C difficile guidelines, for adults and kids

Following yesterday's blog on more virulent strains of C difficile seemingly related to a non-nutritive food additive (see http://gmodestmedblogs.blogspot.com/2018/04/non-nutritive-food-additives-and-c.html ), I will review the newest guidelines on C diff infections from the Infectious Disease Society of America (see cdiff guidelines CID2018 in dropbox or DOI: 10.1093/cid/cix1085). will focus this blog on the relevant guidelines for outpatient C diff infections (CDI), not more seriously ill hospitalized patients

Details:

--C diff is typically defined by symptoms (mostly diarrhea) and a stool test positive for C diff toxin or finding toxigenic C diff, or finding pseudomembranous colitis on colonoscopy

--Diagnosis: test patients with unexplained (eg, not on laxatives), new onset >= 3 unformed stools in 24 hours

    ​--in cases meeting these criteria, use NAAT (nucleic acid amplification test) alone or a multi-step algorithm (eg glutamate dehydrogenase [GDH] plus toxin; GDH plus toxin, arbitrated by NAAT; or NAAT plus toxin) [overall the highest sensitivity is for NAAT and GDH, but low specificity for both; low sensitivity but moderate specificity for toxin immunoassays]

    --in cases not meeting the above criteria, use a stool toxin test (preferably one with high sensitivity, since there are many different ones around) as part of a multi-step algorithm as above

    --do not do repeat testing within 7 days during the same episode of diarrhea, or test asymptomatic patients (except for in epidemiological studies)

    --there is insufficient evidence to recommend fecal lactoferrin or other biological markers

    --in neonates or infants <1 yr old, do not routinely test for C diff (high prevalence of asymptomatic carriers); for those 1-2 yrs old, exclude other causes before testing for C diff; in those >2 yo, test for C diff only if prolonged or worsening diarrhea and high risk (eg IBD, immunocompromise), or relevant exposures (antibiotics, or contact with health care system)

--infection control:

    ​--for outpatients (gleaned from recommendations for inpatients): good hand-washing (soap and water are better than alcohol-based products, since the latter do not reliably remove spores), and continue contact precautions for 48 hours after diarrhea has resolved

    --insufficient data to recommend testing asymptomatic contacts

    --proton-pump inhibitors (PPIs) may increase CDI (epidemiologic data, not fulling accepted), insufficient evidence that they should be stopped (though should be discontinued if not really necessary). see below

    --probiotics: insufficient data to recommend for primary prevention (though, see: http://gmodestmedblogs.blogspot.com/2017/03/probiotics-in-c-diff.html
 )

--treatment:

    --initial episode:

        --discontinue treatment if patient on offending antibiotic (could influence risk of CDI recurrences), if possible

        --start empiric antibiotics for CDI if lab tests have substantial delay

        --therapy for initial CDI: either vancomycin 125mg qid orally, or fidaxomicin 200mg bid for 10 days

        --use metronidazole only if nonsevere CDI, or unable to get the above 2 antibiotics, at 500mg tid for 10 days. and avoid repeated or prolonged courses because of potential irreversible neurotoxicity. effectiveness of metronidazole is significantly less than the other antibiotics

    --recurrent CDI (a case within 2-8 weeks after confirmed prior case), occurs in 10-30% of patients:

        --treat with vancomycin as a tapered and pulsed regimen: eg. 125mg qid for 10-14 days, then 125mg bid for 1 week, then 125 mg daily for 1 week, then 125mg qod for 2-8 weeks

        --or, treat with fidaxomicin for 10 days [the data, by the way, are pretty consistent that the risk of recurrent CDI is lower with initial therapy with fidaxomicin vs vancomycin, and patients are also less likely to develop overgrowth of vancomycin-resistant Enteroccocus and Candida spp]

        --treat with standard 10-day course of vancomycin if metrodinazole was used for the first course

         --probiotics: they have "promise for the prevention of CDI recurrences", esp Saccharomyces boulardii and Lactobacilus spp, but "none has demonstrated significant and reproducible efficacy in controlled clinical trials".

    -- if >1 recurrence:

        --oral vancomycin in tapered and pulsed regimen as above, or standard 10-day course of vanco followed by rifaximin or fidaxomicin

        --fecal microbiota transplant (FMT) if multiple CDI recurrences failing appropriate treatments (eg, see http://gmodestmedblogs.blogspot.com/2016/02/refractory-cdiff-and-frozen-fecal.html  )

    --insufficient evidence to recommend extending the course of CDI treatment or restarting empiric CDI treatment in those requiring continued antibiotic treatment for an underlying infection or needing antibiotics soon after completing CDI treatment

    --pediatrics: 

        --either metronidazole (7.5 mg/kg/dose tid or qid, max 500mg tid or qid) or vancomycin (10 mg/kg/dose qid, max 125 mg qid) for first episode, or first recurrence of nonsevere CDI

        --for 2nd or subsequent CDI: vanco with tapered and pulsed regimen: 10mg/kg/dose for 10-14 days, then 10 mg/kg/dose bid for 1 week, then 10mg/kg/dose daily once per week, the 10 mg/kg/d every 2-3 days for 2-8 weeks; or can give standard vanco for 10 days followed by rifaximin for 20 days (rifaximin not approved by FDA in those <12 yo, and then use standard adult dose with max of 400mg tid)

        ​--or fecal microbiota transplant if multiple recurrences

Commentary:

--estimates are about 500,000 cases of CDI in the US annually, 15-30,000 deaths, cost of $1.2-5.9 billion in 2012 report. CDI incidence is dramatically increasing in kids as well: Olmstead County found increase from 1991 to 2009 of 2.6 then 32.6/100,000.

--though C diff infection (CDI) was first identified in hospitalized patients (and remains the most important cause of health-care associated diarrhea), it has become an important community pathogen.

    --65% of C diff cases are estimated to be in health care facilities in the prior 12 weeks, rest community-based. the acquisition of hospital C diff is dependent on length-of-stay, yet another reason to avoid hospitalization when possible, or try to minimize LOS if hospitalized. the hospital rates of C diff are therefore not expressed per admission but per patient-days in the hospital, and the pooled rate in 2010 was 7.4/10,000 patient-days.

    --The shift to community-acquired cases is concerning: 36% did not have antibiotic exposure, though 31% of those without antibiotic exposure had received PPIs.

--the incidence of C diff is highest among those >65 yo, and higher among females and white persons

--the RT027 strain is more virulent, less often associated with being asymptomatic, and may be selected for by fluoroquinolones (this strain is resistant, others less so) and, i would add, may be related to food additives (see http://gmodestmedblogs.blogspot.com/2018/04/non-nutritive-food-additives-and-c.html )

--this virulent strain RT027 has decreased in incidence, along with CDI in parts of Europe (perhaps attributed to decreased fluoroquinolone use), but it remains one of the most commonly identified C diff strains in the US, accounting for a sizable minority of CDIs

--another virulent strain RT078 (also in http://gmodestmedblogs.blogspot.com/2018/04/non-nutritive-food-additives-and-c.html ) has been increasing, associated with similar virulence as RT027, but has been more prevalent in younger people and is more community-associated

--patients with IBD, especially ulcerative colitis, are at increased risk of CDI, with risk >3% within 5 years of diagnosis, and are 33% more likely to have recurrent CDI (which means that we should not simply attribute diarrhea in a patient with UC as being an exacerbation!!). other high risk people include patients with CKD/ESRD, those with tumors/immunosuppressed

--fidoxomicin is a new, narrow spectrum macrocyclic antibiotic, derived from an actinomycete, and is minimally absorbed into the bloodstream

--0.8% of patients develop candidemias in the 120 days after CDI, increasing with CDI severity and treatment with combo of vanco and metronidazole

--routes of transmission: fecal-oral. But spores spread easily. about 10% of hospital cases are just from occupying the room where prior patient had CDI. About 30% of cases of CDI in hospitals are related to exposure to those with CDI infection, but about the same number are associated with exposure to asymptomatic carriers. CDI also related to antibiotic use on the wards, not just in the individual who gets it. and spores continue to be shed after treatment of a person with CDI

--risk factors: major modifiable one is antibiotics. All are associated with C diff, but esp 3^rd/4^th generation cephalosporins, fluoroquinolones, carbapenems, clindamycin. And the longer the exposure, the higher the risk. Presumably by depleting the normal microbiome and providing a niche for C diff to flourish. Since the microbiome changes attributable to antibiotics last awhile, the risk of CDI increases until the 3 month period after stopping the antibiotics. Also C diff is assoc with chemotherapy, GI surgery or tube feeding, perhaps PPIs (associated also with less microbiome diversity, increased risk of recurrence, ?increased risk of primary CDI: see http://gmodestmedblogs.blogspot.com/2017/04/ppis-and-recurrent-c-diff-infections.html ), and even some suggestion that low vitamin D levels play a role. Kids have more asymptomatic colonization than adults, even with the more virulent strains

--one unclear issue is what to do if the patient has had recent CDI but needs to be on antibiotics for another reason: their advice, in the absence of definitive data, are based on a not-so-great study of those receiving antibiotics within 90 days of CDI treatment, is "it may be prudent to administer low doses of vancomycin or fidaxomicin (eg, 125 mg or 200 mg, respectively, once daily) while systemic antibiotics are administered"​

--there have been effective antibiotic stewardship programs in hospitals to decrease antibiotic resistance and have found important decreases in C diff infections (see http://gmodestmedblogs.blogspot.com/2017/06/decreasing-antibiotic-resistance-by.html )

so, these guidelines add several changes from current management, as detailed above, especially in discounting the role of metronidazole and augmenting that of fidaxomicin​. But perhaps the most important change we can effect to decrease CDI is by decreasing overall antibiotic: decreasing the widespread inappropriate use of antibiotics, using the most specific and narrow-spectrum ones when necessary (eg, really avoiding fluoroquinolones etc whenever possible), and trying to implement antibiotic stewardship programs.  overall, the goal is to optimize and protect our microbiomes.​ And, as is so often the case, a healthy lifestyle (eating a largely vegetarian diet, proper body weight, exercise) is the heart of a strong gut.