Disclosures Consultant: Genentech Clostridium difficile infection - PDF document

Disclosures § Consultant: Genentech Clostridium difficile infection Sarah Doernberg, MD, MAS Associate Professor, Division of Infectious Diseases Medical Director of Adult Antimicrobial Stewardship Some controversy Outline Clostridium versus Clostridioides difficile Brief background and epidemiology § “In summary, both names, Diagnosis § Clostridium difficile and Management—mild, uncomplicated disease § Clostridioides difficile , may Management—moderate-severe disease § be currently used. With time Management—recurrent/relapsed disease § the community of Management—fulminant disease microbiologists dealing with § C. difficile will likely reach Prevention § an agreement upon use of a single name.” Oren A and Rupnik M. https://doi.org/10.1016/j.anaerobe.2018.07.005 1 | [footer text here]

One of CDC’s 3 “Urgent Threats” CDI background Risk factors: Epidemiology • Antibiotics • 15% of HAIs, #2 cause • Carriage is common • Age • < 3% healthy adults • Hospital exposure 500,000 • 20% hospitalized pts • Acid-suppression Biology • up to 50% in LTCF • IBD 3.8 billion • Anaerobic GPR • Tube feeds • Spore-forming • Immune status • Toxins A+B+/-binary • Female gender • Domestic animals? • Multiple strains • Retail food? • Fecal-oral spread • Trehalose? Magill SS et al., N Engl J Med. 2018 Nov 1;379(18):1732-1744. doi: 10.1056/NEJMoa1801550. https://www.cdc.gov/drugresistance/biggest_threats.html Duration, number, and intensity of antibiotics Epidemiology trends, inpatients affect risk for CDI Molecular testing era Epidemic strain http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6034a7.htm Stevens V, et al. Clin Infect Dis 2011; 53: 42-48. 2 | [footer text here]

Spread of CDI in the hospital Antibiotic use affects the population risk Endogenous Asymptomatic 20% carriage carriers Symptomatic cases 30% 25-33% Other • Risk for CDI if prior room occupant got antibiotics = HR 1.22 (1.02-1.45) (environmental contamination, etc) Brown K et al. JAMA Intern Med. 2015 Apr;175(4):626-33 Freedberg DE et al. JAMA Intern Med. 2016 Dec 1;176(12):1801-1808 CDI overdiagnosis Diagnostic testing • 21% +PCR • Of these, 44% + toxin • Toxin-/PCR+ • ↓bacterial load • ↓abx Glutamate dehydrogenase • ↓diarrhea Enzyme immunoassay Polymerase chain • No CDI- Ag (GDH) (EIA) reaction (PCR): complications • Bacterial detection • Protein detection • Toxin-producing gene • Sn but not Sp • ↓Sensitivity • ↑Sensitivity • ↑Specificity • ↓ Specificity Polange CR et al., JAMA Intern Med. 2015 Nov;175(11):1792-801. 3 | [footer text here]

UCSF CDI testing algorithm (for now) New testing guidance PCR only if limited to high pretest probability Multistep algorithm preferred over PCR alone -GDH+toxin à PCR -PCR+toxin Guidance on appropriate testing No tests if on laxatives Test only if new onset ≥ 3 stools/24 hours McDonald LC et al. CID, cix1085, https://doi.org/10.1093/cid/cix1085 Treatment scenario #1. 63 y/o F recently treated for a UTI with levofloxacin, now having watery stools 4x/day, fever to 38.3, WBC 11K, Cr 1.0. Other vitals stable. PCR positive for C. difficile toxin. With what should you treat her? A. Vancomycin 125 mg po qid B. Vancomycin 500 mg po qid C. Metronidazole 500 mg po tid MANAGEMENT D. Fidaxomicin 200 mg po bid 4 | [footer text here]

CDI Rx no longer depends on severity! Initial uncomplicated CDI, severe or non-severe § VAN 125 mg po QID x 10 days (up to 14) (strong, high) § FDX 200 mg PO twice daily x 10 days (strong, high) Severe Mild to moderate -Not well validated -Does not meet criteria for - Favor in patients at high risk for recurrence -IDSA/SHEA: WBC > 15K severe § If above agents are unavailable, can consider metronidazole x or Cr ≥ 1.5 -Diarrhea ≥ 3 stools/24 10-14 days (weak, high) hours -Severe, complicated à “fulminant” -Severe + hypotension, shock, ileus, and/or megacolon Zar F A et al. Clin Infect Dis. 2007;45:302-307; McDonald LC et al. CID, cix1085, https://doi.org/10.1093/cid/cix1085 M cD onald LC et al. C ID , cix1085, https://doi.org/10.1093/cid/cix1085 New evidence to support vancomycin RCTs metronidazole vs. vancomycin 120 p = 0.005 NS p = 0.02 NS 100 80 • aRR death VAN vs MT:Z 60 • Any severity: 0.86 (0.74 to 0.98) MT Z 40 Vanco • Severe: 0.79 (0.65 to 0.97) 20 • NNT to prevent 1 death, severe 0 CDI: 25 Cure, all Cure, m ild- Cure, Recurren ce mod severe • Similar findings for study of MTZ vs VAN vs tolevamer • Cure not differential with regard to levels of severity Zar F A et al. Clin Infect Dis. 2007;45:302-307; Leffler DA and Lamont JT. NEJM 2015; 372:1539-1548; Stevens VW et al. JAMA Intern Med. 2017 Feb 6. doi: 10.1001/jamainternmed.2016.9045. Johnson S et al., Clin Infect Dis 2014;59(3):345-54 5 | [footer text here]

What about fidaxomicin? Real-world fidaxomicin experience • Bottom line vs. VAN: Similar cure (~88%), lower § UK Trust Hospitals pre-post recurrence (13-15% vs. 25-27% ) analysis s/p introduction of • Unclear role in multiply recurrent or severe disease fidaxomicin § Each hospital had a different Cure Relapse FDX VAN MTZ approach Strain $2800 $250-680 $22 Epidemic Same Same Non-epidemic Same ¯ Concomitant abx ­ ¯ • A and B: Fidaxomicin first-line for all Prior CDI Same ¯ • C, E, F, G: Selected episodes • D: Recurrences only Louie TJ, et al. NEJM 2011;364:422-431; Cornely et al, Lancet Infect Dis 2012;12:281-8 ; Petrella LA, et al. Clin Infect Dis 2012;55(3):351-7; Mullane et al., CID 2011;53(5):440-7; Corneley et al., CID 2012;55:s154-s161.; Bartsch SM et al., Goldenberg SD et al. Euro J Clin Microbiol and Infect Dis 2016; 35L 251-9. CID 2013; 57(4): 555-561; Konijeti GG et al., CID 2014; 58:1507-1514. Take-home Additional considerations § Stop unnecessary antibiotics § For initial treatment of non-fulminant CDI, VAN 125 mg po QID x 10-14 days for most patients § Shorten antibiotic courses § Role of fidaxomicin unclear § Narrow antibiotic spectrum - Consider if ↑ risk of relapse or need CA § Stop acid-suppressive medications when possible (though low quality evidence) § No anti-peristaltic agents until acute sxs improve 6 | [footer text here]

First recurrence, non-fulminant CDI Treatment scenario #2: You are seeing a 62 y/o F who has takes chronic amoxicillin/clavulanic acid for suppression of Enterococcal osteomyelitis and has § If MTZ used initially à VAN 125 mg po QID x 10 days developed her second bout of C. difficile colitis. Her first (weak, low) episode was treated with VAN x 10 days. Her WBC count § If VAN used initially, two options: is 9 and Cr is 0.3. With what should you treat her? 1. VAN taper (weak, low) A. MTZ 500 mg po TID x 10 days 2. FDX 200 mg po BID x 10 days (weak, mod) B. VAN 125 mg PO QID x 10 days C. VAN taper D. FDX 200 mg po BID x 10 days M cD onald LC et al. C ID , cix1085, https://doi.org/10.1093/cid/cix1085 Evidence to support VAN taper Vancomycin taper Recurrence § PBO groups from 2 § 125 mg po 4x daily x 14 days RCTs of probiotics 80% N = 10, 71% 70% § 125 mg po 2x daily x 7 days - (n = 163) 60% P = 0.01 § 125 mg po 1x daily x 7 days § 29 got VAN tapers of 50% varying stripes 40% § 125 mg po every other day x 8 days (4 doses) N = 29, 31% 30% - Mean 21.5 +/- 10 § 125 mg po every 3 days x 15 days (5 doses) 20% days 10% § Small #, uncontrolled 0% stand ard VA N VA N tap er Kelly and LaMont, N Engl J Med. 2008;359(18):1932-40. McFarland LV et al. Am J Gastroenterol. 2002 Jul;97(7):1769-75 7 | [footer text here]

Treatment scenario #3. This patient returns one month Risk for recurrent CDI after you have treated her with a 10-day course of PO FDX complaining of ongoing diarrhea. A repeat stool toxin is 100% positive. What do you do? 90% 80% A. VAN followed by rifaximin 70% 60% B. VAN taper No recurr ence 50% C. FDX 200 mg PO BID x 10 days 40% Rec urrence 30% D. Fecal microbiota transplantation 20% E. Any of the above 10% 0% 1st episode 2nd episode 3rd episode Johnson S. J Infect 2009;58(6):403-10; Pepin J et al. Clin Infect Dis. 2005 Jun 1;40(11):1591-7 Incidence of mrCDI has increased 188% Second/subsequent recurrence Risk factors: § VAN taper/pulse (weak, low) • Age § VAN 125 mg po QID x 10 days followed by rifaximin 400 mg • Female gender po TID x 20 days (weak, low) • Nursing home • Antibiotic use § FDX 200 mg PO BID x 10 days (weak, low) • PPI use § FMT (strong, mod) • Steroid use • CKD - “appropriate antibiotic treatments for at least 2 recurrences… should be tried prior to offering [FMT]” Ma GK et al. Ann Intern Med. 2017;167(3):152-158. M cD onald LC et al. C ID , cix1085, https://doi.org/10.1093/cid/cix1085 8 | [footer text here]