Infectious Disease Compendium

Clostridioides difficile

Microbiology

Anaerobic gram positive rod. Was Clostridium difficile until 2018 (PubMed). At least it is still C. difficile.

Epidemiologic Risks

Most Clostridia are found in soil and gi tracts.

C. difficile is driven by antibiotics, with clindamycin and quinolones being the most likely suspects, but any antibiotic can cause it. However, cumulative exposure to antibiotics is also a risk (PubMed).

C. difficile asymptomatic carriage rates are about 12% (PubMed).

Hospitals may till the soil, metaphorically speaking, with antibiotics, but the source is usually NOT the hospital, with 35% of cases genetically linked (PubMed) and in another study 75% of hospital associated C. difficile is not hospital acquired (PubMed); they must have brought it in with them. 15% of patients will have C. difficile colonization on admission (PubMed).

They are not getting it from us, ie health care workers, where in one study zero, nip, nil, nada were colonized with C. difficile (PubMed).

Curiously, doxycycline may be protective when given with other antibiotics (PubMed)(PubMed)(PubMed) as is rifampin.  Being on metronidazole for another reasons decreases odds by 80% (PubMed).

Probiotics are beneficial in preventing C. difficile, in one meta analysis by 66% (Reference) are probably cost effective (PubMed).

The closer the probiotic is given to the first dose of antibiotic, perhaps the better the prevention (PubMed).

C. difficile can be found in up to 20% of ground meat from stores (PubMed), salads and veal. I bet it is found in damn near everything we eat, since everything we eat has a fine patina of human and/or animal stool. It is more a food borne infection than most people suspect.

And Spanish sandboxes. Along with Salmonella. Sandboxes are a disgusting soup of pathogenic fecal flora. Which defines children when you think about it.

Obesity is associated with a different bowel microbiome than is seen in thin people and may be why obesity is a risk (PubMed).

C. difficile can be nosocomial and, pay attention here me bucko, IS NOT KILLED BY THE ALCOHOL FOAM. Sorry I yelled. But you have to wash your hands. Since the turn of the century there is a new strain of C. difficile being driven by quinolone use, both for inpatient and outpatient disease (PubMed). This strain causes severe disease, with toxic megacolon and death is not infrequent.

Diarrhea is common in the ICU, it is usually neither infectious or C. difficile. Not that C. difficile isn't an infection(PubMed).

PPI use is a risk for disease and relapse (44% chance of relapse); as the hippies knew, acid is good, man (PubMed). PPI use is a risk in every study (PubMed).

C. difficile can cause diarrhea with no classic risk factors. In Maryland, as an example, 43 (3.9%) of outpatients had C. difficile as a cause of their diarrhea. 7 had no recognized risk factors, and 3 had neither risk factors nor co-infection with another enteric pathogen (PubMed). "Nearly half of Medicare beneficiaries admitted with CACD have no recent antibiotic exposure (PubMed)."

The incidence of multiple recurrences is going up (PubMed).

Risks to family low, 5 of 1061 spouses and 3 of 501 children developed C. difficile within three months of the index case (PubMed).

Nurses will often say that stool smells like C. difficile, and I have always poo-pooed the idea. All stool stinks (but mine) but if a dog can be trained to sniff out C. difficile (poor beast) why not a human (PubMed)?

Syndromes

C. difficile (2015 NEJM Review): pseudomembranous or antibiotic associated colitis.

The current molecular testing is at least 90% but "Considering that up to 50% of institutionalized individuals may be asymptomatically colonized by toxigenic and that diarrhea may have a variety of causes, false-positive results are likely, especially given the high sensitivity of molecular approaches. Because it is likely that asymptomatic colonization by toxigenic protects patients from CDI, inappropriate therapy under these circumstances may put the patient at greater risk for CDI at a later time. In addition, a significant proportion of patients who have been successfully treated for CDI may have persistent asymptomatic colonization for many weeks (PubMed)."

It is why, with the new assays, you DO NOT test on solid or semi solid stool: "An important side issue here is that many physicians insist that the laboratory test solid and semisolid specimens. It is imperative for laboratories to create and enforce specimen guidelines. Appropriate specimen collection is paramount to CDI detection in any clinical laboratory today. Because individuals can be colonized with C. difficile, testing of formed stool can result in false- positive tests, which may result in unnecessary treatments (PubMed)."

PCR positive, toxin negative do not have the disease.  The PCR by itself is overly sensitive, leading to "over-diagnosis, over-treatment, and increased health care costs" (PubMed).

And do not repeat testing within 7 days during the same episode of diarrhea and do not test stool from asymptomatic patients.

If you treat C. difficile empirically it may result in false-negative PCR: "For PCR, 14%, 35%, and 45% of positive CDI tests converted to negative after 1, 2, and 3 days of treatment, respectively (PubMed)."

There are rare cases of extra-intestinal C. difficile (PubMed) and not always do to toxigenic strains.

Treatment

From the 2018 Guidlines (PubMed)

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. Metronidazole is recommended for disease only if vancomycin or fidaxomicin are not available

For fulminant disease

  •  For fulminant CDI*, vancomycin administered orally is the regimen of choice. If ileus is present, vancomycin can also be administered per rectum. 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 . 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.

    For recurrent disease

    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 , OR

    2. Treat a first recurrence of CDI with a 10-day course of fidaxomicin rather than a standard 10-day course of vancomycin , 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 .

    4. Antibiotic treatment options for patients with >1 recurrence of CDI include oral vancomycin therapy using a tapered and pulsed regimen , a standard course of oral vancomycin followed by rifaximin , or fidaxomicin.

    5. Fecal microbiota transplantation is recommended for patients with multiple recurrences of CDI who have failed appropriate antibiotic treatments.

    So thats the guidelines, here is some other treatment factoids.

    Aft3er the guidelines were released a study suggest the early stool transplant improves survival for severe disease (PubMed), severe being "leukocytes > 15 g/L, albumin < 30 g/L, serum creatinine > 130 μmol/L or > 1.5 times the baseline, peritonitis, occlusive syndrome, megacolon, or signs of shock." I don't leukocytes are measured in grams/liter, so I think they meant WBC > 15,000.

    With severe disease (toxic megacolon, WBC > 20,000) may want to start with vancomycin or even give both if the patient is NPO. Everyone (including me) thinks that vancomycin is superior to metronidazole, a fact that has yet to be definitively demonstrated in the literature, which tends to show they are equal.  In severe disease adding IV metronidazole to po vancomycin is of benefit (PubMed).

    Vancomycin stool levels suggest that a loading dose of 250 mg or 500 mg qid during the first 24-48 hours, then 125 qid may be the optimal dosing (PubMed).

    Vancomycin is also associated with a decrease in 30 day mortality (PubMed).

    Resistance to metronidazole is being reported in some strains, one study as high as 25% of ribotype 1 (PubMed).

    While there is a tendency towards using vancomycin, metronidazole may have less impact on the microbiome and colonization resistance (PubMed).

    Fidaxomicin 200 po bid is equal to vancomycin with fewer relapses (PubMed)(PubMed) and may be superior to vancomycin when used to treat when you have to continue the inciting antibiotics (PubMed).

    There is also extended dosing fidaxomicin (200 mg po twice daily on days 1–5, then once daily on alternate days for days 7–25) which in one study was superior to vancomycin (PubMed).

    Nitazoxanide (250 mg 4 times per day for 10 days or 500 mg 2 times per day for 10 days) is as effective as metronidazole (PubMed). Nitazoxanide, 500 mg twice daily, for 10 days works in several studies for relapses (PubMed).

    PPI use is a risk for disease and relapse (44% chance of relapse); as the hippies knew, acid is good, man (PubMed). Acid suppression is also associated with increased mortality (PubMed).

    ASA decreases the risk, truly the wonder drug that works wonders

    Interestingly, in a small series anti-motility therapy was helpful, not evil (PubMed).

    Linezolid also effective in in vitro studies.

    With relapsing disease, you usually switch to the other agent (magical thinking, no data to support a change is any better).

    And here is a curiosity: having an appendix is protective against relapse (PubMed), so maybe an appendix transplant?

    Stool 'transplants' work (I gag writing this), curing up to 90% of patients (Review) (PubMed). Fortunately they are developing synthetic stool, making acquisition easier. The source is the Senate, where they are full of, well, never mind.

    If you are going to transplant stool, give it from a thin donor; there is a case report of weight gain after a transplant from an obese donor (PubMed). This is why (Pubmed).

    And most curiously, a sterile fecal filtrate is also effective (Pubmed).

    Stool transplants work best if proceeded by a vancomycin taper (PubMed) but are more likely to fail if antibiotics are given within 8 weeks after transplant (PubMed).

    For patients that have had several relapses I recommend a slow taper of one or the other agent as follows qid x 5 d then tid x 5 d then bid x 5 d then qd x 5 d then qod x 5d then stop. It seems to work in my experience. And may be even better if you finish up with a q 3 d dosing (PubMed). A vancomycin taper is no better than a stool transplant (Pubmed)

    This disease may be getting worser: increased relapse and more severe disease being reported due to strains that are making 10 x the toxin as the old strains and is maybe refractory to metronidazole.

    There is increasing data to suggest rifaximin at 400 mg 2 or 3 times daily for 10 to 14 days may be the best option for relapsing disease (PubMed); in several studies relapsing disease was treated with 2 weeks of vancomycin or flagyl then a 'chaser' with 2 weeks of rifaximin (PubMed) approximately halves the reoccurrence rate.

    In one series IVIG for 3 days cured severe, refractory disease (PubMed); other series have shown no efficacy.

    Bezlotoxumab is human monoclonal antibody against C. difficile toxin B. Use prevents recurrence. (PubMed) Costs 4 grand. No drug should cost the same as a fully loaded MacBook Pro.

    In a small series of refractory disease, tigecycline was helpful (PubMed). Adding tigecycline has been effective is a smattering of case reports (PubMed) nand perhaps as part of combination therapy for severe disease (PubMed). Finally. A reason to give tigecycline.

    Toxin can be found days after the diarrhea is resolved, so do not check it.

    If no active disease, then there is no transmission, so when fevers and diarrhea resolve, can take them out of contact precautions but you need to do a terminal cleaning of the room.

    Preemptive (vancomycin) can prevent recurrent in patients who have had prior disease and are going to be exposed to antibiotics again(Pubmed).

    Consider surgery if patient intubated or requires pressors; may be life saving (PubMed).

    C. difficile colitis: do not give anti motility agents (well, maybe, if mild disease and treated with antibiotics one study found anti-motility agents to be safe (PubMed)); they can lead to toxic megacolon and death, generally considered a bad outcome. Same it true of adding rifampin; it kills (PubMed). Diarrhea is good and gets rid of the toxin. Plus, the patient can get some reading done.

    The spores cannot be killed by alcohol, it is why you have to wash your hands. And it may have airborne spread (PubMed).

    Having patients wash their hands may decrease hospital acquired disease (PubMed) but with a p = 0.05 the effect is not likely real.

    And there is also a post C. difficile reactive arthritis (PubMed).

Note