An Outbreak of Clostridium difficile Necrotizing Enterocolitis: A Case for Oral Vancomycin Therapy?

An Outbreak

of Clostridium

difficile

Necrotizing

Enterocolitis:

A Case

for Oral Vancomycin

Therapy?

V.K.M.

Han,

MB,

H. Sayed,

MD, G. W. Chance,

MB, D. G. Brabyn,

MB ChB,

and W. A. Shaheed,

MB, ChB

From the Departments of Paediatrics and Microbiology, University of Western Ontario, London, Ontario Canada

ABSTRACT. During a 2-month period, 13 infants in this

neonatal intensive care unit developed necrotizing

enter-ocolitis, increasing the prevalence in inborns from 5.2 to

20.5/1,000 live births. Fifty-seven perinatal and neonatal factors, many of which have previously been associated

with necrotizing enterocolitis, were compared between

the infants with necrotizing enterocolitis and 17

unaf-fected inborn control infants admitted concurrently.

Cbs-tridium difficile cytotoxin was detected in the stools of 12 affected infants (92.3%) in comparison with two control

infants (11.8%) (P < .001), and the organism was isolated

in eight affected neonates (61.5%) compared to none of

the control infants (P < .001). The outbreak was

termi-nated upon institution of oral vancomycin therapy in

cases and infant contacts, and strict antiinfective

meas-ures in the neonatal intensive care unit. This indicates

an etiologic role of C difficile in the outbreak. Oral

van-comycin in the management of necrotizing enterocolitis

was assessed by therapeutic response, drug levels, and

occurrence of side effects. Oral vancomycin therapy is

indicated in necrotizing enterocolitis outbreaks in units

where C difficik is endemic. Pedit.ztrics 1983;71:935-941;

Clostridium difficik, necrotizing enterocobitis, vancomycin.

After a decade and a half of study,’3 the etiology

and pathogenesis of neonatal necrotizing

entero-colitis (NEC) still remain unclear. As studied in a

multitude of reports,4 it is probably a disease of

multifactorial origin. Currently, it is widely

ac-cepted that NEC is a result of local and systemic

invasion of the damaged intestinal mucosa by

mi-croflora in a stressed neonate.79 However, the not

unusual occurrence of NEC in unstressed term

Received for publication April 9, 1982; accepted Aug 25, 1982. Reprint requests to (G.W.C.) Department of Paediatrics, St Joseph’s Hospital, 268 Grosvenor St, London, Ontario, Canada

NGA 4V2.

PEDIATRICS (ISSN 0031 4005). Copyright © 1983 by the American Academy of Pediatrics.

neonates’#{176} and its development in only a proportion

of similarly stressed preterm neonates concurrently

cared for in the same intensive care situation

can-not be fully explained. Geographical and temporal

clustering of cases of NEC,”2 the termination of

“epidemics” of NEC by strict infection control

measures,” and reports of the possible benefit of

prophylactic oral antibiotics’3’5 have suggested the

central role of infectious agents in its

pathogen-esis.9”6 Organisms that have been associated with

outbreaks include Pseudomonas,’7 Salmpnelkz,’8

Klebsiell.a,’92’ Escherichia coli,22 Coxsackie B2,’

and more recently clostridia.24 Because of their

propensity to infect ischemic tissue and produce

gas and destructive toxins, clostridia have been

proposed to be the most likely pathogen, capable of

producing the pathophysiologic sequence in NEC.9

Cbostridium difficile, in particular, has been

increas-ingly recognized as an important pathogen.3032 We

report our experience with NEC in our neonatal

intensive care unit (NICU) during the period of 1

year, including a 2-month epidemic in which

C

difficile played a major role, and its dramatic

ter-mination by strict antiinfective measures and oral

vancomycin.

PATIENTS AND METHODS

During the period from July 1980 to June 1981,

clinical and laboratory data were collected from all

cases of NEC at the NICU of St Joseph’s Hospital,

London, Ontario, a unit in which fewer than 8% of

the neonates are outborn. Neonates with mild

epi-sodes of intolerance to feeds and other causes of

ileus (eg, ileus of prematurity, sepsis) were

ex-cluded. The cases were then divided into three

stages (I, II, or III) according to Bell et al. The

clinical signs of NEC with radiologic evidence of

bowel wall separation alone without pneumatosis,

portal gas, persistent dilated intestinal loop, or

pneumoperitoneum were classified as stage I rather

than stage II. The incidence was then calculated

for the number of live births, admissions to NICU

and low-birth-weight infants (<2,500 g).34

During the epidemic (March and April 1981),

control neonates (n = 17) (one each for the first

nine neonates and two each for the next four

neo-nates) were selected from unaffected neonates of

similar sex, gestational age (±1 week), birth weight

(±50 g) and postnatal age (±1 week) concurrently

admitted to the NICU. Comparison of the variables

known to predispose to NEC was made between the

epidemic cases and control neonates. Statistical

calculations with unpaired t test and x2 with Yates

correction were used where applicable.35

Compari-son between the nonepidemic cases and control

neonates was not made.34

Stool Collection

Stool specimens were collected into standard

commercially available containers and anaerobic

Vacutainers (Becton-Dickinson) at the time of

di-agnosis from all infants with NEC. Specimens were

collected from the matched control neonates on the

same day. The specimens were immediately

cul-tured for routine aerobic and anaerobic organisms

using standard procedures. C difficile was cultured

on egg yolk-fructose base with cycloserine cefoxitin

(CCFA) media and identified biochemically and by

gas liquid chromatography.36 The toxin of C difficile

was assayed in monolayer cell culture (McCoy) and

the toxin was specifically neutralized by an

anti-toxin to C sordelli.37 When oral vancomycin was

used to control the epidemic, stool specimens were

collected before the start of therapy, at three days

after the start of therapy, and at 24 to 48 hours

after completion of the course.

Vancomycin Levels

Venous blood samples were collected from 12

neonates (six with NEC and six controls) one hour

after the oral dose of vancomycin, for blood levels

using the method of Murray and Christman.38

Radiologic Diagnosis

Because of subjective variations in the radiologic

diagnosis of NEC,39 all abdominal radiographs of

suspect and proven cases were assessed after the

epidemic, by four separate observers. Diagnosis and

staging were then assigned by concensus.

RESULTS

Incidence

During the period from July 1980 to June 1981,

including the 2-month epidemic period in March

and April 1981, 28 of the 683 infants admitted to

the NICU developed NEC. All the affected infants

were inborn. Thirteen cases of NEC were diagnosed

during the epidemic, during which the incidence

increased from 5.2 to 20.5/1,000 live births. The

overall incidence of NEC during the period of July

1980 to June 1981 including the epidemic period

was 7.9/1,000 live births, 4.4% of inborn

admis-sions, and 7.3% of low-birth-weight infants. Of the

28 infants with a diagnosis of NEC 12 (42.8%) were

stage I, ten (35.7%) were stage II, and six (21.4%)

were stage III.

The salient clinical data of the 13 infants with

NEC during the epidemic are shown in Table 1. It

is notable that only one infant was full term.

Six infants (22.2% of all cases, 37.5% of stages II

and III) developed perforation and required surgery.

Two infants died during the acute phase of NEC,

resulting in a mortality from NEC of 7.4% of all

cases and 12.5% of stage II and III cases. Three

infants (11.1% of all cases and 18.75% of stages II

and III) developed strictures 5 to 8 weeks after the

acute episodes.

The salient comparative data between the

epi-demic cases (n = 13) and the unaffected control

neonates (n = 17) (Table 2). Of the 57 variables

studied only two variables were significantly

differ-ent between the two groups, ie, the method of

delivery and Apgar scores. Spontaneous vertex

de-livery was more common in NEC cases (40.2%)

compared to unaffected control neonates (5.9%) (P

< .05). Unaffected control neonates had

signifi-cantly lower Apgar scores at one minute (P < .05)

and five minutes (P < .01); however, cord blood gas

values were not significantly different between the

two groups.

Compared to 2/17 unaffected control neonates

(1 1.8%),

C

difficile cytotoxin was detected in 12/13

infants with NEC (92.3%, P < .001), all eight cases

of stage II and III NEC (100%, P < .001) and 4/5

cases of stage I NEC (80%, P < .05). Of all the

cases of NEC under study for the past year (n =

28) the cytotoxin was detected in the stools of 21

neonates (77.8%).

C

difficile organism was isolated

in none of the control neonates. Eight of 13 NEC

cases (61.5%, P < .001), 6/8 cases of stage II and

III NEC (75%,

P

< .001), 2/5 stage I NEC (40%,

P

< .1), had C difficile organism isolated from the

stools. C butyricum was detected from the stool of

TABLE 1. Salient Clinical Features of Infants with Necrotizing Enterocolitis (NEC) During the Outbreak

Case No.

Maturity (wk)

Birth Weight

(g)

Age at Onset

(d)

Clinic Si

a ROfltflOTIfl Stage Clostridium

diffidile

Toxin

Orga-Course and

Outcome

Intoler- Abdom- Bloody

ance to inal Stools nism

Feeds Disten-sion

1 27 1,090 9 + + ++ Pneumatosis,

perfora-tion

III + + Ileal

resec-tion, ileos-tomy

2 28 1,180 13 + + + Ileus? bowel wall

edema

I - - Recovery

3 31 1,700 4 + + + Ileus? bowel wall

edema

I + - Recovery

4 33 1,880 14 + + + Ileus? bowel wall

edema

I + + Recovery

5 32 1,250 7 - - +++ Pneumatosis,

perfora-tion

III + - Ileal

resec-tion, ileos-tomy

6 32 1,300 14 - - +++ Pneumatosis II + + Recovery

7 27 1,070 50 + + ++ Ileus, fixed bowel loop, bowel wall edema

II + - Recovery

8 30 860 29 - - +++ Mottled, fixed loop,

bowel wall edema

II + + Recovery

9 38 3,470 10 + - + Ileus I + - Recovery

10 32 1,500 20 + + ++ Pneumatosis

perfora-tion

III + + heal

resec-tion, ileos-tomy, dis-seminated

intravascu-lar coagu-lopathy, death

1 1 30 1,580 24 - + ++ Ileus, fixed dilated

loop, bowel wall edema

II + + Recovery

12 31 1,620 26 + + + Ileus, bowel wall

edema pneumatosis

II + + Recovery

13 36 2,430 18 + - ++ Ileus,bowelwall

edema

I + + Recovery

The incidence of NEC dramatically dropped to

two cases of stage I NEC in May (6.5/1,000 live

births, 3.7% of total admissions to NICU) and one

case of stage II NEC in June (3.4/1,000 live births,

2.0% of total admissions to NICU) compared to

eight cases in April (25.8/1,000 live births, 19.4%

of total admissions to the NICU). The imposition

of strict infection control measures and the use of

oral vancomycin in all neonates admitted to the

NICU (both infants with NEC and unaffected

in-fants) were believed to be responsible. Initially, oral

vancomycin was given at a dosage of 15 mg/kg/d4#{176}

for a total of seven days. Stool investigations were

repeated on the third day and 24 to 48 hours after

completion of the course. All the stools investigated

were negative for both the toxin and organism from

the third day onward except for the stools of one

neonate who still had toxin detected after the

sev-enth day (therapeutic success rate of 93%). This

latter infant’s stool became negative after a further

course of vancomycin.

Serum vancomycin levels were measured in six

infants with NEC and six unaffected infants. All

infants had peak serum levels less than 0.2 jzg/mL,

which was much less than the toxic serum levels

previously described.4’ Urine output, serum

electro-lytes, BUN, and creatinine levels were unchanged

during the period of antibiotic administration.

DISCUSSION

The organisms previously associated with NEC’7

29 are commensals commonly found in the neonates’

intestinal tract. The reason why these commensals

become invasive and pathogenic cannot be fully

explained. It is widely believed that ischemic

dam-age of the bowel mucosa suffered during

asphyxiat-ing insults of the perinatal period42 and therapeutic

and management interventions during the neonatal

TABLE 2. Observations on Infants with Necrotizing Enterocolitis (NEC) During

Matched Control Infants (March and April 1981)*

the Outbreak and Unaffected

Infants with NEC Control

Infants (n = 17)

P

All Stages

(n=13)

States II and III (n=8)

-Mean gestational age ± SD (wk) 31.3 ± 3.2 30.1 ± 2.1 31.8 ± 3.3 NS

Range 27-38 27-32 25-37

Mean birth weight ± SD (g) 1,610 ± 693 1,284 ± 270 1,433 ± 564 NS

Range 860-3,470 860-1,580 810-2,640

Sex (M/F) 4/9 2/6 7/10 NS

Spontaneous vaginal delivery 6 (46.2%) 3 (37.5%) 1 (5.9%) <.05t

Mean Apgar scores ± SD

1-mm 6.3 ± 2.1 6.6 ± 1.8t 4.5 ± 2.1 <.05t

Range 2-9 2-9 1-8

5-mm 9.1 ± 0.8 9.1 ± 0.8 7.8 ± 1.1 <.Olt

Range 8-10 8-10 5-9

Mean cord blood gases ± SD

Arterial

pH 7.213 ± 0.055 7.202 ± 0069 7.216 ± 0.130 NS

Pco2 (mm Hg) 46.2 ± 10.2 45.6 ± 10.8 48.5 ± 16.7 NS

P02 (mm Hg) 16.9 ± 9.5 17.5 ± 10.5 22.0 ± 19.3 NS

HCO3 (mEq/L) 17.6 ± 3.9 16.2 ± 4.0 20.1 ± 2.6 NS

Base excess (-) 10.3 ± 4.0 10.4 ± 4.8 6.2 ± 3.4 NS

Respiratory distress syndrome

Type I 5 (38.5%) 3 (37.5%) 9 (52.9%) NS

Type II 4 (30.8%) 2 (25.0%) 5 (29.4%) NS

None 4 (30.8%) 3 (37.5%) 3 (17.6%) NS

Umbilical catheters

Arterial 10 (76.9%) 8 (100%) 13 (76.5%) NS

High 9 (69.2%) 8 (100%) 8 (47.1%) NSt

Low 1 (7.7%) 0 (0) 5 (29.4%) NS

Clinical features

Age at diagnosis or sampling (d) 22 23.6 20.2 NS

Range 9-50 9-50 2-52 NS

Intolerance to feeds 10 (76.9%) 5 (62.5%) 7 (41.2%) NS

Abdominal distension 9 (69.2%) 6 (75%)t 0 (0) <.OOlt

Blood in stools 13 (100%) 8 (100)t 0 (0) <.001

Patent ductus arteriosus 6 (46.2%) 5 (02.5%) 4 (23.5%) NS

Use of antibiotics

Prior to diagnosis or sampling 9 (69.2%) 4 (50%) 13 (76.5%) NS

Mean duration (d) antibiotic discontinued 6.3 6 11.4 NS

Range 3-7 3-7 0-33

Diagnosis of NEC or sampling during anti- 0 0 2 (11.8%) NS

biotic course

* Note: Other variables with no significant statistical difference include sex, maternal age, maternal complications

(antepartum hemorrhage, preeclamptic toxemia, prolonged rupture of membranes, chorioamnionitis, maternal

infec-tion, puerperal sepsis), types of delivery, cord venous gas values, types of resuscitation at birth, apneic spells, use of

aminophylline, types and duration of ventilatory support, umbilical venous catheter, concurrent infections, types of

feeds, and age feeds started. t Discussed in text.

to the invasion by enteric commensals.4 However,

well-controlled prospective studies on NEC have

failed to come up with consistent predisposing

fac-tors.3443’44

Most previous reports of NEC have been

criti-cized for the lack of proper controls.34 Ryder et a1

in their large prospective multicenter investigation

of NEC reported ten significant independent

deter-minants of NEC and ten determinants predictive

of a fatal outcome among the infants they studied.34

In our small number of affected infants we failed

to identify any significant determinant of NEC

between those with NEC and the unaffected control

infants who were matched for sex, gestational age,

birth weight, and postnatal age as described by

Ryder et al.34 The difference in the type of delivery

cannot be fully explained. However, Donta et al

have recently reported that vaginal delivery and

breast-feeding may be associated with higher

fre-quency of

C difficile

colonization in the neonate’s

gut. The one-minute and five-minute Apgar scores

control neonates. This is in contradistinction to

other reports.43’ Other workers have shown no

statistical difference in the occurrence oflow Apgar

scores between infants with NEC and control

sub-jects.47’48 Furthermore, perinatal asphyxia as

deter-mined by cord blood gases49 did not significantly

differ between the two groups. We believe that

determination of cord blood gases may be a more

important objective measurement of perinatal

as-phyxia. The conflicting evidence in the literature

suggests that intrapartum asphyxia is not a factor

common to all instances of NEC. There was no

significant differences in the other variables

stud-ied, and we agree with the view of Stoll et a!47 that

these factors simply represent the descriptive

char-acteristics of a population of sick premature

in-fants.

The use of high umbilical catheters (above T12)

appears to be more common in NEC cases (69.2%

ofall stages and 100% ofstages II and III) compared

to 47% of unaffected control subjects, although

statistically not significantly different. Tyson et al#{176}

and Lehmiller et a15’ showed the occurrence of

mesenteric thromboembolism associated with high

catheters. Our observations agree with their

find-ings and support the recommendation that

umbili-cal arterial catheter tips should be placed lower,

below the origin of the inferior mesenteric artery.

The mean age of diagnosis 22 days (range 9 to 50

days) is not significantly different from that of

matched control subjects with the time of stool

sampling of 20 days (range 5 to 58 days). This is

greater than the mean age at the time of diagnosis

reported by other institutions.6’52 We could find no

significant differences between the two groups in

maternal factors, feeding practices, incidence or

severity of respiratory distress syndrome (RDS),

patent ductus arteriosus (PDA), apneic spells, use

of aminophylline53 or the use of broad-spectrum

antibiotics prior to diagnosis.34

Although, prospective controlled studies’47 have

failed to produce common predisposing risk factors,

the etiologic agent(s) consistently noted in the

pathogenesis of NEC is (are) the intestinal

microor-ganism(s). It is widely accepted that the

clinico-pathologic features, ie, septic shock, pneumatosis

intestinalis, seen in NEC occur as a result of

inva-sion by enteric microorganisms, except for one

sug-gestion that an increased intraluminal pressure

may be responsible.TM A wide variety of

microorga-nisms have been associated with NEC especially

during “outbreaks” in NICUs.17 Clostridia

spe-cies have been increasingly recognized as potential

pathogens in humans.3’ To date four clostridial

species have been associated with NEC:

C

butyri-cum,24 C perfringens,26’’55 C botulinum,27 and

C

difficile.tm

The latter organism has been shown to

be the major pathogen in antibiotic-associated

pseudomembranous colitis in adults,sc which has

pathologic features similar to NEC. The detection

of

C difficile

toxin and isolation of the organism in

the stools does not necessarily imply causal

rela-tionship with the disease. However, based on the

remarkably strong association of the toxin and/or

organism with 12/13 cases of NEC, and the absence

of organism and very limited presence of toxin in

unaffected controls (2/17) in the outbreak reported

we conclude that we must implicate

C difficile

as

the etiologic factor.

Data for the two groups of neonates under study

are compared in Table 2. Isolation rate of

C difficile

in the normal control neonates (12%) is similar to

the 14% reported by Rietra et al57 but less than the

29% reported by Viscidi et al,se the 55% reported

by Donta and Myers, and the more than 50%

reported by Sheretz et a!.59 It appears that

C difficile

is not an uncommon commensal isolated from

healthy neonates. Bartlett et alse failed to isolate

C

difficile from the stools of 24 neonates with NEC, although they did not exclude the clostridia entirely

in its pathogenesis. Cashore et a1 detected

cyto-toxin in 3/11 infants with confirmed NEC and 2/9

infants with suspected NEC. However, they failed

to isolate

C difficile

organism in the stools. The

successful isolation of the organism in a high

pro-portion of our infants cannot be fully explained,

but the anaerobic method ofcollection of stools and

rapid processing could be partly responsible.

C difficile

has been shown to produce two

pow-erful toxins, cytotoxin and enterotoxin,#{176} which

may cause damage to gastrointestinal mucosal cells.

The latter toxin has been noted to be 1,000 times

more powerful than the former. It is possible that

only certain

C difficik

species may produce the more

powerful enterotoxin or that a change in

environ-mental conditions may alter the degree of exposure

or the pathogenicity of the commensal

C difficile.

To our knowledge, oral vancomycin has not been

used to control an outbreak or in the management

of NEC. The dramatic reduction in the incidence

of NEC and the termination of the outbreak by the

use of oral vancomycin in conjunction with strict

infection control measures, further supported the

etiologic relationship of

C difficile

to the outbreak.

Alternatively, oral vancomycin may also have

re-duced the overall colonization of the newborn gut

by other potentially pathogenic organisms.

Clostri-dia species may be resistant to aminoglycosides,6’

and this could partly explain the failure of oral

gentamicin therapy in the management of NEC.62

Oral vancomycin instead, could be a useful adjunct

have been associated with potentially toxic drug

levels in NEC infants with inflamed bowel

mu-cosa.62 Low peak serum vancomycin levels and lack

of clinical and biochemical side effects led us to

conclude that vancomycin is not significantly

ab-sorbed into the circulation, even through the

in-flamed mucosa. The majority of the neonates

treated with oral vancomycin had negative stools

by the third day of antibiotic therapy. Only one

neonate continued to have positive stools after a

seven-day course and required a further course of

oral vancomycin. A similar observation in adult

antibiotic-induced pseudomembranous colitis was

attributed to regermination of clostridial spores.63

The impact of oral vancomycin therapy on the

NEC epidemic that occurred in our NICU was

dramatic. Stricter anti-infective measures were

im-posed, but we believe that the former was of greater

significance. We propose that oral vancomycin

therapy is indicated in NEC outbreaks that occur

in units where C difficile is endemic.

ACKNOWLEDGMENTS

Dr Han was supported by St Joseph’s Hospital, Lon-don, Ontario.

We thank Dr L. Hatch and staff, Department of

Mi-crobiology, St Joseph’s Hospital, the nursing staff of the

NICU, and Laura Broadbear and Marilyn Hassall for

their secretarial assistance.

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Br Med J 1981;282:1913

FALL, FALL

High-wire star of Rmgling Brothers and Barnum and Bailey Circus, Elvin

Bale, is concerned with how motion pictures and tv have changed people’s

responses to the drama of real-life dangers.

In a recent interview he said that young spectators who yell ‘fall, fall’ while he

performs no longer bother him. ‘I’ve gotten used to it. They don’t really mean

it. We’re competing with movies and television. The last few years they’ve put

so many stunts into movies they’ve spoiled the public. People are becoming

immune to seeing accidents and heads cut off. When they come to the circus

you almost have to kill yourself before they appreciate it.’

From Glimpse, September 1982.

1983;71;935

Pediatrics

V. K.M. Han, H. Sayed, G. W. Chance, D. G. Brabyn and W. A. Shaheed

Vancomycin Therapy?

Necrotizing Enterocolitis: A Case for Oral

Clostridium difficile

An Outbreak of

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1983;71;935

Pediatrics

V. K.M. Han, H. Sayed, G. W. Chance, D. G. Brabyn and W. A. Shaheed

Vancomycin Therapy?

Necrotizing Enterocolitis: A Case for Oral

Clostridium difficile

An Outbreak of

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