Childhood Cholera

8/9/2019 Childhood Cholera

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Single Dose

Azithromycin VersusCiprofloxacin for

Cholera in Children:

A RandomizedControlled Trial

Chairperson : Dr.ShivaSharanappa

Presenter: Dr.Mohan.T.Shenoy

5.5.2010


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IN

DI

AN

PEDI

ATRI

CS- VOL 47 APRI

L2010

JAYA SHANKAR KAUSHIK, PIYUSH

GUPTA, MMA FARIDI AND SHUKLA DAS


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REFEREN

CESNelson Textbook of Pediatrics 18th Edition

IAP Textbook of Pediatrics 6th Edition

Ghai Textbook of Pedatrics 6th Edition

Management of Acute Diarrhea- IAP guidelines

WHO Guidelines for Cholera Control; 1993.

http://www.who.int/topics/cholera/en/

http://wwwnc.cdc.gov/travel/


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Diarrhea Causes

Defn - Passage of >3 stools of greater fluiditythan normal/day

Viruses-Rotavirus(15-25%)

Bacteria-Escherichia coli(25%) esp. ETEC,

shigella(10-15%), camp. Jejuni (5-15%),

Salmonella (non-typhoid) 1-5%, cholera

Protozoa- Giardia duodenalis, Entamoeba

histolytica, Cryptosporidium 4


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Greek word for the gutter of a roof

comparing the deluge of water following arainstorm to that of the anus of an infected

person.

Vibrios are highly motile, gram-negative,

curved or comma-shaped rods with a single

polar flagellum,whose natural habitat usually salt or freshwater.

More than 200 different serogroups of

CHOLERA


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Vibrio cholerae


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Vibrio spp. (Family

Vibrionaceae) Associated

with Human Disease


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HistoryHistory of Choleraof Cholera For many centuries Cholera had been endemic in the

region of India.

Epidemic cholera was described in 1563 by Garciadel Huerto, a Portuguese physician at Goa, India.

The mode of transmission of cholera by water wasproven in 1849 by John Snow, a London physician.

In 1883,Robert Koch successfully isolated thecholera vibrio from the intestinal discharges ofcholera patients and proved conclusively that it wasthe agent of the disease.


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Epidemiology Recognized for more than 2 millennia with sporadic

disease and epidemics

Endemic in Southern and Southeastern Asia; origin of

pandemic cholera outbreaks

Generally in communities with poor sanitation

Seven pandemics (possible 8

th

continuing) since 1817attributable to increased world travel

Cholera spread by contaminated water and food

Human carriers and environmental reservoirs


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Classification Scheme

Toxigenic V.cholerae

O1Divisioninto 2 biotypes

inaba ogawa hikojima

A & B(A little C) Antigens

A & C

O139

A, B, C

Each O1 biotype can have 3 serotypes

Classical El Tor

Division into ribotypes

Division into 2 epidemic serotypes


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Vibrio cholerae

The O1 serogroup have caused the majority of cholera outbreaks and

are subdivided in to two biotypes:

Classical

El Tor: relatively mild and asymptomatic.

This biotype produces hemolysins (exotoxins that lyse red blood cells).


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Where Cholera is Most Commonly

Found


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7th Cholera Pandemic: The El Tor Strain

Up until the beginning of the 20th century all strains had been classical.

The 7th Pandemic began in Indonesia and devastated the Philippines.

Strain was not classical it was the El Tor Strain.

The El Tor strain is more dangerous because the duration of carriageafter infection is longer in the El Tor Strain.

El Tor also survives for longer periods of time in the extraintestinalenvironment than does the classical strain.


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The Evolution of the El Tor Strain

The El Tor has evolved into an even more dangerous strain.

In 1992, people in Bangladesh were affected by a large choleraepidemic.

The strain of cholera was comparable to El Tor but its antigenic

structure changed.

There are no existing immunities.

The strain was called O139 Bengal


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Cholera

A severe diarrhoeal illness with production of

rice water stools

Abdominal pain,vomiting and nausea may

accompany

Rapid onset of dehydration causing electrolyte

loss .. Hence severe weakness, prostration,poor

skin turgor, sunken eyes and cheeks, circulatory

and renal failure


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As more fluid is

lost, feces-streaked stool

changes to

Rice-waterstools:

Colorless

Odorless No protein

Speckled with

mucus


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Pathogenesis of V.cholerae

Incubation period: 18 hr to 5 days.

High infectious dose: >108 CFU

103 -105 CFU with achlorhydria or

hypochlorhydria (lack of or reduced stomach

acid)

Abrupt onset of vomiting and life-threatening

watery diarrhea (15-20 litres/day)


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Cholera contd

Typically water borne

Short incubation period

Colonization of the upper small intestine

attaches to epithelium and acts locally toproduce an enterotoxin which causesincreased cyclic AMP production withoutpouring of fluid and electrolytes


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Mechanism ofAction


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Virulence Factors Asso with

Vibrio cholerae O1 and O139


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Laboratory Identification

Transport medium - Cary-Blair semi-solid agar

Enrichment medium - alkaline peptone broth

Vibrios survive and replicate at high pH

Other organisms are killed or do not multiply

Selective/differential medium - TCBS agar V.cholerae grow as yellow colonies

Biochemical and serological tests


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Laboratory Methods (Contd.)


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MANAGEMENT OF

SUSPECTED CHOLERA

Differs from other causes

1. occurs in large epidemics that involve bothchildren and adults;

2. voluminous watery diarrhoea leading rapidly to

severe dehydration with hypovolemic shock;

3. appropriate antibiotics may shorten the duration of

the illness29


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When to suspect ??

when a child older than 5 years develops

severe dehydration from acute watery

diarrhoea (usually with vomiting), or

any patient older than 2 years has acute

watery diarrhoea when cholera is known tobe occurring in the area.

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Treating Cholera


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Cholera contd..

Amount of stool lost is greatest in 1st 24 hours

of illness- average requirement 200 ml/kg.

Patients whose ongoing stool losses are in this

range, usually require IV maintenance therapy

using Ringer's Lactate Solution with added

potassium chloride.

Rice-based ORS is superior to standard ORS

for adults and children with cholera,33


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Rehydration is the most important treatment.

Oral rehydration given plenty is the treatment ofchoice unless the child is obtunded, has an ileus,or is in shock.

Vomiting is not a contraindication to oralrehydration

However, antibiotics are useful in

shortening the duration of illness,

reducing the period of excretion of the organisms, and

decreasing the requirements for fluid replacement.


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Rationale for antibiotics in

Cholera

reduces the total volume of stool,

causes diarrhoea to stop within 48 hours, and

shortens the period of faecal excretion

The 1STdose given as soon as vomiting stops


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Antimicrobial therapy

All cases of suspected cholera with severe

dehydration should receive an oral antimicrobial

effective against strains inthearea

Tetracycline 12.5 mg/kg 4 times a day x 3 days;

2nd choice- erythromycin same dose

Nelson- Doxycycline is preferable in Asian

strains. 6 mg/ kg single dose

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Epidemic Control Measures

Hygienic disposal of human waste

Adequate supply of water

Good food hygiene

Thoroughly cooking food

Eating food while its hot

Preventing cooked foods from contacting raw foods(including water or ice)

Avoiding raw fruits or vegetables

Washing hands after defecation & before cooking

http://www.who.int/mediacentre/factsheets/fs107/en/print.html


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INDIAN PEDIATRICS- VOL 47 APRIL

2010

JAYA SHANKAR KAUSHIK, PIYUSH

GUPTA, MMA FARIDI AND SHUKLA DAS


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WHO recommends a 3-5 day course of

furazolidone, trimethoprim-sulphamethoxazole

or erythromycin for treatment of cholera inchildren; tetracycline may be used for those more

than 8 years of age.

However, strains ofV.choleraeresistant to thesedrugs have been identified in Bangladesh and

elsewhere.

Identification of clinically efficacious alternative

antibiotics is therefore necessary for use in children

with cholera.


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Azithromycin, a synthetic macrolide - an

emerging antibiotic with action against

V.cholerae.

Single dose treatment with azithromycin

has a potential advantage of ease ofadministration, good compliance, and

reduced cost of treatment.

Studies on treatment of cholera in children

with single dose azithromycin are limited to

comparisons with erythromycin


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Objective

To compare the clinical and bacteriological

success of single dose treatment with

Azithromycin and Ciprofloxacin in children

with cholera

Design: Randomized, open labelled, clinical controlled trial

from from March 2006 to February 2007.

Setting: Tertiary care hospital (University CollegeofMedical

SciencesandGuru TegBahadurHospital, DilshadGarden,

Delhi, India.

Clearance was obtained from the institutional ethical committee


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Participants

180 children

between 2-12 years,

having watery diarrhea for 24 hr and

severe dehydration,

who tested positive for Vibrio cholerae by hanging drop

examination or culture of stool

The study protocol was fully explained to the

parents/guardian, and informed written consent was obtained


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EXCLUSION

Children with severe undernutrition (weight for age less than 60% of

50th percentile of CDC 2000 standards)

Coexisting systemic illness

Blood in stool

Received an antibiotic/antidiarrheal within preceding 24 hours


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Data collection

Baseline data were collected:

name, age, address, telephone number

Occupation, education and monthly income of parents

duration of illness, frequency of diarrhea and vomiting prior to

admission, and

presence of associated symptoms including abdominal pain,fever,and abdominal distension.


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Data collection

Evaluation was done for general hygiene, vitals, and signs of dehydration

The present weight was recorded on a standardized weighing scale to the

nearest 0.5 kg.

Height was measured to the nearest 0.1 cm.

The same observer obtained all the measurements


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Randomization and allocation

Eligible children were allotted a study number.

These numbers corresponded to the order of patients entering the trial.

Children were randomized to receive a single dose of

oral azithromycin (20 mg/kg) or ciprofloxacin (20 mg/kg).

A simple randomization was done using a computer generated random

number table on a master list.


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Allocation of the treatment group was concealed by having the names ofboth the study drug stored in identical sealed envelope, which wereopened after a patient had been enrolled in the study and assigned a studynumber.

Randomized children were immediately rehydrated with intravenousRingers lactate solution 30 mL/kg in first hour followed by 70 mL/kgover next 2 hours.

A stool sample was obtained for hanging drop examination and culture forVibrio cholerae, as soon as the child passed stools after admission.

The patient was reassessed for hydration after 3-4 hours and managed

further as per the WHO Guidelines.

METHODS ( Contd.)


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The assigned Study drug was orally administered after initial rehydration,under supervision.

Eligible subjects received either a single dose of azithromycin (20 mg/kg)or ciprofloxacin (20 mg/kg).

Both the drugs were available in 100 mg, 250 mg and 500 mg tablets andthe dose was rounded to nearest 50 mg.

The dose was repeated if the child vomited within 10 minutes of drugadministration.

METHODS ( Contd.)


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Each Study day was defined as 24 hour counted from the administration ofstudy drug.

Children remained in the Study center for 72 hours (day 3) or untilresolution of watery diarrhea, whichever was later.

The parents were asked to bring their child back for a follow-up visit onday 7.

If the patient failed to return on the follow-up visit, the parents werecontacted by telephone and asked to come on the next day.

Clinical monitoring was performed on multiple occasions on the day of

admission and subsequently at the end of day 1, 2, 3 and 7.

METHODS ( Contd.)


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A record was kept of frequency of stool and vomiting for every 24 hrs.

The amount of intravenous fluid and ORS administered was also

recorded at the end of each Study day.

A stool sample or rectal swab was obtained at the end of day 1, 2, 3 andat follow-up visit (day 7).

Authors also noted for any possible adverse effects of the drugadministered like hypersensitivity reaction, phototoxicity, tendinopathyand joint pain or swelling.

METHODS ( Contd.)


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Microbiological evaluation

The motility of V. cholerae was seen by hanging drop preparation.

Stool sample was transported in alkaline peptone water or Cary Blairmedia and processed.

The stool samples were cultured in bile salt agar, MacConkey agar andthiosulphate citrate bile sucrose agar

Plates were incubated at 37C for 24 hours


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The samples were inoculated in fresh alkaline peptone water for

enrichment and subseqent plating

Bacteriological analysis was done by standard laboratory techinques and

V. cholerae isolates were serotyped by slide agglutination test using

specific antisera (Denca Saken).

Antimicrobial susceptibility testing of the strains was performed by

standard methods.

Microbiological evaluation


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Primary Outcome measures

(i) clinical success:defined as resolution of diarrhea within 72 hoursafter the start of therapy; and

(ii) bacteriological success: defined as absence of Vibrio cholerae inthe stool sample from day 3 onwards.

Resolution of diarrhea was considered when

child has passed two consecutive formed stools or

had not passed stool for 12 hours.


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Secondary outcome variables

(i) total duration of diarrhea (recovery time) defined as time elapsed from theentry into study till resolution of diarrhea in hrs;

(ii) total requirement of ORS and / or intravenous therapy;

(iii) duration of excretion of V. cholerae in stool;

(iv) proportion of children with clinical relapse defined as cessation of diarrhea

for 1 day or longer followed by return of diarrhea

or bacteriological relapse defined as a positive stool culture following a

negative culture report.


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Statistical analysis

Data were analysed using SPSS version 13.0.

All quantitative variables (between the groups) were compared byunpaired t-test; categorical variables were compared by Chi-square test

or Fishers exact test.

P


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A total of 89 Study subjects received

ciprofloxacin and 91 received azithromycin

Baseline characteristics of the study

subjects were comparable between the

groups


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RESULTS

407 children were included in the study and were

randomized to receive azithromycin (n=205) or

ciprofloxacin (n=

202).

Of these, 180 children who tested positive forV.

choleraeby hanging drop examination or culture

of the stool were finally included in the analysis,and designated as Study subjects


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Baseline

comparison


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DISCUSSION

Rate of clinical success significantly more in Azithromycin gp ascompared to Ciprofloxacin, although the rate of bacteriologicalsuccess was comparable in the two groups.

Subjects who received Azithromycin had a significantly lesserduration of diarrhea, shorter duration of excretion of V. cholerae,and lower requirement of intravenous fluids.

Rate of bacteriological relapse was found to be comparable andnone of the subjects in either group had clinical relapse.


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Outcome variables


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Symptomatic improvement was assessed by comparing the

frequency of diarrhea and vomiting.

The frequency of stool and vomiting was significantly lower in

children who received azithromycin as compared to

ciprofloxacin group during the first 72 hours.

The rate of decline in frequency of stool and vomiting was

however comparable between ciprofloxacin and azithromycingroups


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The follow-up loss in first 72 hours of hospital stay was only3.3%.

However, the follow-up loss beyond day 3 was 18.8%, which was

significant.


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Clinical and bacteriological success with azithromycin are much

higher in this study

Discrepancy in the success rates could be attributed to differing

definitions of success adopted in these trials and differences in

baseline characteristics of the enrolled population.

Ciprofloxacin resistance might have emerged in direct response to

selective pressure exerted by nalidixic acid coupled withdisproportionate use of fluoroquinolones for all bacterial infections

in our country.


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CONCLUSION FROM

THE STUDY

Single dose azithromycin is a useful alternative for treating

cholera in children.

Considering the clinical efficacy and lack of resistance to

azithromycin, authors advocate that it should be considered asan option for first line treatment of childhood cholera in areas

where V.cholerae infection are caused by susceptible strains.


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If you havent heard of cholera,

be thankful for clean water.

P th i M h i f


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Pathogenesis: Mechanism of

Action: Overview


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Childhood Cholera

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