Clostridium difficileCRISTINA BAKER, MD, MPH

INFECTIOUS DISEASE

PARK NICOLLET/HEALTH PARTNERS

11/9/2018

Disclosures

None

Objectives

Highlight important changes in the management of

Clostridium difficile infection (CDI) according to the

new guidelines

Discuss new therapeutic options available for treatment

Review changes to testing methodology

Explore the role of fecal microbiota transplantation

First…a question

A 76 yo male is hospitalized for weakness, abdominal

cramping and diarrhea. He has been experiencing 5 or

more, watery stools daily for 3 days. He is afebrile and

his vital signs are stable. Laboratory findings are

significant for a WBC of 16,000 cells/mL and a creatinine

of 1.7 mg/dL (baseline is 1.0 mg/dL). He was treated for

severe Clostridium difficile infection 1 month ago with

vancomycin 125mg four times daily for 10 days.

Which of the following is the most

appropriate treatment for this patient?

1. Metronidazole 500 mg po 3 times daily for 14 days + Bezlotuxumab

10 mg/kg IV x 1

2. Vancomycin 500 mg po 4 times daily for 14 days

3. Fidaxomycin 200 mg po twice daily + Metronidazole 500 mg IV 3

times daily x 10 days

4. Prolonged taper and pulsed vancomycin regimen (eg, 125 mg po

4 times a day for 10-14 days, 2 times a day for a week, once per day

for a week and then every 2 or 3 days for 2-8 weeks)

Disease burden

435,000 cases of CDI in US in 2011. Minimal reduction in cases since that time

64.7% were considered to be health-care associated (occurring 3 days after hospital admission)

Acute care inpatient cost in excess of $4.8 billion

National efforts to control and prevent infection

Incentives for public recording of hospital rates of infection

Hospital pay for performance initiatives Lessa FC, et al Burden of Clostridium difficile infection in the United States. N Engl J Med

2015;372:825

Dubberke ER, Olsen MA, Burden of Clostridium difficile on the healthcare system. Clin Inf Dis 2012;55 (Suppl 2): S88-92.

History and epidemiology

First identified in 1978 as organism responsible for antibiotic-associated colitis.

Named “difficult clostridium” – did not grow well in conventional culture

1989-1992 - Large outbreak in 4 hospitals in the US.

Clindamycin-resistance strain associated with an increased risk of developing CDI

2003-2006 – Increasing rates of more severe disease.

New strain identified: Non–North American Pulsed Field type 1 (NAP1/B1/027).

More virulent strain with increased toxin production.

Fluoroquinolone use strongly correlated with emergence of this strain

2005 – Ribotype 078 in the Netherlands.

Affects younger population

Community-acquired

Importance of carriage in community and

LTCFs

C. difficile carriage

8-10% of adults in hospitals or long-term care facilities

3% in healthy adults

Newly exposed patients develop CDI much more frequently than colonized patients (4.5 vs 1.1%)

Persons who remain asymptomatically colonized over longer periods of time are at decreased risk for CDI, likely due to increased antibody levels against toxins A and B

Duration of hospitalization is proxy for duration and degree of exposure so longer hospitalization = increased risk of CDI

McFarland LV et al. Nosocominal acquisition of Clostridium difficile infection. N Engl J Med 1989;320:204

Zachariousdakis IM et al. Colonization with toxogenic C. difficile upon hospital admission and risk of infection: a systematic review and meta-analysis. Am J Gastroenterology 2015;110:381

Toxins

C. difficile can exist in spore and vegetative forms

Spores are resistant to heat, acid and antibiotics and

can survive outside the body on surfaces

In the intestine, the spores convert to a vegetative state

and start to produce toxins. At this stage, they are

susceptible to killing by antibiotics.

C. difficile releases two toxins – Toxin A and Toxin B.

Toxin A causes inflammation, activates neutrophils and

causes mucosal injury

Toxin B is 10x more potent than toxin B

BI/NAP1/027 strain produces binary toxin (an additional

toxin) and more A and B (lacks a gene, tcdC,

responsible for downregulation of toxin production)

N Engl J Med 2015; 372:1539-1548

Risk factors – (greater risk)

Antibiotics

Advanced age - >65 yo

Hospitalization

Chronic kidney disease/ESRD (2-2.5x)

Obesity

Cancer chemotherapy (antimicrobial effect of chemotherapeutic agents and their immunosuppressive effects)

Stem cell transplant (9x)

Solid organ transplant (5x)

Inflammatory bowel disease

Cirrhosis

HIV

Tube feeding

Low vitamin D

Gastric acid suppression (H2 blockers and proton-pump inhibitors) ???

Question #1

Which antibiotics are LEAST frequently associated with CDI?

1. Clindamycin and cephalosporins

2. Fluoroquinolones and penicillins

3. Macrolides and sulfa drugs

4. Tigecycline and aminoglycosides

Question #1

Which antibiotics are LEAST frequently associated with CDI?

1. Clindamycin and cephalosporins

2. Fluoroquinolones and penicillins

3. Macrolides and sulfa drugs

4. Tigecycline and aminoglycosides

Remember that any antibiotic can cause CDI

Increasing risk of CDI

N Engl J Med 2015;

372:1539-1548

Antibiotic classes and their

association with CDI

Recurrent disease

Reappearance of symptoms within 2-8 weeks after treatment

If diarrhea recurs weeks after treatment, repeat C. difficile PCR to determine if post-

infectious diarrhea vs recurrent CDI

Up to 25% of patient will have recurrent infection

Typically older patients with underlying medical illness

Recurrent CDI is associated with a 33% increased risk of mortality at 180 days relative to

patients who do not suffer a recurrence.

Olsen MA. Yan Y, Reske KA et al. Recurrent Clostridium difficile infection is associated

with increased mortality. Clin Microbiol Infect 2015:21:164-70.

New treatment

guidelines - 2017

https://academic.oup.com/cid/article/66/7/e1/4855916

2017 Revised Guidelines - update

A strong recommendation from the panel now favors a 10-day course of

vancomycin or fidaxomicin rather than metronidazole as first-line therapy

for mild/moderate CDI in adults.

This new recommendation was based on several clinical trials

demonstrating a greater cure rate and less frequent recurrence following

vancomycin compared with metronidazole

Fidaxomicin may reduce the risk for recurrent CDI because of its narrow

spectrum compared with vancomycin.

• The rates of clinical cure with fidaxomicin were noninferior to those

with vancomycin

- Modified intention-to-treat analysis (88.2% with fidaxomicin and

85.8% with vancomycin)

- Per-protocol analysis (92.1% and 89.8%).

• Significantly fewer patients in the fidaxomicin group than in the

vancomycin group had a recurrence of the infection

- Modified intention-to-treat analysis (15.4% vs. 25.3%, P=0.005)

- Per-protocol analysis (13.3% vs. 24.0%, P=0.004).

• The lower rate of recurrence was seen in patients with non–North

American Pulsed Field type 1 strains.

• The adverse-event profile was similar for the two therapies.

In 2010 guidelines,

prolonged

taper/pulsed

regimen was

recommended

only after 2nd

occurrence

Cost considerations

Drug

Cost/course (Vancomycin: 125 mg QID x 10 days, Dificid®: 200 mg BID x 10 days)

GoodRx Outpatient pharmacy

Hospital

Firvanc®

(suspension, brand only)

$136-206 $153-156 $62

Vancocin® (cap, brand & generic)

$180(generic)

$162 $170

Dificid® (tablet, brand only)

$3700 $4376 $3436

Extending length of treatment

According to the guidelines, there is insufficient evidence (no prospective, randomized trials) to extend treatment beyond the recommended course of therapy for patients who require continued antibiotic therapy for underlying infection or who require antibiotics shortly after completion of CDI treatment

Secondary prophylaxis –

May reduce likelihood of recurrence in those with >2 prior CDI episodes (54 vs 70%)

No difference in those with only one prior episode

Reasonable regimens include oral vancomycin 125mg po once to twice daily while systemic antibiotics are administered

Do not use metronidazole due to risk of peripheral neuropathy with long term use Carignan A, Poulin, Martin et al. Efficacy of oral vancomycin in preventing recurrent

Clostridium difficile Infections. Am J Gastroenterol 2016;111-1834

New

Therapeutics

Bezlotoxumab – monoclonal antibody that binds to C.

difficile toxin B.

FDA approved in 2016 for secondary prevention of CDI at

high risk for recurrence.

When used with standard antibiotics, the recurrence rate

was 28% (antibiotics alone) vs 17% (Bezlotoxumab +

antibiotic)

Recent innovation so not included in current guidelines

Probiotics

Use of probiotics not currently recommended in guidelines

Several meta-analyses have shown probiotics may be effective at preventing

CDI for patients with no history of CDI

Issues with the data: uncertainty regarding species used in probiotics (differing

results)and strain-specific effects, varied study designs, inclusion criteria

Concern that probiotics can causing infection in hospitalized patients

(bacteremia/fungemia) due to contamination of PICC lines

Goldenberg JZ. Probiotics for the prevention of Clostridium difficile-associated diarrhea in

adults and children. Cochrane Database Syst Rev 2013;5.)

Other therapeutics in the works for CDI

National institute of allergy and infectious disease (NIAID) initiatives

Vaccine development

Two examples of novel antimicrobials supported by NIAID include:

CRS3123 - inhibits an enzyme required by C. difficile to make proteins. In

phase I Clinical Trial Units.

Amixicile - targets an enzyme found in anaerobic bacteria, like C.

difficile, but is absent in beneficial probiotic bacteria. In preclinical

development stage

Lab testing

methodology

Revised testing guidelines in 2017 update

Differentiating infection and colonization remains an

important clinical challenge.

Molecular tests (eg, nucleic acid amplification tests

[NAATs], such as polymerase chain reaction) do not

differentiate between colonization and infection

Updated guidelines strongly reinforce the importance of

practicing good diagnostic stewardship and limiting C.

difficile testing to patients with new-onset, unexplained,

and clinically significant diarrhea (ie, at least 3 unformed

stools in a 24-hour period).

What kind of C. difficile testing is used at

your institution?

1. NAAT/PCR based testing without

restrictions

2. NAAT/PCR based testing with

restrictions (ID approval, only if >3

stools/day, no laxatives, etc)?

3. Multistep algorithm – stool toxin testing

+ NAAT/PCR

Testing based on pre-agreed institutional criteria for stool

submission (2017 Guidelines)

Why it is important to think about who you

are testing?

Consequences of identifying patients who have C.

difficile colonization rather than infection

Unnecessary treatment can select for vancomycin-

resistant enterococci (VRE)

Increased drug costs

Increased total cost of care

Loss of hospital reimbursement based on pay for

performance initiatives

Role of fecal

microbiota

transplantation

Fecal microbiota transplant (FMT)

Options to administer stool in several forms - oral capsules,

colonoscopy, retention enema, NG tube,

Cure rates 80-100% with instillation of feces in colon (UpToDate)

Well accepted by patients

Safe in immunocompromised

Guideline panel recommended antibiotic treatment for at least 2

recurrences (3 CDI episodes) and then consideration of FMT

Should receive an “induction course” of oral vancomycin 3-7 days

prior to FMT to reduce burden of vegetative C. difficile (expert

opinion)

Challenging Case

73 yo female readmitted to the hospital with weakness and syncope 3 weeks

after admission for a wound infection following femoral bypass surgery for

which she was treated with levofloxacin and augmentin.

On admission: WBC – 6,800 cells/mL then increased to 14,000 cells/mL,

Creatinine – normal

CT of the C/A/P on admission showed colitis. However, she had no diarrhea,

no abdominal cramping or abdominal pain.

Urine analysis showed pyuria so antibiotics were started for presumed

UTI. Urine culture subsequently grew Enterococcus and her treatment was

narrowed to Ampicillin/sulbactam

Challenging Case

Her condition initially was stable and then worsened 7 days into her hospitalization. She was

transferred to the ICU with septic shock and need for intubation. Procalcitonin was >100

Vancomycin and piperacillin/tazobactam were started.

A repeat CT scan of the A/P showed free air in the abdominal cavity. She was evaluated by

surgery and it was felt that she would not survive surgical intervention. It became difficult to

support her and she was transitioned to comfort cares.

Blood cultures results obtained after her death were positive for Clostridium difficile

TEACHING POINT: The absence of diarrhea does not exclude the diagnosis of CDI

Back to our question

A 76 yo male is hospitalized for weakness, abdominal cramping and diarrhea. He has been experiencing 5 or more, watery stools daily for 3 days. He is afebrile and his vital signs are stable. Laboratory findings are significant for a WBC of 16,000 cells/mL and a creatinine of 1.7 mg/dL (baseline is 1.0 mg/dL). He was treated for severe Clostridium difficile infection 1 month ago with vancomycin 125mg four times daily for 10 days. Which of the following is the most appropriate treatment for this patient.

1. Metronidazole 500 mg po 3 times daily for 14 days + Bezlotuxumab 10 mg/kg IV x 1

2. Vancomycin 500 mg po 4 times daily for 14 days

3. Fidaxomycin 200 mg twice daily + Metronidazole 500 mg IV 3 times daily x 10 days

4. Prolonged taper and pulsed vancomycin regimen (eg, 125 mg 4 times a day for 10-14 days, 2 times a day for a week, once per day for a week and then every 2 or 3 days for 2-8 weeks)

The correct answer is D - a prolonged taper and pulsed vancomycin regimen.

According to the new 2017 updated guidelines for C. difficile infection (CDI) in

adults and children released by the Infectious Disease Society of America (IDSA)

and Society for Healthcare Epidemiology of America (SHEA), oral metronidazole is

no longer recommended as treatment in adults unless alternative agents are not

available.

Oral vancomycin (125 mg po 4 times per day) or fidaxomicin (300mg po twice

daily) for 10 days are recommended for both non-severe and severe CDI (WBC

>15,000 cells/mL or serum creatinine >1.5 mg/dL without hypotension, ileus or

megacolon.) The change in treatment recommendation was made based on

evidence to support that use of vancomycin or fidaxomicin provide patients with a

higher likelihood of sustained resolution one month after treatment.

In patients who have already received a standard course of oral vancomycin, a

prolonged taper and pulsed course of therapy is recommended for the first

recurrence. In previous guidelines, the same treatment regimen as the initial

treatment was recommended for the first recurrence but stratified by disease

severity. A prolonged taper and pulsed vancomycin regimen was recommended

only after the second or later recurrence.

Bezlotoxumab, a monoclonal antibody directed against toxin B produced by C.

difficile, has been approved as adjunctive therapy for patients who are receiving

antibiotic treatment for CDI and who are a high risk for recurrence but is not recommended in the current guidelines.

Pearls

The absence of diarrhea does not exclude the diagnosis of CDI

Systemic absorption of enteral vancomycin can occur due to mucosal disruption in those

with severe or fulminant colitis.

Consider monitoring vancomycin levels in patients with renal failure (creatinine clearance

<10mL/min) and severe colitis who are receiving oral vancomycin

0.8% of patients develop candidemia in the 120 days following CDI with increased risk if

more severe disease and treatment with metronidazole + vancomycin (Epidemiol Infect

2016; 144:1440-4)