A vaccine now in the latter stages of development takes aim at C. diff, a gut-dwelling bug that causes misery for hundreds of thousands of people in the United States and drains the health care system of billions in badly needed resources. The vaccine trial also underscores a deeper clinical care challenge.

The target of the phase 3 clinical trial, dubbed Clover, is the Clostridium difficile (aka C. diff) bacterium, which secrete toxins capable of inflaming and stimulating the cells that line the intestine to cause severe diarrhea and colitis. A half-million or so people in the United States suffer from C. diff infections each year, with some 15,000 dying as a result. About one in five people who have a first C. diff infection will have at least one more. The infections lengthen hospital stays significantly, spiking health care costs an estimated at $5.4 billion annually.

The Clover vaccine trial has enrolled more than 16,000 patients at more than 400 sites, including the University of Colorado School of Medicine on the UCHealth Anschutz Medical Campus. Participants receive either a placebo or a series of three vaccine shots that contain weakened forms of the two toxins (A and B) that C. diff bacteria secrete. The idea is that these non-harmful versions of the toxins drive the body to produce antibodies that ward off serious infection.

Road-tested approach

It’s a “bread-and-butter” approach to vaccination that has proven successful in protecting millions of people against tetanus and diphtheria, said Dr. Edward Janoff, professor with the University of Colorado School of Medicine’s Infectious Disease Division. Janoff led the trial at CU, which recently completed patient recruitment. He added that the Clover trial focuses on those most vulnerable to C. diff infections: people 50 years and older who have other risk factors, including past hospitalizations, multiple clinic visits and recent use of antibiotics.

“It’s a well-organized, randomized trial for a serious disease,” Janoff said.

Janoff noted that the trial sponsor, Pfizer, will follow participants for at least a couple of years to glean more information about the vaccine’s effectiveness. He sounded a hopeful note based on what he’s seen so far.

“I’m optimistic in that we know the vaccine elicits the [toxins A and B] antibodies, and we know the antibodies inhibit the ability of the toxins to cause injury,” Janoff said. “Is that sufficient to prevent disease in the body? It will take a couple of years to find out, but if it does work, it will be a big splash and the people who receive it will benefit.”

He added that important questions remain, not only about the vaccine’s safety but its long-term benefits.

“It’s important to know how long the vaccine lasts,” Janoff said. “Also, do you need all three shots?” Those questions and others will contribute to determining the cost-effectiveness of the vaccine and its societal benefits, he said.

Thornier problem

Even if a C. diff vaccine proves an unqualified success, Janoff added, the challenge of preventing the infections will remain because of the nation’s and the world’s heavy and often inappropriate use of antibiotics.

The problem is one of competition between flora in the gut. C. diff bacteria naturally dwell there with other microbial residents. C. diff can gain an advantage when antibiotics clear out their competitors, leaving plenty of intestinal playing field on which to proliferate and secrete their damaging toxins.

“We know that far and away the biggest risk for C. diff is antibiotic use,” said Dr. Misha Huang, director of antimicrobial stewardship at UCHealth University of Colorado Hospital and assistant professor in CU’s Infectious Disease Division. “If we are going to try to minimize C. diff risk for our patients, we have to be judicious about our antibiotic use.”

Indeed, the Centers for Disease Control and Prevention (CDC) has estimated that providers in clinics and emergency rooms annually write some 47 million unnecessary antibiotic prescriptions. One result, the CDC says, is that about one-third of the half-million C. diff cases each year did not originate in hospitals, nursing homes or other health care facilities, but in the community.

“A big part of the C. diff story is the rampant use of inappropriate antibiotics, particularly for respiratory infections that are often viral,” Janoff said. He attributed the problem both to patients demanding antibiotics without being aware of the cause of their illness and to providers acceding to those demands to avoid conflict.

Applying the brakes

Huang noted that UCH has in place a number of “mainstays of antimicrobial stewardship,” including daily monitoring of the hospital’s antibiotic use, particularly “broad-spectrum” medications, such as fluoroquinolones. These antibiotics kill not only the infection-causing microbes but other innocent bystanders in the gut, opening the door to C. diff intestinal invasion. When it’s appropriate, the team suggests antibiotics that target a specific infection more narrowly.

“We’re not the antibiotic police,” Huang emphasized. “We’re not trying to restrict providers’ autonomy. We want to be a resource for providers who might not know that something else might be more effective in treating patients.”

The approach has been successful. Huang said over the past two years, the hospital’s use of antibiotics decreased 16 percent overall, while broad-spectrum antibiotic use fell 22 percent. In addition, the microbial stewardship team targets conditions commonly overtreated with antibiotics, such as urinary tract infections (UTIs). The work helped to reduce the average duration of antibiotics for UTIs from 10 days to 7 days, saving thousands of days of exposure over the course of a year.

“From our perspective, every day and every dose of antibiotics matters in reducing the risk of C. diff,” Huang said.

The team also continues to work with the Microbiology Lab at UCH to review resistance rates for different organisms, Huang said. The result is a regularly updated guide for treating different types of infections with first- and second-line antibiotics, with the goal again of delivering the most narrowly focused treatment possible.

Fresh approaches

Of course, many patients must receive broad-spectrum antibiotics to fight serious infections. To counter the risk of C. diff in these patients, UCH has brought in a probiotic, Bio K+, to repopulate the gut with “good” bacteria. Janoff said he is still skeptical of the benefits of the probiotics in the hospital setting, and Huang acknowledged that use of them is still spotty. But she also noted some studies have shown their effectiveness in fighting C. diff infections in patients treated with broad-spectrum antibiotics.

The stewardship effort also includes making sure patients are tested appropriately for C. diff, increasing skin testing for penicillin allergies – many people think they have the allergy but don’t, leading to inappropriate use of antibiotics – and finding more opportunities to work with providers on strategies for communicating to patients the risks of antibiotic overuse, Huang said.

Whatever the eventual outcome of the Clover trial, the vaccine is far from a magic bullet: at least for now, it’s designed for those who have not yet contracted an infection. The strategies at UCH converge on minimizing the collateral damage antibiotics can cause and preventing infections like C. diff from occurring in the first place.

“It’s not about getting to no antibiotic use,” Huang said.. “It’s about optimizing it and making sure that for every patient we use the right antibiotic for their infection.”