SENIOR RESEARCH PROJECT

The Increased Use of Broad Spectrum Antimicrobials and the Increased Incidence

of Clostridium difficile Infection (CDI)

Maisara Rahman, MDSuzette Jumamil MDSoheil Samvatian MDTrena Rich, MSN, ARNP, CIC

BACKGROUND Clostridium difficile infection (CDI) is becoming one of the

most common healthcare associated infection (HAI) in the United States [1]

Emergence of new strain of C. difficileC. difficile (BI/NAP1 (North (BI/NAP1 (North American Pulse type 1)/027) is associated with American Pulse type 1)/027) is associated with increased virulence increased virulence and severity of CDI [13]

Variety of coalescing causes increase incidence of CDI Increasing age of US population Increase use of antimicrobials Inadequate CDI infection control measures delayed

diagnosis, poor hand hygiene, environmental cleaning [1,2,3,4,5]

BACKGROUND (CONT’D)

CDI is a frequent cause of morbidity and mortality 2.3% (overall unadjusted) 6.1% ( ICU CDI) 25% Mortality rate in elderly patients who

are frail

CDI causes increased hospital stays an average of 3.6 days Cost > 1.1 billion dollars/ year

States with BI/NAP1/027 strain of States with BI/NAP1/027 strain of C. C. difficiledifficile (N=38), November 2007 (N=38), November 2007

DC

PRAKHI

www.cdc.gov/ncidod/dhqp/id_Cdiff)_data.html

EPIDEMIOLOGY

•Changing rapidily Changing rapidily and has been and has been marked by marked by significant increase significant increase in incidence and in incidence and and severityand severity

States with BI/NAP1/027 strain of States with BI/NAP1/027 strain of C. C. difficiledifficile (N=40), October 2008 (N=40), October 2008

DC

PRAK

HI

There is a There is a common epidemic common epidemic HVS that HVS that continues to be continues to be reported from reported from hospitals in an hospitals in an exapanding # exapanding # statesstates

Medical Center C. difficile Rates 2005-2009

CDI Rates per 10,000 discharges

0.00

0.50

1.00

1.50

2.00

2.50

3.00

3.50

4.00

4.50

5.00

HAI Community

2005

2006

2007

2008

2009

OBJECTIVEOBJECTIVE

To Determine the incidence , risk factors, and outcomes of CDI as it

relates to the use of broad spectrum antimicrobial agents at a Riverside

County Regional Medical Center

HYPOTHESISHYPOTHESIS

The increased rates and severity The increased rates and severity of CDI is due to the increased use of CDI is due to the increased use

of a variety of broad spectrum of a variety of broad spectrum antimicrobial agents. antimicrobial agents.

Color-enhanced scanning electron micrograph by McCarthy and CavanghColor-enhanced scanning electron micrograph by McCarthy and Cavangh

Key Points on Key Points on C. difficileC. difficile Motile, Motile, gram positive gram positive

spore forming spore forming bacillusbacillus

Obligate anaerobeObligate anaerobe Ubiquitous in natureUbiquitous in nature Produce ToxinsProduce Toxins : :

EnterotoxinEnterotoxin ( (Toxin A)Toxin A)

Cytotoxin Cytotoxin ( Toxin B)( Toxin B)

Binary ToxinBinary Toxin ( ( BI/NAP1/027BI/NAP1/027virulent-virulent-strainstrain))

Microscopically: long, irregular, Microscopically: long, irregular, with sub-terminal non-staining with sub-terminal non-staining sporesspores

BI/NAP1/027 strain of BI/NAP1/027 strain of C. difficileC. difficile

Deletion in the pathogenicityDeletion in the pathogenicity locus gene, locus gene, tcdC,tcdC, A deletion in gene A deletion in gene tcdCtcdC is a proposed negative regulator of the is a proposed negative regulator of the

productionproduction of toxins A and Bof toxins A and Bthat might result in increased that might result in increased concentration of toxins A & B concentration of toxins A & B

Key Points on Key Points on C. difficileC. difficile (cont’d)(cont’d)

It forms part of the normal intestinal flora in children less than one year old

Associated with a spectrum of diseases ranging from asymptomatic colonization to severe diarrhea, toxic megacolon, sepsis and death

MODE OF TRANSMISSIONMODE OF TRANSMISSION

Transmission is via:Transmission is via: Fecal-oral routeFecal-oral route Can occur from patient to patient from Can occur from patient to patient from

contaminated environment (i.e., hands contaminated environment (i.e., hands of HCW's) of HCW's)

C. difficileC. difficile spores are more resistant to a spores are more resistant to a variety of chemical disinfectants variety of chemical disinfectants

C. difficile C. difficile spores can survive up to 5 spores can survive up to 5 monthsmonths

Pathogenicity Starts With Pathogenicity Starts With Disruption of Normal Disruption of Normal

Protective Colonic FloraProtective Colonic Flora

Toxins Bind to Colonic Toxins Bind to Colonic Epithelial Cells Epithelial Cells causingcausing

Mucosal injury, Inflammation, Mucosal injury, Inflammation, Cytoskeletal damageCytoskeletal damage

Antibiotics disrupt flora

                                                                                                                                                                            

Followed By Ingestion of C. difficile Spores

Uncontrolled Proliferation & Colonization With Uncontrolled Proliferation & Colonization With Toxigenic Toxigenic C.D.IC.D.I

Release of Toxin A (enterotoxin )/ B Release of Toxin A (enterotoxin )/ B (cytotoxin)(cytotoxin)

Copyright ©2004 Canadian Medical Association or its licensors

Poutanen, S. M. et al. CMAJ 2004;171:51-58

Pathogenesis of Clostridium difficile-associated diarrhea in adults

Endoscopic View of Endoscopic View of C. difficileC. difficile

Pathology of Clostridium difficile 

RAISED ADHERENT YELLOW PLAQUES VARY IN SIZE FROM 2 MM TO 10 MM

VISIBLE ON COLONIC MUCOSA

More severe lesion shows aninflammatory infiltrate and pseudomembrane

PSEUDOMEMBRANOUS COLITIS: Characteristic manifestation of full-blown Clostridium difficile colitis

Classic pseudomembranes are visible as raised yellow plaques ranging from 2-10 mm in diameter and scattered over the colorectal mucosa

Endoscopic visualization of Courtesy of Gregory Ginsberg, MD, University of Pennsylvania/ Source: www.uptodate.com

Barium Enema Result

Pseudomembranous colitis: Demonstrating typical serrated appearance from trapped barium between the edematous mucosal folds and the plaque- like membranes

STUDY METHODSSTUDY METHODS A Retrospective study of 69 patients with A Retrospective study of 69 patients with

CDI who had a diagnostic code for CDI who had a diagnostic code for C. difficileC. difficile colitis at the time of hospital discharge and colitis at the time of hospital discharge and all patients who otherwise had positive all patients who otherwise had positive cytotoxin assays or pathology reports cytotoxin assays or pathology reports (January 2007-April, 2009)(January 2007-April, 2009)

A detailed Computer directed-chart review A detailed Computer directed-chart review through the RCRMC Infection Prevention & through the RCRMC Infection Prevention & Control Data was analyzed. Control Data was analyzed.

No children were included in this study.No children were included in this study.

STUDY METHODS (cont’d)

Data reviewed included:Data reviewed included: Admitting History and Physical Admitting History and Physical

examinationsexaminations Daily Progress notesDaily Progress notes RCRMC Pharmacy records for RCRMC Pharmacy records for

antimicrobials used on each patient & antimicrobials used on each patient & computerized review of all written computerized review of all written antimicrobials usage at RCRMC from 12/08-antimicrobials usage at RCRMC from 12/08-3/09 3/09

Discharge summary reportsDischarge summary reports

DATA ANALYSIS:DATA ANALYSIS: DemographicsDemographics

Demographics: Age Range

0 5 10 15 20

<19

20-29

30-39

40-49

50-59

60-69

70-79

80-89

90-100

Co-Morbidities

0

5

10

15

20

25

Nutrition

0

5

10

15

20

25

30

35

40

TPN Tube Feedings Regular Diet

Antimicrobials Taken Up to 8 Weeks Prior to Symptoms

0

5

10

15

20

25

30

35

40

45

50

Bet

a la

ctam

s

Car

bape

nem

s

Cep

halo

spor

ins FQ

Ant

ifung

als

Bro

adS

pect

rum

Other Medications Up to 8 Weeks of Symptom Onset

0

2

4

6

8

10

12

14

16

18

20

PP

I

H2

Blo

cker

s

Oth

er A

ntac

ids

Cor

ticos

tero

ids

Cou

mad

in

Ant

idia

rrhe

al

Surgeries

0

2

4

6

8

10

12

14

16

18

20

Prior to 6 w eeks Abdominal Colectomy due to C diff

Clinical Symptoms/Findings

0

10

20

30

40

50

60

Dia

rrhe

a

Blo

ody

Dia

rrhe

a

Ileus

CT

evi

denc

e of

Col

itis

Abd

omin

al P

ain

Co-

infe

ctio

n

Fev

er

No

Dia

rrhe

a

No

docu

men

tatio

n

Lab Analysis

0

10

20

30

40

50

60

70

80

Treatment for Laboratory Confirmed C. difficile

0

5

10

15

20

25

30

35

40

45

50

PO Flagyl IV Flagyl PO Vanco IV Vanco Bactrim None

Select Antimicrobial Usage Select Antimicrobial Usage All ICUs Dec 08- Mar 09All ICUs Dec 08- Mar 09

0

50

100

150

200

250

300

Antip

sudom

onal

PC

N

Antis

taphylo

coccal

PC

N

Flu

oro

quin

olo

nes

Trim

eth

/Sulfa

meth

Vanco-P

O

Vanco-I

V

NHSN Mean

08-Dec

09-Jan

09-Feb

09-Mar

Riverside County Regional Medical Center Infection Prevention and Control & Pharmacy Departments, and the Centers for Disease Control & Prevention, National Healthcare Safety

Network Program

Select Antimicrobial Usage Select Antimicrobial Usage All Non- ICUs Dec 08- Mar 09All Non- ICUs Dec 08- Mar 09

0

20

40

60

80

100

120

140

Ant

ipsu

dom

onal

PC

N

Ant

ista

phyl

ococ

cal

PC

N

Flu

oroq

uino

lone

s

Trim

eth/

Sul

fam

eth

Van

co-P

O

Van

co-I

V

NHSN Mean

08-Dec

09-Jan

09-Feb

09-Mar

Analysis of Antimicrobial Utilization

Compared to the National Healthcare Safety Network (NHSN), RCRMC is in the 97th percentile in prescribing Antipseudomonal Penicillins With a With a p-value of (0.000)p-value of (0.000)

RCRMC is in the 65th percentile of NHSN in prescribing Fluoroquinolones.

Retrospective Case-Control Study of the Effect of Fluoroquinolone on CDAD (Level II-2 Evidence)

Study Risk Factor

Odds Ratio 95% CI Comments

McCusker

2003

Univ. of Maryland

Fluoroquinolones 12.7 2.6. to 61.1 Cases (n=30) VS controls (n=60)

Exposure to Fluoroquinolones was

an independent risk factor

Restricted use of levofloxacin and

other implicated antibiotics may be

required to control outbreak

Clindamycin 0.4 0.1 to 1.5

Piperacillin/

tazobactam

2.2 0.5 to 9.1

Cephalosporins 0.6 0.2 to 1.7

McCusker et al., Emerg Infect Dis. 2003 June; 9(6):730-3

SummationSummation

Based on our data analysis the increased Based on our data analysis the increased rates and severity of CDI is caused byrates and severity of CDI is caused by The increased use or over use of broad The increased use or over use of broad

spectrum antibioticsspectrum antibiotics Not following current treatment guidelines for Not following current treatment guidelines for

CDICDI Lack of adherence in following infection Lack of adherence in following infection

prevention & control practicesprevention & control practices

All of the above can increase the cost of healthcare All of the above can increase the cost of healthcare deliverydelivery

CONCLUSIONCONCLUSION

The Data supports our hypothesis The Data supports our hypothesis that there is an increase in the that there is an increase in the incidence of CDI secondary to incidence of CDI secondary to

the increased use of broad the increased use of broad spectrum antimicrobial agentsspectrum antimicrobial agents

Recommendations

Implement a new system with Pharmacy Implement a new system with Pharmacy and Physicians, for the monitoring and and Physicians, for the monitoring and control of antimicrobial utilizationcontrol of antimicrobial utilization

Reinforce the use of the current “Antibiotic Reinforce the use of the current “Antibiotic Automatic Stop System” Automatic Stop System”

Reduce the use of prophylaxis Reduce the use of prophylaxis antimicrobial agentsantimicrobial agents

Decrease the use of empiric antimicrobial Decrease the use of empiric antimicrobial agentsagents

Recommendations

Hand Hygiene with Hand Hygiene with soap and water onlysoap and water only

Spores only killed by Spores only killed by Sodium hypochlorite Sodium hypochlorite (bleach), (bleach), not killed not killed by by alcohols or alcohols or detergentsdetergents

Follow Transmission Follow Transmission based isolation based isolation precautionsprecautions

Think it about it…..

If you have a patient with albumin levels that are trending downward, would you want to monitor the use of antimicrobial agents???

Consider patients on PPI & H2-Blockers, at a higher risk for CDI

Bartlett JG. Antibiotic-associated diarrhea. N Engl J Med 2002;346:334-339. [2. Bartlett JG, Onderdonk AB, Cisneros RL, Kasper DL. Clindamycin-associated colitis due to a

toxin-producing species of Clostridium in hamsters. J Infect Dis 1977;136:701-705. [3. Bartlett JG, Chang T, Taylor NS, Onderdonk AB. Colitis induced by Clostridium difficile. Rev

Infect Dis 1979;1:370-378. ] 4. Taylor NS, Bartlett JG. Partial purification and characterization of a cytotoxin from

Clostridium difficile. Rev Infect Dis 1979;1:379-385. [5. Taylor NS, Thorne GM, Bartlett JG. Comparison of two toxins produced by Clostridium

difficile. Infect Immun 1981;34:1036-1043. 6. Johal SS, Hammond J, Solomon K, James PD, Mahida YR. Clostridium difficile associated

diarrhoea in hospitalized patients: onset in the community and hospital and role of flexible sigmoidoscopy. Gut 2004;53:673-677. 

7. Johnson S, Samore MH, Farrow KA, et al. Epidemics of diarrhea caused by a clindamycin-resistant strain of Clostridium difficile in four hospitals. N Engl J Med 1999;341:1645-1651. [

8. Rubin MS, Bodenstein LE, Kent KC. Severe Clostridium difficile colitis. Dis Colon Rectum 1995;38:350-354. [

9. Kyne L, Hamel MB, Polavaram R, Kelly CP. Health care costs and mortality associated with nosocomial diarrhea due to Clostridium difficile. Clin Infect Dis 2002;34:346-353. 

10. Archibald LK, Banerjee SN, Jarvis WR. Secular trends in hospital-acquired Clostridium difficile disease in the United States, 1987-2001. J Infect Dis 2004;189:1585-1589. [

11.McDonald LC, Banerjee S, Jernigan DB. Increasing incidence of Clostridium difficile-associated disease in U.S. acute care hospitals, 1993-2001. In: Proceedings of 14th Annual Scientific Meeting of the Society for Healthcare Epidemiology

12.Dallal RM, Harbrecht BG, Boujoukas AJ, et al. Fulminant Clostridium difficile: an underappreciated and increasing cause of death and complications. Ann Surg 2002;235:363-372. [

13. 13. L. Clifford McDonald, M.D., George E. Killgore, Dr.P.H., Angela Thompson, M.M.Sc., Robert L. Clifford McDonald, M.D., George E. Killgore, Dr.P.H., Angela Thompson, M.M.Sc., Robert C. Owens, Jr., Pharm.D., Sophia V. Kazakova, M.D., M.P.H., Ph.D., Susan P. Sambol, M.T., C. Owens, Jr., Pharm.D., Sophia V. Kazakova, M.D., M.P.H., Ph.D., Susan P. Sambol, M.T., Stuart Johnson, M.D., and Dale N. Gerding, M.D. An epidemiology toxin gene variant strain of Stuart Johnson, M.D., and Dale N. Gerding, M.D. An epidemiology toxin gene variant strain of C. difficle. C. difficle. Abstract. Philadelphia.Abstract. Philadelphia.

References

END!

Updated SHEA-IDSA recommendations for the treatment of CDI stratified by disease incidence and severity

Clinical definition Supportive clinical data Recommended treatment

Strength

Initial episode Mild or moderate

WBC < 15,000 cells/mm2

Cr level < 1.5 x prior CDIOral Metronidozale 500 mg TID x 10-14 days

A-I

Initial episode Severe

WBC > 15,000 cells/mm2

Cr level > 1.5 prior CDIOral Vanco 125 mg QID x 10 n-14 days

B-I

Initial episode complicated

Hypotension or shock, mega colon, perforation, severe colitis on CT scan

If no complete ileus:Vanco 500 mg QID Oraly or via NGT and/or Metronidazole 500mg -750 mg IV q 8 hrs

C-II

First recurrent Same as for initial episode

A-II

Second recurrence or further recurrence

Oral Vancomycin taper with or without Pulse dosing

B-II

Adapted from the Latest Advances in Closridium difficile, 45th IDSA and 47th ICAAC meeting

Treatment Options for

C. difficile infection

Jaber et al Am J Gastroenterol 2008; 103:3195–3203