Sweatman - Tx for C. diff

Question 1

What strain of C. diff has esp. INC virulence? Why?

Answer 1

• NAP 1/027: lacks tcdC protein, whose expression normally negatively regulates transcription and production of AB toxin

Question 2

What is the epi of C. diff?

Answer 2

• Leading cause of AB-related diarrhea
• Most common hospital-acquired infection since 2010
• Mortality 7x rate of all other intestinal infections combined
  1. Emergency of hyper-virulent strain assoc with rise in disease severity and mortality

Question 3

What are the risk factors for C. diff?

Answer 3

• Exposure to any antimicrobials, esp. when used in multiple; most commonly with:
  1. Clindamycin, penicillins
  2. Cephalosporins, floroquinolones
• Hospitalization and other healthcare settings
• Age: most common in 65-84 y/o’s
• IBD: INC incidence parallels that of CD
• Gastric acid suppression: not so straightforward link
  1. Recent studies suggest PPI’s are NOT a risk factor

Question 4

How is C. diff diagnosed?

Answer 4

• Clinical suspicion: usually diarrhea in pt with current or recent AB use
  1. Supported by toxigenic C. diff or associated toxins in stool
• EIA’s (immuno-assays) to detect A and B toxins: rapid (2-4 hrs), relatively inexpensive, & convenient, but limited sensitivity w/freq false negative results
  1. More sensitive tests under evaluation as alternatives to toxin EIA’s

Question 5

What are the key points for C. diff tx?

Answer 5

• DOC: oral Metronidazole q8h x 10d for mild-mod
  1. PO Vanc q6h x 10d for severe disease, and pregnant/lactating women
• COMPLICATED DISEASE: high-dose PO Vanc and IV Metronidazole
• Rectal Vanc enemas can be given in pts w/ileus, abdominal distention, and anatomic/surgical abnormalities that prevent oral AB’s from reaching colon
• Tx 1st recurrence w/same protocol; 2nd w/PO Vanc in extende tx course

Question 6

What are the AE’s with Metronidazole?

Answer 6

• 10% of pts have nausea, metallic taste
• Readily crosses placenta -> controversy as to adverse effects in fetus: facial anomalies
  1. PO Vanc in pregnancy
• Expressed in breast milk: INC oral and rectal Candida colonization and loose stools
• Peripheral neuropathy (numbness and paresthesias) of extremities after very high doses/prolonged use
  1. Could occur with repeated tx failures, and multiple courses of Metro tx

Question 7

Why Fidaxomicin?

Answer 7

• Macrolide AB: bactericidal against C. diff, incl. some hypervirulent strains
• INH bacterial RNA polys (via different MOA)
• Minimal/no activity against G- anaerobes, facultative aerobes, and enterobacteriaceae, and limited affect on normal fecal flora
• No cross-resistance w/other antimicrobials, incl. rifamycin class: different sites of action on RNA poly
• Minimal systematization after oral admin; almost completely eliminated in stool
• Comparable pattern/rates of AE’s to Vanc: N/V, abdominal pain, GI bleeding (all <12%)

Question 8

Who wins head-to-head in high-risk groups, Fidaxo or Vanc?

Answer 8

• In “head-to-head” comparison w/Vanc in groups at high risk for CDI recurrence, Fidaxomicin provides:
  1. Superior clinical response
  2. Lower incidence of recurrence

Question 9

How does cost vary in CDI drugs?

Answer 9

• Metronidazole < Vanc << Fidaxomycin
• IF Fidaxomicin could DEC recurrence rate and lower overall tx costs, INC initial investment may be worthwhile

Question 10

What is the protocol for fecal microbiota transport?

Answer 10

• RECIPIENT: stop AB’s 2-3d prior to transplant
  1. Colonoscopy-like prep to DEC stool volume
  2. Loperamide (anti-diarrheal) after transplant
• DONOR: no recent AB use + screened for fecal pathogens (extensive “vetting” and testing of donor)
  1. Tested for Hep A, B, C, syphilis, HIV 1 and 2
  2. Milk of Mg as softener: makes prep of instillate easier
• Suspend stool in non-bacteriostatic saline by blender; filter through gauze
• Instill 60mL via colonoscopy (can also be done via NG tube or gastroscopy)

Question 11

Does fecal microbiota transport work?

Answer 11

• Appears to be effective
• Trend towards lower GI instillation
• No evidence of AE’s
• NOTE: this is a burgeoning field of research, as it is now being tested as a potenital tx for other GI conditions, like UC and Crohn’s (IBD)