Clostridium difficile CRISTINA 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)
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)??? N Engl J Med 2015; 372:1539-1548
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 Increasing risk of CDI 3. Macrolides and sulfa drugs 4. Tigecycline and aminoglycosides Remember that any antibiotic can cause CDI
Antibiotic classes and their association with CDI N Engl J Med 2015; 372:1539-1548
Recurrent disease Reappearance of symptoms within 2-8 weeks after treatment If diarrhea recurs weeks after treatment, repeat C. difficile PCR to determine if postinfectious 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
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 2 nd occurrence
Cost considerations Drug Firvanc (suspension, brand only) Vancocin (cap, brand & generic) Dificid (tablet, brand only) Cost/course (Vancomycin: 125 mg QID x 10 days, Dificid : 200 mg BID x 10 days) GoodRx Outpatient Hospital pharmacy $136-206 $153-156 $62 $180 (generic) $162 $170 $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 vancomycinresistant 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)