T H E E F F I C AC Y O F VA N C O M Y C I N A S A
F I R S T L I N E TR E ATM E N T O F
CLOSTRIDUM DIFFICILE AND ITS
EFFECT ON LENGTH OF HOS PI TAL
S T AY.
Medhat Barsoom, M.D. , Kosta Botsoglou, M.D. , Orooj Khan, M.D., Gopichand Pendurti, M.D.
Michael Hocko, M.D.
INTRODUCTION
 In 1935, Hall and O’Toole first isolated a gram-positive,
cytotoxin-producing anaerobic bacterium from the stool of healthy
neonates.
 Named Bacillus difficilis to reflect the difficulties they encountered
in its isolation and culture.
 No 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.
 Our study explores disease severity and response to therapy.
INCIDENCE AND SEVERITY
 During the 1990s, the reported incidence of C. difficile infection in
the United States at 30 to 40 cases per 100,000 people.
 In 2001, this number rose to 50 per 100,000
 In 2005 it rose to 84 per 100,000—nearly three times the 1996 rate
INCIDENCE AND SEVERITY
 The disease has been presenting with increasing severity and fatal
infection.
 In 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
 Similar increases have been reported in the United States.
 McDonald et al. showed that isolates of a single strain accounted
for at least half the isolates from five facilities
 This epidemic strain was initially named BI
 Currently referred to as North American Pulsed Field type1
(NAP1) and PCR ribotype 027 or NAP-1/027.
EMERGENCE OF A
VIRULENT STRAIN
 The 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
 Toxins A and B are the major virulence determinants of C. difficile
 One of the regulatory genes—tcdC—codes for a negative regulator
of toxin transcription.
 TcdC protein inhibits toxin transcription during the early,
exponential-growth phase of the bacterial life cycle.
EMERGENCE OF A
VIRULENT STRAIN
 NAP-1/027 strains carry deletion mutations in the tcdC
inhibitory gene.
 This 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
 Another 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.
 However, 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
 This included young and previously healthy persons who have not
been exposed to a hospital or health care environment or
antimicrobial therapy.
 Close 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
 Since the late 1970s, effective therapy with either metronidazole or
oral Vancomycin has been reported.
 Despite 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.
 Since 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)
 These data sustain an ongoing debate as to whether vancomycin is
superior to metronidazole as initial therapy for C. difficile infection.
METRONIDAZOLE VS.
VANCOMYCIN
 Recommendations 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
 These 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
 The 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).
 In patients with severe infection, vancomycin was significantly
more effective (97% vs. 76%, P = 0.02).
METRONIDAZOLE VS.
VANCOMYCIN
 Metronidazole 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.
 On 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
 Since 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.
 More-recent case series, however, have shown substantial failure
rates associated with this drug.
SUMMARY
 Two 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
 To 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
 Patient Demographics.
 Co morbidities.
 Severity of infection.
 Recent hospitalization within
 Laboratory Data.
the past 2 months.
 Days to solid stool
 Length of stay.
INCLUSION CRITERIA
 2 or more of the following:
 Age > 60yo
 WBC’s > 15,000
 Temperature > 38.3 C
EXCLUSION CRITERIA
 presence 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.
 297 charts from both sites were reviewed.
 Sixty-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
 41 females and 20 males
 39 received Vancomycin and 22 received Metronidazole.
 Age ranged from 28 to 92 years of age with Median of 76.
 leucocyte count ranging from 3.6 to 40.2. with 2 patients from
each group had normal WBC”s on Admission.
 Mean WBC’s 21.43 in both groups
RESULTS CONT.
 29 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
Age
Leukocytosis
Hospitalization last
3 mo.
days to solid stool
length of stay
Minimum
Maximum
Mean
Std. Deviation
61
28
92
76.31
11.144
61
3.6
40.2
21.441
8.2259
61
0
1
.66
.479
61
0
20
6.30
4.080
61
1
55
15.51
12.009
PRIMARY OUTCOME
 The 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
 Secondary 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
days to solid stool
V
F
length of stay
V
F
N
Mean
Std. Deviation
Std. Error Mean
39
6.08
4.480
.717
22
6.68
3.315
.707
39
17.79
13.376
2.142
22
11.45
7.836
1.671
95% Confidence
Interval of the
Difference
Sig. (2F
days to
Equal
solid stool
variances
assumed
length of
Equal
stay
variances
assumed
Sig.
t
tailed)
df
Mean
Std. Error
Difference Difference
Lower
Upper
2.566
.115
-.553
59
.582
-.605
1.094
-2.794
1.585
10.086
.002
2.031
59
.047
6.340
3.122
.094
12.587
CO MORBIDITIES
 Six 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
 Nine out of the Thirty-nine patients (23%) treated with
Vancomycin were cultured positive for Vancomycin resistant
Enterococcus (VRE) .
DISCUSSION
 Our 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.
 Although 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.
 HOWEVER…..
CONSIDERATIONS
 It 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.
 Our 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.
 Because of the small number of patients, this study may not
have been powered sufficiently to detect a significant
difference between the treatments.
 This 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.
 Because 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 .
 Suggestions 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.
Interestingly, only 25% of infectious
disease physicians who were recently
surveyed use Vancomycin as initial therapy
for CDAD.
CHALLENGES IN CHS
 physician and nurses’ documentation of diarrhea was poor.
 May 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