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C. difficile infection is dependent on the balance of the intestinal microbiota and incidence is increasing in US and Europe

Clostridioides difficile (formerly Clostridium difficile) is an anaerobic spore-forming bacterium that can be isolated from water, vegetables and the hospital environment. Also found in relatively low numbers in the digestive system of healthy adults, it was first described in 1935 as part of the normal gut microbiota of neonates. C. difficile is kept under control by a harmless gut microbiota (i.e., colonization resistance comes from the ability of the healthy microbiota to prevent expansion of potential pathogens). However, disruption to the microbiota’s abundance and diversity may prompt C. difficile to multiply and cause gastrointestinal infection.

This opportunistic pathogen is the leading identified cause of hospital diarrhea associated with antibiotic therapy worldwide and is considered an urgent public health threat by the Centers for Disease Control and Prevention in the United States. In fact, in 2020, 113,451 C. difficile infections were reported in the US among hospitalized patients, including community-onset and hospital-onset infections. More worrisome, C. difficile infection has increased in severity, supported by CDC data showing that 1 out of every 11 patients aged 65 or older with a healthcare-associated C. difficile infection die within 1 month of diagnosis.

CDI incidence is also increasing in the EU, accounting for a total of 7,711 cases in 2016, of which over 75% were acquired in the healthcare setting, according to the Annual Report from the European Centre for Disease Prevention and Control. C. difficile infection is among the six healthcare-associated infections that have a huge impact on the cumulative number of years lost due to ill-health, disability or early death, exceeding the burden of other infections, including influenza and tuberculosis. The emerging burden of C. difficile is also apparent in other parts of the world, including the Western Pacific and Asia.

C. difficile infection has a profound impact on both the healthcare system and patients’ quality of life and that can continue even after infection clearance. Indeed, it is worth noting that the burden is underestimated due to limited EU data and the small number of hospitals that report any data on the condition.

While CDI is often comorbid with other diseases, the reported mortality rate ranges from 6% to 30% and its annual costs range from $8,911 to $30,049 for hospitalized patients.

More worrisome is that CDI often heralds the beginning of a vicious cycle of recurrence, defined as CDI that relapses after the successful treatment of the first episode. It is estimated that nearly one in six patients with CDI will experience recurrent infection within 2 to 8 weeks of their first episode. In addition, up to 65% patients with recurrent CDI often experience two or more additional episodes. The possible return of infection several weeks after patients receive initial antibiotic treatment can both impact their well-being and pose a treatment challenge. Furthermore, it is associated with an annual cost of approximately $2.8 billion.

 

Risk factors for developing C. difficile-associated disease

The pathogenesis of C. difficile involves multiple factors, with debilitating diseases and comorbidities (e.g., gastrointestinal disorders, cancer or kidney disease) combined with antibiotic treatment leading to an alteration of the colonic microbiota, thus favoring the proliferation of C. difficile.

Exposure to antibiotics is the main risk factor for developing C. difficile infection. Antibiotics reduce overall gut microbiota diversity and cause metabolic shifts in important taxa, favoring the subsequent increased susceptibility to colonization and development of bacterial antibiotic resistance. Although antibiotics are the primary recommended treatment against C. difficile, they may perpetuate the loss of colonization resistance and worsen further disruptions to the gut microbiome, which in turn favors recurrences.

Recent and long-term hospitalization, advanced age (>65 years old), impaired immune response, use of multiple antibiotics for long periods of time, proton pump inhibitors, chemotherapy and feeding tubes also increase the risk of CDI.

The disease spectrum varies from asymptomatic carriage and mild diarrhea to severe and life-threatening CDI, particularly in older patients. The transition from asymptomatic C. difficile colonization to CDI is prevented by adequate gastric acid production, the production of bacteriocins by a healthy gut microbiota, bile acid composition and host immune status.

  • Asymptomatic colonization with difficile is particularly common in infants and adults who have contact with the health system (e.g., older adults in long-term care facilities or nursing homes, healthcare workers and patients in rehabilitation centers), which favors exposure to C. difficile spores. Although asymptomatic colonized individuals do not show clinical manifestations, they serve as potential disease carriers and transmit C. difficile.
  • Symptomatic infection with difficile ranges from mild diarrhea to potentially life-threatening conditions including pseudomembranous colitis, toxic megacolon and death.

Several markers of disease severity have been studied and include: age (>70 years), cardiorespiratory failure, ongoing treatment with systemic antibiotics, leukocyte counts and serum creatinine, among others.

It is also worth noting that disease severity has been related to hypervirulent strains that share microbial characteristics and the gut microbiome changes they induce. For instance, the hypervirulent ribotype 027 strain has been the most prevalent strain identified in community-acquired C. difficile infection. The main mechanisms explaining its high hypervirulence include antibiotic resistance, hyperproduction of toxins, improved toxin binding to the host intestinal epithelium and increased sporulation. That situation highlights the need for personalized treatments for infection control and better health outcomes among patients treated with antibiotics.

 

Clinicians should be aware of C. difficile co-infection with COVID-19

Some evidence has suggested that hospitalized patients with COVID-19 can show an altered gut microbiome, which is related to disease severity. In the current situation, therefore, co-infection with C. difficile and COVID-19 may lead to poor outcomes and add to the complexity of CDI diagnosis. That might be explained by risk factors for CDI also being factors that increase the likelihood of COVID-19, causing an overlap between the two conditions. For instance, consumption of non-steroidal anti-inflammatory drugs, antibiotic therapy and older age are among the key factors that explain C. difficile co-infection during COVID-19.

It is also important to bear in mind that some patients with C. difficile infection usually present with several comorbid conditions, including irritable bowel syndrome and inflammatory bowel diseases. Patients with C. difficile infection have a high risk for developing post-infectious IBS. C. difficile infection is also the most common infectious complication associated with IBD explained by alterations in the gut microbiome led by this common diarrheal illness.

Scientists have also speculated about the persistence of SARS-CoV-2 viral particles in the feces of patients with CDI, despite COVID-19 rapid antigen tests turning negative. It is also important to keep in mind that CDI can worsen the health outcomes of patients with COVID-19, especially in cases with risk factors associated with CDI.

 

Take-home messages

  • Clostridioides difficile infection is the most frequent cause of antibiotic-associated diarrhea in the hospital setting, appearing after the gut microbiota is disturbed.
  • difficile infection is more challenging that just a hospital diarrhoea as one in 11 people over age 65 diagnosed with a healthcare-associated C. difficile infection die within one month.
  • Nearly one in six patients with CDI will experience recurrent infection in the following 2 to 8 weeks, highlighting the public threat that recurrent difficile poses worldwide.
  • The transition from asymptomatic difficile colonization to CDI is prevented by adequate gastric acid production, bacteriocin production by a healthy gut microbiota, bile acid composition and host immune status.
  • Hypervirulent strains have been identified in community-acquired CDI and are related to increased severity of infection, increased mortality rates and increased recurrence.
  • IBDs may make patients more susceptible to difficile infection and new-onset IBS is common after C. difficile infection.
  • The gut microbiome is vulnerable to infection with COVID-19 and clinicians should be aware that both conditions can occur at the same time.

Coming soon: A new article in this series focusing on diagnosing and treating C. difficile in adults. Stay tuned for more news about the field!

 

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