Illustration by Sarah Ferone
Illustration by Sarah Ferone.

Defeating C. diff

While Clostridium difficile remains a stubborn infection, new drugs and research findings suggest some ways to more effectively combat it.

While Clostridium difficile remains a stubborn infection to thwart and treat, several recent studies have homed in on ways to more effectively combat it.

C. difficile poses a notable health threat, responsible for an estimated 453,000 infections among U.S. patients in 2011, including 29,300 deaths, according to an analysis of federal data published Feb. 26, 2015, in the New England Journal of Medicine (NEJM). Recurrences also were common, with 83,000 patients experiencing at least one.

Last October, the FDA approved bezlotoxumab (Zinplava) for treatment of recurrent infection. Meanwhile, other research adds to a growing body of evidence that vancomycin is more effective than metronidazole, at least where treatment of severe cases of C. difficile is concerned.

To counteract the highly contagious spores, researchers and physicians have also been striving to stem incidence, via efforts like antimicrobial stewardship programs, and continuing to investigate other treatment options, such as fecal transplants.

The risk of mortality within 30 days of C. diff diagnosis is significant, with death being the result of about 6% of cases, according to a 2012 literature review published in Antimicrobial Resistance and Infection Control. Even among patients who survive but have multiple recurrences, the infection can severely erode quality of life, as evidenced by willingness to consider a fecal transplant, said Richard Nathan, DO, an ACP Member and C. difficile researcher based in Idaho Falls, Idaho.

“If you are having diarrhea every day for months, your idea of treatment actually can change quite a bit,” he said.

A new drug option

Bezlotoxumab, a new monoclonal antibody, is the first drug to be approved specifically for recurrent C. difficile. It's added to one of the usual drugs like vancomycin, explained Dale Gerding, MD, MACP, a C. difficile researcher and research physician at Edward Hines, Jr. VA Hospital in Hines, Ill.

Dr. Gerding was a coauthor on two trials evaluating recurrence rates when bezlotoxumab was used in combination with an oral antibiotic. Results were published in a Jan. 26 NEJM article. Based on pooled data that included both primary and recurrent infections, the researchers determined that only 17% of patients on bezlotoxumab experienced another bout of C. difficile within 12 weeks versus 27% on placebo.

The drug that bezlotoxumab was combined with—the three options were metronidazole, vancomycin, and fidaxomicin—didn't have a “discernible effect” on its efficacy, the researchers wrote. Fidaxomicin, which has been approved for primary treatment of C. difficile, has also been shown in research to be associated with a reduced rate of recurrence, Dr. Gerding noted.

Precisely how hospital physicians will prescribe bezlotoxumab, which is costly and administered intravenously, will play out over time. “I think it will be used selectively,” he said.

A good candidate might be a frail elderly patient who has already experienced one severe case, according to Dr. Gerding. “You would err on the side of doing everything you can to prevent them from having a recurrence,” he said.

But C. difficile researcher John G. Bartlett, MD, MACP, who wrote an editorial accompanying the study, struck a cautionary note. The study was sizable and well designed, with a statistically significant outcome in favor of bezlotoxumab, said Dr. Bartlett, professor emeritus at Johns Hopkins University School of Medicine in Baltimore.

Still, the high price tag might discourage insurance coverage, as it did with fidaxomicin, particularly since the NEJM analysis didn't look at which categories of patients with recurrent relapses were more likely to benefit, Dr. Bartlett said. “If you could drill down on a specific patient population,” he said, “you might be much more comfortable in using the drug on a more restricted population.”

Metronidazole vs. vancomycin

Since 2010, guidelines from the Society for Healthcare Epidemiology of America and the Infectious Diseases Society of America have recommended vancomycin for severe cases of C. difficile.

Yet a recent large-scale observational study comparing the drug to metronidazole found, among other insights, that practice has been slow to shift. While 42% of the C. difficile episodes in the study—diagnosed from 2005 through 2012—were classified as severe, just 4% to 6% of patients were initially prescribed vancomycin, the researchers found. By 2012, just half of patients with severe C. difficile were getting the drug despite the 2010 guidelines, according to results published on Feb. 6, 2017, in JAMA Internal Medicine.

“I don't really have a good explanation for that,” said Michael A. Rubin, MD, PhD, FACP, the study's senior author and section chief of epidemiology at Utah's VA Salt Lake City Health Care System. “Certainly this study would lead me to believe that more people should be on oral vancomycin with severe disease than currently are. For me, it would be the drug of choice at least for first-line therapy for severe disease.”

His study also found no significant mortality difference between metronidazole and vancomycin for patients with mild to moderate infection. Nor did the researchers identify any difference in recurrence rates between the two drugs regardless of disease severity in their analysis of more than 10,000 Veterans Affairs patients.

But vancomycin was associated with lower 30-day mortality in patients with severe infection: 15.3% versus 19.8% for metronidazole. Thus for every 25 patients with severe infection, the researchers calculated, prescribing vancomycin could avert one death.

Another 2014 study—this one a randomized analysis of vancomycin, metronidazole, and tolevamer—also found a clinical payoff with vancomycin in severe cases. Patients who received it were more likely to achieve clinical success, defined as the elimination of diarrhea and severe abdominal discomfort for at least two consecutive days within the first 10 days of treatment. Among those taking vancomycin for severe C. difficile, 78.5% reported success compared with 66.3% taking metronidazole, according to the Aug. 1, 2014, findings in Clinical Infectious Diseases.

So why don't more doctors make the switch for their most severely ill patients? One influential factor is cost, said Dr. Gerding, an author on the 2014 study. “Metronidazole is so inexpensive that it's very hard to get third-party payers to pay for anything else,” he said.

To reduce the price tag, hospital pharmacies will frequently reformulate the intravenous version of vancomycin into an oral form that's far less expensive than the prescribed oral capsules, Dr. Gerding said. “But there aren't many pharmacies that will do that for outpatients,” he said, which can result in far higher and possibly prohibitive costs once the patient is discharged.

Dr. Nathan said that he's lucky to live in an area where outpatient pharmacies will do the necessary compounding, but not every hospital physician does, which complicates prescribing at discharge, he said.

Thus, some patients with recurring C. difficile might remain on metronidazole for longer periods, Dr. Nathan said. While the typical treatment course is 10 to 14 days, Dr. Nathan said he's been referred patients who have been taking the drug for several months.

In those cases of prolonged metronidazole use, he recommends that doctors ask patients about tingling in their hands and feet, as neuropathy can develop in just a few weeks. Patients might not realize why they're experiencing those tingling symptoms, he said.

Fecal transplant insights

Fecal transplant, administered in various ways, has garnered significant interest in recent years as one option for patients with recurrent infections. Initially most of the data looking at the procedure were observational only and sometimes involved multiple transplant attempts, Dr. Gerding said. But more recently, randomized trials have been published, which “are tempering some of the enthusiasm” regarding these transplants, he said.

Dr. Gerding coauthored an editorial, published on Feb. 1, 2017, in Clinical Infectious Diseases, that looked at a study in the same issue comparing transplant to vancomycin treatment administered with a tapering approach. The study, which randomized 30 patients, was terminated early after an interim futility analysis showed that transplants, administered by enema, weren't significantly reducing recurrences. (In fact, at the time the study was halted, vancomycin was somewhat more effective.)

Hospital physicians should still consider fecal transplant as an option in patients with multiple recurrences, Dr. Gerding said. “There is still a benefit from them,” he said. “But it probably isn't the cure-all that many people thought fecal transplant would be.”

Ilan Youngster, MD, MMSc, a C. difficile researcher and infectious disease expert in Israel, agrees that the recent findings published in Clinical Infectious Diseases add “one more important piece of knowledge,” particularly as there's “very little” randomized trial results available on the procedure.

“But it doesn't mean that fecal transplant is not effective,” said Dr. Youngster, a senior physician in pediatric infectious diseases at Assaf Harofeh Medical Center. “It just goes to show that we have a long way to understanding everything there is to know about it.”

At this point, transplant makes more sense than bezlotoxumab in patients with recurrent episodes, as it's cheaper to give, Dr. Youngster said. Meanwhile, encouraging steps are being taken toward the eventual goal of developing a synthetic equivalent to a stool transplant that ideally will capture the benefits without the longer-term uncertainties of introducing foreign material into the body, he said.

In February, the public stool bank OpenBiome issued a press release announcing a collaboration with Finch Therapeutics to develop such a pill. Patients are slated to be enrolled in a phase 2 trial later this year. The bank also currently provides frozen stool for transplant at other facilities, an advance which Dr. Bartlett described as “the most exciting new development in the field.”

Limiting exposure

To be sure, improved treatment is only part of fighting C. difficile. To reduce the onset and transmission of infections in health care settings, CDC officials and others advise that clinicians and hospitals effectively clean surfaces, strive to quickly diagnose and isolate infected hospitalized patients, and more judiciously choose antibiotics.

Numerous studies have looked at the benefits of various antimicrobial stewardship efforts, including an analysis published online on Jan. 24, 2017, in Lancet Infectious Diseases, which delved into why C. difficile cases in England had declined by roughly 80% since 2006.

The researchers found that restricting fluoroquinolone prescribing played a major role, while hand washing and other infection control measures—albeit important to control the spread of other infections—did not.

But changing prescription patterns is far easier in a nationalized health system, U.S. physicians point out. “Trying to reduce fluoroquinolones is certainly a good step toward [reducing C. difficile rates], although it's very difficult,” said Dr. Rubin, citing the drugs' broad-spectrum coverage and easier dosing regimen for patients.

Different patterns of antibiotic resistance in different parts of the world might also limit the applicability of overseas strategies. Antibiotic prescribing practices do vary significantly between countries, noted Dr. Youngster, an author on a March 2017 study in the Journal of Pediatrics that identified wide differences in prescribing among six countries analyzed.

“We can definitely do a much better job at restricting broad-spectrum antibiotics,” he said. “It's a process. You have to educate the public and you have to educate the physicians as well.”