ANTIBIOTIC ASSOCIATED COLILTS

BY SUPAWATANA PHAPUN 4 JUNE 2007

First report of AAC

* 1893 : John Hopkins Hospital by John Finney and Sir William Osler Describe the case of a young woman who died of a severe case of “ diphteric colitis ” after gastric surgery with the use of preoperative ATB

• 1970 : observation of Clindamycin associated pseudomembranous colitis • Demonstrate cytopathic effect of C

difficile-

derived toxin in animal model

DEFINITION

• Antibiotic associated colitis is an inflammation of the intestine that sometimes occur following antibiotic treatment and is caused by toxins produced by the bacterium most Clostridium

difficile

DESCRIPTION

following the use of antimicrobial -Diarrhea is due to change in the composition and function of the intestinal flora - Most common cause of diarrhea in hospitalized patients - No infectious agent is found in most of AAC - Clostridium difficile is frequently identified in patients with S&S of colitis

PREVALENCE

10-15 % of all hospitalized patients treated with ATB develop AAC - All group of ATB may cause AAC - Most common cause : Clindamycin, Ampicillin and Cephalosporins - Infection rate for C.

difficile

are reported to be around 10% after 2 wks of hospitalization , 50% after 4 wks

Risk factor of C.

diffiile

• Length of hospital stay • Older age • Greater severity of illness • Use of electrical rectal thermometer • Enteral tube feeding • Antacid treatment • Gastrointestinal surgery

Pathogenesis model for AAC

(

by C.difficile

) Event 1 : ATB Event 2 : C.difficile acquisition Asymptomatic C.

difficile

colonization Hospitalization C.

difficile

diarrhea Event 3 : Inadequate anamnestic IgG host response to toxin A of toxigenic C.

difficile

PATHOGENESIS Prolong use of ATB , biliary excretion Poor intestinal absorption , High induce Change in the composition and function of intestinal flora Decrease in the colonic anaerobic flora Carbohydrate and bile acid metabolism Osmotic or secretory diarrhea Overgrowth of opportunistic pathogens

Clostridium difficile

Clostridium difficle

Anaerobic gram positive rod - 15-20 % of AAC - Transmitted by the fecal-oral route - Normal flora of infants , isolated ~ 5% of healthy adults - 1 / 3 of asymtomatic or colonized , hospitalized patients

C.difficle

toxin A ( enterotoxin ) toxin B ( cytotoxin ) potent neutrophil chemoattractant toxin A , B disruption of epithelial-cell barrier function pseudomembrane formation diarrhea

PSEUDOMEMBRANOUS COLITIS

Lesions of C. difficile

pseudomembranous

• Initial 1-2 mm whitish yellow plaque • progress pseudomembrane form larger plaques then entried colon wall • Usually involve whole colon • 10 % spare rectum

Microscopic of pseudomembranous

• Mucosal contain necrotic leukocytes, fibrin, mucous , cellular debris • The endothelial is erodes and necrotic in focal area with neutrophil infiltration of the mucosa

SIGN AND SYMPTOM OF AAC

• The cardinal symptom is diarrhea • Mild diarrhea to Fulminant colitis • Common present with loose stools • Minimal signs of colitis • No constitutional symptoms • The diarrhea promptly responds to supportive measures and withdrawal of ATB

• Severity age , comorbidity , host’s immune response , use of antiperistaltic agents • Commonly develops during ATB use • May appear as late as 8 wks after discontinuation of ATB

Clostridium difficile infection ( CDAD)

• Mucous ,foul smell diarrhea • Rare frank bleeding • Cramps and tenesmus • Constitutional symptoms are common : N/V dehydration , low grade fever • Abd : soft ,increase bowel sounds ,mild tenderness at LLQ

• 20 % adynamic ileus : cessation of stool pasage • Stool Occult blood and leukocytes are frequently detected • Leukocytosis • In severe case,

toxic megalon

may occur

DIAGNOSIS AND INVESTIGATION

• Considered in patient recently treat with ATB • Present with new onset of diarrhea • CBC : leukocytosis , stool exam : leukocyte • Film abdomen : Adynamic ileus ~ 20% of case

Diagnosis of AAC (C.difficile)

(CDAD)

• 1

)

Diarrhea (> 3 unformed stools per 24 hr for > 2 days ) with no others cause • 2

)

Toxin A or B detected in the stool by stool culture , or Pseudomembrane seen in colon

* Diagnostic test for AAC ( Clostridium difficile ) - Stool culture for C , difficile - Most sensitive test , specific 71-90% - Cell culture Cytotoxin - Highly specific , not test on stool sensitive as stool culture - ELIZA - Rapid , not sensitive as stool culture - Latex test - Rapid , less sensitive and specific than other tests -Colonoscope or Sigmoidoscopy Highly specific if Pseudomembrame are seen No single test has high sensitivity , high specificity and rapid turnaround

TREATMENT (

from American Collage of gastroenterology)

1

) Discontinue ATB

2

) Initiate supportive therapy. Prophylactic ATB therapy should not be given routinely

3

) Once the diagnosis of C.difficile

diarrhea is confirmed and specific therapy is indicated , metronidazole given orally is preferred

4 )

If diagnosis is highly and the patient is seriously ill ,

metronidazole

may be give empirically before the diagnosis is established

5

)

Vancomycin

given orally is reserved for the following condition : a. the patient has failed therapy with metronidazole

b. the patient ,s organism is resistant to metronidazole c. the patient is allergic , cannot tolerate metronidazole , or is being treated with ethanol containg solutions d. the patient is either pregnant / 10 years child under

• e. the patient is critically ill because of C.difficile associated diarrhea or colitis • f. There is evidence suggest the diarrhea is caused by S.aureus

*expect Rx outcomes base on RCT of oral therapy CDAD Tx or Med Dose and Duration Expected resolution of diarrhea ( % ) Expected recurrence ( % ) - Discontinuation of ATB 21 unknown - Metronidazole - Vancomycin 250 mg qid x 10 d 500 mg qid x 10 d 500 mg qid x 10 d 500 mg qid x 10 d 125 mg qid x 10 d 95 94 94 100 86 5 17 17 15 33 - Fusidic acid - Bacitracin 25 , 125 mg qid x 10 d 500 mg qid x 10 d 000 mg qid x 10 d 75 93 80 unknown 28 42

* Vancomycin as first treat is discouraged because it may increase the incidence of Vancomycin resistance in other nosocromial bacteria , ex.Enterococci

• response rate > 90% • should not deemed a failure until a drug have been given for at least 6 days

RECURRENT CDAD

15-25% - Condition identified as potential marker for recurrent: - CRF - Mark leukocytosis - Continued ATB use - Re-treatment with metronidazole is recommended for first recurrences -

• No standard for multiple recurrences

• 1

. Add vancomycin , Meteronidazole , or bacitracin followed by the yeast :Saccharomyces Boulardii or Lactobacilluss GG - Lactobacillus GG : improve intestinal immunity by increase Ig G and Ig A at the intestinal mucosal level

• Saccharomyces boulardii (a live, non pathogenic yeast ) • Treat of AAC (C.difficile) by binding to the glycoprotein receptor site for toxin A at the intestinal brush border Resist colonization Restore normal flora

2.

Vancomycin in tapering dose over 21 day then followed by anion-exchange binding resin cholestyramine

3. -

combined treatment with Vancomycin and rifampicin ( Vancomycin 125 mg qid , days ) Rifampicin 300 mg bid for 10

FUMINANT COLITIS

• Most difficult treatment • Develop toxic megacolon or ileus • Often do not have diarrhea • sepsis • acute abdomen ( with or without toxic megacolon ) • include obstruction , ileus , , ascites bowel-wall thickening • Often leukocytosis ( > 25 , 000 )

• TREATMENT • Vancomycin via NG and retaintion enema plus Metronidazole IV • Surgery is indicate for • Perferation • No response of medical • Surgical mortality > 50 %

• Prognosis : Mortality 0.6-3.5 % • Prevention and control 1. Prevent of transmission ex : Glove 2. Reduce risk ex : Restrict use of ATB

KLEBSIELLA OXYTOCA

• N ENGL J DEC 7 2006 • Antibiotic associated hemorrhagic colitis • Which Clostridium difficile is absent • Suggest a role of Klebsiella oxytoca

METHOD

• Studies 22 pts : AAHC, negative C.difficile

• Underwent colonoscopy • Culture for K.oxytoca

• Culture stool of 385 healthy for K.oxytoca

• In vivo animal model

RESULT

• 6 had finding on colonoscope: AAHC • 5 in 6 pts : Culture positive for K .oxytoca

• All 5 were receive peniciilin, 2 pts also taking NSAID • K.oxytoca was found 1.6

% of the healthy

• In animal model • Rat receive amoxy-clavulonic +K.oxytoca

-> AAHC • Rat receive only amoxy-clavulonic -> no AAHC

• K.oxytoca • Gram negative bacterium • Found in AAHC • 1.6 % in healthy people • Produce cytotoxin inducing cell death

CLINICAL MENIFESTATION

• AAHC : Negative for C.difficile

• Mainly in young ( C .difficile : oldder) • Colitis was segmental mainly in Rt side of colon ,usually spare rectum • Leukocytosis • Elevate CRP

• Colonoscope finding : • Mucosa edema ,mucosa hemorrhage may have erosion longitudinal ulceration

TREATMENT

• When ATB discontinuous all patients complete recovery

THANK YOU