Low magnification micrograph of colonic pseudomembranes in Clostridium difficile colitis, also known as pseudomembranous colitis. Source: Nephron. Commons.wikimedia.org/w/index.php?curid=8171031
People are funny about their stools. We all pass solid waste on a regular (or for some, an irregular) basis. This waste is comprised of leftover food material (fiber!) as well as numerous types of bacteria—literally billions of bacteria, and they are the cause of the rather distinct odor of our stool. We joke with new parents about the perils of diaper duty, and most of them look forward to the days when their babies acquire the bowel control of toddlers. Children get a kick out of bathroom jokes but adults dance around the subject and come up with different names for it. In my research for this article I was graced to find over 100 slang terms for diarrhea ranging from “the trots” to “the runs” to the “GIs”—and it deteriorated rapidly from there.
Thomas Morrow, MD
In this country, the vast majority of diarrheal illness is viral in origin and not severe enough to require the intervention of a physician. It’s unpleasant and possibly embarrassing but, basically, just an inconvenience.
But some cases of acute diarrheal illness can deteriorate into a life-or-death situation. One in particular, Clostridium difficile infection, is associated with the use of antibiotics. C. diff, as it is often called, has become a major scourge of American hospitals and nursing homes.
Clostridium difficile is not a newcomer to the human GI tract. John Finney and Sir William Osler at Johns Hopkins Hospital described what was likely C. difficile infection in 1892. The actual organism was first described about 80 years ago as obligate anaerobic, gram-positive, spore forming, and rod-shaped after being isolated from the intestinal tract of healthy newborns. It was deemed harmless. But because it was tricky to grow, it was named Bacillus difficilis before the scientists settled on Clostridium difficile. There are numerous strains, some of which produce potentially deadly toxins.
C. diff’s innocuous reputation changed after the development and widespread use of antibiotics in the 1940s. Researchers believe that we are protected against pathogenic organisms by the competitive balance among the trillions of bacteria that colonize the gut. When the makeup of the different kinds of bacteria changes and that balance is thrown off, pathogenic bacteria can become dominant, resulting in the symptoms associated with what is then termed a C. difficile infection. Antibiotics can wreak havoc in the gut and throw the population of bacteria completely out of whack. The risk of a C. difficile infection isn’t limited to when people are taking antibiotics. It remains elevated months after they stop taking them while the gut bacteria are still recovering. Moreover, the problem isn’t limited to just a few antibiotics that physicians might avoid prescribing. Nearly all antibiotics have been associated with the development of C. difficile infections.
Currently, C. difficile is now the major cause of antibiotic-associated diarrhea and is responsible for about 1 in every 4 cases. During the last decade and a half, the incidence has increased manyfold. Moreover, a previously rare hypervirulent strain, called ribotype 027 (one of several), has now become endemic in many North American heath care settings. The CDC reported in 2015 that nearly half a million people had suffered C. difficile infections the previous year, resulting in 15,000 deaths.
Several factors are at play that would worsen the C. difficile situation, including the aging of the American population and the growing use of potent immunosuppressive agents in the treatment of cancer and inflammatory disease.
The hypervirulent strains of C. difficile wield many weapons that can create potentially deadly mischief. It pumps out toxins A and B, and the toxins bind especially tightly to the target cells. Increased sporulation and mutations in the proteins lining the surface of the bacteria make it “sticky,” so it adheres to the intestinal lining. The toxins are important because they cause cell death, separation of the epithelial cells, increased vascular permeability, and hemorrhaging. As a result, the colon takes on a thin, membranous appearance, hence a descriptive diagnostic name of pseudomembranous colitis. Although toxin A was thought to be the most damaging, toxin B has recently been found to play an increasingly important role.
The pharmaceutical industry has invested time and money into finding treatments for C. difficile. The obvious approach is to kill the actual bacteria. In 2011, the FDA approved a new antibiotic, fidaxomicin (Dificid), which does just that.
Another approach is to try to neutralize the toxins associated with C. difficile. Merck has recently received FDA approval for bezlotoxumab (Zinplava), a monoclonal antibody that binds to toxin B. It is approved as a treatment to reduce recurrence of C. difficile in patients 18 years of age or older who are receiving antibiotic treatment for the infection and for whom there is a high risk of recurrence. Because the antibodies have rather long half-lives, the Zinplava component of treatment consists of a single intravenous dose of 10 mg/kg over 60 minutes.
Of note, Zinplava does not actually treat the infection itself; it has no antibacterial properties and must therefore be used in conjunction with an antibiotic.
Zinplava was studied in two placebo-controlled phase 3 trials. The first enrolled 391 people and the second, 396. Patients received a single dose of Zinplava with concomitant standard care, which consisted of treatment with the antibiotics metronidazole, vancomycin or fidaxomicin. The endpoints included clinical cure, recurrence, and a combination of the two over time, termed sustained clinical response. Clinical cure was defined as no diarrhea for two consecutive days following the completion of 14 or more days of treatment with the antibiotic component of therapy. Sustained clinical response was defined as a clinical cure and no recurrence during the 12-week period following the therapy with Zinplava.
Overall, Zinplava improved the sustained clinical response from 55% to 60% in the first trial (dubbed Modify 1) and from 52% to 67% in the second (Modify 2). The clinical failure rates were similar when combining trials 1 and 2, and the recurrence was reduced by roughly 10% (absolute) in both trials.
Adverse events included an increase in heart failure (primarily in those with a history of congestive heart failure), which resulted in a warning. Other adverse events included a slight increase in nausea (7% vs. 5%), pyrexia (5% vs. 3%), headache (4% vs. 3%) and infusion reactions (10% vs. 8%).
Merck, which expects to launch Zinplava in the first quarter of 2017, has not set a price but it’s expected to be expensive.
Zinplava is a step forward in the efforts to combat C. diff. But it is hardly a panacea. The high price is more evidence that the country needs to come to grips with pharmaceutical expenditures. A search of www.ClinicalTrials.gov shows 253 different C. diff trials testing everything from probiotics to fecal transplant to vaccines against toxins A and B.
But C. diff is true to its origin and nothing if not difficult. We are only at the beginning of the beginning of the war against this nasty infectious disease.