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INFECTION CONTROL AND HOSPITAL EPIDEMIOLOGY JANUARY 2009, VOL. 30, NO. 1
ORIGINAL ARTICLE
Skin and Environmental Contamination With Vancomycin-Resistant
Enterococci in Patients Receiving Oral Metronidazole or Oral
Vancomycin Treatment for Clostridium difficile-Associated Disease
Ajay K. Sethi, PhD; Wafa N. Al-Nassir, MD; Michelle M. Nerandzic, BS; Curtis J. Donskey, MD
BACKGROUND.
Oral metronidazole has been recommended for treatment of mild-to-moderate Clostridium
difficile-associated
disease
(CDAD), in part because of concern that use of vancomycin may be more likely to promote colonization and transmission of vancomycin-
resistant enterococci (VRE). The objective of our study was to compare the frequency of skin and environmental VRE contamination
associated with metronidazole treatment for CDAD with such frequency associated with vancomycin treatment for CDAD.
DESIGN.
Prospective, observational study. This study was performed at the Cleveland Veterans Affairs Medical Center (Cleveland, OH).
For patients with CDAD who had concurrent VRE colonization, stool, skin, and environmental samples were cultured for VRE before,
during, and up to 3 weeks after therapy with metronidazole or vancomycin. The proportions of skin and environmental contamination
were compared before and after resolution of diarrhea and during treatment with metronidazole or vancomycin.
RESULTS.
Of the 34 patients, 17 were treated with vancomycin and 17 were treated with metronidazole. The proportion of environmental
cultures that were positive for VRE was significantly higher during resolution of diarrhea than it was after resolution of diarrhea (38% vs
28%;
P = .025), whereas the proportion of skin cultures positive was not different during and after resolution of diarrhea (78% vs 71%;
P = .60). There were no differences between patients who received metronidazole and patients who received vancomycin in the proportions
of skin culture results (73% vs 77%; P = .80) or environmental culture results (37% vs 32%; P = .359) that were positive for VRE. Eleven
patients (32%) had chronic fecal incontinence, and 28 (82%) had incontinence at least once during their CDAD episode.
CONCLUSIONS.
In VRE-colonized patients with CDAD who experienced frequent fecal incontinence, skin and environmental VRE
contamination was common during and after resolution of diarrhea. The frequency of VRE contamination was similar between patients
treated with metronidazole and patients treated with vancomycin.
Infect
Control
Hosp
Epidemiol
2009; 30:13-17
For treatment of mild-to-moderate Clostridium difficile-asso- colonization.7 Here, we investigated the frequency of skin and
ciated disease (CDAD), oral metronidazole has been rec- environmental contamination with VRE during CDAD treat-
ommended as the preferred agent, in part because of concern ment for patients with pre-existing VRE colonization. Because
that use of vancomycin may be more likely to promote col- both metronidazole and vancomycin therapy promote over-
onization and transmission of vancomycin-resistant entero- growth of VRE,3 we hypothesized that the frequency of con-
cocci (VRE).1"5 However, metronidazole has also been asso- tamination would be similar among patients treated with ei-
ciated with VRE colonization in case-control studies.6 We ther agent. We compared the frequency of contamination
recently reported that both oral metronidazole and oral van- before resolution of diarrhea with the frequency of contam-
comycin therapy promoted persistent overgrowth of VRE in ination after resolution of diarrhea, as well as the frequencies
stool samples obtained from colonized patients during CDAD of contamination in the presence of high-density stool col-
treatment.3 Such overgrowth in stool may potentially facilitate onization and low-density stool colonization,
transmission, particularly in patients with diarrhea or fecal
incontinence.7,8 For example, in VRE-colonized patients with METHODS
fecal incontinence, high-density colonization of stool (ie,
more than 4 log10 colony-forming units [cfu] per gram of
stool) was associated with a significantly increased frequency From September 2007 through March 2008, we performed a
Setting and Study Design
From September 2007 thro
of environmental contamination, compared with low-density prospective observational study involving patients with CDAD
From the Departments of Epidemiology and Biostatistics (A.K.S.) and Infectious Diseases (W.M.A.-N.), University Hospitals of
Cleveland,
Case
Western
Reserve University School of Medicine, and the Research Service (M.M.N.) and the Geriatric Research Education and Clinical Center, Cleveland Veterans
Affairs Medical Center (C.J.D.), Cleveland, Ohio
Received June 14, 2008; accepted August 15, 2008; electronically published December 1, 2008.
© 2008 by The Society for Healthcare Epidemiology of
America.
All rights reserved. 0899-823X/2009/3001-0004$15.00. DOI: 10.1086/592710
Downloaded from https://www.cambridge.org/core, subject to the Cambridge Core terms of use.
14 INFECTION CONTROL AND HOSPITAL EPIDEMIOLOGY JANUARY 2009, VOL. 30, NO. 1
in the acute care and long-term care facilities at the Cleveland
Veterans Affairs Medical Center (Cleveland, OH), where there
is an endemic high rate of VRE colonization.7 Patients received
a diagnosis of CDAD on the basis of symptoms of diarrhea
and a positive stool toxin assay result (C.
difficile
Tox A/B II;
Wampole Laboratories). Coexisting
VRE
stool colonization was
identified by plating samples onto Enterococcosel agar (Becton
Dickinson) containing vancomycin at a concentration of
6
jug/
mL;
identification and susceptibility testing were then per-
formed according to Clinical Laboratory Standards Institute
guidelines.9 The choice of therapy for CDAD was made by the
physicians caring for the patients. Information regarding de-
mographic characteristics, coexisting illnesses, antibiotic ther-
apy, and fecal incontinence was obtained through standardized
medical chart review. For fecal incontinence, it was noted
whether the patient had chronic incontinence or at least 1
occurrence of incontinence during their CDAD episode, as
documented in the daily nursing notes.
All patients with CDAD who had coexisting VRE stool
colonization during the study period were enrolled unless
they refused to provide informed consent, were scheduled for
hospital discharge within 2 days after the diagnosis, or had
received empirical therapy with oral metronidazole or oral
vancomycin before the diagnosis of CDAD. Patients whose
therapy was switched from metronidazole or vancomycin to
another agent were included if they received at least 5 days
of treatment with the agent; for these patients, only the culture
samples collected during treatment with the initial agent were
included in the analysis. The hospital's institutional review
board approved the study protocol.
Stool, skin, and environmental samples were cultured for
VRE before initiation of treatment, every 2-3 days during
treatment, and each week for up to 3 weeks after completion
of treatment while the patients were hospitalized or were
residents of the affiliated long-term care facility. Skin speci-
mens (from the chest and abdomen) were obtained by swab-
bing a 5 x 20-cm area with a premoistened rayon swab.
Environmental samples (from toilet seats, call buttons, bed
rails,
and bedside tables) were obtained by swabbing a des-
ignated area of each surface (5 x 20 cm for bed rails and
bedside tables, the entire surface area of the call button, and
the top surface of the toilet seat). To ensure that the envi-
ronmental culture samples represented ongoing shedding of
VRE in the environment, the environmental sites were dis-
infected with 10% bleach after each set of samples was ob-
tained; additional culture samples were obtained after bleach
disinfection to ensure that VRE was eradicated. No specific
interventions were undertaken to decrease the burden of VRE
on the patients' skin, but routine bathing practices were per-
formed. The nursing staff encourages daily bathing for all
patients, and bed baths with moist towels and nonantimi-
crobial soap are provided for patients who are unable to bathe
themselves.
The skin and environmental swab specimens were incu-
bated for 2 days in Enterococcosel broth (Becton Dickinson)
containing vancomycin at a concentration of 6 ntg/mL and
were then plated onto Enterococcosel agar (Becton Dickin-
son) containing vancomycin at a concentration of 6 ^g/mL.
For a subset of
22
skin and environmental isolates, speciation
and broth-dilution minimum inhibitory concentrations for
vancomycin were determined by using standard methods.9 If
VRE was present in a stool sample, the concentration was
quantified as described elsewhere.7
Statistical Analysis
Data were analyzed by using SPSS, version 10.0 (SPSS), and
Stata, version 9.1 (StataCorp). Distributions of clinical and
TABLE. Characteristics of
34
Patients Who Were Colonized With Vancomycin-Resistant Enterococci
(VRE) and Received Either Oral Metronidazole or Oral Vancomycin Treatment for
Clostridium
difficile-
Associated
Disease (CDAD)
Characteristic
Metronidazole Vancomycin
All patients group group
(n = 34) (n = 17) (n = 17)
Age,
years
Baseline VRE density, log10 cfu per g of stool
Long-term care facility resident
Chronic fecal incontinence
Fecal incontinence reported at any time
during the CDAD episode"
Diabetes mellitus
Chronic pulmonary disease
Underwent surgery in prior 3 months
End-stage renal disease
Cancer
Dementia
Spinal cord injury
72.5 (65-79)
7 (6-8)
16 (47.1)
11 (32.4)
28 (82.4)
13 (38.2)
11 (32.4)
3 (8.8)
10 (29.4)
7 (20.6)
2 (5.9)
4 (11.8)
73 (64-76)
7 (6-8)
9 (52.9)
5 (29.4)
14 (82.3)
4 (23.5)
6 (35.3)
1 (5.9)
5 (29.4)
3 (17.6)
0 (0.0)
2 (11.8)
71 (67-80)
7 (6-8)
7 (41.2)
6 (35.3)
14 (82.3)
9 (52.9)
5 (29.4)
2 (11.8)
5 (29.4)
4 (23.5)
2 (11.8)
2 (11.8)
.470
.581
.492
.714
>.99
.197
>.99
>.99
>.99
>.99
.485
>.99
NOTE. Data are median value (interquartile range) or
no.
(%) of
patients,
cfu, Colony-forming units.
" Determination of
fecal
incontinence
was
based on review of
daily
nursing progress notes.
Downloaded from https://www.cambridge.org/core, subject to the Cambridge Core terms of use.
SHEDDING
OF VRE IN
PATIENTS WITH CDAD
15
11-15
16-20
Days from start of treatment
Skin
Toilet
Call Bed rail
button
Site cultured
Bedside
table
FIGURE
1. Density of vancomycin-resistant enterococci (VRE) in
stool (A) and skin contamination and environmental shedding of
VRE (B) in VRE-colonized patients who received oral metronidazole
treatment for Clostridium difficile-associated disease (CDAD; n =
17),
compared with VRE-colonized patients who received oral van-
comycin treatment for CDAD (n = 17). Day 0 was the day that
CDAD was diagnosed (before treatment). Error bars indicate stan-
dard error, cfu, Colony-forming units.
demographic characteristics were compared between patients
who received treatment with oral vancomycin and patients
who received treatment with oral metronidazole. The Student
unpaired t test and the Kruskal-Wallis test were used for
normally and nonnormally distributed data, respectively. The
Pearson x2 test and Fisher exact test were used for categorical
data. The Student unpaired f test was used to compare the
densities of VRE in stool in the 2 treatment groups at different
times.
The Fisher exact test was used to compare the pro-
portions of skin and environmental culture results that were
positive between patients who received metronidazole and
those who received vancomycin; the comparisons were made
both during and after resolution of diarrhea. Comparisons
between groups were also made with regard to VRE density
in stool (greater than 7, 4-7, and less than 4 log10 cfu/g).
RESULTS
Of 64 total patients who received a diagnosis of CDAD during
the study period, 42 (66%) had coexisting VRE colonization.
Of these 42 patients, 8 were excluded from analysis, including
1 who did not provide consent and 7 who had their therapy
switched from metronidazole to an alternative agent before
completing 5 days of treatment. Of the 34 study patients, 17
received oral metronidazole treatment and 17 received oral
vancomycin treatment. The mean durations of treatment
(±SD) with metronidazole and vancomycin were 11.7 ±
1.2 days and 12.4 ± 2.3 days, respectively. The Table shows
a comparison of the characteristics of the patients who re-
ceived vancomycin treatment with those of the patients who
received metronidazole treatment. All of the patients were
male. There were no statistically significant differences be-
tween patients treated with vancomycin and patients treated
with metronidazole. Thirty-two percent of the patients had
chronic fecal incontinence. However, of note, 82% of the
patients in each treatment group were documented as having
fecal incontinence on at least 1 occasion by the nursing
staff;
for patients who did not have chronic incontinence, the in-
continence almost always occurred during the acute episode
of CDAD.
There were no statistically significant differences in the
density of VRE in stool between the metronidazole and van-
comycin treatment groups before initiation of CDAD therapy,
during therapy, or up to approximately 2 weeks after com-
pletion of therapy (P ^ .239) (Figure 1A). In both groups,
high-density VRE colonization was maintained during ther-
apy. The proportions of skin and/or environmental cultures
showing contamination were not statistically significantly
dif-
ferent (P > .280, for all comparisons) between patients treated
with metronidazole and patients treated with vancomycin
(Figure 15). The toilet seat was the most commonly contam-
inated environmental site.
Figure 2 shows a comparison of the proportions of skin
and environmental cultures with positive results before and
after resolution of diarrhea. The proportion was statistically
significantly higher when diarrhea was present than it was
after resolution of diarrhea (103 [38%] of 272 vs 29 [26%]
of 112 cultures; P = .025), but the proportion of skin cultures
demonstrating contamination was not statistically signifi-
cantly different during and after resolution of diarrhea (53 [
78%] of 68 vs 20 [71%] of 28 cultures; P = .60).
Figure 3 shows a comparison of skin and environmental
cultures demonstrating contamination, stratified by the den-
sity of VRE in the patient's stool; culture samples obtained
when diarrhea was present were excluded to eliminate in-
*: 80-1
lit
£ 70-
>
2 m-
o SO-
il
40 -
|30-
<8 20 -
s
A„
2 0 -
u
0
H
Skin Environment
FIGURE
2.
Skin
contamination
and
environmental
shedding
of
vancomycin-resistant enterococci
(VRE) in
VRE-colonized
patients
during
and
after resolution
of
diarrhea
associated
with
Clostridium
difficile-associated
disease.
Downloaded from https://www.cambridge.org/core, subject to the Cambridge Core terms of use.
16 INFECTION CONTROL AND HOSPITAL EPIDEMIOLOGY JANUARY 2009, VOL. 30, NO. 1
>7 4-7 <4
Density of VRE in stool, log10cfu/g of stool
FIGURE 3. Skin contamination and environmental shedding of
vancomycin-resistant enterococci
(VRE),
stratified
by density
of VRE
in stool (excluding culture samples obtained while patients had di-
arrhea), cfu, Colony-forming units.
creased shedding caused by diarrhea as a confounding factor.
Contamination of the environment was associated with in-
creased stool density of VRE: there were positive environ-
mental culture results for
3
(9%) of 32 samples obtained when
stool density was less than 4 log10 cfu/g, for 14 (44%) of 32
samples obtained when stool density was 4-7 log10 cfu/g, and
for 28 (58%) of 48 samples obtained when stool density was
more than 7 log10 cfu/g of stool, respectively (P< .001). Of
the 22 VRE isolates for which speciation and susceptibility
testing were performed, all were Enterococcus faecium, and 20
(91%) had vancomycin minimum inhibitory concentrations
of 256 jiig/mL or greater.
DISCUSSION
During the study period, more than one-half of patients with
CDAD in our institution had concurrent VRE colonization.
The observation that patients with CDAD frequently have
coexisting VRE colonization is consistent with a previous
study in which
41%
of patients with CDAD had VRE detected
by surveillance stool cultures.10 As we have previously dem-
onstrated,3 both oral metronidazole and oral vancomycin
treatment of CDAD promotes persistent high-density VRE
overgrowth in stool samples from colonized patients. The
major new finding of the current study is that skin contam-
ination and environmental shedding of VRE is very common
among patients colonized with VRE who are receiving treat-
ment for CDAD. There was no difference in the frequency
of VRE contamination between patients who received met-
ronidazole treatment and patients who received vancomycin
treatment.
Our findings suggest that metronidazole and vancomycin
treatment of CDAD may promote transmission of
VRE,
be-
cause these agents promote persistent high-density coloni-
zation. For culture samples obtained in the absence of di-
arrhea, the proportions of skin and environmental cultures
demonstrating contamination were significantly higher if the
samples were obtained when the stool density of VRE was
greater than 4 log10 cfu/g than when it was less than 4 log10
cfu/g. These data are consistent with our previous study of
VRE-colonized patients with fecal incontinence; environ-
mental contamination was significantly more common when
the VRE density in stool was greater than 4 log10 cfu/g than
when the VRE density in stool was less than 4 log10 cfu/g.7
It is necessary to develop new treatments for CDAD that are
less likely to promote overgrowth and shedding of
VRE.
In
theory, treatments that cause less disturbance of the indige-
nous colonic microflora than do metronidazole or vanco-
mycin or that inhibit VRE in the colon would be less likely
to promote VRE colonization and shedding.
Boyce et al.11 and Drees et al.12 have previously reported
that VRE-colonized patients with diarrhea have an increased
prevalence of environmental VRE contamination. Our find-
ings provide further evidence that diarrhea is associated with
shedding of VRE in the environment. However, of
note,
shed-
ding of
VRE
remained common even after diarrhea resolved
(ie,
26% of environmental culture results were positive after
the resolution of diarrhea). Moreover, the proportion of skin
cultures with positive results was equally high during and
after the resolution of diarrhea. These data suggest that the
risk of transmission of
VRE
by patients with CDAD who had
coexisting VRE colonization is likely to be high both during
and after resolution of diarrhea.
Thirty-two percent of the study patients had chronic in-
continence, and a remarkably high proportion (82%) were
reported by the nursing staff to be incontinent on at least 1
occasion, almost always during the period of CDAD treat-
ment. Some overstatement of the frequency of incontinence
by the nursing staff was possible; however, it was apparent
to the investigators that many ill elderly patients with de-
creased mobility had difficulty reaching their toilet or com-
mode before moving their bowels. Although it is plausible
that the high prevalence of fecal incontinence may have con-
tributed to the high frequency of skin and environmental
contamination, it should be noted that environmental con-
tamination may also be frequent for continent VRE-colonized
patients.8 In fact, we demonstrated that the frequency of en-
vironmental contamination and the numbers of cfu recovered
by direct plating were not significantly different between 15
continent and 15 incontinent VRE-colonized patients (60%
vs 73%).8
Our study has some limitations. The study was observa-
tional, and a small number of patients were studied. Our
patient population included only male veterans, many of
whom were long-term care facility residents. In addition, a
high proportion of the study patients had chronic or transient
fecal incontinence. Therefore, additional studies in other set-
tings are needed. Because all of the patients were treated for
CDAD, there was no untreated control group. Therefore, we
cannot definitively state that metronidazole and vancomycin
treatment were the cause of the persistent VRE overgrowth
or shedding. However, we have previously revealed that the
concentration of VRE in stool samples from colonized pa-
tients decreases significantly by 1-2 weeks after discontinu-
Downloaded from https://www.cambridge.org/core, subject to the Cambridge Core terms of use.
SHEDDING OF VRE IN PATIENTS WITH CDAD 17
ation of antibiotic treatment.3,7
We
did not collect information
on bathing practices of patients and, therefore, cannot com-
ment on possible effects of different bathing practices on VRE
skin contamination.
In summary, we found that both oral vancomycin and oral
metronidazole treatment of
CDAD
in patients with coexisting
VRE colonization are associated with VRE skin contamina-
tion and environmental shedding. Diarrhea and increased
density of VRE in stool were associated with increased risk
of contamination. Additional studies are needed to assess skin
contamination and environmental shedding for VRE-colo-
nized patients with CDAD who have a low frequency of fecal
incontinence. Additional research is also needed to assess
whether strategies, such as skin decolonization and environ-
mental decontamination, can reduce the risk of VRE trans-
mission by VRE-colonized patients with CDAD.1314
ACKNOWLEDGMENTS
Financial support. Department of Veterans Affairs, Geriatric Research Ed-
ucation and Clinical Center, Cleveland VA Medical Center, and ViroPharraa
Pharmaceutical (to C.J.D.).
Potential
conflicts
of
interest.
All authors report no conflicts of interest
relevant to this article.
Address reprints request to Curtis J. Donskey, MD, Geriatric Research
Education and Clinical Center, Cleveland VA Medical Center, 10701 East
Blvd., Cleveland, OH 44106 (curtisdl23@yahoo.com).
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