THE EFFICACY OF VANCOMYCIN AS A FIRST LINE TREATMENT OF CLOSTRIDUM DIFFICILE AND ITS EFFECT ON...
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Transcript of THE EFFICACY OF VANCOMYCIN AS A FIRST LINE TREATMENT OF CLOSTRIDUM DIFFICILE AND ITS EFFECT ON...
THE EFFICACY OF VANCOMYCIN AS A FIRST LINE TREATMENT OF
CLOSTRIDUM DIFFICILE AND ITS EFFECT ON LENGTH OF HOSPITAL STAY.
Medhat Barsoom, M.D. , Kosta Botsoglou, M.D. , Orooj Khan, M.D.,
Gopichand Pendurti, M.D.
Michael Hocko, M.D.
INTRODUCTION
I
n 1935, Hall and O’Toole first isolated a gram-positive, cytotoxin-
producing anaerobic bacterium from the stool of healthy neonates.
N
amed Bacillus difficilis to reflect the difficulties they encountered in
its isolation and culture.
N
o we are unable to contain the growth and spread of the same
bacterium, now called Clostridium difficile.
INTRODUCTION
C
. dificile is a frequent cause of infectious colitis,
usually occurring as a complication of antibiotic
therapy, in elderly hospitalized patients.
O
ur study explores disease severity and response to
therapy.
INCIDENCE AND SEVERITY
D
uring the 1990s, the reported incidence of C. difficile infection
in the United States at 30 to 40 cases per 100,000 people.
I
n 2001, this number rose to 50 per 100,000
I
n 2005 it rose to 84 per 100,000—nearly three times the 1996
rate
INCIDENCE AND SEVERITY
T
he disease has been presenting with increasing
severity and fatal infection.
I
n England, for example, C. difficile infection was
listed as the primary cause of death for 499 patients
in 1999—and 3393 in 2006.
EMERGENCE OF A VIRULENT STRAIN
S
imilar increases have been reported in the United States.
M
cDonald et al. showed that isolates of a single strain accounted for at least
half the isolates from five facilities
T
his epidemic strain was initially named BI
C
urrently referred to as North American Pulsed Field type1 (NAP1) and PCR
ribotype 027 or NAP-1/027.
EMERGENCE OF A VIRULENT STRAIN
T
he increased virulence of this NAP-1/027 strain:
• Increased production of toxins A and B
• Fluoroquinolone resistance
• Production of binary toxin
EMERGENCE OF A VIRULENT STRAIN
T
oxins A and B are the major virulence determinants of C. difficile
O
ne of the regulatory genes—tcdC—codes for a negative regulator
of toxin transcription.
T
cdC protein inhibits toxin transcription during the early,
exponential-growth phase of the bacterial life cycle.
EMERGENCE OF A VIRULENT STRAIN
N
AP-1/027 strains carry deletion mutations in the
tcdC inhibitory gene.
T
his has been associated with a ten fold increase of
toxins production that mediate colonic tissue injury
and inflammation in C. difficile infection.
EMERGENCE OF A VIRULENT STRAIN
A
nother potential virulence determinant of NAP-1/027
strains is the production of a third toxin—binary
toxin—that is unrelated to the pathogenicity locus
that encodes toxins A and B.
EXPANDING EPIDEMIOLOGY
C
. difficile infection predominantly affects elderly and
frail hospital and nursing home patients.
H
owever, a recent advisory from the Centers for Disease
Control and Prevention warns of a risk of the infection
in populations not previously considered at risk.
EXPANDING EPIDEMIOLOGY
T
his included young and previously healthy persons who have
not been exposed to a hospital or health care environment
or antimicrobial therapy.
C
lose contact with patients who have C. difficile infection was
the only evident risk factor in some pediatric cases,
indicating the importance of direct person-to-person spread.
METRONIDAZOLE VS. VANCOMYCIN
S
ince the late 1970s, effective therapy with either
metronidazole or oral Vancomycin has been reported.
D
espite the dramatic increases in the incidence and
severity of C. difficile infection during the past decade,
these same two agents remain the treatments of choice.
METRONIDAZOLE VS. VANCOMYCIN
A
review of controlled trials of therapy for C. difficile
infection conducted before the year 2000 indicates that the
cumulative failure rates for treatment with metronidazole
and vancomycin were virtually identical.
S
ince 2000, substantially higher failure rates have been
reported for metronidazole therapy. Muschr DM 2005
METRONIDAZOLE VS. VANCOMYCIN
A
retrospective study also reported that the time to resolution of
diarrhea in patients who were treated with metronidazole was
significantly longer than in those treated with vancomycin.
(Wilcox MH 1995)
T
hese data sustain an ongoing debate as to whether vancomycin is
superior to metronidazole as initial therapy for C. difficile
infection.
METRONIDAZOLE VS. VANCOMYCIN
R
ecommendations from multiple professional societies
advocate vancomycin as the first-line agent for
patients with severe infection, since a small
increment in efficacy may be critical in patients with
fulminant disease.
METRONIDAZOLE VS. VANCOMYCIN
T
hese recommendations are supported by the findings
of a recent prospective, randomized, placebo-
controlled trial that compared metronidazole with
Vancomycin in 172 patients stratified according to
the severity of C. difficile infection.
METRONIDAZOLE VS. VANCOMYCIN
T
he two agents showed similar efficacy in mild infection,
although the response rate with vancomycin (98%) was
greater than that with metronidazole (90%, P = 0.36).
I
n patients with severe infection, vancomycin was
significantly more effective (97% vs. 76%, P = 0.02).
METRONIDAZOLE VS. VANCOMYCIN
M
etronidazole remains the first-line agent for treatment of mild
infection because of its lower cost and concerns about the
proliferation of vancomycin-resistant nosocomial bacteria.
O
n the basis of recent prospective, controlled trials, vancomycin
can now be recommended as the first-line agent in patients with
severe infection because of more prompt symptom resolution
and a significantly lower risk of treatment failure.
SUMMARY
S
ince the mid-1980s, metronidazole has been widely used in
preference to vancomycin, on the basis of studies that
suggested equivalency of effect and because of concerns over
excessive cost and selection of vancomycin-resistant bacteria.
M
ore-recent case series, however, have shown substantial
failure rates associated with this drug.
SUMMARY
T
wo direct comparisons have shown metronidazole to be
inferior to vancomycin in treating CDI, except in patients
with mild disease, although somewhat paradoxically, a
recent retrospective analysis has suggested that disease
specifically due to the so called epidemic or hypervirulent
strain (BI/NAP1/027) may not respond better to
vancomycin than to metronidazole.
OUR STUDY
AIM OF THE STUDY
T
o asses the use of Vancomycin vs. Metronidazole as
a first line treatment for Clostridium dificille
infections (CDI) and its affect on the length of
hospital stay in a community hospital measured by
days to solid stool.
METHODOLOGY
A
retrospective analysis of charts on patients
diagnosed with CDI at Sisters of Charity Hospital
and St. Joseph Hospital in the calendar years of
2008 to 2010 and their respective treatment
regimes.
DATA COLLECTION
INCLUSION CRITERIA
2
or more of the following:
A
ge > 60yo
W
BC’s > 15,000
T
emperature > 38.3 C
EXCLUSION CRITERIA
p
resence of suspected or proven life-threatening intra abdominal
complications, including a perforated viscous or bowel obstruction.
pregnancy.
history of allergy to either study drug.
or treatment with oral Vancomycin or parenteral or oral metronidazole
during the previous 14 days.
2
97 charts from both sites were reviewed.
S
ixty-One patients met clinical criteria for having moderate to
severe CDI. Outcomes were studied between patients who
received Vancomycin vs. metronidazole alone at admission.
Primary outcome was measured as days to sold stools. Secondary
outcomes were seen as length of hospital stay and incidence of
Vancomycin resistant Enterococcus (VRE).
RESULTS
4
1 females and 20 males
3
9 received Vancomycin and 22 received Metronidazole.
A
ge ranged from 28 to 92 years of age with Median of 76.
l
eucocyte count ranging from 3.6 to 40.2. with 2 patients from each group had
normal WBC”s on Admission.
M
ean WBC’s 21.43 in both groups
RESULTS CONT.
2
9 out of the 39 patients in the Vancomycin group had
been hospitalized in the previous 3 months to
admission (74%) as compared to 11 out of the 22 in
the Metronidazole group (50%).
TABLE 1
N Minimum Maximum Mean Std. Deviation
Age61 28 92 76.31 11.144
Leukocytosis 61 3.6 40.2 21.441 8.2259
Hospitalization last
3 mo.61 0 1 .66 .479
days to solid stool61 0 20 6.30 4.080
length of stay61 1 55 15.51 12.009
PRIMARY OUTCOME
T
he primary outcome of the days to solid stool showed
mean days to solid stool of 6.08 days for the
Vancomycin group and 6.68 days to solid days for
patients treated with Metronidazole. The analysis of
this comparison revealed a P value of 0.115 with
95% confidence interval of -2.794 – 1.585.
FIGURE 1
SECONDARY OUTCOME
S
econdary outcome of the length of stay showed that
the Vancomycin group stayed for a mean of 17.79
days as compared to 11.45 days for the
Metronidazole group. This difference revealed a P
value of 0.002 with a 95% confidence interval of the
difference of 0.94 – 12.587.
TABLE 2
Vanco/Flagyl N Mean Std. Deviation Std. Error Mean
days to solid stool V39 6.08 4.480 .717
F22 6.68 3.315 .707
length of stay V39 17.79 13.376 2.142
F22 11.45 7.836 1.671
F Sig. t df
Sig. (2-
tailed)
Mean
Difference
Std. Error
Difference
95% Confidence
Interval of the
Difference
Lower Upper
days to
solid stool
Equal
variances
assumed 2.566 .115 -.553 59 .582 -.605 1.094 -2.794 1.585
length of
stay
Equal
variances
assumed 10.086 .002 2.031 59 .047 6.340 3.122 .094 12.587
CO MORBIDITIES
S
ix disease processes were analyzed to account for
medical co morbidities in all patients. These were
Congestive Heart Failure, Atrial Fibrillation, Coronary
Artery Disease, Chronic Kidney Disease, Hypertension
and Diabetes Mellitus. Each Individual analysis
revealed a P value range from 0.259 to 0.774 with 95%
Confidence interval of the difference of -0.405 to 0.111.
VRE
N
ine out of the Thirty-nine patients (23%) treated with
Vancomycin were cultured positive for Vancomycin
resistant Enterococcus (VRE) .
DISCUSSION
O
ur analysis revealed there was no difference in the number of days to
solid stool and/or resolution of diarrhea. Further more our data
showed that people who were treated with Vancomycin stayed longer
by 6 days than the Metronidazole group.
A
lthough the 6 co morbidities we studied and analyzed did not show any
difference in the two groups. We did not analyze the severity of each of
these processes.
H
OWEVER…..
CONSIDERATIONS
I
t was evident from the beginning that 74% of the
Vancomycin group had been hospitalized in the past 3
months as compared to 50% of the Metronidazole group.
O
ur study did not include typing of the bacterial strain
especially the hypervirulent strain, NAP1, Ribotype 027
strain that has recently been reported for high failure rate
of both Vancomycin and Metronidazole.
B
ecause of the small number of patients, this study may not
have been powered sufficiently to detect a significant
difference between the treatments.
T
his leads us to the possible conclusion that patients in the
Vancomycin group may have been significantly more ill or
affected by a hypervirulent strain and thus were non
responsive to treatment.
B
ecause Metronidazole is less expensive and Vancomycin has the
potential to increase the prevalence of Vancomycin-resistant
organisms, Metronidazole has been commonly recommended as first-
line therapy .
S
uggestions have been made that Vancomycin therapy may be used for
severe or refractory cases, and 1 study revealed a trend toward lower
incidence of complications when Vancomycin was the initial therapy.
I
nterestingly, only 25% of infectious
disease physicians who were
recently surveyed use Vancomycin
as initial therapy for CDAD.
CHALLENGES IN CHS
p
hysician and nurses’ documentation of diarrhea was
poor.
M
ay be we need to involve the nurses aids in
documenting the BM.
FINAL MESSAGE
A
prospective clinical study with a high power which
might help to determine the risk benefit profile for
the use of Vancomycin, the risk of VRE and the
justification of the costs involved to prevent patients
complications.
THANK YOU