DRUG THERAPY IN URINARY TRACT INFECTION

Dr.AnoopResident pediatrics

LEARNING OBJECTIVES

• Introduction and Outline of UTI• Age and clinical features specific approach.• To diagnose complicated and uncomplicated

UTI.• Treatment and drug therapy

INTRODUCTION

• UTI imply invasion of urinary tract by pathogens,which may involve the upper or lower tract depending on the infection in the kidney,ureters or bladder and urethra.

• Common cause of morbidity that in a/w abnormalities of the urinary tract, contribute a long term complications, including HTN and CRF.

EPIDEMIOLOGY• Common bacterial infection in children.• Non-specific signs and vague symptoms in very young

children,so may remain unrecognized.• Commonest age for the occurrence of the first

symptomatic UTI in the first year of life,particulerly in boys,when it mainly affects the upper urinary tract.

• Approx Incidence in term-1 % and in preterms-3% with M:F ratio of 5:1.

• During infancy risk of UTI is equal in boys and girls and thereafter higher in girls.

• Risk of symptomatic UTI before the age 14 yr is 1-2% in boys 3-8% in girls.

• Risk is higher in children with malnutrition and chronic diarrhoea.

• Obstructive lesions 10% boys• VUR 30-40%• Occurrence below 2yrs, delay in starting

treatment and presence of VUR or obstruction are risk factors a/w RENAL SCARRING.

ETIOLOGY

• 90% of first symptomatic UTI and 70% of recurrent infections E.coli.

• Proteus,klebsiella,staphylococcus epidermidis and streptococcus faecalis occassionally responsible

• Proteus and pseudomonas recurrent UTI,instrumentation,and noscomial infections.

• Fungi i.e candida albicans common in immunocompromised, preterm infants and following prolonged antibiotic therapy.

Case scenario 1

• A 24 days male baby brought to the emergency with chief complaints of lethargy,unstable temperature, poor feeding

And feed intolerence.

APPROACH Sepsis screening- crp+ve Blood culture- no growth CSF analysis- normal Urine routine and culture were sent.- growth of E.Coli Sensitive to

cefotaxime ,ceftriaxone, amikacin.

USG abdomen- normal

• Admission in NICU• Parentral antibiotics according

to the hospital protocol to begin with .

• Then changed according to the sensitivity

• IV antibiotics for 10-14 days continued

• In less than 3 months rule out congenital conditions

• Repeat urine culture usually not required

CLINICAL FEATURES IN NEONATES AND INFANTS

• NEONATES• Featurs of sepsis such as

lethargy,seizures,shock,unstable temperature and persistance of physiolgical jaundice.

• Non specific symptoms including FTT, vomiting, diarrhoea ,foul smelling urine.

• INFANTSunexplained fever may be the only symptom of acute pyelonephritis In <2yrs.

• They are at higher risk of acute renal injury.

Case scenario 2

• A 10 yr old female with chief complaints of• Increased frequency, urgency,• abdominal pain, and cloudy urine.

APPROACH• Urine routine and culture

along with other routine investigations.

• USG abdomen –normal• Urine pus cells -8-12/HPF• Urine culture –growth of

E.coli.• Sensitive to cefftriaxone ,

cefixime,Norfloxacin .

• Due to acute condition the child admitted and treated with IV( ceftriaxone) antibiotics for 3-4 days then as the clinical condition improved .

• Oral antibiotics for 3 days-- cefixime

acc to sensitivity.

HOW TO SUSPECT UTI?A good clinical history and physical examination is

cornerstone in diagnosis of UTI with emphasis on following points.

Age( all febrile infants<1 year)Gender( male< 1 year, female>1 year)Predisposing factors like bladder bowel dysfunction,

neurogenic bladder, anatomic malformations of genitourinary system,voiding dysfunction.

Clinical signs of upper or lower urinary tract involvement.

Severity of illness.

CLINICAL FEATURES are variable depending on age and site of infection

age Most common to least common

Infancy 0-1 year High index of suspicion as symptoms are nonspecificAny infant with fever > 39*C should be investigated for UTI.Fever, vomiting,lethargy,irritability,poor feeding, FTT,jaundice, hematuria ,offensive urine.

1-5 years Fever, abdominal pain, vomiting, loin tenderness, hematuria, offensive urine

>5yrs Increase frequency,dysuria,urgency,dysfunctional voiding,abdominal pain, fever, vomiting,hematuria, cloudy urine.

Number of bacteria required Methods of collection Colony count Probability of infection

Suprapubic aspiration(best method)

Any number of pathogen 99%

Transurethral catheterisation(next best)

>5* 10^4 CFU/mL 95%

Mid stream clean catch >10^5CFU/mL 90-95%

MANAGEMENT

The goals of Treatment• Elimination of infection and prevention of

urosepsis• Prevention of recurrence and long-term

complications including hypertension, renal scarring, and impaired renal growth and function

• Relief of acute symptoms (eg, fever, dysuria, frequency)

Clinical condition, route of administration and duration of treatment

Clinical condition Route of administration duration

Infants<3 months with febrile/complicated UTI

parentral 10-14 days

Infants < 3 months with lower urinary tract involvement

parentral 7-10 days

Children > 3 months with upper UTI

IV antibiotic for 2-4 days followed by oral antibiotics

10 days

Children > 3 months with simple UTI.

Oral antibiotic 3 days

Breakthrough UTI As per culture-not higher dose of same antibiotic

7-10 days

Asymptomatic bacteuria. No treatment

ANTIBIOTICSDRUG DOSE(MG/KG/DAY) REMARKSORALAMOXICILLIN,COAMOXICLAV 30-50 in 2-3 divided doses Of choice for uncomplicated

UTI,risk of resistance

CEPHELEXIN 30-50 in 3 divided doses For uncomplicated UTI, not effective againest proteus

CEFADROXIL 30-40 in 2 divided doses “

CEFIXIME 10 In 2 divided doses Broad spectrum agent

CIPROFLOXACIN 10-20 in 2 divided doses Avoid-<3m,G6PD def., lowers seizure threshhold

PARENETRAL

GENTAMYCIN 5-6 in 1-2 divided doses Once daily dosing effective

AMIKACIN 15-20 in 1-2 divided doses Alone or combined with ampicillin

CEFOTAXIME 100 in 2-3 divided doses Safe and convenient to use as single medication

CEFTRIAXONE 75-100 in 2 divided doses “

AMPICILLIN Combine with aminiglycoside

Empirical choice of antibiotic for UTIDRUGS DOSES(mg/kg)

PARENTRAL

ceftriaxone 75-100 in 2 divided doses IV

cefotaxime 100-150 IN 2-3 divided doses IV

amikacin 10-15 single dose IV /IM

gentamicin 5-7 Single dose IV/IM

ORAL

cefixime 8-10 In 2 divided doses

coamoxiclav 30-35 of amoxy in 2 divided doses

ciprofloxacin 10-20 mg in 2 divided doses

Ofloxacincephalaxin

15-20 mgin 2 divided doses50-70 in 2-3 divided doses

CEPHALOSPORINS• FIRST GENERATION PARENTRALCefazolin ORALCephelexinCefadroxil

• SECOND GENERATION PARENTRALCefuroxime ORALCefaclor, cefuroxime axetil,

cefprozil

• THIRD GENERATION PARENTRALCefotaximCeftizoximeCeftriaxoneCeftazidimeCefoperazone ORALCefiximeCefopodoxime proxetilCefdinirCefibutenCeftamet pivoxilFOURTH GENERATION PARENTRALCefepimeCefpirome

• CEFTRIAXONE:-• Longer duration of

action (t1/2-8hr)• CSF penetration is good• Elimination equally in

urine and bile.• High efficacy in a wide

range of serious infections including complicated UTI.

• s/e-hypersensitivity reactions.

• Nephrotoxicity-low grade• Dose- 50-75mg/kg/day

• CEFOTAXIME:-Potent againest aerobic gram negetive as well as some gram positive bacteria but no effect on anerobes.

• Attains high CSF levels• Dose- 50 mg/kg/dose

in neonates and infants bd or tds.

• In older children 100-150 mg/kg/day in 2 or 3 divided doses.

• CEFIXIME:-

• Third generation cephalosporin

• Orally active gainest enterobacerecie,H.Influenzae,strep. Pyogenes

• Resistent to many beta lactamases

• Not active on staph aureus,most pnemococci and pseudomonas

• Longer acting(t1/2-3 hr)

• s/e- stool changes and dirrhoea

• CEFTAZIDIME:-• High againest

pseudomonas aeruginosa• Specific indications are-

febrile neutopenic pts,with hematological malignancies , burn etc

• Less active on staph aureus

• Plasma t1/2-1.5-1.8 hr• s/e-

neutropenia,thrombocytopenia,rise in plasma transaminases and blood urea have been reported.

• CEPHALEXIN:-• Orally effective First generation cephalosporin• Less active againest penicillinase producing

staphylococci and H.Influenzae• Plasma protein binding is low,attains high

concentration in bile and is excreted unchanged in urine

• T1/2 60 min• Dose- 25-100 mg/kg/day..

AMINOGLYCOCIDES• SYSTEMIC Streptomycin Gentamycin Kanamycin Tobramycin Amikacin Sisomycin Netilmycin Paromomycin

Gentamycin - more of vestibuler toxicity and nephrotoxicity

Amikacin – more cochlear toxicity and nephrotoxicity.

• Ionize in solution and not absorbed orally,

• do not penetrate brain or CSF.• Excreted unchanged in urine by

glomerular filtration• All are bactericidal and more active

in alkaline Ph.• Act by interfering with bacterial

protein synthesis• Active againest aerobic gram

negetive bacilli and do not inhibit anaerobes.

• Only partial cross resistance among them.

• Exhibit ototoxicity and nephrotoxicity.

• * E coli has developed resistance to streptomycin

• Avoided in pregnancy-fetal ototoxicity• Avoid concurrent use of other nephrotoxic

drugs like NSAIDS,amphotericin B ,vancomycin etc

• Caution in pts with kidney damage.

QUINOLONES• NALIDIXIC ACID:-• Seldom employed• To preserve efficacy use should

be preserved• Urinary antiseptic• Active aginest gram negetive

bacteria- E.Coli, klebsiella, proteus, enterobacter but not pseudomonas

• Acts by inhibiting bacterial DNA gyrase and is bactericidal.

• Resistance developes rapidly.• Absorbed orally.

• s/e- gi upsets, rashes.• May cause seizures in

children, visual disturbances, vertigo. Hedache and drowsiness.

• c/I in infants., G6pd def.

• DOSE-0 .5-1gm tds or qid

FLOROQUINOLONES• FIRST GENERATION Norfloxacin Ofloxacin Ciprofloxacin Perfloxacin• SECOND GENERATION Levofloxacin Morifloxacin Lomefloxacin Sparfloxacin Gemifloxacin Prulifloxacin Inhibit the enzyme bacterial DNA

gyrase.

• CIPROFLOXACIN:-• Bactericidal , most potent active

againest broad range of bacteria.• E.coli highly susceptible• Good safety record• Caution needed in children-

cartilage damage in growth bearing joints

• NSAIDS may enhance CNS toxicity-seizures are reported.

• Antacids,sucralfate and iron salts reduce absorption.

• High cure rates in UTI.• Oral and IV available.

EXTENDED SPECTRUM PENICILLINS

• AMINOPENICILLINS- Ampicillin Becampicillin Amoxicillin• CARBOXYPENICILLINS- Carbenecillin• UREIDOPENICILLINS- Piperacillin mezlocillin

• AMOXICILLIN:-• Close congener of

ampicillin, similer to it in respects except-

Oral absorption is better,food does not interfere with absorption,incidence of dirrhoea are lower.

Dose-25-50mg/kg/day 8-12 hr orally.

• SEVERE OE COMPLICATED UTI:-

Fever>39*C,marked toxicity,persistent vomiting,dehydration and renal angle tenderness

Children <2m and with CUTI should be hospitilized and treated with parenteral antibiotics.

IV therapy witb single dose of aminoglycoside is found to be safe and effecive

• For older pts parentral therapy for first 2-3days

Then oral antibiotics if condition improves.

• UNCOMPLICATED UTI:- AGE>3m,accepting by

mouth,not toxic may be given oral antibiotics.

Emerging resistance of E.Coli to ampicillin and cotrimoxazole.

Norfloxacin and ciprofloxacin should be reserved for serious infections.

• Nalidixic acid and nitrofurantoin should not be used in febrile children in whom renal parenchymal involvement cannot be excluded as they are excreted in the urine without achieving therapeutic levels in blood.

• Symptomatic treatment for fever and pain.

• Liberal fluid intake should be ensured.

• SULFONAMIDES:- dependibility in UTI has decreased.

• COTRIMOXAZOLE:-respnose rate has decreased but can be employed empirically in acute UTI without bacteriological data.

Indication and duration of treatment

INDICATION DURATION

UTI< 1 yr of age Till imaging studies done

VUR grade 1 &2 Till 1 yr old, afterthat resatart if breakthrogh UTI

VUR grade 3 & 4 Till 5 yrs of age. Surgery indicated if breakthrough febrile UTI, beyond 5 yrs prophylactic antibiotic continued if bladder and bowel dysfunction continued

Choice of antibiotic for prophylaxisMedication Dose mg/kg/day remarks

cotrimoxazole 1-2 of trimethoprim, usually given as single bedtime dose.

Avoid in infants<3 months, G6PD def. ensure fluid intake

nitrofurantoin 1-2 May cause vomiting and nausea, avoid in < 3 months, G6PD def., renal insufficiency,bacterial resistance rare

Cephelexin 10 Drug of choice in 3-6 months of life

CefadroxilCefaclorCefiximenorfloxacin

55-102400

An alternative agent in early infancy where use of NFT and cotrimoxazole is restricted.

FUNGAL UTI• Most commonly encountered in infants and

children who receive immunosuppressive agents and broad spectrum antibiotic therapy.

• Incidence is high in ICU’s.• Commonest organism is Candida albicans.• Rarely aspergillus or cryptococcus• Presence of pseudohyphae in urine.• Oral fluconazole in candida cystitis.• IV amphoterecin-B(.6-.7 mg/kg) or fluconazole(5-

10mg/kg for 2-4 weeks is neccesary.

• AMPHOTERECIN-B:- Active gainest wide range of fungi

and yeasts. Administered I.V Penetration in CSF poor. Urinary concentration of active

drug is low. Toxicity is high In long term may cause

nephrotoxicity Bone marrow depression Uses-gold standard of antifungal

therapy febrile neutropenia Leishmaniasis Caution with

aminoglycosides,vancomycin

• FLUCONAZOLE:- Excreted unchanged in

urine Dose reduction needed in

renal impairments. Fewer side effects.-

nausea,vomiting,rashes,and headache.

Orally or I.v. No nephrotoxicity.

GENERAL MEASURES • Increase fluid intake.• Regular bowel habits with avoidance of

constipation and complete bladder emptying.• Wiping action in girls –anterior to posterior• Child should not delay emptying the bladder.

RESPONSE TO TREATMENT• With appropriate treatment urine becomes sterile

after 24 hrs. within 2-3 days symptoms disappear.Failure to respond therapy suggests:-Non sensitivity of pahogensPresence of complicating factorsNoncompliance If no response after 2 days of therapy another urine

specimen shpuld be cultured and USG performed to exclude complicating factors.

Short term treatment for 1-3 days is not reccomended in children.

ISPN LATEST GUIDELINES• The importance of urine culture on a correctly collected specimen is reemphasized.

The diagnosis of urinary tract infection (UTI) must be based on a positive urine culture

• Patients with UTI should be evaluated for the presence of complications, underlying anomalies or voiding dysfunction.

• Detailed investigations are done in infants. In older children, micturating cystourethrography is done in those who show abnormalities on ultrasonography and DMSA scintigraphy.

• Patients with recurrent UTI and/or vesicoureteric reflux should be evaluated for bowel bladder dysfunction.

• Patients with grades I and II reflux should receive antibiotic prophylaxis till they are 1 year old. Those with higher grades of reflux are given prophylaxis till 5 years of age, or longer in case of bowel bladder dysfunction or breakthrough UTI.

AAP GUIDELINES• Specific recommendations in the new Clinical

Practice Guideline include the following:• Diagnosis of UTI is made from an appropriately

collected urine specimen based on the presence of pyuria as well as 50,000 colonies per mL or more of a single uropathogenic organism.

• To facilitate prompt diagnosis and treatment of recurrent UTIs, close clinical follow-up monitoring should be maintained after 7 to 14 days of antimicrobial therapy.

• To diagnose anatomic abnormalities, ultrasonography of the kidneys and bladder should be performed.

• Because evidence from the most recent 6 studies does not support the use of antimicrobial prophylaxis to prevent febrile recurrent UTI in infants without VUR or with grade 1 to 4 VUR, VCUG is not recommended routinely after the first UTI.

• However, VCUG is indicated if renal and bladder ultrasonography results show hydronephrosis, scarring, or other evidence of high-grade VUR or obstructive uropathy, as well as in other atypical or complex clinical circumstances.

• Infants and children who have recurrence of a febrile UTI should also undergo VCUG.

KEY MESSAGE• Urinary tract infections (UTI) are common in infants and children.• Any child with unexplained fever should be evaluated for UTI by

urine microscopy and culture.• Prompt treatment of UTI is necessary to prevent renal injury.• UTI and associated renal injury are more common if

vesicoureteric reflux is also present.• All children with UTI should undergo an ultrasound examination

to screen for significant abnormality of the urinary tract.• Infants are at increased risk of urinary infections and its

complications, and should undergo detailed evaluation.• Attention to regular voiding and bowel habits are important

measures in preventing recurrent UTI.

THANK YOU

PATHOGENESIS• In neonates renal parenchymal infection is due to

hematogenous spread.• Acute bacterial pyelonephritis may cause or follow

septicemia.• At all other ages bacteria reach urethra and bladder

by ascending route and ureters and kidney by VUR.• Bacteria causing UTI generally arise from bowel• Bacteria under prepuce in boys reach bladder by

ascending route which explains circumcised boys have fewer UTI.

HOST DEFENCE MECHANISMS• Very rapid multplication of

bacteria normal voiding cannot eliminate all bacteria

• Some are destroyed by intrinsic defense of the bladder epithelial cells

• Other defense mechanisms secretory IgA in in urine and blood group antigens in secretions impede bacterial adhesion

• Breastfeeding protective in first 6 months of life

• Human milk provides adhesive factors in urine and stablizes intestinal flora with less pathogenic enteropahogens.

BACTERIAL VIRULENCE• Bacterial adhesion by pili

bind to cell surface by recognizing a glycosphingolipid recepter. Which is critical in the genesis of pyelonephritis.

• Leads to activation of cytokines which produces adhesion molecules and chemotaxix of leukocytes.

VIRULENCE FACTORS-O antigen of E.Coli induces

inflammation and fever and capsular

K antigen for resistance to phagocytosis and the bactericidal effect of serum.

Bacteria produce hemolysin and damages the uroepithelium and aerobactin for scavenging iron from urine needed in metabolism.

• BIOFILM:- once bacterial adhesion occurs forms a biofilm on epithelial surface.

• Such films have been shown to form on uroepithelial surface, polymer surfaces of indwelling catheters and fibre of infant diapers.

• Virulent bacteria quickly form biofilm and whereas bacteria on the surface are killed by antibiotics, those in deeper layers resist treatment.

Case scenario 3

• A 5-year-old boy presents with complaints that “it hurts when I pee.” He has no other symptoms. On examination, he is afebrile and noncircumcised.

FIRST UTI

AGE < 1 yr AGE 1-5 yr AGE >5 yr

USGMCU

DMSA

USG DMSA

MCU IF USG OR DMSA abnormal

USGIF ABNORMAL

DMSA AND MCU

RECURRENT UTI in any age group

USGMCU

DMSA

PREDISPOSING FACTORS• Obstructive uropathy• Stones in UT• Incomplete emptying of

bladder with residual urine

• Constipation • Thread worm

infestation.• Noncircumsised infants-

10 times > common

• Broad spectrum antibiotics for other infections may abolish the normal bacterial flora of perineum predispose to UTI.

• Short female urethra.• Babies born to

mothers with bacteuria

Case scenario 2• 14 month old female • chief complaint of fever, vomiting, and loose stools.• 5-6 episodes of emesis on the first day of illness.

Stools were liquid on the first and second days of illness.

• She was seen at an emergency room 2 days ago, where the impression was gastroenteritis was made and treatment given.

• No labs or x-rays were done in the emergency department.

• She returns to the emergency now because of persistent fever. Vomiting and diarrhea have resolved, but she is breast-feeding less well than usual.

• Her mother notes that her urine seems "strong" and that she is not as playful as usual. She has had no known ill contacts.

• She has no cough, URI symptoms, or rash• Past history is unremarkable and she is on no

medications.

VARIOUS IMAGING MODALITIES , INDICATION AND TIMINGS

Imaging modality indication timing

DMSA( dimercaptosuccinicacid) scanning

Most sensitive test for upper urinary tract involvement detects renal parenchymal infection and cortical scarring.

2-3 months after successful treatment

ultrasound Information on kidney size,location,hydronephrosis, urinary bladder anomalies and post void residual urine.

Soon after diagnosis of UTI.

MCU Information on posturethral valve, VUR, urethral anomaly

2-3 weeks later prophylactic anibiotic given orally for 3 days with MCU on 2nd day

Diuretic renographyDTPA/MAG3

Quantitaive assessment of renal function and drainage of dilated collecting system.

ROLE OF IMAGING STUDIES

To identify children at high risk of renal damage especially < 1 yr of age

To identify children with VUR or obstructive uropathy

To identify upper urinary tract involvement.

HOW TO PLAN INVESTIGATIONS.Diagnosis of UTI is based on routine and

microscopic urine analysis(provisional) and positive culture of a properly collected specimen(confirmatory ).

COLLECTION OF SAMPLE:- most important step.Inspite of busy hospital practice, we should

spend time in explaining the parents, how to collect sample and preserve.

• Urine culture gold standard test • Rapid dipstick test which detects leukocyte

esterase and nitrite, is useful in screening for UTI.

• Some studies have also recommended that in a suspected case of UTI 3 samples for urine culture must be send for 3 consecutive days.

• A clean catch mid stream specimen is ideal after cleaning the genitalia with soap and water in toilet trained children.

• In neonates suprapubic catheterisation or transurethral bladder catheterisation are safe and easy to perform.

• Collections from urobags are not recommended.• If delay is anticipitated in analysis of sample, it

should be refrigerated at 4*C for 12-24 hrs.

NORFLOXACIN:-Less potent than

ciprofloxacinGiven for 8-12 weeks in

chronic UTI.Unchanged drug and

metabolites excreted in urine.

• OFLOXACIN:-• Less effective than

ciprofloxacin againest gram negetive bacteria but equally efective for gram positive ones.

• Alternative drug for non specific uretheritis.

POINTS TO REMEMBERUTI are common in infants and toddlers,but

underdiagnosed since clinical features are non-specific.Most UTI are caused by E.Coli,derived from

periurethral fecal flora.Pseudomonas and proteus are common in presence of

obstruction and instrumentation.Fever,toxicity,leucocytosis indicate renal parenchymal

disease.Report of a few pus cells in an asymptomatic child is

insufficient to start antibiotics.

Neonates and young infants must be treated as inpatients with IV antibiotics for 10-14 days.

Quinolones are avoided as initial therapy.In < 2 yrs congenital anomalies and VUR are

common and need to be excluded.An expert USG must be performed in each case.Fungal balls may occasionally cause obstruction.