Stanford Division of Infectious Diseases Guidelines for the Treatment of Clostridium Difficile Infection (CDI)
May 1, 2014
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Special Report
Stanford Division of Infectious Diseases Guidelines for the Treatment of Clostridium Difficile Infection (CDI)
By Paul Ravi Waldron, MD, MPH
Division of Infectious Diseases and Geographic Medicine, Stanford University, Stanford, CA, (email: [email protected])
Dr. Waldron reports no financial relationships in this field of study.
There have been several advances in medical understanding of the prevention, diagnosis and treatment of CDI since the last national guidelines were published in 2010. A lack of more contemporary guidelines incorporating these new innovations led to heterogeneity of practice at our institution, which could increase cost and decrease efficacy of care. For that reason, the Infectious Disease Division developed these guidelines for use at Stanford University Hospital and Clinics and believe they may be of use to other institutions while awaiting new U.S. national guidelines.
DIAGNOSIS:
Diagnostic Criteria (Distinct from Testing Criteria Below):1,2
1. Diarrhea (≥3 loose or watery stools per day for at least 2 consecutive days or ≥8 loose stools in 48 hours) OR significant worsening in patients with chronic diarrhea (e.g. inflammatory bowel disease) OR increased output from any ostomy site in the setting of recent antibiotic use. These criteria are most useful for diagnosis in the absence of obvious alternative explanations such as laxative use or recent initiation of enteral feedings.
AND
2. A positive stool PCR for C. difficile toxin B or visualization of pseudomembranes on endoscopy.
OR
Abdominal distension and severe pain after a period of diarrhea without current stooling may be a rare finding if ileus or toxic megacolon present. In this setting, effort should be made to send toxin PCR from a rectal swab trace amount of stool (notify microbiology lab prior to sending, swab specimens will be rejected unless prior approval from lab is given).
Testing Criteria (Must be met for lab to accept sample):
1. ≥3 loose or watery stools per 24 hr.
2. Unformed stool specimen (conforms to the shape of the container). Exceptions include patients with ileus or toxic megacolon. Please contact the lab if you are requesting an exception to this policy.
3. No repeat testing within the last 7 days.
Important:
Stool PCR for C. difficile toxin B is thought to be 98% sensitive for disease or colonization, there is no indication for repeat testing within 7 days of a negative result. Repeat testing after that only if initial symptoms resolve and new diarrhea starts.3 Asymptomatic colonization with toxigenic C. difficile is relatively common and treatment is not indicated for this. It is therefore important that patients meet testing criteria for CDI, before sending stool for C. difficile toxin PCR. Currently there is not an indication for a test of cure for CDI. Patients with CDI should be followed clinically for improvement.
Table 1. Stanford Division of Infectious Diseases Suggested Guidelines for the Treatment of Clostridium Difficile Infection (CDI). |
||
Clinical Severity/Stage |
First Line Regimen |
Alternative Therapy |
Mild/Moderate |
Metronidazole 500mg PO TIDx10-14d |
Vancomycin 125 mg PO q6h x 10-14d. |
Severe (WBC >= 15K and |
Vancomycin 125 mg PO q6h x 10-14d. |
Fidaxomicin 200mg PO BIDx10d. |
Severe Complicated |
SURGICAL AND INFECTIOUS DISEASES CONSULT Vancomycin 500mg PO q6h + Metronidazole IV 500mg TID. Consider PR Vancomycin 500mg in 100ml NS enema q6h |
Replace Metronidazole IV with Tigecycline IV 50mg BID. |
First Recurrence |
Same as above based on severity |
|
Multiple Recurrence |
For Severe Complicated Treat as above until stable. For all others if not previously used: Fidaxomicin 200mg PO BID x 10d |
OR Vancomycin 125mg PO q6h for 14d followed by Rifaximin 400mg PO BID for 21d OR Vancomycin PO 125mg q6h x10d, then BID x7d, then qd x7d, then qod x21d OR Fecal Microbiota Transplant. Consult ID and GI |
Staging Disease:
After the diagnosis is made, it is important to stage the disease to guide treatment by both severity (mild -> severe complicated) and symptom recurrence (first occurrence-> multiple recurrence):1,2
• Mild disease- Diarrhea only, no systemic inflammatory response as assessed by other symptoms (fatigue, fever), leukocytosis, or elevated serum creatinine.
• Moderate disease- Systemic symptoms present and or moderate elevations in white blood cell count (WBC) <15,000 cells/µL AND serum creatinine elevation <1.5 times the premorbid level.
• Severe disease WBC >=15,000 cells/µL OR serum creatinine elevation >=1.5 times the premorbid level due to CDI.
• Severe Complicated meets criteria for septic shock due to CDI OR radiographic and clinical evidence of ileus (lack of stooling/flatus, abdominal distension with air fluid levels on radiography) OR toxic megacolon (severe disease with colonic distension on radiography 6cm< in any segment) OR has peritonitis on exam, free air in abdomen by radiography AND/OR colonic perforation.
• Recurrent-renewed disease meeting the above diagnostic criteria after initial resolution of symptoms has occurred AND occurring within 8 weeks of previous episode or after new systemic antibiotic use. Note: After clinical response, it may take weeks for stool consistency and frequency to become entirely normal.
• Multiply Recurrent disease - >1 recurrence of disease, with each distinct episode meeting the diagnostic criteria above.
Table 2. Cost Table of Recommended Antimicrobial CDI Therapies• |
||||
Drug |
Unit |
*AWP Cost |
AWP Cost |
AWP 14 |
Metronidazole tablet |
500mg tablet |
$0.82 |
$2.46 |
$34.44 |
Metronidazole injection |
500mg bag |
$2.16 |
$6.48 |
$90.72 |
Vanc oral solution |
125mg solution |
$4.03/vial |
$4.03 |
$56.42 |
Vanc capsule (generic) |
125mg capsule |
$31.30 |
$125.20 |
$1,752.80 |
250mg capsule |
$57.77 |
$231.08 |
$3,235.12 |
|
Vanc capsule (brand name) |
125mg capsule |
$34.80 |
$139.20 |
$1,948.80 |
250mg capsule |
$64.20 |
$256.80 |
$3,595.20 |
|
Fidaxomicin** |
200mg tab |
$177.47 |
$354.94 |
$4,969.16 |
Tigecycline injection |
50mg bag |
$114.71 |
$229.42 |
$3,211.88 |
Rifaximin |
200mg TID |
$16.03 |
$48.09 |
$1,009.89 |
400mg BID |
$32.08 |
$64.16 |
$1,347.36 |
|
*Average wholesale price (data provided by Emily Mui PharmD).
**Various programs are available for cost reduction in specific circumstances.
TREATMENT:
In addition to recommendations below, discontinue administration of unnecessary antibacterial agents and proton pump inhibitors (PPIs).
Mild/Moderate disease1,2 Metronidazole 500mg PO TID for 10-14 days (note median time to symptom resolution is 5-6 days). If symptoms resolve within 7 days, 10 days of therapy is sufficient; if >7 days, 14 days may be preferred (do not use for more than 14 days due to potential neurotoxicity). ALTERNATIVE THERAPY: Vancomycin 125 mg PO q6h (generic liquid formulation) for 10-14d.
Severe disease1,2,5- Likely requires hospitalization, also consider serial abdominable X-rays if patient has abdominal distension, tenderness. Consultation with Infectious Diseases is recommended. Antimicrobials: Vancomycin 125 mg PO q6h (generic liquid formulation) for 14d. ALTERNATIVE THERAPY: Fidaxomicin 200mg PO BID for 10d may be considered in failures of prior therapy, particularly if concurrent antibiotics are required, but there are no data available regarding the efficacy of this drug in severe life-threatening disease. Fidaxomicin use is restricted at Stanford. An ID consult not required only if patient meets following criteria:
a. Proven C. difficile disease AND
b. Recurrent disease AND
c. ≥3 of the following:
i. Age >65 years
ii. Significantly immunocompromised
iii. ≥2 SIRS criteria
iv. meets criteria for severe CDI disease
v. Continued broad-spectrum antibacterial therapy.
Severe-Complicated1,2,6,7- SURGICAL AND INFECTIOUS DISEASE CONSULTATION STRONGLY INDICATED. Serial AXRs necessary if surgery deferred. Antimicrobials: Vancomycin 500mg PO q6h and IV metronidazole 500mg TID. Consider PR vancomycin 500mg in a 100ml normal saline retention enema q6h unless toxic megacolon (high perforation risk), total course at least 10d but longer courses can be determined from time of symptom resolution. ALTERNATIVE THERAPY: Replace IV metronidazole with IV tigecycline 50mg BID.
Surgical intervention is indicated in case of:
• Perforation of the colon
• Systemic inflammation and deteriorating clinical condition despite maximal antibiotic therapy; this includes the clinical diagnoses of toxic megacolon, acute abdomen and severe ileus. Colectomy should preferably be performed before colitis becomes very severe. Serum lactate may serve as a marker for severity (operate before lactate exceeds 5.0 mM/dL).
A potential alternative to colectomy may be diverting loop ileostomy and colonic lavage, combined with antibiotic treatment — a method that remains under investigation.
First Recurrence Same therapy as for initial episode, adjusted for severity as above.
Multiply Recurrent Disease1,2,8-10 Infectious Diseases consultation strongly indicated. If severe-complicated, treat as above until stabilized, then continue as discussed below.
Can choose from the following options:
1. Fidaxomicin 200mg PO BID for 10d. See Stanford restriction criteria above.
2. Vancomycin 125mg PO q6h for 14d followed by Rifaximin 400mg PO BID for 21d.
3. Vancomycin PO 125mg q6h for 10d, then BID for 7d, then daily for 7d, then every other day for 21d or until symptoms tolerate.
4. Fecal Microbiota Transplant. Requires BOTH Infectious Diseases and Gastroenterology consults.
Recurrence prevention:
Limit repeat antibiotic use and proton pump inhibitor (PPI) use- these are the epidemiologic risk factors most associated with recurrence. Call ID consult or make urgent ID outpatient referral if possible prior to starting systemic antibiotics in patient with known CDI history, as it may be possible to minimize antibiotic use and duration. Would consider prior CDI, particularly severe or multiply recurrent disease as a relative contraindication to antibiotics and PPIs, e.g use only if absolutely necessary. If antibiotic use necessary in a patient with a history of CDI, if possible AVOID clindamycin, cephalosporins, monobactams, carbapenems, flouroquinolones and b-lactamase inhibitor combinations. Macrolides, sulfonamides, penicillin or aminopenicillins and aminoglycosides are possibly associated with a relatively lower risk of CDI than the other antibiotic classes listed above. Metronidazole and tetracyclines, particularly doxycycline, are the antibiotic classes associated with the least risk of CDI and may even be protective. Lower risk antibiotics should be used preferentially where appropriate. Using multiple antibiotics simultaneously should be avoided if possible as each additional agent used increases the risk of CDI, therefore regimens should be kept as simple as possible.11-13
Probiotics14,15: Available evidence for use of probiotic preparations (capsules, powder, yogurts) to prevent CDI occurrence is equivocal, but risk is low in immunocompetent patients. IF USED: Preparations should include greater than 1 x 109 colony forming units (CFU) of either Saccharomyces cerevisiae subtype boulardii (a strain within the species), bifidobacterium spp or lactobacillus spp. Use should be restricted to prevention in patients currently requiring systemic antibiotics, NOT in patients with active CDI. Use should be carefully considered in immunocompromised patients as risk may outweigh benefit in this population.
INFECTION CONTROL:
Current recommendation is for inpatients with positive C difficile toxin PCRs to be placed in contact isolation. Hand washing with soap and water (not alcohol based cleansers) is necessary with soiling of hands or bodily fluids after contact with CDI patients OR in outbreak situations, otherwise standard hand hygiene recommendations apply as per CDC/SHEA guidelines1.
Acknowledgements:
The author would like to acknowled Niaz Banaei M.D., Stan Deresinski M.D., and
Upinder Singh M.D. for their contribution to this work.
References
1. Cohen SH, et al. Society for Healthcare Epidemiology of America (SHEA); Infectious Diseases Society of America (IDSA). Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by SHEA and IDSA. Infect Control Hosp Epidemiol 2010;31(5):431-55.
2. Debast SB, et al. European Society of Clinical Microbiology and Infectious Diseases: update of the treatment guidance document for Clostridium difficile infection. Clin Microbiol Infect 2014;20:Suppl 2:1-26.
3. Musher DM, et al. Diagnosis of Clostridium difficile infection. Clin Infect Dis 2012;54(11):1675-6.
4. Luo RF, et al. Is repeat PCR needed for diagnosis of Clostridium difficile infection? J Clin Microbiol 2010;48(10):3738-41.
5. Crook DW, et al; Study 003/004 Teams. Fidaxomicin versus vancomycin for Clostridium difficile infection: meta-analysis of pivotal randomized controlled trials. Clin Infect Dis 2012;55:Suppl 2:S93-103.
6. Larson KC, et al. Tigecycline for the treatment of severe Clostridium difficile infection. Ann Pharmacother 2011;45:(7-8):1005-10.
7. Neal MD, et al. Diverting loop ileostomy and colonic lavage: an alternative to total abdominal colectomy for the treatment of severe, complicated Clostridium difficile associated disease. Ann Surg 2011;254(3):423-7; discussion 427-9.
8. Louie TJ, et al. Fidaxomicin preserves the intestinal microbiome during and after treatment of Clostridium difficile infection (CDI) and reduces both toxin reexpression and recurrence of CDI. Clin Infect Dis 2012;55:Suppl 2:S132-42.
9. Johnson S, et al. Interruption of recurrent Clostridium difficile-associated diarrhea episodes by serial therapy with vancomycin and rifaximin. Clin Infect Dis 2007;44(6):846-8.
10. van Nood E, et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med 2013;368(5):407-15. PMID: 23323867
11. Hebert C, et al. Electronic health record-based detection of risk factors for Clostridium difficile infection relapse. Infect Control Hosp Epidemiol 2013;34(4):407-14.
12. Pakyz AL, et al. Medication risk factors associated with healthcare-associated Clostridium difficile infection: a multilevel model case-control study among 64 US academic medical centres. J Antimicrob Chemother 2013 [Epub ahead of print]
13. Doernberg SB, et al. Does doxycycline protect against development of Clostridium difficile infection? Clin Infect Dis 2012;55(5):615-20.
14. Johnston BC, et al. Probiotics for the prevention of Clostridium difficile-associated diarrhea: a systematic review and meta-analysis. Ann Intern Med 2012;157(12):878-88.
15. Allen SJ, et al. Lactobacilli and bifidobacteria in the prevention of antibiotic-associated diarrhoea and Clostridium difficile diarrhoea in older inpatients (PLACIDE): A randomised, double-blind, placebo-controlled, multicentre trial. Lancet 2013;382(9900):1249-57.
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