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1986;77;477Pediatrics

Ivor D. Hill, Michael D. Mann, Keith C. Househam and Malcolm D. BowieSevere Persistent Diarrhea in Infants

Use of Oral Gentamicin, Metronidazole, and Cholestyramine in the Treatment of

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P ED IA TR IC S V o l. 77 N o . 4 Ap ril 1 986 477

U se o f O ra l G en tam ic in M etro n ida zo le an d

C h o le s ty ram ine in the T rea tm en t o f S eve re

P e rs is ten t D ia rrh ea in In fan ts

Iv o r D . H ill M D F C P M ich ae l D . M an n M M ed P hD

K eith C . H o useh am F C P an d M a lco lm D . B ow ie M D F R C P

F ro m th e In s titu te o f C h ild H e a lth R e d C ro ss W ar M e m oria l C h ild ren s H o s p ita l

ondebosch R e p u b lic o f S o u th frica

A B S T R A C T . Ora l

gen tam ic in , m e tro n id azo le , and ch o le s-

ty ram in e w ere g iv en ei the r as s in g le agen ts o r in va rio us

com b ina tion s to in fan ts w ho still requ ired trea tm en t a fte r

seven d ay s in the h osp ita l fo r p ers is ten t d ia rrhea . T h e

e ffec t o f the se d ru gs and th e in te ra c tion s b etw een them

w ere a sse ssed by com pa ring da ily s to o l ou tpu t du ring

treatm en t w ith tha t in the p re trea tm en t pe riod . T he

e ffec t o f th e d rug s o n ap pa ren t n itro gen and fa t abso rp -

tio n w as a lso stud ied . O n the firs t day of trea tm en t th e

p resence o f cho le sty ram ine w as asso cia ted w ith a sig n if-

ican tly g rea ter dec rease in stoo l ou tpu t. T h is effec t ap -

p ea red to b e la rg ely du e to an in tera c tion w ith gen tam i-

cm . T h ereafter, o n ly gen tam icin p ro du ced a s ig n ifican tly

g rea te r d ec re ase in s to o l w eig h t. A t no s tage w as m e tro -

n idazo le o f bene fit. G en tam icin and cho les ty ram in e a lso

in d ire c tly im pro ved app aren t n itro gen an d fa t abso rp tio n

b y red uc ing s to o l o u tp u t. T h e com bin a tion o f o ra l g en -

tamic in

an d ch o le s ty ram ine is recom m ended a s a sa fe

and e ffe ctive w ay o f tre at ing in fan ts w ith sev ere p e rsis t-

en t d ia rrhea fo llow in g acu te g as troen te r itis . Ped ia tr ics

1986;77 :477-481; persis ten t d ia rrhea , gen tam ic in , ch o les -

ty ramine .

B ecau se the lo sses o f n u trien ts from th e bow el a re

d ire c tly re la ted to sto o l w e igh t, m ain tenance o f

n u tri tion b y th e o ral rou te is usua lly n o t po ss ib le

in in fan ts w ith fe ca l lo sse s exceed ing th is v alu e .2

T erm in ation o f the d iarrh ea is cru cia l in p rev en ting

th e v ic io us cy cle o f g as tro en te ritis an d m a ln u tri-

t ion.

A prev ious , u ncon tro l led tria l dem onstra ted th at

a com bin at ion o f o ra l gen tam ic in , m e tron idazo le ,

and ch o le s ty ram ine the rap y w as e ffec tiv e in s top -

p ing pe rs is ten t d ia rrhea in the m a jo rity o f case s .3

T h e p resen t s tud y w as unde rtaken to tes t th is in a

con tro l led fa sh ion and to d eterm ine w hich o f th e

d rug s used s ing ly o r in com b ina tio n w as m o st effe c -

tive . T h e e ffec t o f in d iv idu a l d ru gs and com b ina -

tions o f d ru gs w as assessed by com pa ring the de -

cre ase in s to o l ou tp u t fo llow ing th e in s titu tio n o f

trea tm en t. T he effe ct o f in d iv idu al d rug s on ap pa r-

en t n itro gen and fa t ab so rp tion during treatm en t

w as a lso eva lua ted .

M ost ch ild ren adm itted to R ed C ross W ar M e-

m ona C h ild ren s H o sp ita l in C ap e T ow n w ith g as-

troen terit is have a se lf-lim itin g i llne ss , an d th e

d iarrh ea d im in ish es a fter a few days . In 10 to

1 5 o f pa tien ts , sev ere d iarrh ea con tinu es and re -

qu ire s the rap y fo r m o re than seven day s. P ers is t-

en t d ia rrhea is d efin ed a s a con tinu in g d aily s too l

ou tpu t exceed ing 3 0 g /k g o f b ody w eigh t fo r seven

days a fte r com m encem en t o f h osp ita l trea tm en t.

R ece ived fo r pub lica tion Jan 31 , 198 5 ; accep ted A ug 1 , 1 985 .

R eprin t requ es ts to (M .D .B .) In stitu te o f C hild H ea lth , R ed

C ross W ar M em oria l C h ild ren s H o sp ita l, R ondebosch , 770 0 ,

R epub lic o f S ou th A frica .

PED IA T R IC S (ISSN 0031 4005). C opy righ t 1986 by the

A m erican A cad em y of Ped ia tric s.

P A T IE N TS A N D M E TH O D S

In fan ts be tw een the age s o f 6 w eek s and 1 y ea r

req u irin g adm iss ion to the h osp ita l fo r d eh yd rating

d ia rrhea w e re assessed . O n ly b oy s w e re s tud ied

becau se o f th e ease in sepa rat ing u rine an d s to o l

co lle c t ion s. In fan ts w ith a h is to ry o f d ia rrhea fo r

m o re th an 72 hou rs and any w ith a h is to ry o f hav ing

had d ia rrhea o r re ce iv ing an tib io t ics in the 2 w eeks

p reced in g th e p re sen t illne ss w e re exc lud ed . N on e

had kw ash io rko r, m ara sm ic kw ash io rk o r, o r an y

sk in le sions as soc iated w ith nu tr ition al de ficienc ie s .

The d ay o f adm iss ion to ho sp ita l w as de s ign ated

d ay 0 , an d in i tia l tre a tm en t w as the sam e in a ll

cases. R ou tin e investig atio ns inc luded m ic ro scop ic

exam ina tio n o f stoo l an d u rine spec im en s fo r p ar-

a s ite s and s to o l and urine cu ltu re s . B loo d spec im en s

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478

TRE TM ENT O F SEVERE PERS ISTENT I RRHE

w ere cul tured and measured f or serum electrol y tes

and acid-base status. A n inadequate ci rculating

blood v olume, detected cl ini cal l y by poor peripheral

capi l l ary perf usi on, w as corrected by rapid inf usi on

of a plasma volume ex pander (H aem accel ). T here-

af ter, the patients w ere m anaged in the same w ay

as those w i thout thi s si gn.

Severe metabol i c acidosi s (pH

.05).

T here w ere no di f f erences in stool w eights betw een

the groups in the pretreatment per iod (days 5 to 7);

nor w ere there si gni f i cant changes w i thin each

group betw een those day s. A l l inf ants had severe

diarrhea w i th a

stool w eight of 105.7

8.5

g/kg/d

mean SEM .

T he mean decrease i n stool w eight f rom pretreat-

m ent levels on days 8, 9, 10, and 11 in the presence

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5/7

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E

20

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I

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7

8

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10

D A Y O F H O S P IT A L TR EA TM EN T

480 T R E A T M E N T O F S E VE R E P ER S IST E N T D IA R R H E A

DI SCUS S I ON

Prior to treatm ent, al l of the inf ants in this study

had equal l y severe persistant di arrhea. T he m ean

dai l y stool w ei ght w as m ore than 100 g/kg of body

w ei ght, and a prev ious study has show n that at this

magni tude of diarrhea ni trogen and energy requi re-

ments cannot be met w i th oral nutr i ent i ntake.2

Such inf ants are in negativ e ni trogen balance and

apparent f at absorption i s of the order of 30% of

intake. Carbohy drate absorpti on is also im pai red.6

T erm ination of the diarrhea is essenti al i f nutri ti on

is to be m aintained.

T o assess the ef f ects of the drugs, a 2 x 2 X 2

f actorial m ethod of analy sis w as chosen to over-

come the probl em of hav i ng sm al l num bers in each

group. U se of this method al l ow s the main ef f ect of

a parti cular drug to be assessed by com paring al l

patients recei v ing the preparati on w i th al l of those

not receiv ing i t. I n ef f ect, this m eans that f or each

drug used in this study 20 patients receiv ing a

parti cular drug w ere com pared w i th 20 not recei v ing

it .

D uring the f i rst 24 hours of treatment, inf ants

w ho receiv ed cholestyram ine treatm ent (groups

GM C, Gm C, gM C, gmC) had a signi f i cantl y greater

decrease in stool w eight than those w ho did not

receive the drug (T able 2). T hereaf ter, on days 9 to

1 1, al though the decl i ne in stool w eight w as greater,

the di f ference w as not signi f i cant. I nf ants receiv ing

gentamicin treatm ent (groups GM C, GM c, Gm C,

Gm c) did not have a signi f i cantl y greater decrease

in stool output in the f i rst 24 hours of treatm ent

com pared w i th those not receiv ing gentam ici n. On

day s 9 to 11, the adm inistrati on of gentam icin w as

accompanied by a si gni f i cantl y greater decrease in

stool w eight in com parison to those not receiv ing

the drug (T able 2). I t appears that the ef f ect of

cholestyrami ne on day 8 is largely due to an inter-

action w i th gentam icin. D uring the f i rst 24 hours

of treatm ent, the decrease in stool w eight of inf ants

receiv ing cholestyram ine but not gentami cin

(groups gM C and gm C) w as sim i lar to the ef f ect in

those receiv ing gentam icin w i thout cholesty ram ine

(groups GM c and Gm c) or nei ther drug (groups

gM c and gmc). T he ef f ect on stool w eight of inf ants

receiv ing both gentamicin and chol esty ram ine

(GM C and Gm C) compared w i th those receiv i ng

nei ther (gM c and gm c) is i l l ustrated in the Figure.

M etroni dazole treatment appears to hav e l i ttl e ef -

f ect on stool w eight ei ther al one or in combination

w i th the other drugs.

T he f actors responsible f or the persi stence of

severe diarrhea are not enti rely clear. N one of the

i nf ants included in this study had a recogni zed

bacteri al pathogen in thei r stool s. A prev ious study

using the same cri teria f or patient selection dem -

onstrated a grossly abnorm al overgrow th of m icro-

organisms in the sm al l bow el of i nf ants w i th diar-

rhea persisting f or seven day s af ter admission.7

20

F igu re .

D ecrease in stool w eight f rom pretreatment levels in inf ants receiv ing a combi -

nation of gentami cin and cholestyramine - and those receiv ing nei ther of these drugs

- - - . H orizontal l i ne at

0 represents the mean dai l y stool w eight (g/k g of body w eight

d) of each group bef ore starti ng treatment.



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A RT IC LE S 481

A lthough the duodenal microflora of the infants in

this study was not investigated, there is no reason

to believe it should be any different from those in

the previous study. W e believe the bacterial over-

growth plays a role in the pathogenesis of persistent

diarrhea. The microorganisms may be directly in-

volved by damaging the intestinal mucosa.8 A lter-

natively, or in addition, they may be indirectly

involved by the elaboration of toxins or by decon-

jugating and dehydroxylating the bile salts.8 The

early beneficial effect noted with the use of choles-

tyramine treatment supports the indirect mecha-

nism as a cause of persistent diarrhea. The domi-

nant role of gentamicin noted after the first 24

hours of treatment supports the view that elimi-

nation of the bacterial overgrowth is most impor-

tant in controlling ongoing diarrhea.

A s has been noted in a previous study, the greater

the stool weight the poorer is apparent nitrogen

and fat absorption.2 N itrogen and fat absorption

decreased by about 0.4 with each gram per kilo-

gram of body weight increase in stool output Table

3). Gentamicin treatment had a major effect on

stool weight and indirectly on apparent nitrogen

and fat absorption. A s the stool weight decreased,

apparent nitrogen and fat absorption improved. N o

direct effect of gentamicin was noted. In contrast,

metronidazole treatment did not produce a decrease

in stool weight; therefore, no indirect effect on

apparent nitrogen and fat absorption occurred. Nei-

ther was a direct effect noted.

By reducing stool weight Table 2), cholestyra-

mine indirectly improved nitrogen absorption, but

no direct effect was demonstrated. T he decrease in

stool weight also improved fat absorption, but the

drug directly impaired uptake of fats Table 3).

This is not surprising because cholestyramine is a

bile salt-binding resin. The net effect on fat absorp-

tion is a balance between the improvement derived

from the reduction of stool weight and the direct

effect of cholestyramines impairment of fat ab-

sorption. By calculation, a decrease in stool weight

exceeding 32 g/kg of body weight per day would

offset the reduction in fat absorption associated

with cholestyramine treatment. Between days 9 and

11, infants receiving cholestyramine had a mean

reduction in daily stool weight that was 32 g/kg of

body weight greater than those not receiving the

drug Table 2). On average, cholestyramine treat-

ment alone neither improved nor impaired fat ab-

sorption. The overall effect of gentamicin and cho-

lestyramine together was a marked reduction in

daily stool output and an improvement in nitrogen

and f at absorpti on.

I t is a minority of infants with acute gastroenter-

itis who go on to have persistent diarrhea of the

severity of the infants in this study. In patients

such as these, maintenance of nutrition via the oral

route is not possible because of the large stool

nitrogen and energy losses. Termination of the

diarrhea and reduction of these losses is essential.

This study has shown the use of a combination of

oral gentamicin and cholestyramine to be an effec-

tive and rapid means of achieving this. I t is also

safe and, except for a mild metabolic acidosis during

the administration of cholestyramine, no compli-

cations have been encountered in 8 years of using

this treatment. M easurements of serum gentamicin

levels in a number of similar infants receiving oral

gentamicin in the dose prescribed have shown ab-

sorption to be insignificant unpublished data). I t

is recommended that oral gentamicin and choles-

tyramine be given to infants with severe, persistent,

dehydrating diarrhea who show no signs of im-

provement after seven days of hospital treatment.

KNOWLEDGMENTS

This work was supported by the South A frican M edical

Research Council.

W e thank the M obil Research Associateship for tech-

nical assistance.

R F R N S

1. Bowie M D , M ann M D , H ill ID : The bowel cocktail.

Ped i

atr ics

1981;67:920-921

2. M ann M D , H ill ID , Peat GM , et al: Protein and fat absorp-

tion in prolonged diarrhoea in infancy.

Arch D is C hild

1982;57:268-273

3. H ill ID , M ann M D , Bowie M D : Successful management of

persistent diarrhoea in infants. S Afr Med J 1980;58:241-

2 4 3

4. Snedecor GW , Cochrane W G:

Sta t istica l M eth od s

ed 6.

Ames, Iowa, I owa State U niversity Press, 1967

5. Bottenberg RA , W ard JH :

App lied Mu ltip le Lin ea r Regr es

s i an .

Lackland AF Base, TX . 6570th Personnel Research

Laboratory, A erospace M edical D ivision, report N o. PRL -

TD R-63-6, 1963

6. M ann M D , H ill I D , M oore L , et al: X ylose absorption in

infants with severe prolonged diarrhoea. S Afr Med J

1 8 ; 5 8 : 5 9 8 5 9 9

7. H ill I D ,

M ann M D , M oore L , et al: D uodenal microflora in

infants w ith acute and persistent diarrhoea.

Arch D is Chi ld

1983;58:330-334

8. L ifshitz F: The enteric flora in childhood disease-diar-

rhoea.

Am J C lin Nu tr

1 9 7 7 ; 5 : 1 5 1 1 1 5 1 6



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1986;77;477PediatricsIvor D. Hill, Michael D. Mann, Keith C. Househam and Malcolm D. Bowie

Severe Persistent Diarrhea in InfantsUse of Oral Gentamicin, Metronidazole, and Cholestyramine in the Treatment of

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