Table 1. Adult Treatment Strategies 1:
| Severity | Severity Definition | Treatment |
| First time, non-severe | WBC ≤15000 cells/mL and Cr <1.5 mg/dL | • vancomycin PO 125 mg QID x 10 days, OR |
| • fidoxamycin 200 mg BID x 10 days | ||
| • Alternate: flagyl, 500 mg PO TIDx10 d | ||
| First time, severe | WBC ≥15000 cells/mL or Cr >1.5 mg/dL | • vancomycin PO 125 mg QID x 10 days, OR |
| • fidoxamycin 200 mg BID x 10 days | ||
| First time, fulminant | Hypotension or shock, ileus, megacolon | • vancomycin 500 mg QID x 10 days PO or per NGT. If ileus, consider adding rectal instillation of vanc + IV metronidazole (500 mg every 8 hours) |
| Recurrence | • Vancomycin in a tapered and pulsed regimen, OR • Vancomycin for 10 days followed by rifaximin for 20 days, OR • Fecal microbiota transplantation |
• 125 mg qid • Vancomycin: 500 mg qid; rifaximin: 400 mg tid |
Table 2. Pediatric Treatment Strategies1
| Definition | Treatment | Dose |
| First time, non-severe | • Metronidazole PO ×10d OR • Vancomycin PO ×10d |
• 7.5 mg/kg/dose tid • 10 mg/kg/dose qid |
| Initial episode, severe/ fulminant | • Vancomycin PO or PR +/-
Metronidazole IV ×10d |
• 10 mg/kg/dose qid • 10 mg/kg/dose tid |
| First recurrence, non-severe | • Metronidazole ×10d PO
OR |
• 7.5 mg/kg/dose tid or qid • 10 mg/kg/dose qid |
Figure 1. Possible Testing Algorithm Recommendation 5
Let’s start with a few of the important recommendations on C. Diff Infections (CDI) from IDSA:
THE GUIDELINES1
Whom to Test – Adults
Patients with unexplained and new-onset ≥3 unformed stools in 24 hours are the preferred target population for testing for CDI. NEVER test formed stool
Whom to Test – Kids
Because of the high prevalence of asymptomatic carriage of toxigenic C. difficile in infants, testing for CDI should never be routinely recommended in infants ≤12 months of age with diarrhea. Clostridium difficile testing should not be routinely performed in children with diarrhea who are 1–2 years of age unless other infectious or noninfectious causes have been excluded. In children ≥2 years of age, C. difficile testing is recommended for patients with prolonged or worsening diarrhea and risk factors (e.g., underlying inflammatory bowel disease or immunocompromising conditions.
How to Test
Use a stool toxin test as part of a multistep algorithm. There are insufficient data to recommend use of fecal lactoferrin. See Figure 1 below.
How to Isolate
Accommodate patients with CDI in a private room with a dedicated toilet to decrease transmission to other patients. Do not group patients with CDI who have other multidrug-resistant organisms. Patients with suspected CDI should be placed on preemptive contact precautions pending the C. difficile test results. In CDI outbreaks settings, perform hand hygiene with soap and water preferentially instead of alcohol-based hand hygiene products before and after caring for a patient with CDI. There is increased efficacy of spore removal with soap and water. Handwashing with soap and water is preferred if there is direct contact with feces or an area where fecal contamination is likely.
Treatment
See Table 1 and 2 below for treatment.
Probiotics
There are insufficient data at this time to recommend probiotics for primary prevention of CDI.
THE COMMENTARY
The above are the IDSA guidelines. But how does this affect us in practice? We all often treat patients with limited resources so how will using PO vancomycin as first line affect cost? To that end I offer up these two studies. This first study2 in 2018 of a MATHEMATICAL MODEL of IN-PATIENT data showed that overall percentage of patients cured was: fidaxomicin (96.53%), vancomycin (95.19%) and metronidazole (94.23%). The expected cost of treatment was lowest for vancomycin ($1,306.62), followed by metronidazole ($1,553.01) followed by fidaxomicin ($5,095.70). Next up is this 2017 Cochrane review3 for efficacy of the same antibiotics. The authors looked at using mostly outpatient cases but few had severe C. diff. When comparing cure for vancomycin to metronidazole they found 79% (339/428) for vancomycin versus 72% (318/444) for metronidazole. When comparing fidaxomicin to vancomycin they found fidaxomicin more effective for achieving symptomatic cure with 71% (407/572) for fidaxomicin versus 61% (361/592) for vancomycin. Using 2016 costs they found metronidazole cost to be the least expensive at $13, vancomycin to be the next more expensive at $1779, and fidaxomicin to be the most at $3454.83. Lastly the guidelines say there is insufficient evidence for treatment of probiotics. However, it is probably helpful and not harmful to recommend a probiotic for the prevention of antibiotic associated CDI when prescribing high risk antibiotics like the fluoroquinolones and clindamycin. This Cocharane4 review found a benefit and reduced the risk of adverse events when recommending probiotics along with antibiotics by 17% (RR 0.83, 95% CI 0.71 to 0.97).
Commentary on Treatment
For in-patient treatment I think the data shows pretty well that oral vancomycin is more effective and presents a cost savings. Of course, we have to realize that the first study makes A LOT of assumptions but I think its face value probably makes sense. The big difference here is WETHER OR NOT YOUR HOSPITAL compounds vancomycin from the IV form or gets it de novo.
For out-patient treatment I called a compounding pharmacy and was told that this past January a dedicated oral vancomycin product came out. Therefore, they can no longer compound vancomycin. So now, if my patient has low resources and “follow up” (i.e. come back to the ED seems to be the default lately) then I would continue to go with metronidazole. You should explain to the patient there is a small chance that the metronidazole won’t work (1-5%, or for every 20 people choosing metronidazole one will fail to be cured; Number needed to fail). However, this beats no treatment at all if you can’t afford the pharmaceutical-company-gouging prices of non-compounded vancomycin. When I called a local pharmaceutical company with stores nationally I was told the cost for a course of vancomycin 125 mg PO WITHOUT insurance was $6100 and the cost for a course of metronidazole was $31.69…
Take Home on Treatment
For outpatient ONLY use vancomycin 125 mg PO QID IF the patient has insurance and maybe GIVE THEM A BACK UP Rx FOR METRONIDAZOLE otherwise metronidazole may still be the best bet with a small but significant treatment failure rate. Recommend a probiotic when prescribing antibiotics with a high risk of C. Diff.
For inpatient use vancomycin compounded and this should be efficacious and cost effective.
Commentary on Testing:
There are a LOT of tests and even more acronyms when it comes to C. Diff testing. I’m going to try to simplify them. First there are the NAATs. These are the PCR tests or nucleic acid amplification tests. These are highly sensitive. Almost too sensitive as the can detect C. Diff even after a patient has been clinically cured. So, they are great for first timers but not if you have had C. Diff in the past. Then there are the toxin tests. These detect free toxins in stools and are therefore believed to correlate to clinical symptoms plus they are cheap and easy. Don’t celebrate yet because, sensitivity of Toxin A/B immunoassay (EIA) is suboptimal. Lastly, there are the GDH immunoassays. They are also easy to perform and cheap. They detect glutamate dehydrogenase (GDH), an enzyme that is produced by both toxigenic and non-toxigenic strains and therefore also may not correlate to clinical symptoms. This is why, algorithms are usually recommended. Even then it might still find only colonization and not pathogenic bacteria. Luckily for us there is a definitive treatment: STOOL TRANSPLANT! Where do I sign up to be a donor? The best thing to do (as with any test) is find out what your specific lab does for algorithms and what are the weaknesses. A common algorithm is below. Sometimes a fecal lactoferrin can help distinguish active disease from non-active disease so I added it in but it’s not really part of the algorithm.
Take Home on testing:
Talk to your lab and find out what the recommended algorithm is. Never test formed stool. Use some combination of PCR and Toxin seems to be best. Consider adding fecal lactoferrin.
REFERENCES
- McDonald, L. C. et al. Clinical Practice Guidelines for Clostridium difficile Infection in Adults and Children: 2017 Update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA). Clin Infect Dis 66, e1-e48 (2018).
- Ford, D. C., Schroeder, M. C., Ince, D. & Ernst, E. J. Cost-effectiveness analysis of initial treatment strategies for mild-to-moderate Clostridium difficile infection in hospitalized patients. Am J Health Syst Pharm (2018).
- Nelson, R. L., Suda, K. J. & Evans, C. T. Antibiotic treatment for Clostridium difficile -associated diarrhoea in adults. Cochrane Database of Systematic Reviews (2017).
- Goldenberg, J. Z. et al. Probiotics for the prevention of Clostridium difficile-associated diarrhea in adults and children. Cochrane Database Syst Rev 12, CD006095 (2017).
- Crobach, M. J. T., Baktash, A., Duszenko, N. & Kuijper, E. J. Diagnostic Guidance for C. difficile Infections. Adv Exp Med Biol 1050, 27-44 (2018).
Reviews in EM (REM) 