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Antibiotics for the treatment of dysenteryin childrenBeatrix S Traa,1 Christa L Fischer Walker,2 Melinda Munos2 and Robert E Black2

1Department of Molecular Microbiology and Immunology, The Johns Hopkins Bloomberg School of Public Health, Baltimore, MD,

USA and 2Department of International Health, The Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.

Corresponding author. JHSPH, 615 North Wolfe St. Rm E5535, Baltimore, MD 21205, USA. E-mail: [email protected]

Background Ciprofloxacin, ceftriaxone and pivmecillinam are the antibioticscurrently recommended by the World Health Organization (WHO)

for the treatment of dysentery in children; yet there have been noreviews of the clinical effectiveness of these antibiotics in recent years.

Methods We reviewed all literature reporting the effect of ciprofloxacin,ceftriaxone and pivmecillinam for the treatment of dysentery inchildren in the developing countries. We used a standardizedabstraction and grading format and performed meta-analyses todetermine the effect of treatment with these antibiotics on rates oftreatment failure, bacteriological failure and bacteriological relapse.The CHERG Standard Rules were applied to determine the finaleffect of treatment with these antibiotics on diarrhoea mortality.

Results Eight papers were selected for abstraction. Treatment with cipro-floxacin, ceftriaxone or pivmecillinam resulted in a cure rate of499% while assessing clinical failure, bacteriological failure andbacteriological relapse.

Conclusions The antibiotics recommended by the WHOciprofloxacin, ceftriax-one and pivmecillinamare effective in reducing the clinical andbacteriological signs and symptoms of dysentery and thus can be

expected to decrease diarrhoea mortality attributable to dysentery.

Keywords Ciprofloxacin, ceftriaxone, pivmecillinam, diarrhoea, dysentery,morbidity, mortality, treatment

BackgroundDysentery is a major cause of childhood morbidity

and mortality in developing countries. Most dysenterycases in the tropics are caused by Shigella,1 whereasdysentery in the developed countries is usually caused

by Salmonella.2 Death rates as high as 6.2% have beenreported during epidemics of Shigella dysenteriae

type 1.3 The provision of effective anti-microbial ther-

apy is important especially for reducing the prevalence

of Shigella and other organisms causing dysentery in

children. Decreasing the bacterial load excreted by a

child with dysentery also reduces the probability of

fecaloral transmission to close contacts, such as

neighbours, friends or members of the childs house-hold.4 Anti-microbial therapy is particularly importantin developing countries, where prolonged diarrhoea

episodes, including dysentery, can significantlydecrease the growth and nutritional status in theaffected children.5,6

The World Health Organization (WHO) recommendsthat all episodes of diarrhoea with blood in the stoolbe treated with antibiotics. The WHO currently recom-mends treatment with ciprofloxacin (a quinolone) orone of the three second-line antibiotics, pivmecillinam,azithromycin and ceftriaxone (a third-generationcephalosporin).7 Here, we review the scientific evidencesupporting the WHO-recommended antibiotics

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/

by-nc/2.5/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Published by Oxford University Press on behalf of the International Epidemiological Association.

The Author 2010; all rights reserved.

International Journal of Epidemiology 2010;39:i70i74

doi:10.1093/ije/dyq024

i70
http://creativecommons.org/licenses/http://creativecommons.org/licenses/


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studies reported data exclusively for children aged 45years, we expanded our study population to includechildren aged up to 16 years. Eight papers wereincluded in the final dataset with some papers con-tributing data for multiple antibiotics or more thanone outcome measure (Supplementary Table 1). Wefound eight studies that reported on clinical failure

(12 unique data points),1,1117

with most studiesevaluating clinical failure status 3 days after treat-ment was initiated (range 36 days). Four studiesreported on bacteriological failure (six unique datapoints),11,1416 and five reported on bacteriologicalrelapse (seven unique data points)1012,14,15 (Table 1).

All abstracted studies were randomized controlledtreatment studies. We identified very few studies

with limitations based on study design and execution.In Table 1, we report the quality assessment of trials

by study outcome as well as results from correspond-ing meta-analyses. Based on 12 data points from eightstudies, treatment with one of the three antibioticsresulted in a clinical failure rate of 0.1% (95% CI0.2 to 0.5%). Based on six datasets abstractedfrom four studies evaluated in this review, the effectsize of antibiotic therapy on a childs relative risk ofbacteriological failure is 0% (0.1 to 0.1%). Sevendatasets from five studies indicate that the effectsize of antibiotic therapy on a childs relative risk ofbacteriological relapse is 0.0% (0.1 to 0.1%).

Assuming treatment failure rate to be an extremelyconservative proxy for dysentery deaths not prevent-able with prompt antibiotic treatment, it can be esti-mated that treatment of dysentery with ciprofloxacin,ceftriaxone or pivmecillinam will reduce diarrhoeamortality attributable to dysentery by 99% (Figure 2).

DiscussionDiarrhoeal disease, including dysentery, is a majorcause of morbidity and mortality among children indeveloping countries. This systematic review of theliterature summarizes the evidence supporting theuse of the antibiotics recommended by WHO: cipro-floxacin, ceftriaxone and pivmecillinam. It also sug-gests that the bacteria isolated from a stool sample ofa child with dysentery rarely relapses if the child hasreceived full-course treatment with one of these anti-biotics, and the disease-causing bacteria is sensitive tothe antibiotic. Reducing a childs risk of bacteriologi-

cal relapse is beneficial, because the likelihood of sub-sequent episodes of dysentery occurring in that child,and of transmission occuring to others, are reduced asa result.

The studies contibuting data in this review wereconducted in middle- and low-income countriesincreasing their generalizability to paediatric popula-tions in countries with the highest diarrhoea mortalityrates. Extrapolating clinical failure to mortality,our meta-analyses indicate that 499% of dysenterydeaths can be prevented with ciprofloxacin, T

able1Qualityassessment

oftrialsofantibioticsforthetreatmentofdiarrhoea

Quality

assessment

Summary

offindings

Directness

No.ofevents

No.ofstudies

(ref)

Design

Limitations

Consistency(b

ased

ontheheterog

eneity

ofthemeta-an

alysis)

Generalizability

topopulation

ofinterest

Gen

eralizability

tointervention

ofinterest

Intervention

Control

Pooledfailure

rate(95%

CI)

Clinicalfailure:moderateoutcome-specificquality

Eight1,1117

RCT

RCTbutonlyableto

usetreatmentfailure

rates(0.5

)

0.5

5/12datapoints

from

Israel

7/12

hospitalbased;

2/12multicentre

82

0.1

%

(0.2

to0.5

%)a

Bacteriologicalfailure:moder

ateoutcome-specificquality

Four1

1,1416

RCT

RCTbutonlyableto

usetreatmentfailure

rates(0.5

)

Borderlinehet

erogeneity

basedonthemeta-

analysis(P

0.0

77)

(0.5

)

3/6datapoints

from

Bangladesh

Gen

eralizable

9

0%

(0.1

to0.1

%)a

Bacteriologicalrelapse:moderateoutcome-specificquality

Five

1113,15,16

RCT

RCTbutonlyableto

usetreatmentfailure

rates(0.5

)

Consistentbas

edon

meta-analysis

3/7datapoints

from

Israel

Gen

eralizable

7

0%

(0.1

to0.1

%)

aRandom

effectsmeta-analysis

.

RCT,

Randomizedcontrolledtr

ial.

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ceftriaxone or pivmecillinam treatment. For applica-tion in the Lives Saved Tool, it is essential to extrap-olate severe morbidity to mortality, although this leaphas many limitations. Children with functioningimmune systems do not always progress to death asa result of dysentery. It is possible for some childrento successfully fight the infection without antibioticsand make a full recovery. In addition, many children

who present for medical care and are prescribed oneantibiotic are put on a second-line treatment if thefirst choice fails, thus further reducing the treatmentfailure rate.

Nearly, all studies were conducted in a clinic or hos-pital, where staff could monitor treatment. In a com-munity or outpatient setting, the therapeutic effect ofthe antibiotics reviewed here may not be as great asour analyses indicate, because caregivers may notcomply with the dosage and duration specificationsof the treatment. Caregivers may also fail to managethe dehydration that often accompanies diarrhoea,thereby increasing a childs risk of death.

The 99% reduction in diarrhoea mortality that weestimate is attributable to the treatment of dysentery

with ciprofloxacin, ceftriaxone or pivmecillinam and

assumes antibiotic susceptibility. The variability inthe types of dysentery-causing organisms thatoccur worldwide18 and their sensitivity to the antibi-otics recommended for treatment by the WHO maydecrease the generalizability of the findings presentedin this review. Because bacteria that cause dysenterycan acquire resistance to antibiotics, drugs used for

treatment should be selected based on resistance pat-terns prevalent in the community. Future research

with regard to site-specific antibiotic resistance mayprovide additional data and help refine recommenda-tions for national or local planning.

There is strong evidence in favour of the continueduse of the antibiotics recommended by WHOcipro-floxacin, ceftriaxone and pivmecillinamto reducemorbidity and mortality in children with dysentery.

Supplementary dataSupplementary data are available at IJE online.

FundingUS Fund for UNICEF from the Bill & Melinda GatesFoundation (grant 43386 to Promote evidence-baseddecision making in designing maternal, neonatal andchild health interventions in low- and middle-incomecountries). MKM is supported by a training grantfrom the U.S. National Institutes of Health (grantT32HD046405 for International Maternal and ChildHealth).

AcknowledgementWe thank our colleagues at WHO and UNICEF fortheir review of the manuscript and valuable feedback.

Conflict of interest: None declared.

KEY MESSAGES

The evidence supporting antibiotics for the treatment of dysentery includes 8 studies demonstrating abenefit on clinical and bacteriologic outcomes.

Antibiotics for the treatment of diarrhea results in a cure rate of 99%.

Antibiotics for the treatment of dysentery is critical to reducing dysentery deaths and should be easilyaccessible especially in areas where dysentery rates are high.

References1 Guerin PJ, Brasher C, Baron E et al. Case management of

a multidrug-resistant Shigella dysenteriae serotype 1 out-break in a crisis context in Sierra Leone, 19992000. TransR Soc Trop Med Hyg 2004;98:63543.

2 Amieva MR. Important bacterial gastrointestinal patho-gens in children: a pathogenesis perspective. Pediatr ClinNorth Am 2005;52:74977, vi.

3 Huppertz HI. An epidemic of bacillary dysentery inwestern Rwanda 19811982. Cent Afr J Med 1986;32:7982.

Bacteriologic Relapse (n=5; 7 events)

Antibiotics successfully prevent bacteriologic relapsein 100% (95% CI: 99-100%) of cases

Rule 7: APPLY

Strong evidence of serious morbidity reduction:

Highly plausible

Rules 1 -6: Do not applyClinical Failure (n=8 ; 82 events)Antibiotics reduce clinical signs of dysenteryin 99.9% (95% CI: 99.5-100%) of cases

Possible OutcomeMeasures

Application ofStandard Rules

Bacteriologic Failure (n=4; 9 events)

Antibiotics successfully clear dysentery pathogensfrom 100% (95% CI: 99.9 100%) of cases

Figure 2 Application of the CHERG Guidelines for theeffect of antibiotics on dystenteric morbidity and mortality

ANTIBIOTICS FOR DYSENTERY IN CHILDREN i73


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4 el Bushra HE, Bin Saeed AA. Intrafamilial person-to-person spread of bacillary dysentery due to Shigelladysenteriae in southwestern Saudi Arabia. East Afr MedJ1999;76:25559.

5 Kabir I, Butler T, Khanam A. Comparative efficacies ofsingle intravenous doses of ceftriaxone and ampicillin forshigellosis in a placebo-controlled trial. Antimicrob AgentsChemother 1986;29:64548.

6 Boyce JM, Hughes JM, Alim ARet al. Patterns of Shigellainfection in families in rural Bangladesh. Am J Trop MedHyg 1982;31:101520.

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survival. Int J Epidemiol 2010;39(Suppl 1):i2131.11 Alam AN, Islam MR, Hossain MS, Mahalanabis D,

Hye HK. Comparison of pivmecillinam and nalidixicacid in the treatment of acute shigellosis in children.Scand J Gastroenterol 1994;29:31317.

12 Eidlitz-Marcus T, Cohen YH, Nussinovitch M, Elian I,Varsano I. Comparative efficacy of two- and five-daycourses of ceftriaxone for treatment of severe shigellosisin children. J Pediatr1993;123:82224.

13 Prado D, Liu H, Velasquez T, Cleary TG. Comparativeefficacy of pivmecillinam and cotrimoxazole in acuteshigellosis in children. Scand J Infect Dis 1993;25:71319.

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Salam MA, Dhar U, Khan WA, Bennish ML. Randomisedcomparison of ciprofloxacin suspension and pivmecilli-nam for childhood shigellosis. Lancet 1998;352:52227.

15 Varsano I, Eidlitz-Marcus T, Nussinovitch M, Elian I.Comparative efficacy of ceftriaxone and ampicillin fortreatment of severe shigellosis in children. J Pediatr1991;118:62732.

16 Zimbabwe, Bangladesh, South Africa (Zimbasa)Dysentery Study Group. Multicenter, randomized,double blind clinical trial of short course versus standardcourse oral ciprofloxacin for Shigella dysenteriaetype 1 dysentery in children. Pediatr Infect Dis J 2002;21:113641.

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acute invasive diarrhea in children. Pediatr Infect Dis J2000;19:106067.

18 Murray BE. Resistance of Shigella, Salmonella, and otherselected enteric pathogens to antimicrobial agents. RevInfect Dis 1986;8(Suppl 2):S172S81.

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