Rates of Serious Complications Rise with Each Recurrent C diff Infection

Among patients living with Clostridioides difficile, rates of sepsis and colectomy increased as the number of recurrent infections increased, a new study found.

The longitudinal, retrospective study, published in SAGE Open Medicine, included 46,571 patients aged 18-64 with index C. difficile infections (CDI) occurring from January 2010 through June 2017. It evaluated clinical complications, including colectomy and sepsis, documented during a 12-month follow-up period after the initial infection.

“C difficile isn’t just an infection that causes acute symptoms. There are other things that happen over time to people who have this,” lead study author, Paul Feuerstadt, MD, of the Yale University School of Medicine and the PACT Gastroenterology Center in Connecticut told Contagion. “One of those is the risk of colectomy. This study specifically showed that with a greater number of recurrences, you’re more likely to get those sorts of complications over the long term that you might not necessarily directly associate with the infection.”

The average Charlson comorbidity index score rose with each successive recurrence of CDI from 1.2 (1.9 standard deviation) in initial cases to 2.3 (2.5) for patients with 3 or more recurrences. Incidences of sepsis rose during the 12-month follow-up period, from 16.5% to 43.3% of patients with 3 or more recurrences. Subtotal colectomy or diverting loop ileostomy rose from 4.6% of patients to 10.5% of those with 3 or more recurrences.

“These are really significant numbers and a really significant burden on our nation that I think is important for us to really elucidate,” Feuerstadt said.

Of the 46,571 patients included in the study, 3129 (6.7%) had 1 CDI recurrence, 472 (1%) had 2 recurrences, and 134 (0.3%) had 3 or more recurrences. The study also found that the presence of autoimmune diseases was higher among patients with multiple recurrences, from 18.1% of those with 1 CDI to 39.6% of those with 3 or more CDI recurrences.

“It’s really important for all of us to understand that we have two main goals when we treat C. difficile,” Feuerstadt said. “One is to keep the bacteria under good control. The way we do that is typically with antimicrobials. But the second is what gives C difficile that knock-out punch and that’s our microbiota.”

Feuerstadt said fidaxomicin is associated with significantly lower rates of CDI recurrence. He said the monoclonal antibody bezlotoxumab also can be given along with a standard of care antimicrobial.

Recurrent CDI leaves the microbiota depleted, creating a need for microbiota replacement therapy or fecal microbiota transplantation to fortify the deficiencies and decrease rates of recurrence.

“Those who have initial infection, their microbiota is bent, but it’s not broke,” Feuerstadt said. “Once patients get recurrent disease, it’s broke and it’s so much more challenging to replete on its own without the supplementation. That’s why these patients get stuck in this cycle of recurrence after recurrence after recurrence.”

Recurrence rates are about 25% in patients treated with vancomycin, which is a guideline-driven treatment for CDI, compared with about 15% for fidaxomicin. Microbiota replacement therapy brings recurrence rates down further to about 8%, Feuerstadt said, calling the combination of treatments a “super treatment.”

RBX 2660 is a broad-spectrum microbiota replacement therapy that is in development.

“Their phase 2 study had positive topline results. Their phase 3 study also reported positive topline results last May, and we’re awaiting to see the definitive numbers for that,” Feuerstadt said. “And, there are other products also that are in clinical trials. We’re really at a great time point when it comes to microbiota replacement therapy.”

He said FDA approval of such products will be a game changer in treating CDI.

“When we think about steps moving forward with C difficile, we’re on the precipice of greatness,” Feuerstadt said.

The burden of CDI is high, including the increasing risk of colectomy and sepsis, along with psychiatric impacts such as PTSD, anxiety and depression, and financial costs.

“There’s just a broad trickle-down effect of multiple recurrent C. difficile, and this is why it’s so imperative that we are aggressive upfront with our treatment to reduce that cycle,” Feuerstadt said.