Urinary Tract Infections in Children: a Changing Paradigm R Bhimma Department of Paediatrics and Child Health Nelson R Mandela School of Medicine University of KwaZulu-Natal

 UTIs most common serious bacterial infection in childhood.  UTI occurs in 1.6% of boys and 7.8% of girls.  1 st 3 months of life: more common in boys (3.7% vs 2.0%).  Higher incidence in older children presenting with BBD.  Febrile UTIs in children, with or without VUR renal scarring HPT and CKD.  Early guidelines advocated aggressive treatment and extensive imaging to detect VUR and kidney scarring. Introduction

Renal Scarring Normal kidney Scarred kidney

In the last decade there is a more targeted approach to UTIs More judicious use of resources Harmful procedures and interventions are avoided Introduction

 Unnecessary exposure to radiation.  Invasiveness of some procedures  Higher risk of infusion Oral antibiotics as effective as intravenous antibiotics. No differences:time to recovery rates of kidney scarring. Hoberman A etal Paediatrics 104:79-86, 1999, Montini G BMJ 335:386,2007, Hewitt IK etal Ital J Pediatr 37: 57, 2011 Concerns

 Varies according to:  method of urine collection  number of bacterial species  clinical presentation.  Culture negative urine:  prior antibiotic Rx  complete UT obstruction  infected cyst Diagnosis of UTI

Pediatr Res, 2015 Jul; 78(1):48-55.doi: /pr Epub 2015 Mar 19. Plasma neutrophil gelatinase-associated lipocalin predicts acute pyelonephritis in children with urinary tract infections. Sim JH, Yim HE, Choi BM, Yoo KH BACKGROUND: The identification of acute pyelonephritis (APN) is still a challenge. RESULTS: A total of 123 patients were enrolled (53 APN and 70 lower UTI). NGAL levels were higher in the APN group than in the lower UTI group (233 ( ) ng/ml vs. ( ) ng/ml, P< 0.001). CONCLUSION: Plasma NGAL can be a sensitive predictor for identifying APN and monitoring the treatment response of pediatric UTI.

 Fastidious and anaerobic bacteria may not be detected using standard culture.  Molecular approach 16s DNA PCR, denaturing HPLC, sequencing and bioinformatic analysis.  Recommended when have leukocyte esterase positive and culture negative specimens. Imirzaliogln C. Andrologia 40: (2008) Occult UTI

Children with fever (5% baseline risk)Children who have had one Previous UTI (20% baseline risk) PositiveNegativePositiveNegative Post test probability of UTIPost test Probability of UTI Dipstick Leucocyte esterase alone Nitrite alone Leucocyte esterase and nitrite Leucocyte esterase or nitrite Microscopy White cell count Bacteria Gram stained bacteria Diagnosis of UTI – dipsticks and microscopy Post-test probability of UTI with varying baseline risk of UTI for the common near patient tests

Collection methodColony forming units per litre Number of bacterial species Definite UTI Voided samples Bag collection Midstream catch ≥10⁸1 Catheter samples≥ 10⁷1 Suprapubic bladder aspirate Any number1 Microbiological threshold for the diagnosis of UTI Williams G et al. J Paediatr Child Health (2012), 48:

Collection methodColony forming units per litre Number of bacterial species Probable UTI Voided samples Bag collection ≥10⁷1 Midstream catch≥10⁸1 Clean catch≥10⁶1 Catheter sample ≥10⁷2 Suprapubic bladder aspiration Any number2 Microbiological threshold for the diagnosis of UTI Williams G et al. J Paediatr Child Health (2012), 48:

Is defined as a growth of a significant number of an isolated organism [usually >100,000 colony-forming units (CFU/ml) from urine culture found in children without symptoms with no pyuria. This should not be treated as the inappropriate use of antibiotics may promote antibiotic resistance leading to symptomatic disease and does not confer any long-term benefit Classification of UTI Asymptomatic bacteraemia

Is defined as infection limited to the urethra and bladder; symptoms include frequency, urgency, dysuria, lower abdominal discomfort or pain and or cloudy urine. Is defined as the presence of high ≥ 38.5°C and/or systemic involvement, except in some very young infants Classification of UTI cont… Cystitis Acute pyelonephritis

Denotes features of lower urinary tract involvement. These children have only mild pyrexia, but are able to take fluids and oral medication. They are only slightly or not dehydrated and generally have good compliance with medication. Is defined as the presence of fever of ≥ 39°C, the feeling being ill, persistent vomiting, and moderate or severe dehydration. When a child with a simple UTI has a low level of compliance, such a child should be managed as one with a severe UTI Classification of UTI cont… Simple UTI Severe UTI

Is defined as the invasion of a structurally and functionally normal urinary tract by a non-resident infectious organism. Refers to the occurrence of infection in patients with an abnormal structural or functional urinary tract, or both, that involves the upper urinary tract and thus manifests as pyelonephritis. Is defined as the following: ≥ 2 episodes of UTI with acute pyelonephritis plus one episode of UTI with acute pyelonephritis plus one or more episodes of UTI with cystitis or lower UTI or three or more episodes of UTI with cystitis or lower UTI. Classification of UTI cont… Uncomplicated UTI Complicated UTI Recurrent UTI

Are defined as those that fail to respond after 48 hours of appropriate antibiotic treatment, have poor urine flow, abnormal kidney function, bladder or abdominal mass, infection by an organism other than E.coli and onset of septicaemia. Is defined as a prompt recurrent infection with the same organism that occurs following treatment and implies there has been failure to eradicate the infection Is defined as a renal mass caused by focal infection with liquefaction and may lead to the development of a renal abscess later on. Classification of UTI cont… Atypical UTIs Relapsing UTI Acute lobar nephronia (acute lobar nephritis)

 Colonisation of distal urethral and peri-urethral area from GIT tract competitively inhibits colonisation by potential pathogenic bacteria.  Assent of pathogenic bacteria into UT occurs if there is colonisation by pathogenic bacteria.  Systemic spread of infection to kidneys uncommon except in uncompromised patients. Pathogenesis of UTI

 Enhanced by the following factors:  Use of broad spectrum antibiotics  Soiling around perineum  Catheters  Spermicidal agents  Turbulent urinary flow e.g. voiding dysfunction, instrumentation.  UT obstruction – overdetention of epithelial lining and pooling of urine  Genetic factors – defects in CXCR1 receptor  Bacterial virulence factors. Pathogenesis of UTI cont..

 Age <6 months  Female sex  Bladder and bowel dysfunction  Grade of reflux (III – V)  Constipation  Infrequent voiding  Poor perineal hygiene Other factors predisposing to recurrent UTI

Pathogens Common contaminants of urine cultures Enterobacteriaceae - E. coli (most common) - K. pneumoniae - Enterobacter spp. - Proteus spp. Candida species Enterococcus spp. Gardnerella vaginalis Mycoplasma hominus Ureaplasma urealyticum Coagulase negative staphylococci - S. saprophyticus Group B streptococcus Enterococcus spp. Common pathogens causing UTI

a.Fever  most common symptom  may take several days to resolve  temp >38⁰C b.Malodorous urine  % of children  may be present in children with UTI. c.Feeding problems d.FTT, pallor, lethagy e.Diarrhoea and vomiting Clinical presentation

Older children  FOM  Dysuria  Hesitancy  Enuresis  Nausea  Vomiting  Flank pain  Suprapubic tenderness  Dribbling and prolonged voiding Must exclude sexual abuse, particularly in female patients. Clinical presentation

 Used to detect genitourinary tract abnormalities.  Modifying correctable factors decreases number of UTIs and prevents renal scanning. Imaging of children with UTIs

 US  VCUG  Radionuclear cystography  Renal scintigraphy  DMSA  DTPA  MAG3  Others e.g. CT, MRI, video urodynamics Imaging studies

Grades of VUR

 VUR is the retrograde flow of urine from the bladder into the ureter and renal pelvis.  Prevalence 1-6%  Diagnosed in 1/3 of children first UTI.  More likely to have long-term sequelae with subsequent scarring in 10-40% of children.  Children <1 year more likely to complicate. Impact of VUR in UTI in children

Management Under 3 months IV antibiotics until systemic signs resolve. Followed by oral antibiotics for days Over 3 months Oral or IV depending on clinical state. IV if systemically ill, septic appearance or persistent vomiting duration 7-10 days. Shorter courses (3-4days) in children with cystitis Early initiation of antibiotics decreases risk of kidney scarring. Delayed treatment may lead to complications such as systemic sepsis and abscess formation. Choice depended of local sensitivity pattern. Final choice based on pathogen identification and sensitivity testing. Children on antibiotic prophylaxis usually develops UTIs from resistant organisms

Infant >1 -5 years >5years USUS +DMSA US If abnormalIf US or DMSA abnormal if US abnormal VCUG +DMSA VCUG VCUG and DMSA Management of the first episode of UTI

Common Antimicrobial agents used Antimicrobial agent Dosage Common adverse effects Parenteral Amoxicillin/clavulanate (>3 months) mg/kg body weight 8 hourly Gastrointestinal upsets, urticaria, pruritis, stomatitis, oral and perineal candidiasis, elevated liver enzymes, anaphylaxis Astreonam (>3 months) mg/kg daily Phlebitis, gastrointestinal upsets, elevated liver enzymes, eosinphilia, nephrotoxicity Ceftriaxone75 mg/kg, every 24 h Eosinophylia, elevated liver enzymes, thrombocytosis, leukopenia, diarrhoea Cefotaxime 150 mg/kg per day, divided every 6-8 hours Rash, pruritus, fever, eosinophilia, fever Ceftazidine mg/kg per day, divided every 8 hours Gastrointestinal upsets, rash, pruritus, headaches, elevated liver enzymes, nephrotoxicity Gentamicin 5 mg/kg per day, (8 or 24 hourly >12 months) Nephrotoxicity, dizziness, vertigo, tennitus, hearing loss Tobramycin 5 mg/kg per day, divided every 8 hours Same as gentamycin Piperacillin300 mg/kg per day, divided every 6-8 hours Gastrointestinal upsets, cardiac disturbances, central nervous system effects, allergic reactions, micturition disorders.

Antimicrobial agentDosageCommon adverse effects Oral Amoxicillin clavulanate20-40 mg/kg per day in three dosesDiarrhea, nausea/vomiting, rash Trimethoprim sulfamethoxazole 6-12 mg/kg trimethoprim and mg/kg sulfamethoxazole per day in two doses Diarrhea, nausea/vomiting Photosensitivity rash Sulfisoxazole mg/kg per day in four doses Cefixime8 mg/kg per day in one doseAbdominal pain, diarrhea, Flatulence, rash Cefpodoxime10 mg/kg per day in two doseAbdominal pain, diarrhea, nausea, rash Cefprozil30mg/kg per day in two dosesAbdominal pain, diarrhea, elevated results on liver function tests, nausea Cefuroxime axetil20-30 mg/kg per day in two dosesAnaemia, eosinophilia, nephrotoxicity, diarrhoea, elevated liver enzymes Cephalexin mg/kg per day in two dosesDiarrhea, headache, nausea/ vomiting, rash Common Antimicrobial agents used cont…

 Swedish Reflux Trial – support the role for prophylaxis in girls younger than 4 years old with grade III to IV reflux.  No benefit in children with no reflux or low grades (I-II).  No data in optimal duration of prophylaxis but most prospective studies suggest 1- 2 years. Antimicrobial Prophylaxis

Randomized Intervention for Children with Vesicoureteric Reflux (RIVUR) study  50% reduction of risk of recurrent UTIs in children <72 months.  Few adverse events with use of prophylaxis (>5% developed fever, otitis media, diarrhoea, phargyngitis, rash, viral infections)  40% developed UTI with sensitive E.coli (SMZ/TMP).  This may suggest that compliance may have been poor in these children.  No statistically significant difference in the development of TMP/SMZ–resistant UTI in both groups.  No impact or renal scanning Antimicrobial Prophylaxis cont…

 Indicated in following groups of children.  Higher grades of VUR (III – V) with breakthrough infections being Rx with prophylactic antibiotics.  Non compliance with prophylaxis.  Parenteral preference.  Deteriorating kidney function  Correction may be by ureteric re-implantation or endoscopic injection of a bulking agent (dextranomer/hyaloronic copolymer).  Endoscopic treatment has a significant recurrence rate after 2 years necessitating repeating the procedure. Surgical correction of VUR

 UTIs are common in childhood.  Requires appropriate management of acute episode as well as prevention to minimise risk of kidney scarring as well as CKD.  Prophylaxis may be associated with low risk of recurrent infection in selected groups of children.  Surgical intervention required in only a small number of patients.  Endoscopic surgery is now used increasingly in most centres. Conclusion