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Antibiotic Resistance in CDI
Antimicrobial Resistance in Clostridioides difficile Infection

Released: May 18, 2023

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Key Takeaways
  • Antimicrobial resistance testing for C. difficile is not routinely performed, but the emergence of resistance has been reported with antibiotics commonly used to treat CDI (eg, fidaxomicin, metronidazole, vancomycin).

Clostridioides difficile infection (CDI) is the most common  healthcare-associated infection in the United States, with approximately 500,000 cases—resulting in 30,000 deaths—per year. C. difficile , which is considered a threat level urgent  pathogen by the CDC, has notorious antimicrobial resistance (AMR)  to many of the commonly used antibiotics. This high level of AMR is a hallmark for the pathogenesis of CDI, as use of antimicrobials kills the healthy microbiota that reside in our gut, allowing C. difficile to germinate, produce toxins, and cause disease. 

Testing for  Antimicrobial Resistance
Despite this known association between AMR and CDI, we do not routinely test for resistance to the antibiotics commonly used to treat CDI—namely fidaxomicin, metronidazole, or vancomycin. There are multiple reasons for this lack of testing. 

First, C. difficile is a strict anaerobe and is difficult  to isolate from stool without specialized equipment—equipment that is commonly absent from clinical microbiology labs.

Second, CDI is diagnosed by detection of C. difficile toxins, so there is no clinical imperative to identify novel mechanisms to grow C. difficile and perform antimicrobial susceptibility testing.

Finally, there are variabilities in drug concentrations among available CDI therapies. Two of the 3 commonly used antimicrobials (vancomycin and fidaxomicin) are not absorbed systemically when given orally, which results in very high concentrations in the colon—the site of infection for CDI. By contrast, metronidazole is almost completely systemically absorbed, so its colon concentration is dependent on diffusion across the colonic epithelium into the colon. Stool concentrations of metronidazole are negligible  , unlike what is seen with vancomycin or fidaxomicin. Because of these variable drug concentrations from drug to drug, establishing appropriate pharmacokinetic/pharmacodynamic parameters from stool samples to mirror the drug’s concentration at the colonic site of infection remains a challenge. 

Reduced Susceptibility to CDI Agents
My research team recently completed a clinical trial evaluating metronidazole resistance and poor outcomes in patients with CDI . We evaluated 356 hospitalized patients with CDI, 18% of whom had isolates with reduced susceptibility to metronidazole. In patients infected with reduced-susceptibility isolates, receipt of metronidazole was associated with 2.27 times higher likelihood of clinical failure. This was the first demonstration that antimicrobial susceptibility testing can predict clinical outcomes in patients with CDI.

Separately, in our preliminary investigations with vancomycin, we collected a small number of isolates with reduced vancomycin susceptibility, and we found a resistance mutation associated with changing the bacterial cell wall. This specific type of resistance was associated with decreased killing of C. difficile when using the vancomycin concentrations that are achieved in the gut. Clinical evaluation of these isolates is ongoing but does demonstrate that AMR resistance for C. difficile may be relevant for vancomycin.

The emergence of resistance  with fidaxomicin has been demonstrated in a phase III clinical trial from a single strain isolated from a cured patient with an elevated fidaxomicin minimum inhibitory concentration of 16 µg/mL. This remains an active area of research. 

A Focus on AMR Going Forward
CDI is a common and devastating healthcare-associated infection with a limited number of effective antibiotics. We need to start paying attention to resistance to these antibiotics to make sure they remain effective in the future. We also need to direct our attention to antimicrobial discovery in this space. This will continue to allow for the best care of our patients now and in the future. 

Your Thoughts? 
Have you encountered antimicrobial resistance with CDI therapies? How have you addressed this in your practice? Join the discussion by posting a comment.