C difficile Infections Increasing, Becoming More Difficult to Treat

Jason Gallagher, PharmD

Treating multidrug-resistant (MDR) infections, such as Clostridium difficile, is challenging for practitioners, but new treatment alternatives are on the horizon.

According to the US Centers for Disease Control and Prevention (CDC), there are at least 18 common drug-resistant threats in the United States, 15 of which pose urgent or serious threats. C difficile is among the drug-resistant pathogens posing an urgent threat.

Research indicates that rates of C difficile infection among those typically not considered at high risk of infection are increasing, and these infections are becoming more frequent, severe, and difficult to treat. What is fueling these changes?

“Most likely health care contact and antibiotic exposure [are causing this increase in infections],” said Dale Gerding, MD, FACP, FIDSA, professor of medicine at Loyola University Chicago and research physician at the Edward Hines Jr. VA Hospital, in an interview with MD Magazine®. “The epidemic NAP1/027 strain has now declined in the US to about 20% or less of cases.”

“On daily rounding consults with physicians, I see plenty of patients with both MDR infections and C difficile,” said Jason Gallagher, PharmD, FCCP, FIDSA, BCPS, Editor-in-chief of Contagion® and clinical professor and clinical specialist, Infectious Diseases at Temple University. “Sometimes they occur at the same time, sometimes one is the consequence of treating the other—specifically, treating the MDR pathogen puts the person at risk of a C difficile infection.”

Because antibiotic treatment options for MDR infections are limited, and will become even more limited in the near future, experts tout a nonantibiotic strategy. This approach includes surveillance, infection control procedures such as isolation, and a sense of antimicrobial stewardship.

“C difficile infections occur when someone who has already been colonized with C difficile spores is treated with something, or received some therapy, that disrupts their normal microbiota,” Gallagher explained. “The therapies that we use for MDR infections [disrupt the flora] universally. I cannot think of any that are sparing to the gut flora.”

Two things happen in the gut at the same time when C difficile is present. There is a reservoir of spores, but there are also the vegetative cells, which are active, growing and dividing.

“Those cells are fairly easy to kill with antibiotics, but since the antibiotics do nothing at all to the spores, you end up basically in this race after the therapy is over and what happens next,” Gallagher said. “Do the spores start to germinate and start to grow again? Do the spores revert to the vegetative form and the C difficile takes over? Or does the normal bacterial flora come back in time basically to crowd it out and prevent that from happening?”

In other words, the spores are the treatment problem, not the active cells—which can be killed fairly easily with treatment drugs for C difficile.

“The antibiotic resistance issue with C difficile infection is not resistance to treatment drugs, but rather resistance to other antibiotics used to treat other infections such as urinary tract and respiratory infections,” Gerding said. “C difficile can be resistant to these drugs—which include fluoroquinolones and cephalosporins in particular—and can infect patients taking these drugs while the drug is in the gut.”

In most cases, a person who has acquired C difficile spores is asymptomatic, because under normal conditions, other gut microbiota “crowd out” the spores, preventing them from entering their vegetative state and growing. The spores are dormant, but are still resistant to antibiotic treatment.

“There are only a few viable options against it; but, the resistance to those few things is actually very low,” Gallagher said. “The issue of C difficile is intriguing, because unlike other bacterial infections, failures are not due to antibiotic resistance. When treatment fails, it's because we have failed to eradicate the spores that are left behind after killing the vegetative cells. That's unique.”

This is why contact transmission is such a challenge when treating C difficile, according to Gerding. “It makes spores which are difficult to remove from the environment (requiring bleach) and are resistant to common disinfectants like alcohol hand rubs.”

New Research into Drugs and Other Treatment Strategies for C difficile

Based on the need for a nonantibiotic approach, new research into fecal microbiota transplants (FMT) for treating C difficile infections is offering hope for patients, although there is no FDA-approved FMT treatment yet.

“It's been shown that normal flora is significantly changed in people who develop C difficile,” Gallagher said. “That makes sense, because something happened to give the C difficile a chance to grow in that person. The C difficile bacteria itself isn't the problem; it's the altered microbiology plus the spores being there that leads to the development of the disease. The rationale of FMT is to restore normal flora to that area to crowd out the C difficile and prevent it from regrowing.”

In addition to FMT, there are new enema-administered microbiota-based treatments such as RBX2660 in development.These therapies are “essentially the same, except for how the stool is processed and the donors are screened and tested for pathogens,” Gerding said. “RBX2660 meets FDA requirements for good manufacturing practice and carefully screens all donors and tracks patients for side effects who receive transplants from these donors.”

There are also other emerging options for the diagnosis, management, and treatment of C difficile infections. “New, more sensitive tests for stool toxin are under development for diagnosis, as well as new narrow-spectrum antibiotics for treatment, FMT for prevention of recurrence, vaccines for prevention, and biologics for prevention (in the case of nontoxigenic C difficile),” Gerding explained.

As we learn more about the many ways the gut microbiome affects overall health, we can expect to see more breakthrough treatments enter the pipeline.

“We are still learning a great deal about the microbiome,” Gallagher added. “It's a really amazing area. You have more nerve receptors in your gut than anywhere else in your body, and your gut has more bacterial cells than the whole rest of your body has human cells by a factor of 5 to 10.”

For now, practitioners can prepare to handle patients with MDR bacteria and/or C difficile infections by remaining vigilant and reaching out for help as needed.

“[Practitioners should] send appropriate cultures and carefully monitor antibiograms for resistance to antibiotics,” Gerding concluded. “When in doubt or concerned, ask for an infectious disease consult.”