Joe’s Note: In 2016, the Clinical and Laboratory Standards Institute (CLSI) took the infectious diseases world by storm when they changed our forever beloved Clostridium to Clostridioides difficile. This reclassification was a result of “scientific evidence, specifically improved genetic testing and sequencing revealing a taxonomic shift.”

Even the Brave Little Toaster misses the Clostridium nomenclature. (Image)

Whatever the heck that even means. I don’t know about you, but I much prefer Clostridium. It’s just so much easier to say. Rolls off the tongue so much better than Clostridioides. It’s been 9 years since the change, and I still don’t know if I even say it correctly. So for the sake of my sanity and to honor our lost friend Clostridium, I will refer to it as C. difficile from now on.

Thanks for listening to my useless rant. I appreciate it :). Anyway, let’s get started.

Introduction to C. difficile

So what is C. difficile? C. difficile is an infectious gram-positive spore-forming bacillus microorganism of the gastrointestinal tract. Believe it or not, C. difficile is considered a member of the normal gut microflora. In fact, up to 10% of the population may carry C. diff and not even know it. The rate of colonization in the human gut is different for each age group and is typically highest in early infancy and decreases with age.

Clostridioides difficile in the flesh (as it were…). Nasty looking little bugger, eh? (Image)

But hold on, let’s take a step back. Did I say 10% of the population may be chronic colonizers of C. diff and have no symptoms? Yup, you read that correctly. There’s even a chance that you or me are chronic colonizers.

But then how come colonizers don’t have daily symptoms? It’s because large growth of C. diff is suppressed by the more dominant anaerobic bacteria of the gut. It’s almost like C. diff is a little baby soldier. It’s there, but it can’t make a big army because the other anaerobic bacteria keep it in check.

But then patients are started on prolonged courses of antibiotics. These antibiotics inadvertently destroy the other normal anaerobic bacteria in the gut, giving C. diff more room to grow and prosper. This leads to a full brown acute C. diff infection. Make sense? More on antibiotics later.

Signs & Symptoms of a C. difficile Infection

Symptomatology of C. diff is generally dependent on the severity of infection. Obviously, more severe infections present with more intense symptoms and vice versa. To get a better understanding, let’s classify C. diff.

Mild/Moderate Infections:
- Watery diarrhea 3 or more times a day for more than one day
- Mild belly cramping and tenderness
- Nausea
- Loss of appetite
Severe Infections:
- Watery diarrhea as often as 10 to 15 times a day
- Severe cramping and pain
- Severe dehydration secondary to fluid loss
- Tachycardia
- Hypotension
- Fever
- Nausea
- End organ damage (e.g., acute kidney injury)
- Loss of appetite
- Weight loss
- Blood or pus in the stool

So then, what are the risk factors for developing this infection? Believe it or not, the biggest risk factor for C. diff infection is recent and prolonged use of broad-spectrum antibiotics. As pharmacists, it’s our responsibility to be the drug experts. And not all antibiotics are created equally. We all know that clindamycin is one of the biggest offenders. But what about all the other antibiotics?

Which antibiotics are safe to use in patients at high risk for developing C. diff? Which ones should be avoided at all costs? Well, because I’m so nice, I created a little table for you that goes over all of that information:

Other risk factors for developing C. diff include age ≥65 years, hospitalization, immunosuppression, and concomitant use of other medications such as proton pump inhibitors and chemotherapy.

Diagnosing C. difficile

C. difficile testing should generally only occur in patients with high clinical suspicion for infection. Meaning, your patient should most definitely have diarrhea (at least 3 watery stools/day), fever, abdominal pain, cramping, nausea, and possibly anorexia.

Remember earlier we talked about how patients could be chronic colonizers? And how the rate of colonization in the human gut is typically highest in early infancy? Therefore, due to the higher rates of asymptomatic carriage, stools from children <3 years of age should be interpreted cautiously, and testing infants <1 year of age is generally not recommended.

Okay, now what tests should we collect to help with the diagnosis? Your standard basic metabolic panel (BMP) and complete blood count (CBC) should be collected on all possible patients to assess the severity of C. diff. Other than that, an accurate and simple test recommended to diagnose C. diff is a stool sample. This stool sample is commonly tested for C. diff toxins and toxin genes. Okay now what the heck are these different C. diff tests, and what do they mean? Before we go into all of that, let’s review what C. diff toxin even is.

As you may already know, C. diff bacteria release toxins. Specifically, TcdA and TcdB, which then travel to the gut lining and cause inflammation, leading to diarrhea, nausea, abdominal pain, and colitis. Therefore, to get an accurate diagnosis of C. diff, it’s important we test the stool sample for toxins. Generally, we have two different tests that help us differentiate between an acute C. diff infection vs a chronic colonizer. Just because one of the tests comes back positive doesn’t automatically mean that treatment is necessary. Let’s review.

C difficile toxin PCR test, or nucleic acid amplification test (NAAT): a rapid and sensitive method to detect the presence of C. difficile toxin genes in stool samples
- Test sensitivity: high → High negative predictive value but moderate positive predictive value
C. difficile toxin EIA (Enzyme Immunoassay) test: Also detects the presence C. diff toxin but is less sensitive
- Test sensitivity: less sensitive → improves the positive predictive value of detecting active C. diff infection

So then, what if one test comes back positive and the other results as negative. How do we actually interpret these results? Take a look below:

C. difficile Infection Classification

According to the IDSA guidelines, C. diff is classified into one of the following criteria: non-severe, severe, and fulminant. Why does classification matter? Because treatment of C. diff is dependent on the disease classification and severity. So let’s review:

There is also a caveat here. Technically it can also be classified as recurrent C. diff infection if the patient experiences C. diff that occurs within 8 weeks of completing therapy for previous episode.

Prevention of C. difficile

Before we dive deep into the treatment of C. diff, let’s first discuss how to prevent the transmission from person to person. Speaking of transmission, C. diff is transmitted through the fecal-oral route. That sounds pretty wild so let me explain it better.

Not to turn everyone into germaphobes, but when you break it down like that, the germs…they’re *everywhere*. Just waiting to get us!!! (Image)

Let’s say you have a C. diff positive family member who lives with you. This individual obviously has diarrhea and will be using the bathroom pretty regularly. As do all humans, once we’re done passing stool, we wipe. Unfortunately, it’s not always the most hygienic method and some stool may make contact with their hand. Then they go to turn the faucet on to wash their hands. A little while later, you go to use that same bathroom. You touch the same faucet that they touched. Then you decide to eat some food. Boom, you just transmitted C. diff to yourself through the fecal-oral route. So, how can we prevent transmission?

Here are some good educational points to relay to your patients:

C diff passes back into your intestinal system when you swallow it. Wash your hands with warm water and soap after each trip to the bathroom and before you eat to remove the bacteria.
Many common cleaning products will not destroy C diff. C. diff is a spore forming bacteria and is intrinsically resistant to all alcohol-based hand sanitizers. If cleaning products are used, ensure that you use products that contain bleach.
Keep high-use areas of your home clean. These areas include bathrooms, kitchens, doorknobs, and electronic devices.
Don’t take antibiotics if they’re not prescribed to you. These medications are only effective for bacterial infections and may increase your risk for a C. diff infection.
C. diff can live on the skin, so you should bathe with soap and warm water daily during and immediately after an infection.
If you have diarrhea, try to use a separate bathroom from everyone else in your home and clean it regularly to avoid spreading the bacteria.
Bacteria can live on linens and other soft materials, like towels, clothing, and underwear. Use the hottest water the fabrics can handle, and wash with bleach if possible.

Treatment of C. difficile

As we alluded to earlier, treatment of C diff is heavily dependent on the severity of infection. So instead of using a million words to show you what the IDSA recommends, why don’t I just sum it up in a table. This is tl;dr pharmacy after all.

Vancomycin vs. Fidaxomicin vs. Metronidazole - What the Literature Really Says

Gosh, if I haven’t already heard this argument 5 million times. We can all agree that metronidazole isn’t the best for C. diff treatment given its high resistance rates over the years. That’s why we only utilize it as alternative therapy or add-on therapy to patients with fulminant C. diff. In case you don’t believe me, here is a 2017 article published by JAMA that compares vancomycin and metronidazole for the prevention of recurrence and death in patients with C. diff infection. In case you don’t want to read it, here is the tl;dr version:

Study Population: 10,137 C. diff positive patients were included
Primary Outcome: C. diff recurrence and all-cause 30-day mortality
Results: Recurrence rates were similar among patients treated with vancomycin and metronidazole. However, the risk of 30-day mortality was significantly reduced among patients who received vancomycin.

Now onto the bigger argument…fidaxomicin vs vancomycin. Yes, guidelines and literature generally favor fidaxomicin over vancomycin for initial treatment. Why is that? Let’s review one of the landmark studies.

The first trial was published by NEJM in 2011 and compared fidaxomicin versus vancomycin for C diff infection. Once again, here is the article, and below is the tl;dr version:

Study Population: 548 C. diff positive patients were included
Primary Outcome: Clinical cure
Secondary Outcomes: Recurrence of C. diff and global cure
Results: The rates of clinical cure after treatment with fidaxomicin were noninferior to those after treatment with vancomycin. However, fidaxomicin was associated with a significantly lower rate of recurrence of C. diff infection.

Okay, so clinically, fidaxomicin seems to be preferred due to lower recurrence rates when compared to vancomycin. However, efficacy for initial non-recurrent episodes seems to be equal between vancomycin and fidaxomicin. So which to pick? If a patient has recurrent non-severe C. diff, then fidaxomicin might be a better option. If a patient has an initial episode of non-severe C. diff, then either vancomycin or fidaxomicin can be used effectively.

However it’s important to note that fidaxomicin is NOT readily available and according to Lexi-comp, each 200 mg tablet costs $312.30. That means a 10-day course of fidaxomicin could cost a patient $6,246.

On the other hand, each 125 mg vancomycin oral capsule costs $31.31. So a 10-day course of vancomycin will cost $626.20.

Almost exactly 10 times the price difference between the two. So, if you have the money and want fidaxomicin (or if insurance is kind enough to cover it…), then sure. But if money is a concern, the literature is NOT strong enough to recommend fidaxomicin over vancomycin, especially for initial episodes.

Tl;dr of C. difficile Infections

C. difficile is an infectious gram-positive spore-forming bacillus microorganism of the gastrointestinal tract. It is considered a member of the normal gut microflora, and about 10% of the population are chronic colonizers of C. diff.

C. diff is transmitted through the fecal-oral route. Many common cleaning products will not destroy C. diff. C diff is a spore forming bacteria and is intrinsically resistant to all alcohol-based hand sanitizers. If cleaning products are used, ensure that you use products that contain bleach.

Symptomatology of C. diff is generally dependent on the severity of infection. Obviously, more severe infections present with more intense symptoms and vice versa. Both the C. diff toxin PCR test and toxin EIA test should be collected when testing for C diff. The C. diff toxin PCR test has high negative predictive value but moderate positive predictive value. On the other hand, the C. diff toxin EIA is less sensitive but should be collected to improve the positive predictive value of detecting acute C. diff infection.

C. diff is classified into one of the following criteria: non-severe, severe, and fulminant. Severity of infection and whether or not it’s a repeat occurrence determines course of treatment.

Metronidazole monotherapy is only recommended as alternative treatment for acute C. diff infection.
Either fidaxomicin or vancomycin may be used to treat an initial episode of C. diff.
- Fidaxomicin seems to be preferred due to lower recurrence rates when compared to vancomycin. However, efficacy for initial non-recurrent episodes seems to be equal between vancomycin and fidaxomicin.

Cost of fidaxomicin is significantly higher than oral vancomycin therapy. Therefore, it is important that we take price into consideration when recommending one agent over the other.

The Pharmacist's Primer on Clostridioides Difficile Associated Diarrhea (CDAD)