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

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 with 2 patients from each group had normal WBC”s on Admission.  Mean WBC’s 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 NMinimumMaximumMeanStd. Deviation Age Leukocytosis Hospitalization last 3 mo days to solid stool length of stay

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 with 95% confidence interval of –

FIGURE 1

SECONDARY OUTCOME  Secondary outcome of the length of stay showed that the Vancomycin group stayed for a mean of days as compared to days for the Metronidazole group. This difference revealed a P value of with a 95% confidence interval of the difference of 0.94 –

TABLE 2 Vanco/FlagylNMeanStd. DeviationStd. Error Mean days to solid stoolV F length of stayV F

FSig.tdf Sig. (2- tailed) Mean Difference Std. Error Difference 95% Confidence Interval of the Difference LowerUpper days to solid stool Equal variances assumed length of stay Equal variances assumed

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 to with 95% Confidence interval of the difference of to

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