The efficacy of Vancomycin as a first line treatment of Clostridum Difficile and its effect on length of hospital stay.

1
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.

2
Introduction

• In 1935, Hall and OToole 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.

3
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.

4
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 100,000nearly three
  times the 1996 rate

5
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 1999and 3393 in 2006.

6
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.

7
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

8
Emergence of a virulent strain

• Toxins A and B are the major virulence
  determinants of C. difficile
• One of the regulatory genestcdCcodes for a
  negative regulator of toxin transcription.
• TcdC protein inhibits toxin transcription during
  the early, exponential-growth phase of the
  bacterial life cycle.

9
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.

10
(No Transcript)
11
Emergence of a virulent strain

• Another potential virulence determinant of
  NAP-1/027 strains is the production of a third
  toxinbinary toxinthat is unrelated to the
  pathogenicity locus that encodes toxins A and B.

12
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.

13
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.

14
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.

15
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

16
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.

17
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.

18
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.

19
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).

20
(No Transcript)
21
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.

22
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.

23
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.

24
Our study
25
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.

26
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.

27
Data collection

• Patient Demographics.
• Severity of infection.
• Laboratory Data.
• Days to solid stool
• Length of stay.
• Co morbidities.
• Recent hospitalization within the past 2 months.

28
Inclusion Criteria

• 2 or more of the following
• Age gt 60yo
• WBCs gt 15,000
• Temperature gt 38.3 C

29
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.

30

• 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).

31
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 WBCs on
  Admission.
• Mean WBCs 21.43 in both groups

32
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).

33
Table 1
  N Minimum Maximum Mean Std. Deviation
Age 61 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 stool 61 0 20 6.30 4.080
length of stay 61 1 55 15.51 12.009
34
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.

35
Figure 1
36
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.

37
(No Transcript)
38
Table 2
  Vanco/Flagyl N Mean Std. Deviation Std. Error Mean
days to solid stool V 39 6.08 4.480 .717
days to solid stool F 22 6.68 3.315 .707
length of stay V 39 17.79 13.376 2.142
length of stay F 22 11.45 7.836 1.671
39
    F Sig. t df Sig. (2-tailed) Mean Difference Std. Error Difference 95 Confidence Interval of the Difference 95 Confidence Interval of the Difference
    F Sig. t df Sig. (2-tailed) Mean Difference Std. Error 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
40
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.

41
vre

• Nine out of the Thirty-nine patients (23)
  treated with Vancomycin were cultured positive
  for Vancomycin resistant Enterococcus (VRE) .

42
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..

43
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.

44

• 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.

45

• 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.

46

• Interestingly, only 25 of infectious disease
  physicians who were recently surveyed use
  Vancomycin as initial therapy for CDAD.

47
Challenges in chs

• physician and nurses documentation of diarrhea
  was poor.
• May be we need to involve the nurses aids in
  documenting the BM.

48
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.

49
Thank you