Sudung O.

Pardede

Department of Child Health

Faculty of Medicine
University of Indonesia –
Cipto Mangunkusomo Hospital
Jakarta
 Introduction

Definition

 Condition in which there is growth of bacteria

within the urinary tract in significant amount
 Renal parenchymal infection
 Infection or the urinary bladder
 Terminology
• Significant bacteriuria
The presence of > 100.000 CFU/ml fresh voided clean catch or
catheterized urine specimen
• Symptomatic UTI
Clinical symptoms: dysuria, frequency, urgency
with or without fever and flank pain
1. Acute cystitis (lower UTI)
2. Acute pyelonephritis
• Asymptomatic bacteriuria (ABU)
• Recurrent UTI
- Repeated symptomatic episode of UTI with symptom-free intervals
- Caused by reinfection
• Relapse UTI:
persistence of the same bacterial species
UTI in children
•  A common health problem
•  Cumulative incidence: 2%-8% by 10
years of age
•  Unexplained fever in neonates
140

120

100

80

60

40

20

0
0-1 1-2 2-3 3-4 4-5 5-6 6-7 7-8 8-9 9 - 10

Pyelonephritis Cystitis UTI unspecified

Age, Years,
(Male)
200
180
160
140
120
100
80
60
40
20
0
0-1 1-2 2-3 3-4 4-5 5-6 6-7 7-8 8-9 9 - 10

Pyelonephritis Cystitis UTI unspecified

Age, Years
(Female)
Jodal U. Clinical Paediatric Nephrology, 2 nd ed., 1994, p.151-9
 Causative organisme
• Escherichia coli : 85%
• Enterobacter aerogenes
• Klebsiella
• Proteus
• Streptococcus faecalis
• Pseudomonas
• Acinetobacter
• Staphylococcus aureus

Lambert H, Coulthard M. Clinical Paediatric Nephrology, 3 rd ed., 2003,p.197-226

• Proteus:
• Urease: urea ammonia + CO2
» Urine alkali: Ca and Mg precipitate
» Formation of renal stones
(staghorn- calculi)
Table : Organisme isolated from periurethral area of 59 boys
with vesicoureteric reflux and 36 boys undergoing circumcision

Organism Isolated Boys with VUR Boys undergoing

(n=59) circiumcision (n=36)
Escherichia coli (%) 6 (10) 2 (5.6)
Pseudomonas (%) 6 (10) 2 (5.6)
Proteus (%) 3 (5) 1 (2.7)
Enterococcus (%) 4 (7) 3 (8.3)
Streptococci (%) 2 (3) 2 (5.6)
Klebsiella (%) 1 (2) --
Commensals/no 37 (63) 26 (72.2)
growth(%)
Total 59 36
 Host factors associated with prevention
of bacterial adherence to uroepithelium

• Mechanical action of voiding

• Tamm-Horsefall protein
• Bacterial interference by endogeneous
periurethral flora
• Urinary oligosaccharides
• Spontaneous exfoliation of uroepithelial cells
• Urinary Ig
• Mucopolisaccharide lining the bladder wall
Recognising the child at risk for UTI

 Over diagnosis
 Unnecessary treatment
 Unnecessary imaging evaluation

 Under diagnosis
 Missing the opportunity to treat the acute
infection & possible the underlying
abnormality

IMPORTANT: Accurate diagnosis

Risk factors for UTI
 Condition that cause urinary stasis
- VUR, calculi, voiding disorders
- Anatomic abnormalities
 Previous UTI
 History of VUR or UTI in siblings/parents
 Race : whites > blacks
 Constipations or encoporesis
 Prematurity
 Systemic or immunologic diseases
 Uncircumsised
Table : Factors predisposing to UTI in children (1)

Host factors

Anatomic factors:
VUR and intrarenal reflux
Urinary tract obstruction
Foreign body in urinary tract
Duplicated collecting system
Ureterocele
 uroepitelial cell adherence
Nonsecretors with blod group antigens
Table : Factors predisposing to UTI in children (2)

Host factors

Maternal UTI
Lack of breast feeding
Receptors for uropathogen
Defective bladder mucosal factor
Presence of the prepuce
Antibacterial eradication of vaginal flora
Urinary secretory IgA 
Table. Factors predisposing to UTI in children
Bacterial factors

P-fimbriae
Capsul
Adhere to uroepithelium
Belongs O and K serotype
Produce hemolysin
Produce colistin V
Produce aerobactin
Resistant to antibacterial action
Ability to grow
Rapid doubling time
Ability to colonize the gut
 Route of infection

• Hematogenous route
(neonates)
• Ascending from urethral
orifice  bladder
• Lymphogenic (?)
 Clinical manifestations
• Vary depends on age and location of infection
• Neonate:
• Non specific
• Slow weight gain
• Temperature instability
• Feeding difficulties
• Irritability
• Vomiting
• Diarrhea
• Abdominal distention
• Jaundice
• Sepsis : 30%
Table: Clinical manifestations
in neonates / young infants %

Failure to thrive 50
Fever 39
Vomiting 37
Diarrhea 25
Cyanosis 23
Jaundice 18
Irritability or lethargy 17
• < 1 years:
• Fever
• Irritability
• Sickly appearance
• Refusal of food
• Vomiting
• Diarrhea
• Abdominal distention
• jaundice
• Preschool and school aged
• Dysuria
• Urgency
• Increased frequency
• Enuresis
• Flank pain
• Fever, chills
• Costovertebral tenderness
• Macroscopic hematuria : 26%
 Diagnostics tests for UTI

Purpose
• Confirm diagnosis
• Identify urologic malformations
• To localize site of infection
 Laboratory investigation of
UTI
• Urine culture
» Obtaining the specimen
» Culture technique
• Urinalysis:
• Urinary white blood cells
• Hematuria
• Leucocyte esterase test
• Nitrite stick tests
– Most bacteria that cause UTI produce nitrite
– Specificity : 90-100%, sensitivity 53% (15-82%)
» Bacteria take time to produce nitrite
» UTI: tends to void more frequent

• Phase-contrast microscopy

Lambert H, Coulthard M. Clinical Paediatric Nephrology, 3 rd ed., 2003,p.197-226

Table : Sensitivity and specificity or components of the
urinalysis alone and combination

Test Sensitivity % Specificity %

(Range) (Range)
Leukocyte esterase 83 (67-94) 78 (64-92)
Nitrite 53 (15-82) 98 (90-100)
Leukocyte esterase or 93 (90-100) 72 (58-91)
nitrite positive
Microscopy: WBCs 73 (32-100) 81 (45-98)
Microscopy: bacteria 81 (16-99) 83 (11-100)
Leukocyte esterase or 99.8 (99-100) 70 (60-92)
nitrite or microscopy
positive
Table : The sensitivity of clinical findings in the diagnosis
of upper UTI according to DMSA scan

Investigation Sensitivity (%)

1. Clinical findings 53,84

2. WBC count > 15.000/mm3 25,92
3. ESR > 25 mm/h 29,62
4. CRP > 20 mg/L 14,81
5. ACB (+) 62,96
6. US parenchymal involv. 25,00
7. IVP parenchymal involv. 9,09

* Ref. Bircan et al. 1993

Urine culture is recommended

All infant
Young children age 2 months – 2 year
with unexplained fever

Girl < 2 years old

Boy < 6 months old
with fever and probable source of fever
Methods of urine collection

 Mid-stream specimen
 Bag sample: high false positive rate
 Suprapubic puncture: gold standard
 Catheterization: Sensitivity: 95%
Specificity: 99%
 Table : Criteria for the diagnosis of urinary tract infection*
Method of collection Colony count Probability of infection
(pure culture)
Suprapubic aspiration Gram-negative bacilli: > 99%
any number
Gram-positive cocci:
> a few thousand
Transurethral 95%
catheterization > 105 Infection likely
104 to 105 Suspicious; repeat
103 to 104 Infection unlikely
< 103
Clean void Infection likely
Boy: > 104
95%
Girl: 3 specimens ≥ 105 90%
2 specimens ≥ 105 80%
1 specimens ≥ 105 Suspicious; repeat
5 x 104 to 105 Asymptomatic: infection
10 to4 5 x 104 unlikely

< 104 Infection unlikely

 Classification of UTI
• Type of UTI
• Simplex UTI = uncomplicated UTI
• Complex UTI = complicated UTI
• Site of infection
• Upper UTI
• Lower UTI
• Symptomatic
• Symptomatic UTI
• Asymptomatic UTI
 Complex UTI
• UTI with anatomical and functional urinary
tract abnormalities which cause stasis of
urine:
• Vesico-uretero reflux (VUR)
• Hydronephrosis
• Urolithiasis
• Neurogenic bladder, etc)
• Acute pyelonephritis
• UTI in neonate
 Differentiated APN and lower UTI

• Clinical parameter
• Laboratory marker
» Leucocyte count
» Neutrophil counts
» ESR
» CRP
» ACB
• Inflammatory marker
» TNF-α
» IL-6
» IL-1β
» Procalcitonin (PCT)
• DMSA = dimercaptosuccinic acid

Gurgoze MK, dkk. Pediatr Nephrol 2005;20:1445-8

 Localizing the site of infection

• Lower UTI = Cystitis:

• Dysuria
• Frequency
• Urgency of micturition
• Upper UTI = Pyelonephritis:
• Fever
• Tenderness
• ESR 
• Urine concentrating ability 
• White blood cell cast
• C-reactive protein (CRP) 
• Urinary beta-2 microglobulin 
• Antibody coated bacteria (ACB)
• Scar (DMSA)
 Table. Values of WBC, neutrophil count., ESR, CRP, PCT & proinflammatory
cytokines in children with urinary tract infection (CRP C-reactive protein,
PCT procalcitonin, IL-1β interleukin-1β, IL-6 interleukin-6, TNF-α,
WBC white blood cell count)

Acute pyelonephritis Lower UTI p

(n = 34) (n=42)
WBC/mm3 14.258,8 ± 7.090,6a 10,314.3 ± 4,423.9 0.004
Neutrophil/mm3 7.984,5 + 1.848,3a 4,245.1 ± 1,898.2 <0.001
CRP (mg/l)b 44,0 (20 – 202) 7.5 (2-22) <0.001
ESR (mm/h)b 40,0 (8-82) 11.0 (2-85) <0.001
PCT(ng/ml)b 1.68 (0,14 – 5,4) 0.1 (0.1-3.2) <0.001
IL-1β (pg/ml)b 32,3 – (1,63 – 70,2) 1.64 (0.0-14.55) <0.001
IL-6 (pg/ml)b 59,0 ( 0,0 – 357,2) 10.0 (0.0-64.0) <0.001
TNF-α (pg/ml)b 13,3 ( 1,8 – 34,0) 1.60 (0.0-18.0) <0.001

a
Mean ± standard deviation
b
Median (range)
Gurgoze MK, dkk. Pediatr Nephrol 2005;20:1445-8
 Table: Sensitivity and specificity of PCT,
CRP, proinflamatory cytokines for APN

----------------------------------------------------------------
Sensitivity (%) Specificiy (%)
-----------------------------------------------------------------
PCT (>0,5 ng/ml) 58 76
CRP (> 20 mg/l) 94 58
IL-1β (> 6,9 pg/ml) 97 59
IL-6 (> 18 pg/ml) 88 74
TNF-α (>2,2 pg/ml) 88 80

Gurgoze MK, dkk. Pediatr Nephrol 2005;20:1445-8

 Management
Principles:
1. Eradication of acute infection
2. Detection and treatment (surgery) of
functional or anatomical urinary tract
abnormalities
3. Detection, prevention, and treatment of
recurrent infection
• Start “best guess” antibiotic as soon as
urine obtained
• Change antibiotic if indicated by culture
result
• Antibiotics: 7-10 days
• If clinical condition does not improve after
48 hours, repeat urine culture and
consider urgent investigations to exclude
urological problems
• Increasing fluid intake and treatment of
constipation

Lambert H, Coulthard M. Clinical Paediatric Nephrology, 3 rd ed., 2003,p.197-226

• Prevention of further infection pending
investigation
• Adequate investigation of first known UTI
• Arrangement for appropriate further
treatment
• Follow-up until symptoms are controlled
 General rules in management

 Symptomatic medication:
fever, vomiting
 Fluid intake
 Empty the bladder completely
 Proper perineal hygiene
 Pyridium 7 – 10 mg/kg/day
 Lowering urine pH to 5 or less
 Hospitalization
Indications for hospitalized
• Severe systemic symptoms:
• Dehydrated
• Toxic
• Oral intake difficulties
• Acute pyelonephritis
• Hypertension
• Renal failure
• Neonates

Smellie JM. Clinical Paediatric Nephrology, 1994, p.160-74

Lamber H, Coulthard M. Cilical Paediatric Nephrology, 2003,197-226
Wong SN. Practical Paediatric Nephrology, 2005, 160-7.
 1. Eradication of acute
infection
Antibacterial treatment:
The choice of drugs and route of
administration depends on:

a. Age, condition of the child: oral/parenteral route

b. Local community of hospital antibacterial
resistance
c. History of recent antibacterial treatment
d. The possible effect of the chosen drug on the
bowel flora resistance
 Table : Some antimicrobials for oral treatment of UTI

Antimicrobial Dosage
Amoxicillin 20-40 mg/kg/d in 3 doses
Sulfonamide
6-12 mg TMP, 30-60 mg
TMP in combination
SMX per kg per d in 2 doses
with SMX
120-150 mg/kg/d in 4 doses
Sulfisoxazole
Cephalosporin
50-100 mg/kg/d in 3 doses
Cephalexin 8 mg/kg/d in 2 doses
Cefixime 10 mg/kg/d in 2 doses
Cefpodixime 30 mg/kg/d in 2 doses
Cefprozil
 Table: Some antimicrobials
for parenteral treatment of UTI
Antimicrobial Daily dosage
Ceftriaxone 75 mg/kg/d
Cefotaxime 150 mg/kg/d
Ceftazidime 150 mg/kg/d
Cefazolin 50 mg/kg/d
Gentamicin 7.5 mg/kg/d
Tobramycin 5 mg/kg/d
Ticarcillin 300 mg/kg/d
Ampicillin 100 mg/kg/d
 Acute pyelonephritis
• Hospitalization
• Broad antibiotic, parenteral (intravenous)
• Nitrofurantoin should not used
• 10 – 14 days
• Parenteral AB maybe replaced by oral AB after 5
days:
• Patient has improved symptomatically
• Systemic signs of toxicity have disappeared
• Patient: afebrile for 48 hours
• Organisme is sensitive to an orally AB
• Low dose AB prophylaxis for prolonged period
 Cystitis
• Oral antibiotics
• Do not require hospitalization
• Severe cystitis (pain, vomiting,
dehydration): hospitalization
• 7-10 days
 UTI in neonate

• Commonly associated with sepsis

• IV antibiotics
• AB: 10 – 14 days
2. Detection and treatment (surgery) of
functional or anatomical urinary tract
abnormalities

• Physical examinations
• Radiological examinations
 Radiologic evaluation

The aims
1. To uncover any underlying urologic
abnormality (VUR, duplicated collecting
system, obstruction)
2. To identify patients with chronic renal
damage / scarring from previously UTI
3. To assist the diagnosis of acute PN
Indication for radiological
examinations

 All neonates with first UTI

 All males with first UTI at any age
 All patients with recurrent UTI
 All patients with PN
 Technique

1. Renal US
2. IVP
3. Voiding cystourethrogram (VCUG =
MCU)
4. Scintigraphy: 99m-Tc Dimercapto-
succinic acid (DMSA)

William G, Craig JC. Diagnosis and management of urinary tract infections. Comprehensive Pediatric
Nephrology, Mosby Elseviar, Philadelphia, 2008,p.539-47.
Hidronefrosis
(pelebaran ginjal)

Gambar: Penyempitan pada hubungan ginjal dan saluran ureter

Gambar: batu buli-buli
 R L

VCUG
Gambar:
Sindrom prune
belly
DMSA scan
• Evaluates percent function of
renal parenchyma and shows
scarring
• Useful to determine
utility/risk/benefit of surgery
in structurally abnormal
kidney or advanced reflux
• May be done in anyone over
the age of one month
 Timing of investigations
• Ultrasound
• In acute phase or subsequently

• MCU
• There is suggestion, an increased detection of
VUR at time of UTI
• Be arranged before discharge
• DMSA
• Individual
• Acute pyelonephritis: DMSA highly specific and
sensitive
• Permanent scar: 2-3 months after UTI

Lambert H, Coulthard M. Clinical Paediatric Nephrology, 3 rd ed., 2003,p.197-226

Department of Child Health Faculty of Medicine Univ. of Indonesia
recommendation
UTI

< 2 yrs 2 – 5 yrs > 5 yrs

  
USG USG USG
MCU
normal abnormal normal abnormal
normal abnormal    
  observe MCU observe IVP/DMSA
observe IVP/DMSA

normal abnormal normal abnormal

   
observe IVP/DMSA observe MCU

Fig . Algorithm for imaging after urinary tract infection in children

 3. Detection, prevention, and
treatment of recurrent infection

• Urine culture
• 2-3 days after acute phase treatment
• 1 month
• every 3 months
• Treat predisposing factors
• Prophylaxis
• antibiotics
• probiotics
Table: Antibacterial drugs for
prophylaxis of UTI
• Trimetoprim :1-2 mg/kgbw/d
• Cotrimoksazol
• Trimetoprim : 1-2 mg/kgbw/d
• Sulphamethoxazole : 5-10 mg/kgbw/d
• Cephalexin : 10-15 mg/kgbw/d
• Nitrofurantoin : 1 mg/kgbw/d
• Nalidixic : 15-20 mg/kgbw/d
• Cefaclor : 15-17 mg/kgbw/d
• Cefixime : 1-2 mg/kgbw/d

Smellie JM. Clinical Paediatric Nephrology, 1994, p.160-74

Lamber H, Coulthard M. Cilical Paediatric Nephrology, 2003,197-226
Wong SN. Practical Paediatric Nephrology, 2005, 160-7.
 Limitation of antimicrobial prophylaxis

Anti-microbial resistance

Adverse reactions:
Gastrointestinal symptoms, skin rashes, hepatotoxicity,
hematological complications with SMZ-TMP,
marrow supression, Stevens-Johnson syndrome

Compliance

Inconvenience to patients  repeated follow up VCUG

 cost of procedure

* Matto TK. Pediatr Nephrol 2007;22:1113-1120.

 Antibiotic prophylaxis
PROS. CONS.
AAP 1999: recommendation - Williams et al, 2001*
non significant
- After 7-14 days of course AB
- Hellerstein & Nicheel (2002)
 continued with prophylactic low grade reflux did not increased
dosage the risk of UTI.
- Wald, 2006** (VUR cases)
no benefit
- Garin et al, 2006***
did not prevent recurrence of UTI

Low grade reff: Not effective

High grade reff: use prophylactic+
* American academy of pediatrics. Pediatrics 1999;103:843-52
** William G, et al. J Pediatr 2001:138:868-74
*** Hellerstein S, Nicheel E, Pediatr Nephrol 2002:17:506-510.
**** Garin EH, et al. Pediatrics 2006;117:626-632
+
Wald ER. Pediatrics 2006:117;919-22
Others prophylaxis for children:
• Probiotics
• As effective as antibiotic prophylaxis
• Lactobacillus rhamnosus
• Lactobacillus reuteri (L. fermentum)
• Cranberry juice

Lee S.J, et al. Pediatr Nephrol 2007;22:1315-20

Jepson R, Mihaljevic L, Craig J. The Cochrane Library 2000;3
 Long-term problems

• Renal scarring
• Hypertension
• Renal failure

Smellie JM. Clinical Paediatric Nephrology, 1994, p.160-74

Lamber H, Coulthard M. Cilical Paediatric Nephrology, 2003,197-226
Wong SN. Practical Paediatric Nephrology, 2005, 160-7.
 Renal scarring
• Risk factor for renal scar:
• young age
• delay in treatment
• recurrent infection
• VUR
• obstruction of urinary tract
• Timing: is not clear
 Vesico-ureteral reflux
• Regurgitation of urine from the bladder
into ureter and potentially to renal
parenchym
• Diagnosis: VCUG (radio-contrast or radio-
isotop)
 Primary VUR

1. Ureter intramural A - Reflux

B – Possible reflux
2. Ureter submucosal
C – No reflux
 GRADE OF REFLUX

I. Ureter only
II. Ureter, pelvis and calyces : no dilatation, normal fornices
III. Mild or moderate dilatation of renal pelvis, no or slight bunting of fornices
IV. Moderate dilatation and or turtuosity of ureter, moderate dilatation of pelvis
and calyces
V. Gross dilatation and turtuosity of ureter gross dilatation of pelvis and calyces
Medical VS Surgical Treatment With VUR

 International reflux study committee (1981)

 Birmingham reflux study group (1987) No
 International reflux study (1992) Significant
 Australia and New Zealand Dialysis & Difference
Transplant Registry (ANZADATA) (2000)

 important: rapid diagnosis & prompt treatment

 the choice of medical surgical:
 Social: Poor compliance
 Geographical factors
 Local expertise
 Parental choice
 Follow up
 Normal kidneys
1 year IVP or DMSA
 Scarred kidneys: monitoring
 BP
 Renal growth
 Plasma creatinine/GFR/DTPA
 Urine culture
 Somatic growth
 Urine culture
 Infants /early childhood
- every 3 months
- fever   culture  antibacterial drugs
 Older children
- regular supervision
- prophylactic
Management of recurrent infection
 Low dose prophylactic antibiotic (?)
 Treatment of predisposing factors:
 Thread-worms
 Avoidance of bubble bath
 Vulva irritation
 The perineum: kept clean
 Relief of constipation
 Neurogenic bladder
 Poor habit
 VUR
 UTI in neonates

• Prevalence:
1% for full term
3% for premature
10% for low birth weight
5-11% for febrile neonates

7.5% among jaundiced infants

(95% CI 3.9 – 12.7%)
 UTI in jaundiced infants
 Onset of jaundice mostly after 8 days of age
 Hyperbilirubinemia associated with UTI:
 unconjugated : hemolysis caused by E.coli
 conjugated : cholestasis
 Mechanism of cholestasis in UTI ?
• microcirculatory changes in liver
• direct effects from bacterial products
• endotoxin-induced mediators
Urinalysis in neonates/young infants

 Pyuria is not a sensitive marker

 Only 28 % - 50 % of infants with UTI had an abnormal
urinalysis (> 5 WBC/HPF)
 Pyuria maybe caused by several conditions
other than UTI

Gold standard :
Quantitative urine culture
Clinical condition associated
with pyuria
• Dehydration
• Vaginitis
• Meatal and urethral irritation
• Renal stones
• Renal tubular acidosis
• Interstitial nephritis
• Cystic renal disease
• Glomerulonephritis
• Appendicitis

Kher KK, Leichter HE. Clinical Pediatric Nephrology. McGraw-Hill, New York, 1992;277-321
UTI in 0 – 2 years old (Critical period)

 Peak incidence
 Clinical manifestations: unspecific
 Urine sample: difficult
 Early diagnosis & prompt treatment
may prevent Chronic PN  CRF  †
 The clinical decision rule to identify
the risk for UTI for girls
≤ 2 years of age

1. Temperature of 39º C or more

2. Fever for 2 days or more
3. White race
4. Age less than one year
5. Absence of another potential source of fever

≥ 2 variables  Predicted UTI:

- Sensitivity: 0.95 (95% CI: 0.85; 0.99)
- Specificity: 0.31 (95% CI: 0.28; 0.34)

 Gorelic and Shaw, 2000

American Academy of Pediatrics (AAP) 1999
Subcommitte on UTI

2 month – 2 years old

with suspected UTI

- toxic
- dehydrated YES - Parenteral antibiotic
- unable to retain - Hospitalization
oral intake

NO Urine culture
Oral or parenteral positive?
antibiotics
YES
NO
7-14 days
antibiotic therapy
No UTI
Prophylactic dose
American Academy of Pediatrics (AAP), 1999
Subcommitte on UTI

Infant (2 mo) – young children (2 yr)

with unexplained fever

CONSIDER UTI

Does the infants YES Urine SPA or catheherization

toxicy warrant immediate
AB therapy? Urine culture

NO
- Parentheral AB
OPTION OPTION - Hospitalization
Urinalysis SPA / cath.
 LE
 Nitrite  Urine culture
 WBCs
(-)
OBSERVATION
 Conclusions
UTI in children :
• A common health problem
• Affects many children
• May cause acute illness and symptoms
• Frequently over- or underdiagnose
• May have longterm seguelae:
» Renal scarring
» Hypertension
» Renal failure