Treatments Adults & Pediatrics

Treating C  diff.  is becoming more challenging to physicians, frustrating to patients, and costly to the health care industry.

ADULT :   What are important ancillary treatment strategies for CDI?

Recommendations
  1. Discontinue therapy with the inciting antibiotic agent(s) as soon as possible, as this may influence the risk of CDI recurrence (strong recommendation, moderate quality of evidence).
  2. Antibiotic therapy for CDI should be started empirically for situations where a substantial delay in laboratory confirmation is expected, or for fulminant CDI (described in section XXX) (weak recommendation, low quality of evidence).

ADULT: What are the best treatments of an initial CDI episode to ensure resolution of symptoms and sustained resolution 1 month after treatment?

Recommendations
  1. Either vancomycin or fidaxomicin is recommended over metronidazole for an initial episode of CDI. The dosage is vancomycin 125 mg orally 4 times per day or fidaxomicin 200 mg twice daily for 10 days (strong recommendation, high quality of evidence) (Table 1).
  2. In settings where access to vancomycin or fidaxomicin is limited, we suggest using metronidazole for an initial episode of nonsevere CDI only (weak recommendation, high quality of evidence). The suggested dosage is metronidazole 500 mg orally 3 times per day for 10 days. Avoid repeated or prolonged courses due to risk of cumulative and potentially irreversible neurotoxicity (strong recommendation, moderate quality of evidence). (See Treatment section for definition of CDI severity.)
Table 1.

Recommendations for the Treatment of Clostridium difficile Infection in Adults

Clinical Definition Supportive Clinical Data Recommended Treatmenta Strength of Recommendation/ Quality of Evidence
Initial episode, non-severe Leukocytosis with a white blood cell count of ≤15000 cells/mL and a serum creatinine level <1.5 mg/dL • VAN 125 mg given 4 times daily for 10 days, OR Strong/High
• FDX 200 mg given twice daily for 10 days Strong/High
• Alternate if above agents are unavailable: metronidazole, 500 mg 3 times per day by mouth for 10 days Weak/High
Initial episode, severeb Leukocytosis with a white blood cell count of ≥15000 cells/mL or a serum creatinine level >1.5 mg/dL • VAN, 125 mg 4 times per day by mouth for 10 days, OR Strong/High
• FDX 200 mg given twice daily for 10 days Strong/High
Initial episode, fulminant Hypotension or shock, ileus, megacolon • VAN, 500 mg 4 times per day by mouth or by nasogastric tube. If ileus, consider adding rectal instillation of VAN. Intravenously administered metronidazole (500 mg every 8 hours) should be administered together with oral or rectal VAN, particularly if ileus is present. Strong/Moderate (oral VAN); Weak/Low (rectal VAN); Strong/Moderate (intravenous metronidazole)
First recurrence • VAN 125 mg given 4 times daily for 10 days if metronidazole was used for the initial episode, OR Weak/Low
• Use a prolonged tapered and pulsed VAN regimen if a standard regimen was used for the initial episode (eg, 125 mg 4 times per day for 10–14 days, 2 times per day for a week, once per day for a week, and then every 2 or 3 days for 2–8 weeks), OR Weak/Low
• FDX 200 mg given twice daily for 10 days if VAN was used for the initial episode Weak/Moderate
Second or subsequent recurrence • VAN in a tapered and pulsed regimen, OR Weak/Low
• VAN, 125 mg 4 times per day by mouth for 10 days followed by rifaximin 400 mg 3 times daily for 20 days, OR Weak/Low
• FDX 200 mg given twice daily for 10 days, OR Weak/Low
• Fecal microbiota transplantationc Strong/Moderate

Abbreviations: FDX, fidaxomicin; VAN, vancomycin.

aAll randomized trials have compared 10-day treatment courses, but some patients (particularly those treated with metronidazole) may have delayed response to treatment and clinicians should consider extending treatment duration to 14 days in those circumstances.

bThe criteria proposed for defining severe or fulminant Clostridium difficile infection (CDI) are based on expert opinion. These may need to be reviewed in the future upon publication of prospectively validated severity scores for patients with CDI.

cThe opinion of the panel is that appropriate antibiotic treatments for at least 2 recurrences (ie, 3 CDI episodes) should be tried prior to offering fecal microbiota transplantation.

What are the best treatments of fulminant CDI?

Recommendations
  • 1. For fulminant CDI*, vancomycin administered orally is the regimen of choice (strong recommendation, moderate quality of evidence). If ileus is present, vancomycin can also be administered per rectum (weak recommendation, low quality of evidence). The vancomycin dosage is 500 mg orally 4 times per day and 500 mg in approximately 100 mL normal saline per rectum every 6 hours as a retention enema. Intravenously administered metronidazole should be administered together with oral or rectal vancomycin, particularly if ileus is present (strong recommendation, moderate quality of evidence). The metronidazole dosage is 500 mg intravenously every 8 hours.*
  • *Fulminant CDI, previously referred to as severe, complicated CDI, may be characterized by hypotension or shock, ileus, or megacolon.
  • 2. If surgical management is necessary for severely ill patients, perform subtotal colectomy with preservation of the rectum (strong recommendation, moderate quality of evidence). Diverting loop ileostomy with colonic lavage followed by antegrade vancomycin flushes is an alternative approach that may lead to improved outcomes (weak recommendation, low quality of evidence).

ADULT:  What are the best treatments for recurrent CDI?

Recommendations
  1. Treat a first recurrence of CDI with oral vancomycin as a tapered and pulsed regimen rather than a second standard 10-day course of vancomycin (weak recommendation, low quality of evidence), OR
  2. Treat a first recurrence of CDI with a 10-day course of fidaxomicin rather than a standard 10-day course of vancomycin (weak recommendation, moderate quality of evidence), OR
  3. Treat a first recurrence of CDI with a standard 10-day course of vancomycin rather than a second course of metronidazole if metronidazole was used for the primary episode (weak recommendation, low quality of evidence).
  4. Antibiotic treatment options for patients with >1 recurrence of CDI include oral vancomycin therapy using a tapered and pulsed regimen (weak recommendation, low quality of evidence), a standard course of oral vancomycin followed by rifaximin (weak recommendation, low quality of evidence), or fidaxomicin (weak recommendation, low quality of evidence).
  5. Fecal microbiota transplantation is recommended for patients with multiple recurrences of CDI who have failed appropriate antibiotic treatments (strong recommendation, moderate quality of evidence).
  6. There are insufficient data at this time to recommend extending the length of anti–C. difficile treatment beyond the recommended treatment course or restarting an anti–C. difficile agent empirically for patients who require continued antibiotic therapy directed against the underlying infection or who require retreatment with antibiotics shortly after completion of CDI treatment, respectively (no recommendation).

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TREATMENT (PEDIATRIC CONSIDERATIONS)

What is the best treatment of an initial episode or first recurrence of nonsevere CDI in children?

Recommendation
  1. Either metronidazole or vancomycin is recommended for the treatment of children with an initial episode or first recurrence of nonsevere CDI (see Pediatric treatment section for dosing) (weak recommendation, low quality of evidence) (Table 2).
Table 2.

Recommendations for the Treatment of Clostridium difficile Infection in Children

Clinical Definition Recommended Treatment Pediatric Dose Maximum Dose Strength of Recommendation/ Quality of Evidence
Initial episode, non-severe • Metronidazole × 10 days (PO), OR
• Vancomycin × 10 days (PO)
• 7.5 mg/kg/dose tid or qid
• 10 mg/kg/dose qid
• 500 mg tid or qid
• 125 mg qid
Weak/Low
Weak/Low
Initial episode, severe/ fulminant • Vancomycin × 10 days (PO or PR) with or without
metronidazole × 10 days (IV)a
• 10 mg/kg/dose qid
• 10 mg/kg/dose tid
• 500 mg qid
• 500 mg tid
Strong/Moderate
Weak/Low
First recurrence, non-severe • Metronidazole × 10 days (PO), OR
• Vancomycin × 10 days (PO)
• 7.5 mg/kg/dose tid or qid
• 10 mg/kg/dose qid
• 500 mg tid or qid
• 125 mg qid
Weak/Low
Second or subsequent recurrence • Vancomycin in a tapered and pulsed regimenb, OR
• Vancomycin for 10 days followed by rifaximinc for 20 days, OR
• Fecal microbiota transplantation
• 10 mg/kg/dose qid
• Vancomycin: 10 mg/kg/dose qid; rifaximin: no pediatric dosing
• …
• 125 mg qid
• Vancomycin: 500 mg qid; rifaximin: 400 mg tid
• …
Weak/Low
Weak/Low
Weak/Very low

Abbreviations: IV, intravenous; PO, oral; PR, rectal; qid, 4 times daily; tid, 3 times daily.

aIn cases of severe or fulminant Clostridium difficile infection associated with critical illness, consider addition of intravenous metronidazole to oral vancomycin.

bTapered and pulsed regimen: vancomycin 10 mg/kg with max of 125 mg 4 times per day for 10–14 days, then 10 mg/kg with max of 125 mg 2 times per day for a week, then 10 mg/kg with max of 125 mg once per day for a week, and then 10 mg/kg with max of 125 mg every 2 or 3 days for 2–8 weeks.

cNo pediatric dosing for rifaximin; not approved by the US Food and Drug Administration for use in children <12 years of age.

What is the best treatment of an initial episode of severe CDI in children?

Recommendation
  1. For children with an initial episode of severe CDI, oral vancomycin is recommended over metronidazole (strong recommendation, moderate quality of evidence).

What are the best treatments for a second or greater episode of recurrent CDI in children?

Recommendation
  1. For children with a second or greater episode of recurrent CDI, oral vancomycin is recommended over metronidazole (weak recommendation, low quality of evidence).

Is there a role for fecal microbiota transplantation in children with recurrent CDI?

Recommendation
  1. Consider fecal microbiota transplantation for pediatric patients with multiple recurrences of CDI following standard antibiotic treatments (weak recommendation, very low quality of evidence).

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The most recent antibiotic, Dificid (fidaxomicin) www.dificid.com is the first medication approved by FDA to treat C diff. Associated-Diarrhea CDAD in more than twenty five years with superiority in sustained clinical response (5)

ZINPLAVA (bezlotoxumab) is now available for prescription. Ordering information is available on the brand website:

http://www.zinplava.com/

What is Zinplava™ ?   ZINPLAVA™ is indicated to reduce recurrence of Clostridium difficile infection (CDI) in patients 18 years of age or older who are receiving antibacterial drug treatment of CDI and are at a high risk for CDI recurrence.

ZINPLAVA is not indicated for the treatment of CDI.

ZINPLAVA is not an antibacterial drug.

ZINPLAVA should only be used in conjunction with antibacterial drug treatment of CDI.

Full prescribing information can be accessed by clicking on the following link:

http://www.merck.com/product/usa/pi_circulars/z/zinplava/zinplava_pi.pdf

Organizations In Clinical Trials focused on C. difficile prevention, and treatments including recurrent C. diff. infections.  Click on the following link to be redirected to the Clinical Trials Page:

https://cdifffoundation.org/clinical-trials-2/

 

Loperamide (Immodium), diphenoxylate and bismuth medications are contraindicated as they slow the fecal transit time which extends the toxins in the gastrointestinal system.  The use of Cholestyramine has demonstrated positive results as toxins A and B bind to the resin as it passes through the intestines aiding in slowing bowel motility and assists in decreasing dehydration (9).  ** Always discuss symptoms and treatments with the physician/s treating this infection.

The use of probiotics during treatment and prophylactic may decrease diarrhea by interrupting either of the potential mechanisms; by maintaining the flora of the gut and ongoing carbohydrate fermentation; and/or by competitively inhibiting the growth of pathogens (6).

The latest treatment for patients with CDI (CDAD) is the fecal microbiota transplant (FMT) and aka stool transplant preliminarily been effective in curing C diff. This procedure is not FDA approved and is a hopeful treatment.

**  Treatment to Reduce Recurrent C. difficile infections In Patients 18 Yeas Of Age And Older:

On October 22, 2016 announced that the U.S. Food and Drug Administration (FDA) has approved ZINPLAVA™ (bezlotoxumab) Injection 25 mg/mL.

ZINPLAVA is indicated to reduce recurrence of Clostridium difficile infection (CDI) in patients 18 years of age or older who are receiving antibacterial drug treatment of CDI and are at high risk for CDI recurrence.

ZINPLAVA is not indicated for the treatment of CDI.

ZINPLAVA is not an antibacterial drug. ZINPLAVA should only be used in conjunction with antibacterial drug treatment of CDI.

Please see Prescribing Information for ZINPLAVA (bezlotoxumab) at http://www.merck.com/product/usa/pi_circulars/z/zinplava/zinplava_pi.pdf 

Patient Information for ZINPLAVA at http://www.merck.com/product/usa/pi_circulars/z/zinplava/zinplava_ppi.pdf

 

Since  November 2012, the  CDC has been sharing public announcement regarding antibiotic use;   Colds and many ear and sinus infections are causes by viruses, not bacteria. Taking antibiotics to treat a virus can make those drugs less effective when you and your family really need them (7).  Limiting the usage of antibiotics will also help limit new cases of CDI.

C.diff. spores are able to live outside of the body for a very long period of time and are resistant to most routine cleaning agents.

It has also been proven that alcohol based hand sanitizers remain ineffective in eradicating C. diff. spores.  In 2009 Clorox Commercial Solutions Ultra Clorox Germicidal Bleach ® was named the first and only product to obtain Federal EPA registration for killing C. diff. spores on hard, non porous surfaces when used as directed (1).  The CDC also recommends a 1:10 ( 1 cup bleach to 9 cups of water) dilution of bleach and water for cleaning hard non-porous surfaces keeping areas covered with solution for 10 minutes and the solution is to be mixed fresh daily.

Hand hygiene remains #1 in Infection Prevention.

Following guidelines in infection control; it is important to wash hands upon entering and before exiting a patient’s room (4). The spores are difficult to remove from hands; Universal Contact Precautions remain best practice for healthcare personnel and Contact Precautions for patients with a confirmed diagnosis of CDI. Prevention through education about CDI has proven effective and beneficial to environmental housekeeping departments, health care professionals, administration, patients, and their families (2)

For More Information On Hand Washing Click On The Following Link:

https://cdifffoundation.org/hand-washing-updates/

 

References:

(1) Clorox registered EPA
http://www.ahe.org/ahe/learn/press-releases/2009/20090402_clorox_epa_cdiff.shtml

(2) Clostridium difficile (CDI) Infections thttp://www.cdc.gov/hai/pdfs/toolkits/CDItoolkitwhite_clearance_edits.pdf
(3) Lab Tests and Diagnosis Mayo Clinichttp://www.mayoclinic.com/health/c-difficile/DS00736/DSECTION=tests-and-diagnosis
(4) CDC Hand washing
http://www.cdc.gov/Features/HandWashing/

(5) FDA announcement Dificid
http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm257024.htm

(5) Dificid.com
http://www.dificid.com

(6) Probiotics in the prevention of antibiotic-associated diarrhea
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3105609/

(6) Danimals PRNewswire8/Jan2012;
http://www.prnewswire.com/news-releases/dannonr-danimalsr-adds-proven-benefits-of-probiotics-53347947.html

(7) Get smart antibiotics week CDC
http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6144a7.htm

(8) Metronidazole
http://www.everydayhealth.com/drugs/flagyl

(9) Cholestyranine
http://www.globalrph.com/cholestyramine.htm