c.difficile

MANAGEMENT OF CLOSTRIDIUM DIFFICILE INFECTION (CDI):

A TOPIC REVIEW

Tauhid Ahmed Bhuiyan, PharmDPGY-1 Resident (Year 1)

Pharmacy Practice Residency

King Faisal Specialist Hospital and Research Center (KFSHRC) is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. (UAN# 0833-0000-14-039– L01-P, 0833-0000-14-039– L01-T)

http://www.acpe-accredit.org/pdfwebtool/Common/images/logo/ACPE_489_469.jpg

Objectives

Familiarize with the background, epidemiology, and general overview of CDI

Identify key elements for diagnosing CDI

Discuss contemporary management strategies of CDI

Recognize key infection control measures as well as understand pharmacists’ role in prevention of the disease

I do not have financial relationship and no actual or potential conflict of interest in relation to this activity

Background Gram-positive, anaerobic, spore forming organism, first isolated in 1935

Found in soil, human and animal feces, and food products (e.g. processed meats)

Produce two types of toxin Toxin A Toxin B (primary toxin responsible for CDI)

Most common causes of hospital acquired infection along with methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococci (VRE)

Common cause of infectious diarrhea in hospitals and long-term care (LTC) settings

Khanna S. et al. Ther Adv Gastroenterol 2014; 7(2):72-86

Case Definition of CDI

An episode of CDI is defined as: Presence of diarrhea

Passage of ≥ 3 unformed stool in 24 hours or fewer consecutive hours

Positive stool test result for presence of toxigenic C. difficile or its toxins or histopathologic findings demonstrating pseudomembranous colitis

Rarely (<1% of cases), a symptomatic patient will present with ileus and colonic distension with minimal or no diarrhea

Cohen SH. et al. Infect Control Hosp Epidemiol 2010; 31(5):431-455

Epidemiology

C. difficile is recognized as: Primary pathogen responsible for antibiotic-associated colitis 15%-25% of cases of nosocomial antibiotic-associated diarrhea

Disease burden: 20%-30% of cases of antibiotic-associated diarrhea The cost attributed to CDI in the US varies from $2470.00−$3669.00

per episode

According to Center for Disease Control (CDC) C. difficile causes diarrhea links to 14,000 deaths each year

Cohen SH. et al. Infect Control Hosp Epidemiol 2010; 31(5):431-455Silva M. Einstein 2012; 10(1):105-9

Clostridium Difficile Infection. www.cdc.gov

Surveillance Definition Community onset, healthcare facility-associated (CO-HCFA)

Symptom onset in the community or within 48 hours of hospital admission + discharge from healthcare facility within the previous 4 weeks

Hospital onset, healthcare facility-associated (HO-HCFA) Onset of symptoms >48 hours after admission or <4 weeks after discharge from health care

facility

Intermediate Symptom onset occurs in the community between 4-12 weeks after discharge from a hospital

Community associated Not discharged from healthcare facility in the previous 12 weeks


Natural History

CDAD: Clostridium Difficile Associated DiarrheaHCW: Health Care Worker http://www.clevelandclinicmeded.com/medicalpubs/

diseasemanagement/infectious-disease/clostridium-difficile-infection

Pathogenesis

http://www.cdiff-support.co.uk/about.htm

Etiology

Exogenous Transmission through

Fecal-oral route Person to person spread Fomites Hospital equipment or furniture

Endogenous Small amount found in natural flora in the small intestine Exposure to antibiotic suppresses natural flora “niche” for C.

difficile to flourish


Risk Factors

Major risk factor Likely risk factor

Age >64 years Immune compromised (e.g. AIDS, cancer)

Recent hospitalization Consumption of contaminated food products

Increased length of hospital stay Inflammatory bowel disease

Long term care (LTC) facility residence Use of proton-pump inhibitors

Antibiotic exposure Gastrointestinal endoscopic procedures

Contact with active carriers

Khanna S. et al. Mayo Clin Proc. 2012; 87(11):1106-1117

Complications of Severe CDI

Dehydration

Electrolyte disturbances

Hypoalbuminemia

Toxic megacolon

Hypotension

Renal Failure

Systemic inflammatory response syndrome (SIRS)

Bowel perforation


Diagnosis

Clinical Presentation

Symptomless carriage—mild or moderate diarrhea–fulminant and sometimes fatal pseudomembranous colitis

Watery diarrhea is the cardinal symptom accompanied by Lower abdominal pain and cramping (20%-33%) Fever (30%-50%) Leukocytosis (50%-60%)

Patient with severe disease may develop colonic ileus or toxic dilatation with minimal or no diarrhea


Assessment of Severity

Clinical definition Supportive clinical data

Mild to moderate Leukocytosis with WBC< 15,000

cells/μL Serum Creatinine (Scr) < 1.5 X baseline

Severe Leukocytosis with WBC ≥ 15,000

cells/μL Scr ≥ 1.5 X baseline

Severe-complicated Hypotension or shock, ileus, toxic megacolon


Laboratory Investigations

Confirmatory test Stool examination

Other test for disease severity Complete blood count (CBC) Electrolytes Albumin levels Serum lactate levels

Stool Tests

Test Sensitivity (%)

Specificity (%) Advantages Disadvantages

Cell Cytotoxicity Assay 80-90 99-100Considerably high sensitivity and specificity; considered as gold standard

Takes 24-48 hr to complete; requires tissue culture facility; cost; detects only toxin B

Enzyme Immunoassay (EIA) Toxin test 65-85 95-100 Fast (2-6 hr), easy to

perform, high specificityLack of sensitivity than cell cytotoxicity assay; detects both toxin A and B

Stool Culture 90-100 98-100 Most sensitive, essential for epidemiologic studies

Takes 2-5 days to complete; labor intensive; not specific for toxin-producing bacteria

Latex Agglutination Assay for Glutamate Dehydrogenase (GDH)

58-68 80-96 Fast, inexpensive, easy to perform

Poor sensitivity and specificity needed to establish diagnosis; requires confirmatory test

PCR assay toxin gene detection 92-97 100

Excellent sensitivity and specificity compared with cytotoxin assay

Not in routine practice

Aberra FN. et al. Clostridium Difficile Colitis. www.medscape.com. March 17, 2014

Imaging

Endoscopy Not generally used in making initial diagnosis Used in high suspicion despite normal stool tests or ileus

secondary to CDI Findings of pseudomembranes are not specific but sensitive to

CDI diagnosis

Computed tomography (CT) Suggestive of CDI include bowel wall thickening, peri-colonic

stranding Dilated colon may indicate severe-complicated CDI


Management

Goals of Therapy

Short term: Resolution of signs and symptoms of CDI infections Progression of the disease

Long term: Prevention of recurrences

General Measures

Supportive care and careful management of fluid and electrolyte

Discontinuation of unnecessary antimicrobial therapy

Avoidance of anti-motility agents

Reviewing of PPI use


Treatment

Pharmacological Agents with activity against C. difficile organisms

Non-pharmacological Fecal Microbiota Transplantation (FMT) Surgical Management

Pharmacological Agents

Approved Unapproved/Unlabeled

Vancomycin Metronidazole

Fidaxomicin Nitazoxanide

Rifaximin

Immunotherapy

Treatment Guidance (Adults)

Clinical Definitions Recommended Treatment Initial episode, mild or moderate

Metronidazole, 500 mg orally every 8 hours for 10-14 days

Initial episode, severe Vancomycin, 125 mg orally every 6 hours for 10-14 days

Initial episode, severe, complicated

Vancomycin 500 mg orally every 6 hours + Metronidazole 500 mg every 8 hours intravenously (IV)Note: consider adding rectal instillation

First recurrence Same as initial episodeSecond recurrence Vancomycin tapered and/or pulse regimen*

First 2 weeks: 125 mg PO q6hThird week: 125 mg PO BIDFourth week: 125 mg PO dailyNext 2-8 weeks: 125 mg every 2 to 3 days

*


Metronidazole

Inexpensive, widely used as a first-line treatment for CDI

Compared to vancomycin alone: Similar efficacy for mild to moderate infection Not recommended beyond the first recurrence/long term therapy;

“possible cumulative neurotoxicity” Only 6%-15% excreted in stool

Adverse effects: Nausea, disulfiram-like reaction, metallic taste, peripheral neuropathy

Not routinely recommended for use in children or in women during lactation or pregnancy


Vancomycin First FDA approved labeled indication for treatment of CDI

More expensive than metronidazole; minimal oral absorption

Use is discouraged as initial treatment to decrease selection pressure for the emergence of VRE

Usage: When metronidazole is found to be ineffective If metronidazole is contraindicated or not well tolerated Initial treatment option of severe CDI

For severe complicated CDI, higher dose (250-500 mg 4 times a day) is used as a supplemented therapy along with IV metronidazole


Comparative Effectiveness

Initial Cure:

Drekonja DM. et al. Ann Intern Med. 2011;155:839-847

Fidaxomicin (Dificid®)

FDA approved (2011) for indication of C. difficile-associated diarrhea (CDAD)

Narrow spectrum macrocyclic antibiotic that targets bacterial RNA polymerase

Activity against gram-positive aerobic and anaerobic organisms

Dose & duration: 200 mg by mouth twice a day for 10 days

Safe and effective for the first episode of C. difficile infection, however, there is limited evidence for recurrent infection


Initial Episode of Mild-to-Moderate CDI

Fidaxomicin (200 mg twice daily) was compared to oral vancomycin (125 mg 4 times daily) in 2 randomized control trials (RCT) for duration of 10 days

Both trial found fidaxomicin noninferior to vancomycin in terms of clinical cure

Fidaxomicin was also associated with a lower recurrence rate within 28 days of clinical cure relative to vancomycin

Louie TJ et al. N Engl J Med 2011; 364:422-431

Pharmacokinetic Advantage

Minimal systemic absorption after oral administration

>92% excreted in the feces as unchanged drug and metabolites

Concentrations in feces substantially exceed the 90% MIC of C. difficile

Postantibiotic effects against C. difficile in clinical studies range from 6-10 hours

Lexi-Comp OnlineTM , Lexi-Drugs Multinational , Hudson, Ohio: Lexi-Comp, Inc.; September 19, 2014

Alternative Agents

Nitazoxanide

Rifaximin

Immunotherapy

Probiotics

Nitazoxanide

Antiparasitic agent, active against C. difficile

Musher et al. compared nitazoxanide in at 2 durations to metronidazole in a prospective, randomized, double-blinded study involving 142 patients with CDI Results showed that nitazoxanide is as effective as metronidazole with

similar response rate (90% vs. 82%) and recurrence rates ( 18% vs. 23%)

Lacks long term safety and efficacy data


Rifaximin

Used as an adjunct to treat patient with multiple CDI recurrences

Course is given in a form of “rifaximin chaser” (400 mg orally for 14 days)

A recent RCT found that rifaximin was similar to vancomycin (57% vs. 64%) in attaining clinical success and was non-inferior in resolution of diarrhea (80% vs. 81%) and recurrence (9% vs. 14%)


Immunotherapy (IVIG)

Variable success

No RCT trials showing benefit of IVIG for CDI

Its mechanism may relate to antibodies against C. difficile toxin A and toxin B

In a large, randomized, controlled trial of monoclonal antibody against C. difficile toxin A and toxin B in addition to antibiotic therapy Rate of recurrence rate was lower among patient treated with

monoclonal antibody (7% vs. 25%; p <0.001)Khanna S. et al. Ther Adv Gastroenterol 2014; 7(2):72-86

Probiotics

Goal is to repopulate the colonic microflora

Commonly used species Lactobacillus, Bifedobacterium, and Saccharomyces

Currently has no role in the primary prevention of CDI


Non-pharmacological Treatment

Fecal Microbiota Transplantation (FMT)

Alternative to standard antibiotic therapy to treat recurrent CDI

Restoration of colonic flora with the use of intestinal microorganisms from a healthy donor (via infusion of a liquid suspension of stool)

A systemic review of 317 patients with recurrent CDI treated via FMT found overall success rate of 92%, with 89% of patients responding after a single treatment


Surgical Management

Indicated for treatment of refractory CDI not responding to medical therapy, or for fulminant colitis or toxic megacolon

Traditional surgical approach—subtotal or total colectomy

Poor outcome with mortality as high as 50%


Recurrent CDI

Major drawback in management of CDI

Occurs 20%-25% of patients after first dose

Defined as “occurrence of symptomatic diarrhea or abdominal pain, with positive stool test within 56 days of previous episode after interim symptom resolution”


Management of Recurrent CDI


Infection Control Measures

Hand hygiene

Contact precautions Glove use Gowns

Isolation rooms or cohorting

Environmental cleaning, disinfection, or use of disposables Patient room, equipment between uses Elimination of rectal thermometer usage Use of hypochlorite for disinfection


“Three Big Role”

Identify potential risk factors

Evaluate antibiotic usage

Education

Summary

Clostridium difficile is a Gram-positive, anaerobic, spore forming organism that produces two types of toxin: A & B

Major risk factors of CDI include elderly (age >64 years), antibiotic exposure, recent hospitalization or LTC facility residence

Toxin detection assay such as cell cytotoxic assay or EIA are considered as suitable alternatives

Metronidazole is considered as first line for initial episode of mild-to-moderate infection and should not be used beyond first recurrence

Vancomycin is reserved for severe CDI and the dose is 125 mg PO 4 times a day for 10-14 days

Summary

Fidaxomicin has been shown to be non-inferior to vancomycin in terms of clinical cure in addition to lower rates of recurrences, however, use is limited by high cost

Alternate agents such as, nitazoxanide, rifaximin, IVIG, or probiotics, do not get used routinely in clinical practice due to lack of substantial evidence

Non-pharmacological management such as FMT, or surgery is indicated in the case of multiple recurrences or refractory CDI

Proper hand hygiene and contact precautions are considered to be the cornerstone when it comes to infection control and nosocomial transmission

Self Assessment Questions????

Q1: Identify the CORRECT statement regarding Clostridium difficile infection (CDI):

a) It caused by aerobic, Gram-negative bacilli

b) The primary toxin responsible for causing the infection is toxin A

c) It is a common cause of infectious diarrhea in the community

d) Use of broad spectrum antibiotic is responsible for most CDI cases

Q2: Which of the following is one of the means of acquiring CDI?

a) Alteration of gut flora using antibiotic

b) Fecal-to-oral transmission

c) Through contaminated environment

d) All of the above

Q3: Case R.J is a 65 year old female who was recently discharged from

hospital after being treated for hospital acquired pneumonia. For past 2 days R.J has been passing watery stool for >3-4 times a day. She was brought to the Emergency and was diagnosed with CDI. Which of the following treatment regimen is appropriate for R.J?

a) Vancomycin 125 mg PO 4 times a day for 10-14 daysb) Fidaxomicin 200 mg PO twice a day for 10 daysc) Vancomycin 500 mg orally every 6 hours + Metronidazole 500 mg

every 8 hours intravenously d) Metronidazole 500 mg orally every 8 hours for 10-14 dayse) None of the above

Q4:Which of the following statement is FALSE regarding management of CDI?

a) Oral vancomycin is initial treatment option for severe CDI

b) Fidaxomicin is FDA approved for treatment of CDAD

c) Rifaximin is used as adjunct to treat multiple CDI recurrences in the form of “rifaximin chaser”

d) Use of Probiotics has clinical role in the primary prevention of CDI

e) None of the above

Q5: Which of the following is FDA approved for treatment of C. difficile?

a) Vancomycin

b) Metronidazole

c) Fidaxomicin

d) Vancomycin + Fidaxomicin

c.difficile

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