PEDIATRIC URINARY TRACT INFECTION

Scott Weissman, MD

Fellows’ orientation

7 July 2010

PEDIATRIC UTI BY AGE

Non-toilet-trained children (NTTC)Newborn/infants (up to 60 d)

Present with non-specific signs/symptoms Managed by ‘rule out sepsis’ guideline

Toddlers (up to 2-3 yr) Unable to express themselves well Present with fever, abd pain, vomiting/diarrhea

Toilet-trained children (TTC)Pre/school-age (up to 12 yr)

Can describe/localize sx Present like adults: dysuria, frequency

Adolescent (13 yr and older) Potentially sexually active

NEW RECOMMENDATIONS: DIAGNOSIS

Diagnose UTI in NTTC via high quality urine specimen (ie, not a bag) Catheter Suprapubic tap

In adolescents, document external GU exam and test for GC/Chlamydia Nucleic acid amplification tests; send-out to UW NOT clean catch or midstream - collect first 20 cc

NEW RECOMMENDATIONS: EMPIRIC RX When to start empiric therapy

In NTTC – for clinical suspicion In TTC – for clinical findings plus (+) UA/urine

dip/microscopy What to start

Newborns (0-30 d) IV amp + gent

Infants (over 30 d): IV ceftriaxone if admit; IV amp + gent if suspect E-coccus

Infants (30-60 d) not admitted: IM ceftriaxone

Older children (over 60 d): PO cephalexin; if CS allergy, PO Bactrim IM ceftriaxone

NEW RECOMMENDATIONS: EMPIRIC RX Length of therapy

Newborn (0-30 d): 7 d IV followed by 7 d PO Infant (31-60 d): IV until afebrile x 24 h and BCx (-) x

36 h, followed by PO to complete 14 d Adolescents: 3 d PO

GRAM NEGATIVE ORGANISMS No.

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Acinetobacter species 38 92 94 90 95 13 90 87 95 84 84 87 90Achromobacter xylosoxidans- CF _ 32 19 81 6 13 81 78 88 13 69Citrobacter freundii 39 0 53 97 51 54 82 87 100 92 69 94 36Enterobacter cloacae 92 0 79 100 74 75 99 98 100 73 88 100 85Escherichia coli 774 49 62 58 98 88 99 97 97 90 92 94 100 99 98 95 69Haemophilus influenzae 50 54 100 98 100 78Klebsiella oxytoca 93 0 76 94 63 100 99 99 85 89 90 100 94 94 90 88Klebsiella pneumoniae 150 0 85 98 95 98 98 98 93 92 96 99 85 97 98 81Proteus mirabilis 57 83 92 96 95 98 98 98 97 100 98 100 0 96 98 86Pseudomonas aeruginosa- nonCF 315 93 77 96 94 96 86 90 94 81 2.9Pseudomonas aeruginosa- CF 508 45 80 86 78 74 63 79 74 73 59Salmonella species 22 95 100 100 100 100 100 86 100 95Serratia marcescens 80 0 91 99 93 92 96 98 100 0 99 97 96Stenotrophomonas maltophilia 250 23 72 97 29 86

Enterobacter , Citrobacter and Serratia may develop resistance during therapy with 3rd generation cephalosporins. Fluoroquinolone-susceptible strains of Salmonella that test resistant to nalidixic acid may be associated with clinical failure or delayed response to such treatment.

ANTIBIOGRAM 2008

NUMBERS ARE PERCENT SUSCEPTIBLE

This number includes clinical CF isolates only.

ANTIBIOTIC RESISTANCE

PBLR ENTEROBACTERIACEAE SEATTLE CHILDREN’S 1999-2009

Year

# is

olat

es

0

5

10

15

20

25

30

35

40

45

1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009

Num

ber o

f iso

late

s

0

5

10

15

20

25

30

35

40

45

1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009

ESBL AmpC CPN All PBLR

0

5

10

15

20

25

30

35

40

45

1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009

ESBL AmpC CPN All PBLR

0

5

10

15

20

25

30

35

40

45

1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009

ESBL AmpC CPN All PBLR

0

5

10

15

20

25

30

35

40

45

1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009

ESBL AmpC CPN All PBLR

AMPC ENZYMES ARE ENCODED ON CHROMOSOMES AND PLASMIDS

E. coliSalmonella

SPICEMSerratia, Providencia, indole-positive Proteus,

Citrobacter, Enterobacter, Morganella

active ampCinactive ampC

chromosome

plasmid

ETIOLOGIC AGENTS AND RESISTANCE

Host / setting Agent Resistance issues

Treatment

Normal E. coli Plasmid ESBL (CTX-M-15)

Fosfomycin

Hospitalized E. coli, GNR Plasmid AmpC (CMY-2)

Cefepime

Hospitalized SPICEM Chromosomal AmpC

Cefepime

Underlying condition:Urologic

P. aeruginosa Many Ciprofloxacin

Underlying condition: Oncologic

K. pneumoniae

KPC-2 TigecyclineColistinRifampin

EMERGING RESISTANCE Escherichia coli

Class A enzyme CTX-M-15 associated with emerging clone ST 131 (serotype O25:H4)

Class C enzyme CMY-2 associated with multiple clones (and multiple species, e.g., Salmonella Typhimurium)

TEM-1

CTX-M-15tetA

OXA-1

aac(6’)-Ib

aac(3)-IIMultidrug resistance region of plasmid pC15-1a, carried by widely-disseminated E. coli clone ST131.

CIPROFLOXACIN Toxicity concerns re damage to cartilage in

multiple juvenile animal models Record of safety in Europe, in cystic fibrosis Per AAP, increasing resistance is a growing

concern Clinical indications

UTI caused by P. aeruginosa or other multidrug-resistant gram-negative bacteria (per AAP)

Complicated E. coli UTI and pyelonephritis attributable to E. coli in pts 1-17 yrs of age (per FDA)

Patient/family counseling “If use of an FQ is recommended for a patient younger

than 18 y/o, the risks and benefits should be explained to the pts and parents” (AAP Red Book, 2006)

FOSFOMYCIN

Bactericidal PO antibiotic with one-time dosing that inhibits bacterial cell wall synthesis Inactivates pyruvyl transferase – first committed step

in cell wall synthesis High urinary levels > 48 h

90% of SCH ESBL-producing E. coli susceptible Approved for >12 yr Powder form, comes in sachet, dissolved in water Not on SCH formulary but available in community Adverse reactions: headache, diarrhea, nausea,

vaginitis

CEFIXIME

PO third-generation cephalosporin with once-daily dosing (dose amount doubled on day one)

Not for use in infants less than 3 months of age Suspension contain sodium benzoate

(metabolite of benzyl alcohol) Large amounts of benzyl alcohol associated with

fatal toxicity in newborns: ‘gasping syndrome’ Metabolic acidosis, resp distress, gasping CNS dysfunction (sz, ICH) Hypotension, cardiovascular collapse

Benzoate displaces bilirubin from protein

NEW RECOMMENDATIONS: IMAGING

Paradigm shift: Reduction in use of VCUG for initial imaging in children with first-time UTI

Infants and non-toilet-trained children Renal ultrasound OR high-quality 3rd trimester US

read as normal VCUG only if atypical UTI - one of the following:

Seriously ill Poor urine flow Abdominal or bladder mass Elevated creatinine Septicemia Failure to respond to appropriate rx within 48 h Infection caused by organism other than E. coli

DMSA scan 12 months after atypical UTI

NEW RECOMMENDATIONS: IMAGING

Toilet-trained children and adolescents Renal ultrasound for boys with first UTI and for girls

with atypical UTI If VUR found, prophylactic antibiotics given

UNDERLYING PATHOPHYSIOLOGY Vesicoureteral reflux (VUR)

Up to 35% of children w/UTI under age 12Highest in 1 y/o (50%)

Posterior urethral valves (boys)May be missed at birthAsk parents about voiding stream

Dysfunctional voiding (girls)Recurrent cystitis commonVoiding history is useful

ANTIBIOTIC PROPHYLAXIS IN VUR

Historically, pts w/documented VUR of any grade have been rx’d prophylactically TMP/SMX, TMP only, SMX only Nitrofurantoin

Based on data from poorly-controlled studies and biological assumptions Chronic prophylactic abx reduce risk of UTI Prevention of UTI will prevent renal scarring

ANTIBIOTIC PROPHYLAXIS IN VUR

Cochrane Review finds significant lack in evidence supporting these assumptions, need for methodologically-sound studies (see Williams et al)

RIVUR (Randomized Intervention for children with VesicoUreteral Reflux) study announced 2/08 Multicenter, double-blind, randomized, placebo-

controlled trial, to enroll 600 children 2-72 mos with grades I-IV VUR, to receive TMP/SMX or placebo

Collaboration of 15 clinical trial centers throughout N.A., data coordinated at UNC

Increasing use of cystoscopic Deflux (hyaluronic acid gel) injection at vesicoureteral junction

REFERENCES

Committee on Infectious Diseases (2006) Pediatrics 118:1287-1292.

Committee on Quality Improvement, Subcommittee on Urinary Tract Infection (1999) Pediatrics 103:843-52.

Cooper CS et al (2000) J Urol 163:269-73.

DeMuri GP & ER Wald (2008) PIDJ 27:553-4.

Garin EH et al (2006) Pediatrics 117:626-32.

Greenfield SP et al (2008) J Urol 179:405-7.

Lavollay M et al (2006) AAC 50:2433-8.

Reddy PP (1997) Pediatrics 100:555-6.

Robicsek A et al (2006) Nat Med 12:83-8.

Williams G et al (2006) Cochrane Database Syst Rev 3:CD001534.