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