A tapered and pulsed regimen with vancomycin — with diligent follow-up — can achieve significant cure rates in recurrent Clostridium difficile (C. difficile) infected patients, according to a new study.
Researchers from Loyola Medicine retrospectively studied 100 vancomycin taper and pulse treatment patients treated for recurrent C. difficile infection between January 1, 2009 and December 31, 2014. Their clinic, the study authors wrote, has been a referral center for the infection for the past decade.
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However, despite the guidelines for treatment of recurrent C. difficile infection being not too different than recurrent episodes – except for the use of vancomycin when the case is severe – there have not been many studies on this vancomycin taper and pulsed dosing.
The researchers observed that after a referral, the confirmed recurrent C. difficile patients were treated with a vancomycin taper and pulse regimen: a taper of vancomycin to once-daily, followed by alternate day dosing; or once-daily followed by alternate day dosing; followed by every third day, for at least 2 weeks. After this regimen, all patients had 90-day follow-up documentation.
On average, the patients in the clinic were on their third C. difficile diarrhea episode. Half of the patients had also received a standard course of vancomycin, while another third had received some type of vancomycin taper regimen, the researchers said.
Despite the fact that many of these patients were a “treatment experienced” population, 75% of the patients who received a supervised vancomycin taper and pulsed regimen achieved a cure, study author Stuart Johnson MD, . He added that the results were further improved for patients who received the expended pulse phase: 81% achieved a cure.
“The findings were not unexpected to us, but I think that many clinicians will be surprised how well a deliberate, prolonged vancomycin taper and pulse regimen – with careful follow up – works,” Johnson said.
There were no significant differences among the patients in terms of gender, age, concomitant antibiotics, proton pump inhibitor use, histamine receptor-2 blocker use, or patients with a regimen greater than 10 weeks in length, the researchers continued.
The researchers added that their finding of improved cure rates with alternate-day dosing plus every third day dosing over strictly alternate-day dosing is consistent with the hypothesis that pulsed dosing can promote a cyclical decrease in spore burden, they wrote. This can also permit the resetting of normal microbiota in the gut.
Johnson concluded that the clinical implications of the study show most recurrent C. difficile patients do not need fecal microbiota transplant (FMT).
“FMT has received an enormous amount of press and this procedure is now widely available throughout the US,” Johnson said. “FMT is attractive because it addresses one of the primary mechanisms involved with recurrent C. difficile infection, a marked disruption of the resident bacteria that populate the intestine and provide an important host defense against C. difficile.
Although physicians screen donor feces for “known pathogens,” not all is known of the potential complications to come from FMT, Johnson said.
“In addition, it appears that efficacy with a carefully supervised vancomycin taper and pulse regimen compare to that achieved with FMT,” Johnson said.
The study, “Vancomycin Taper and Pulsed Regimen with careful Follow up for Patients with Recurrent Clostridium difficile Infection,” was published in the journal Clinical Infectious Diseases.
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And that new knowledge about Clostridium difficile (a bacterium also known as “C. diff“) may lead to better treatment for the most vulnerable patients.
The discovery, made in research laboratories at the University of Michigan Medical School and the U.S. Food and Drug Administration, is published in the online journal PLoS Pathogens.
It helps solve a key mystery about C. diff: What triggers it to germinate, or break its dormancy, from its hard spore form when it reaches the gut.
Though the findings were made in mice, not humans, the researchers say the crucial role of calcium may help explain another mystery: Why some hospital patients and nursing home residents have a much higher risk of contracting C. diff infections and the resulting diarrhea that carries its spores out of the body.
That group includes people whose guts are flooded with extra calcium because they’re taking certain medications or supplements, have low levels of Vitamin D in their blood or have gut diseases that keep them from absorbing calcium.
The new discovery shows that C. diff can recognize this extra calcium, along with a substance called bile salt produced in the liver, to trigger its awakening and the breaking of its shell.
Previous research had suggested it couldn’t do this without another key component, an amino acid called glycine. But the new findings show calcium and the bile salt called taurochlorate alone are enough. Mouse gut contents that were depleted of gut calcium had a 90 percent lower rate of C. diff spore germination.
“These spores are like armored seeds, and they can pass through the gut’s acidic environment intact,” says Philip Hanna, Ph.D., senior author of the new paper and a professor of microbiology and immunology at U-M. “Much of the spore’s own weight is made of calcium, but we’ve shown that calcium from the gut can work with bile salts to trigger the enzyme needed to activate the spore and start the germination process.”
Ironically, the researchers say, one way to use this new knowledge in human patients might be to add even more calcium to the system.
That could awaken all the dormant C. diff spores in a patient’s gut at once, and make them vulnerable to antibiotics that can only kill the germinated form. That could also prevent the transmission of more spores through diarrhea to the patient’s room. That could slow or stop the cycle of transmission that could threaten them or other patients in the future.
Hanna’s graduate student, Travis Kochan, made a key observation that led to the discovery. He noted that the fluid “growth medium” that the researchers typically grow C. diff in for their studies had calcium in it. He realized this could artificially alter the results of their experiments about what caused C. diff spores to germinate.
So, he used a chemical to remove the calcium while leaving all the other nutrients that keep C. diff growing. The result: no new spore germination happened in the calcium-free growth medium.
FDA’s Center for Biologics Evaluation and Research conducted further research in laboratory dishes and in the guts of mice. FDA’s Paul Carlson, Ph.D., a former U-M research fellow, and fellow FDA scientists in his laboratory found that C. diff spores that were mutated so that glycine couldn’t act on them could still germinate and colonize mice. This suggested that calcium, and not glycine, was critical for this process.
Both mutant and regular forms of the bacteria could still activate an enzyme inside the C. diff spore that led the bacteria to start dissolving their hard shell. This released the store of calcium that the spore had been harboring inside itself, and increases the local level of the nutrient even further.
“These spores don’t want to germinate in the wrong place,” says Kochan, whose grandfather suffered from a severe C. diff infection which ultimately led to his death. “C. diff spores have specialized to germinate in the gut environment, especially in the environment of the small intestine, where calcium and the bile salt injection from the liver comes in.”
Hanna notes that the bile salt connection to C. diff spore germination was first discovered at U-M in 1982 by a team led by Ken Wilson, M.D.
Calcium and the gut
Certain ailments and treatments cause defects in calcium absorption, but are also risk factors for C. diff infections. For example, patients with vitamin D deficiency are five times more likely to get C. diff.
Medications aimed at calming acid reflux – such as proton pump inhibitors – and steroids can increase the amount of calcium in the gut. A Vitamin D deficiency can keep the body from reabsorbing calcium through the gut wall, allowing it to build up.
And people with inflammatory bowel diseases such as Crohn’s and colitis also have a harder time absorbing calcium from food through their gut walls.
Older adults are also often counseled to take calcium supplements to compensate for lower calcium levels and protect their bones from fracturing.
Hanna cautions that the new findings should not cause any patients to stop taking their medications or doctor-recommended supplements, or to start taking new ones. But he hopes to work with clinicians at U-M and beyond to test the new knowledge in a clinical setting. Meanwhile, he and Kochan and their FDA and U-M colleagues will continue to study C. diff germination in mice and look for ways to block the enzymes crucial to spore germination.
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As part of a multicenter study, investigators from the University of Oxford, the University of Leeds, Astellas Pharma Europe, and elsewhere used a combination of ribotyping, sequencing, phylogenetics, and geographic analyses to retrace the genetic diversity and potential sources of C. difficile isolates involved in infections in European hospitals.
Recent research suggests a proportion of Clostridium difficile cases in Europe involve not only hospital-acquired infections but also infections associated with other sources, such as food.
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David Eyre, a clinical lecturer at the University of Oxford, was slated to present the work at the European Congress of Clinical Microbiology and Infectious Diseases annual 2017 meeting in Vienna this past weekend. The study was funded by Astellas Pharma’s Europe, Middle East, and Africa (EMEA) program.
“We don’t know much about how C. difficile might be spread in the food chain, but this research suggests it may be very widespread,” Eyre said in a statement. “If that turns out to be the case, then we need to focus on some new preventative strategies such as vaccination in humans once this is possible, or we might need to look at our use of animal fertilizers on crops.”
“This study doesn’t give us any definitive answers,” he explained, “but it does suggest other factors [than hospital infections] are at play in the spread of C. difficile and more research is urgently needed to pin them down.”
Some of the strains clustered by locale, consistent with spread from one individual to the next, for example in a healthcare setting. But more unexpectedly, the team also saw strains smattered across seemingly unconnected sites. And because at least one of those strains had previously been linked to pig farming, the researchers speculated that some infections may have been transmitted through food sources.
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