Antibiotic Stewardship Key, but Multifaceted Strategies Needed to Combat C. difficile Epidemic

Clostridium difficile infection is the most common cause of hospital-acquired diarrhea in the world, affecting North America and Europe for decades, and recently emerging as a public health challenge in Asia. Since the hypervirulent strain NAP1/BI/ribotype 027 emerged around the turn of the century, CDI incidence and severity spiked, especially in older patients. Additionally, the prevalence of community-onset infections has increased, and the management of disease recurrence remains challenging.

CDI incidence appears to have plateaued in Western nations, but national CDI control efforts have produced varied results, with marked success seen in the U.K. Incidence rates have declined by about 80% in England since the NHS implemented national control policies in 2007. Conversely, CDI remains the most frequent health care-associated infection in the U.S., with about half a million infections occurring in 2011, which were linked to about 29,000 deaths and cost acute care facilities upward of $4.8 billion. Further, the CDC reported that CDI incidence rates declined by only 8% in the U.S. between 2009 and 2014, and the Department of Health and Human Services reported CDI-related hospitalizations increased by 18% during the same period.

The key differences between the approaches to CDI control in the U.K. and U.S. are twofold, according to experts interviewed by Healio Gastroenterology. First, the national health system in the U.K. allowed for strict implementation of a nationwide CDI control policy, but more importantly, that policy included a mandatory antibiotic stewardship initiative restricting the use of fluoroquinolones, which investigators have recently credited as being the primary driver of the reduction.

Given that CDI rates remain at epidemic levels in the U.S. and Canada, where fluoroquinolones remain unrestricted, experts agreed that antibiotic stewardship should play a major role in CDI control programs moving forward, but advocate a multi-strategy approach that includes infection control and emerging therapeutics to combat this notoriously “clever” pathogen.

Antibiotic Restriction vs. Deep Cleaning

The successful national CDI control policies implemented a decade ago in the U.K. specifically restricted the use of cephalosporin and fluoroquinolone antibiotics while improving deep cleaning and other hospital infection control measures. Recently, Mark H. Wilcox, MD, FRCPath, professor of medical microbiology at the University of Leeds, and colleagues evaluated national data on CDI incidence and antimicrobial prescriptions spanning 1998 to 2014, to determine which of these policy components was the major driver behind the reductions in CDI.

To account for the proportion of CDIs caused by fluoroquinolone-resistant or -susceptible strains, they assessed whole genome sequencing data from thousands of C. difficile isolates. If the outbreak was halted by antibiotic restriction, then the infections caused by strains resistant to fluoroquinolones would show decline faster, whereas if the outbreak was halted by infection control measures, then infections of both resistant and susceptible strains would decline at the same rate.

“We showed very clearly that following the reduction in use of fluoroquinolones in the U.K., the fluoroquinolone-resistant strains causing CDI were the ones that went away, and that was solely responsible for the reduction in CDI cases,” Wilcox told Healio Gastroenterology. “The cases caused by fluoroquinolone-susceptible strains did not change in incidence, which is indirect but very powerful evidence that it was indeed the restriction of fluoroquinolones, in conjunction with an outbreak due to various fluoroquinolone-resistant strains, that was responsible for the control of the outbreak.”

Rolling out a similar restriction would be prohibitively difficult in the U.S. given its fractionated health care system, but it appears that virtually any antimicrobial stewardship intervention has a positive affect on CDI rates, according to Daniel E. Freedberg, MD, of the division of digestive and liver diseases at Columbia University Medical Center.

“We cannot do what they did in the U.K. because there’s no single payer that can make a nationwide formulary change like that,” he told Healio Gastroenterology. “What I do know from U.S.-based stewardship studies is that even though stewardship is implemented in different ways in almost every study, it seems to have a benefit no matter how it’s implemented. There’s a lot of evidence that stewardship works regardless of how it’s done.”

New guidelines released last year by the Infectious Disease Society of America and the Society for Healthcare Epidemiology of America acknowledge that more research is needed to identify optimal antimicrobial stewardship strategies. However, the societies said in a press release that in addition to preauthorization and prospective review policies forming the “cornerstone” of stewardship programs, the best evidence suggests that syndrome-specific interventions, involving “focused multifaceted” strategies, are most effective.

Freedberg and others share the view that antibiotic stewardship is “the key pillar” of CDI prevention considering the herd effect of antibiotic-associated CDI risk.

“The more people who receive antibiotics on a given ward, the higher that ward’s CDI risk, even if an individual is not receiving the antibiotics,” he said. “Because antibiotics have the potential to alter not just one patient’s microbiome, but everybody’s, even if they’re not in the room at the same time, they’re really the key target for CDI prevention.”

Freedberg and colleagues recently reported retrospective data on this phenomenon at DDW 2017, which showed that after hospitalized patients who received antibiotics were discharged, the next patient who occupied the same hospital bed had an increased risk for CDI, even after adjusting for other risk factors.

However, some experts caution against concluding that antibiotic restriction alone is enough. In correspondence commenting on Wilcox’s study, Esther van Kleef, PhD, of Oxford University, and colleagues, argued that an increased use of liquid hand soap associated with a national hand-hygiene campaign also played an important role in the reduction of CDI in the U.K.

Lynne V. McFarland, PhD, of University of Washington Medical Center in Seattle, said that antimicrobial stewardship is best viewed as an essential component of multifaceted infection control bundles, which she argued in Expert Review of Gastroenterology and Hepatology is supported by the strongest evidence compared with other primary prevention strategies.

Infection Control Bundles

Many hospitals implemented bundled interventions to reduce CDI, and while their components and effects vary, they appear to be effective. In a recent systematic review published in Infection Control and Hospital Epidemiology, all 26 studies evaluating different CDI control bundles showed they reduced CDI rates.

“We’re finding that a multi-strategy approach is best,” McFarland told Healio Gastroenterology. “Infection control bundles are multi-tactics to attack spreading the disease through the hospital, using infection control practices,” like increased hand washing, room disinfection, patient isolation and antibiotic stewardship. These are simple strategies, “but they require you to be ever vigilant, which can be tough when you’re stressed, busy and short-staffed, but this is what we need to do,” she said.

More research is needed to determine which bundled strategies work best, but in addition to being cost-effective, CDI control bundles instigated improvement of basic infection control efforts, from interrupting horizontal transmission through better disinfection practices, to reducing patient risk factors with probiotics, McFarland added.

“Patients become susceptible when they are exposed to antibiotics, which disturbs the normal flora that is usually protective, and that’s where probiotics may play a role, as some strains have been shown to be very effective in combatting CDI,” she said.

Probiotics

While current guidelines do not recommend the use of probiotics for CDI prevention, McFarland concluded in her review article that moderate-level evidence supports their use. More recently, a meta-analysis published in Gastroenterology showed probiotic use associated with a reduced CDI risk in hospitalized patients who received antibiotics, especially if given closer to the first dose of antibiotics, which reduced the risk by at least 50%.

However, there was significant heterogeneity in probiotic dose and species between the studies, and the lack of knowledge regarding which probiotics are effective impedes widespread use as a CDI prevention strategy, according to Sahil Khanna, MBBS, of the division of gastroenterology and hepatology at the Mayo Clinic in Rochester, Minn.

“We don’t completely understand which probiotics are effective, so we are not close to mainstream use at this time,” he told Healio Gastroenterology. “It’s possible that they may play a role in CDI prevention but the number needed to treat will be high, because while there’s about a 50% risk reduction, the overall CDI risk in hospitalized patients is low, and the overall risk in patients who receive antibiotics is roughly 5% to 10%.”

On the other hand, Colleen R. Kelly, MD, assistant professor of medicine at The Alpert Medical School of Brown University, and the Center for Women’s GI Medicine in Providence, Rhode Island, argued that the risk–benefit ratio of probiotics is favorable in most patients, and said she would like to see them used more often in at-risk hospitalized patients.

“It’s a couple of bucks for a probiotic to prevent a CDI that could cost the health care system $30,000,” she told Healio Gastroenterology. “Hospitals can sometimes be penny-wise and dollar-foolish. There is a small cost, but they’re safe for most patients. If I was in the hospital and receiving an antibiotic, I would demand a probiotic.”

Kelly noted that the negative results of the large PLACIDE trial — which found no benefit of a multistrain preparation of lactobacilli and bifidobacterial for preventing antibiotic- and C. difficile-associated diarrhea in older hospitalized patients — are often cited as a reason not to use probiotics. However, she argued that the study’s location — in the U.K. after successful national CDI control policies were implemented — certainly impacts how the data should be interpreted.

“At baseline, the CDI risk in those hospitals was only about 1%, so it’s hard to improve on that,” she said.

While studies on facility-wide probiotics are sparse, important data from a 10-year observational study at a community hospital in Quebec showed that such a program can be not only effective, but sustainable, McFarland said. After a major outbreak in 2003, the hospital gave all adult inpatients treated with antibiotics a mixed-strain probiotic called Bio-K+ (Bio-K Plus International Inc.), a combination of Lactobacillus acidophilus CL1285, Lactobacillus casei LBC80R, and Lactobacillus rhamnosus CLR2. More than 40,000 patients received the probiotic over 10 years, during which the hospital’s CDI rate dropped from 18 to 2.3 cases per 10,000 patient days, which were consistently lower than similar hospitals in the region.

“Here’s a program that suggests this is sustainable, cost-effective, and doesn’t seem to encumber the normal routine of the hospital, so it’s a very exciting approach that looks like a nice add-on component to infection control bundles,” McFarland said.

In addition to infection control bundles, experts agreed that emerging therapeutics will play a role in the multifaceted approach to prevent primary CDI, and address the challenge of treating the 20% of patients whose infections recur. According to a review by McFarland, the recent pipeline included 13 investigational antibiotics, two antibiotic inactivators, seven bacteria or yeasts to augment the microbiome, seven immunizing agents and three toxin binders, a quarter of which showed efficacy in phase 2 or 3 trials and are being actively developed as new CDI therapies. In fact, the FDA approved the first drug for prevention of recurrent CDI just last October.

Prevention of Recurrence

Zinplava (bezlotoxumab, Merck) is a fully human IgG1 monoclonal antibody that reduces the rate of recurrent CDI by neutralizing C. difficile toxin B. A post hoc analysis of the global phase 3 MODIFY trials, in which Wilcox was an investigator, showed 15% of patients given bezlotoxumab had recurrent CDI compared with 24.2% of those given placebo.

“We’ve clearly demonstrated that when given alongside standard of care, bezlotoxumab can reduce the risk of recurrence, notably in patients with a high baseline risk of recurrent CDI and poor outcomes,” he said. “The infusion can be given early on in standard of care treatment or perhaps patients can be brought back to the hospital for the infusion if there’s no need to stay in hospital or be admitted in the first place.”

Merck announced bezlotoxumab would become available in the first quarter of 2017, but the experts interviewed had no clinical experience with the agent at the time of press. According to Freedberg, it remains unclear where it will fit into the treatment algorithm, considering its cost, route of administration and relatively narrow indication in patients 18 years of age or older who are receiving antibacterial drug treatment of CDI and are at a high risk for CDI recurrence.

“The benefit over vancomycin was not enormous, but it was statistically significant,” Freedberg said. “It is an IV drug so obviously that impacts how it will be used, and my impression is the manufacturers envision it as a drug that might be used for a patient who’s had multiple recurrences, has been on oral vancomycin, has improved, and is now ready for hospital discharge, and as he or she is out the door they might get a shot of this as the hospital hopes to prevent another recurrence or another admission. I think the jury is out on whether it will be used like that. Cost will also be a big issue because the drug is quite expensive.”

Kelly agreed that the role of bezlotoxumab in clinical practice remains to be seen, particularly given the relative effectiveness of fecal microbiota transplantation for treating recurrent CDI.

“By the time people come to me with recurrent infection, they don’t want to try another drug that’s 10% better than placebo, they want something that’s 90% effective, and that’s what I can give them with FMT,” she said. However, she noted that bezlotoxumab would likely be appropriate for use in elderly or immunocompromised patients for whom FMT may not be a good option, and added that the IDSA and SHEA guidelines expected later this year may suggest a clinically useful place in the algorithm for bezlotoxumab.

While bezlotoxumab and a handful of other monoclonal antibodies in early development for CDI provide passive immunity to patients, several active vaccines are in development for primary prevention.

Vaccines, Immunotherapies

Sanofi Pasteur initiated the phase 3 “Cdiffense” trial evaluating its CDI vaccine, a “toxoid vaccine which targets the toxins generated by the C. diff bacteria,” in January 2016, with plans to enroll up to 15,000 adults at 200 sites spanning 20 countries. More recently, Pfizer announced positive results from a phase 2 trial of its CDI vaccine candidate (PF-06425090), which works by “inducing a functional antibody response capable of neutralizing the two main disease-causing toxins produced by C. difficile (toxins A and B).” The company said it planned to begin a phase 3 trial in the first half of the year, with a similar number of participants as the Cdiffense trial.

These vaccines aim at “a much more population-based approach to preventing CDI,” Wilcox said. “The idea would be to immunize relatively healthy individuals who are thought to have an increased chance of developing CDI, either by virtue of age or exposure to hospitals and/or antibiotics, and give them longer lasting protection by immunizing them. A vaccine approach means you have to first of all think of who to vaccinate and vaccinate them soon enough so that they can develop protection before they become at risk of CDI.”

Timing and targeting the right patients uniquely challenge the vaccine approach in CDI, according to McFarland.

“My concern is not that [vaccines] won’t work, but how you can target a high-risk population,” she said. “Think of all the people who get the flu vaccine; most of us are susceptible to the flu, but C. diff doesn’t have that kind of prevalence in the population. So vaccinating a great deal of people may not be worth the cost, and if you’re giving a vaccine it takes a while for the antibody levels to get up to a protective level, so the timing of it on a practical level may be difficult.”

While the vaccines represent a “broader brush” approach, other immunotherapies like ribaxamase (SYN-004, Synthetic Biologics) are “more targeted to individual patients in the acute risk scenario,” Wilcox said.

Ribaxamase is an oral enzyme (beta-lactamase) given with certain IV antibiotics to prevent primary CDI by degrading excess antibiotics in the large intestine, thereby preserving gut microbiome diversity. This approach was shown to be effective, with a 71.4% relative risk reduction in CDI among 412 patients treated with IV ceftriaxone for lower respiratory tract infections, according to the results of a phase 2b proof of concept study presented at DDW 2017.

The drug is “clever” in its design allowing for antibiotic treatment of infections “while limiting the collateral damage to gut microbiota,” Kelly said, adding that if phase 3 trials are positive and it is “priced smartly, ... it could become standard for it to be co-administered with beta-lactam antibiotics in high-risk patients.”

Along with these approaches to prevention, narrow spectrum antibiotics are advancing in the pipeline, and the most recently approved, Dificid (fidaxomicin, Merck), is slowly making its way into clinical use.

Narrow-Spectrum Antibiotics

Fidaxomicin, approved by the FDA in 2011, is not endorsed by current CDI guidelines, but experts agreed this is not for lack of promise in its effectiveness. Khanna and colleagues, for example, recently reported it was highly effective for treating initial and recurrent infections based on the results of a multicenter retrospective study.

“The overall response rate ... was 90%,” he said in a prior interview. “Patients with no prior CDI episodes had significantly higher response and lower recurrence rates compared with patients with prior episodes,” suggesting that early use of fidaxomicin may be more beneficial than later use in the CDI course.

Kelly agreed that the microbiome-sparing aspect of fidaxomicin makes it a promising first-line CDI antibiotic, but said the high price of the drug is cost-prohibitive.

“Insurance companies have not been approving it for first-line use, so it’s being used after a patient has had a second or third recurrence, and by that point they’re 60% to 80% likely to have another recurrence no matter what you give them,” she said. “It costs $2,000 to $3,000 and is not much more likely to work than vancomycin at that point. If you use a narrow spectrum antibiotic like fidaxomicin early on, at the time of a first infection, then you might end up with less recurrent infection, but they’ve got to price them appropriately.”

According to Khanna, these types of narrow spectrum antibiotics dominate the pipeline, and represent the future of antibiotic development for CDI.

“Future antibiotics have to be more microbiome-sparing, so they should be narrow spectrum rather than broad spectrum, or selective, targeted CDI-specific antibiotics rather than antibiotics that clobber overall microbial species in general,” he said.

While fidaxomicin continues to “percolate into clinical practice,” another significant change regarding CDI antibiotics is the move from metronidazole to vancomycin as a first-line antibiotic, according to Freedberg.

“The most recent shift is a recognition now that oral vancomycin should probably be the first drug for everybody,” he said. “The only benefit to metronidazole over oral vancomycin is cost, and metronidazole actually has a profound effect on the anaerobes in the colon. The only reason it’s not a risk factor for CDI is that it also kills C. diff, so when you have someone with a gut colonization resistance problem it seems unappealing to prescribe a drug that also wipes out their colonic microbiome.”

Kelly agreed, citing a large VA study recently published in JAMA Internal Medicine that showed 30-day mortality was significantly reduced among patients who received vancomycin vs. metronidazole for CDI, though recurrence rates were comparable. Further, a recent Cochrane review found that moderate quality evidence suggests vancomycin is superior to metronidazole, and that fidaxomicin is superior to vancomycin.

“Metronidazole is not a terrible thing to try first-line in someone who’s got a mild infection, who is young and doesn’t have a lot of comorbidities, because it’s cheap,” Kelly said. “Elderly patients, patients with IBD or other significant comorbidities or anybody admitted to the hospital for their CDI should definitely get vancomycin rather than metronidazole. It is more expensive but there isn’t yet any kind of known drug resistance, so we’re all pretty comfortable with it and we know it works most of the time.”

However, when patients get into the cycle of multiple recurrences, “the problem is restoring the gut microbiome so that when you stop therapy, the C. diff doesn’t relapse again within a couple of weeks,” Kelly said. “That’s why when you get to those later infections people are going to FMT.”

While FMT is becoming increasingly recognized as an effective treatment for recurrent CDI, the science behind it continues to advance, particularly in the realm of the optimal route of administration.

Frozen, Encapsulated FMT

Frozen and freeze-dried FMT appears to be as effective as fresh donor stool. For example, Herbert L. DuPont, MD, director of the Center for Infectious Diseases at University of Texas Health School of Public Health, and colleagues showed in a double blind randomized controlled trial that cure rates were highest with fresh FMT (100%), followed by frozen (83%) and then lyophilized (78%), though these were all administered via colonoscopy. More recently, Dina H. Kao, MD, of University of Alberta, Canada, presented randomized controlled trial results at DDW 2017 that showed colonoscopic vs. encapsulated FMT were both 96% successful.

According to Freedberg, these findings suggest that the days of traditional fecal transplant are numbered, as the potential for standardized encapsulated FMT would alleviate safety concerns.

“It seems that once we have a defined mixture of bacteria — maybe in 5 to 10 years — that would probably be preferable to FMT,” he said.

Khanna added that the main advantage of encapsulated FMT would be its practical benefits.

“A product that can be prescribed to patients, bought from a pharmacy and administered as a single dose without the need for sedation or colonoscopy, that’ll be a game changer, especially for patients who have difficult anatomies, can’t tolerate a bowel prep, or are too sick to undergo the procedure,” he said.

The two leading human feces-derived products in the pipeline are SER-109 (Seres Therapeutics), an oral capsule prepared from healthy donor stool containing dormant Firmicute spores that are activated in the lower GI tract, and RBX2660 (Rebiotix), a broad-spectrum microbiota suspension delivered to the intestinal tract via enema.

Seres announced that it plans to initiate a new phase 2 clinical study of SER-109, after a positive Type B meeting with the FDA following the failure of its previous phase 2 trial. Rebiotix said it expects RBX2660 to enter phase 3 clinical development after reaching its primary endpoint in a phase 2 trial, which examined responses from 132 patients versus a historical control of 110 patients.

Despite clear evidence that FMT is effective and noninferior via easier routes of administration, Wilcox cautioned that it should still be used as a last resort considering its safety concerns.

“FMT is being promoted and used earlier in CDI patients, yet there are still significant safety concerns with manipulating a patient’s microbiome such that we should be reserving this effective treatment option for when other treatment options have not worked rather than doing it the other way around,” he said. “It’s good that frozen or encapsulated product appears to be as effective as fresh FMT as that does solve some practical issues, but that shouldn’t be translated into a more widespread use in place of other effective therapies.”

Kelly said that the AGA’s newly launched FMT National Registry aims to address these safety issues, and hopes to enroll its first patient in the summer of 2017. The registry investigators plan to follow 4,000 patients from 75 sites for up to 10 years after FMT to gather real-world efficacy results, as well as the short- and long-term side effects of FMT delivered via different administration routes, Kelly said. Further, the registry will include a biobank of pre- and post-FMT patient stool specimens, so investigators can analyze changes to the microbiome following the treatment.

The complexity of the microbiome represents both the challenge and the promise inherent in the wide variety of approaches to treating and preventing CDI, yet the simplest strategies remain most effective through all these advances, McFarland said.

“As the science progresses we will have more innovative treatments, but what continues to be the best way of preventing CDI is washing your hands with soap and water — such a simple thing. The development of new treatments is exciting, but the reliance on basic infection control practices is probably the best weapon in our arsenal,” she said. – by Adam Leitenberger

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• For more information:
• Daniel E. Freedberg, MD, can be reached at def2004@cumc.columbia.edu.
• Sahil Khanna, MBBS, can be reached at Khanna.Sahil@mayo.edu.
• Colleen R. Kelly, MD, can be reached at colleen_r_kelly@brown.edu.
• Lynne V. McFarland, PhD, can be reached at lvmcfarl@u.washington.edu.
• Mark H. Wilcox, MD, FRCPath, can be reached at mark.wilcox@nhs.net.

Disclosures: Khanna reports financial relationships with Rebiotix and Summit Therapeutics. Kelly reports a financial relationship with Summit Therapeutics. McFarland reports she has received fees as a speaker for Biocodex, France and Lallemand, France, and is on the scientific advisory board of BioK+, Canada. Wilcox reports financial relationships with Actelion, Cubist, Astellas, Optimer, Sanofi-Pasteur, Summit, Biomerieux, Qiagen, Merck, Seres, Valneva, Alere, Da Volterra, Cerexa, Abbott, the European Tissue Symposium, AstraZeneca, Pfizer, Durata, Nabriva, Roche, The Medicine Company, and Basilea.