel control

Int J Antimicrob Agents. 2001 Apr;17(4):259-68.

04/08/23

Sexual Activity and UTI “Honeymoon cystitis” Trauma to the female urethra

during intercourse forces bacteria into the bladder. Spermicide use alters the normal vaginal

flora (Lactobacillus and Corynebacterium sp) frequent intercourse

Treatment: Voiding after intercourse Post-coital antibiotics

Int J Antimicrob Agents. 2001 Apr;17(4):259-68.

Clin Exp Obstet Gynecol. 2005;32(3):180-2.

J Infect Dis. 2000;181:595-601

04/08/23

Risk Factors for HTN, nephrosclerosis and ESRD

Recurrent UTI Delay in antimicrobial treatment Dysfunctional voiding Obstructive malformations (PUV, Uretero

Vesical Junction, Uretero Pelvic Junction) Vesicoureteral reflux (> grade III) Congenital malformations (aplastic/

hypoplastic/ dysplastic kidneys) Young Age

Pediatr Nephrol 2000 Sep;14(10-11):1006-10. 04/08/23

Likelihood Ratios

L.R. 2, 5, 10 increase probability of disease by 15%, 30% and 45%

L.R. 0.5, 0.2, 0.1 decrease probability of disease by 15%, 30%, 45%

04/08/23

Febrile boy 3 mo - 2 y/oJAMA. 2007;298(24):2895-2904

04/08/23

Febrile girl 3 mo - 2 y/oJAMA. 2007;298(24):2895-

2904

04/08/23

Verbal Children > 2 y/oJAMA. 2007;298(24):2895-

2904

04/08/23

The “three day” rule

The infant or child with unexplained fever should not be allowed more than 3 days of fever without a urine examination

Clinical and experimental data show that delay in the treatment of pyelonephritis increases the risk of kidney damage

Ped Clin North Am 1995:42:1433-1457

04/08/23

Pyelonephritis (Febrile UTI) Fever (Rectal T >39°C)

Costo-Vertebral angle tenderness Systemic symptoms Elevated APR (CRP or ESR) Leukocytosis with bandemia Voiding symptoms may not be

present Initial diagnosis

Urinalysis + urine microscopy Final diagnosis

Quantitative urinary culture

04/08/23

Cystitis

Fever Urinary urgency Urinary frequency Dysuria New-onset nocturnal enuresis Foul smelling urine

04/08/23

Differential diagnosis In children vaccinated against H. influenzae and

S. pneumoniae: probability of UTI (7 %) probability of occult bacteremia (<1 %)

Urinary symptoms and bacteriuria occurs in: nonspecific vulvovaginitis Nephrolithiasis STD (Chlamydia) Vaginal foreign body

Triad of fever, abdominal pain, and pyuria: GAS Appendicitis Kawasaki disease

Dysfunctional eliminationJAMA. 2007 Dec 26;298(24):2895-904.Arch Pediatr Adolesc Med 2004 Jul;158(7):671-5.Pediatrics. 2006 May;117(5):1695-701.

04/08/23

Diagnosis

04/08/23

J Pediatr (2000):137;221Pediatrics 1999

Apr;103(4):e54.

Use of “bagged” urine “bagged urine specimen is valid for UTI

evaluation only when there is no growth in the urinary culture “

5127 bagged urines vs. 2457 catheterized specimens from infants < 24 months of age

Contaminated specimen Sterile bagged specimen 62.8% Catheterized specimen 9.1%

04/08/23

Urinalysis: Findings for a presumptive diagnosis of UTI

Method Findings

Bright field or phase contrast microscopy

Bacterial rods or cocci identified in urinary sediment

Gram stain of urinary sediment

Gram-negative rodsGram-positive cocci

Urine dipstick test

Positive for nitrite and/or leukocyte esterase Infect Med 2002;19:554-

6004/08/23

Urinalysis

04/08/23

Diagnosis

THE DEFINITIVE DIAGNOSIS MUST BE CONFIRMED BY THE QUANTITATIVE URINARY CULTURE

04/08/23

Urine cultureMethod of collection Quantitative culture: UTI

present

Suprapubic aspiration

Growth of urinary pathogens in any number (exception is <2,000 to 3,000 CFU/mL of coag-negative Staph)

Catheterization in females or midstream void in circumcised males

Febrile infants or children usually have >50,000 CFU/mL of a single urinary pathogen.Infection may be present with counts >10,000 CFU/mL (most commonly encountered in pt with ur. frequency)

Midstream clean void Symptomatic patients: usually >100,000 CFU/mL of a single urinary tract pathogenAsymptomatic patients: at least 2 specimens on different days with >100,000 CFU/mL of the same organism

Infect Med 2002;19:554-60.

04/08/23

Imaging Studies in UTI Identify anatomical abnormalities of the genitourinary tract Modify the risk of subsequent renal damage (surgery, antibiotic

prophylaxis). Imaging should be done on:

Girls < 3 y/o with a first UTI Boys of any age with a first UTI Children of any age with a febrile UTI Children with recurrent UTI w/o previous imaging studies First UTI in a child with:

family history of nephropathy abnormal voiding pattern poor growth Hypertension Genitourinary abnormalities

NEJM 2003; 348:195-202Pediatrics. 2009 Feb;123(2):e239-46.

04/08/23

Ultrasound in UTI Are there two kidneys in normal location?

ectopic, horseshoe, solitary Are the kidneys normal?

Echogenicity? Size? Scars? Pyelonephritis (enlarged kidney) Lobar nephronia Dysplasia

Obstruction Posterior urethral valves Uretero Pelvic Junction Uretero Vesical Junction

Suggestion of VUR Dilatation of the collecting system Duplication of the urethers

Arch Dis Child 2004 May;89(5):466-8. 04/08/23

US in UTI: Other indications Congenital hydronephrosis Palpable abdominal mass Abnormal urine stream Poor response to UTI treatment (r/o

abscess) Recurrent febrile UTI At risk for poor follow-up VUR

04/08/23

Voiding Cystourethrogram (VCUG)

40 % of children with a first febrile UTI have VUR

VUR grade III – increased risk of UTI It may be performed as soon as the

patient is asymptomatic Anatomic or neurogenic

abnormalities Bladder trabeculation Urethral dilatation (Spinning top

urethra) Residual urine volume

04/08/23

Vesicoureteral Reflux (VUR)

04/08/23

Suggested management of boys after first febrile UTI

Infant or older Obtain an US and VCUG (important to

rule-out bladder outlet obstruction) If normal, suppressive antibiotic for 6

months Circumcision of an uncircumcised infant Close follow-up for a febrile UTI. If VUR is present, the duration of Rx is

determined by the grade, persistence and severity of the reflux

04/08/23

Suggested management of girls after first febrile UTI Infants or older

If there is prompt response to therapy, no imaging studies

Suppressive antibiotic Rx for 6 months.

Close follow-up for a febrile UTI If one occurs, VCUG and US If VUR is present, the duration of

antibiotic Rx is determined by grade, persistence and severity of reflux

04/08/23

VCUG: Indications

Good response to treatment Afebrile > 24 hrs.

Bacteria susceptible to antibiotic Voiding pattern back to baseline Younger infant

No pain on urination & behavior back to baseline

If VCUG is not done during initial treatment period (10 days) the child should be on suppressive antibiotic until it is obtained

04/08/23

Nuclear scan - DMSA Dimercaptosuccinic acid (DMSA) Dx of acute pyelonephritis and renal scarring Doubtful diagnosis:

Fever and sterile pyuria Acute pyelonephritis on abx who remain

febrile for > 72 hrs (detects extent of inflammation)

Evaluation of children with VUR who have a breakthrough infection

04/08/23

Rx of UTI: infants < 8 wks Febrile infants < 8 wks with (+) Cath UA

Admit and administer parenteral abx Use appropriate neonatal abx doses

3rd generation cephalosporin until afebrile for 24 hours Continue rx with therapeutic doses of an effective p.o.

abx to complete a 10–14 day course Continue with a suppressive abx until a VCUG is done Avoid nitrofurantoin in infants <1 month because of

risk of hemolytic anemia Avoid sulfonamides in those <2 months because of

competition with bilirubin for binding sites on albumin

04/08/23

Parenteral Antibiotic Agents Drug Dose Frequency Comments

Ceftriaxone 50-75 (mg/kg/day) Given as a single dose or divided every 12 hours (IV or IM)

Not suitable for Rx of those <6 wks of age.

Cefotaxime 150 (mg/kg/day) Divided every 6-8 hours (IV or IM)

Also used in combination with Ampicillin in infants 2-8 weeks of age

Ampicillin 100 (mg/kg/day) Divided every 8 hours

Used in combination with Gentamicin for infants<2 weeks of age and when enterococcus is suspected

Gentamicin

Full term neonates <7 days old (2.5 mg/kg/dose)

Every 12-18 hours (depending on weight) Used in

combination with Ampicillin. Blood levels and kidney function if therapy extends >48 hours.

Term infants >7 days old and children <5 yr (2.5 mg/kg/dose)

Every 8 hours

Children >5 yr old (2-2.5 mg/kg/dose)

Every 8 hoursInfect Med 2002;19:554-6004/08/23

Oral Antibiotic Agents

Infect Med 2002;19:554-60

Antibacterial Agent Daily dose and intervals

Trimethoprim/sulfamethoxazole (TMP/SMX)

6-12 mg/kg TMP, 30-60 mg/kg/d SMX in divided doses q12h

Amoxicillin 25-50 mg/kg in divided doses q12h

Amoxicillin and Clavulanic acid 25-45 (Amoxicillin component)/kg per day in divided doses q12h

Cephalexin 20-50 mg/kg in divided doses of q6h

Cefixime 8 mg/kg in divided doses q12h

Cefpodoxime 10 mg/kg in divided doses q12h

Loracarbef 15-30 mg/kg in divided doses q12h

Nitrofurantoin 5-7 mg/kg in divided doses q6h04/08/23

Febrile UTI Rx: 2 mo to 2 y/o If immediate antibiotic treatment is

indicated Urine should be obtained by suprapubic

aspiration or bladder catheterization

Suprapubic aspiration is necessary for Male with a tight foreskin Girl with marked labial adhesions Any child with a severe perineal rash

Pediatrics 1999:103:843-852

04/08/23

UA - positive for a UTI Prompt parenteral antibiotic Rx has

usually been recommended Daily IM or IV treatment until afebrile

and clinically improved Hospitalize toxic or dehydrated child

Febrile UTI Rx: 2 mo to 2 y/o

Pediatrics 1999:103:843-852

04/08/23

RCT (N=306 febrile infants) 153 = IV cefotaxime (3d) PO cefixime (11d) 153 = PO cefixime (14d) No difference in the short or the long term

outcome (clinical response, reinfection, renal scars at 6 Months)

Febrile UTI Oral Rx: 1 mo to 2 y/o

Pediatrics 1999;104:79-86

04/08/23

P.O. Rx of pyelonephritis: Suggested criteria

Oral antibiotics 2nd or 3rd generation

cephalosporin Amoxicillin/clavulanate Co-trimoxazole (TMP/SMX)

The child should be non-toxic No vomiting should be present Close follow-up is expected

Curr Opin Pediatr (2004):16:85-88.

04/08/23

Rx of Febrile UTI in > 2 y/o Complicated pyelonephritis

High fever, acutely ill or toxic Persistent vomiting Moderate to severe dehydration Poor compliance anticipated Hospitalize

IV fluids and abx until afebrile for 24 hrs Outpatient treatment to complete 10 to

14 days with therapeutic doses of p.o. abx

04/08/23

Uncomplicated pyelonephritis Febrile, but not acutely ill Able to take p.o. fluids & medications Mild dehydration Good compliance anticipated Rehydrate as an outpatient prn. Oral or IV antibiotic

Repeat IV or IM Rx in 24 and 48 hrs if fever persists Complete 10 to 14 days of Rx with therapeutic

doses of oral antibiotic

Rx of Febrile UTI in > 2 y/o

04/08/23

Cystitis: Rx

Mild symptoms Supportive care until culture report

Moderate or severe symptoms Oral antibiotic and supportive care

Supportive care High fluid intake With severe voiding symptoms,

phenazopyridine (for no longer than 2 days)

04/08/23

Optimal duration of antibiotic Rx

No difference between 2–4 days and 10-14 days of oral treatment in the number of children with bacteriuria at the end of treatment or in recurrences after 1 and 15 months

Single dose or single day treatment - unsatisfactory

Cystitis: Rx

The Cochrane Library 2005;2:1-25

04/08/23

Satisfactory response to Rx: Child afebrile after 48 to 72 hrs of Rx Voiding pattern has returned to that

present prior to Dx of febrile UTI Younger infant appears to have no

pain on urination and behavior is generally back to normal

04/08/23

Suppressive Antibiotic Rx

After a 1st febrile UTI - 30% of children will have a recurrence in 1 year

Risk greatest within 2 – 6 months after UTI No VUR or Grade I – II VUR

No support for Abx to prevent reinfection or renal scarring

04/08/23

Recommendations for Suppressive Antibiotics

Children with VUR > Grade III are at risk for recurrence of UTI Young infants have very distensible

collecting systems in which marked VUR is often reversible over 1 – 3 years

They “may” benefit from suppressive antibiotic

Rx for 18 – 24 months In absence of recurrence of a febrile UTI,

follow-up VCUG after 24 months

04/08/23

Cranberries and UTI Used to treat and prevent UTIs before the discovery of

antibiotics For decades cranberry-derived beverages have been

thought to reduce the incidence of bladder infections Facts

Decrease of urinary pH, but not enough to keep below 5.5

Increased hippuric acid production (but levels not great enough to cause bacteriostasis)

Prevention of bacterial adherence of uropathogens in urine Fructose - interfere with adhesion of type 1

fimbriated E. coli to uroepithelium Proanthocyanidins - inhibit adherence of P-

fimbriated E. coli High oxalate content

J Urol 1984 May;131(5):1013-6N Engl J Med 1998 Nov 5;339(19):140804/08/23