Wide Use of Antibiotics Allows C. Diff to Flourish
You might say Jacob Epstein, a lean, healthy, 88-year-old Floridian,
died in early May from a broken arm. Following surgery to reset the bone,
he was given an antibiotic to prevent postoperative infection, a common hospital practice.
His daughter, Beth Fidanza, recalled that within a week her father developed diarrhea caused by a particularly nasty intestinal bacterium called Clostridium difficile, or C. diff. Another antibiotic seemed to eradicate the disease, but a month later the gut infection recurred. Mr. Epstein was given another antibiotic, but within days developed a fatal combination of kidney failure, dangerously low blood pressure and gastrointestinal bleeding.
Although this sounds like an example of “the operation was a success but the patient died,” Mr. Epstein’s demise is really the result of inappropriate use of antibiotics, which has given rise to a virulent, antibiotic-resistant strain of C. diff., an organism that now causes close to 500,000 new cases and 30,000 deaths a year in the United States alone.
C. diff. is a spore-forming, toxin-producing bacterium that can colonize the large intestine and wreak havoc there, causing frequent watery stools and severe dehydration. The spores are resistant to heat, acid and antibiotics; they can be washed away with soap and water but are not inhibited by the alcohol-based hand sanitizers now widely used in health facilities. Thus, poor bathroom hygiene can spread this nearly ubiquitous organism to vulnerable individuals.
Dr. Dale N. Gerding, an infectious diseases specialist at Loyola University Chicago, said in an interview: “C. diff. is found in soil and water, even chlorinated water, and is a low-level contaminant in food. Most of us ingest C. diff. every day.”
However, he explained that in most people the myriad micro-organisms that normally reside in the gut protect against C. diff. infection. That is, until antibiotics disrupt the healthy balance of micro-organisms. Freed of competition, C. diff spores can germinate and reproduce unchecked, and not only in people with compromised immune systems.
“The healthy gut microbiota has three features: a large number of micro-organisms, a large number of different species, and an increased representation of certain bacterial phyla and a decreased representation of other phyla,” Maja Rupnik wrote in The New England Journal of Medicine last month. “The disruption of any of these features can result in increased susceptibility to the growth of C. difficile,” Dr. Rupnik added.
Since the early 2000s, hospitals have reported drastic increases in severe C. diff. infections, Dr. Daniel A. Leffler and Dr. J. Thomas Lamont of Beth Israel Deaconess Medical Center in Bostonreported in the same journal. The predominant virulent strain, known as NAP1, has a mortality rate three times as high as that associated with the less virulent forms most prevalent in decades past.
“The most important risk factor for C. difficile infection remains antibiotic use,” the doctors wrote. “Ampicillin, amoxicillin, cephalosporins, clindamycin and fluoroquinolones are the antibiotics that are most frequently associated with the disease, but almost all antibiotics have been associated with infection.”
Dr. Gerding said most antibiotics “are being used inappropriately, for things like upper respiratory infections that are caused by viruses.” And eating yogurt or taking commercially available probiotics while on an antibiotic have not proved protective, he said. However, in England, where a program of more judicious use of antibiotics was put into effect, C. diff. infections have declined.
The risk and severity of a C. diff. infection rises with age, as does the risk of a recurrence. In a study of an outbreak in a Quebec hospital, people over 65 were 10 times as likely as younger patients to become infected. Even after infected individuals recover, about 5 percent continue to harbor the toxic strain in their stool for six months, and if they take another antibiotic during that time, the illness can recur, Dr. Gerding said.
Although traditionally associated with hospitals and other inpatient medical facilities, C. diff. infections acquired outside hospitals have “increased dramatically in the past decade and may now account for up to a third of new cases,” Dr. Leffler and Dr. Lamont wrote.
But Dr. Gerding, who has studied C. diff. for three decades, said that among those infected outside hospitals, “about 80 percent had a recent health care exposure,” for example, at a clinic or a doctor’s office, where they may have been prescribed antibiotics and exposed to the spores.
The good news, he said, is that new treatment approaches are proving capable of preventing recurrences in infected individuals, and may be able to prevent an initial infection in the future.
This month in JAMA, Dr. Gerding and his colleagues described treatment using a nontoxin-producing strain of C. diff. in patients who initially recovered from an infection. While not a permanent solution, the strain persists in the intestine long enough to allow the normal healthy microbiota to repopulate the gut and greatly reduce the risk of a recurrence.
In another approach, Dr. Israel Lowy of Medarex in Princeton, N.J. (now with Regeneron Pharmaceuticals), Dr. Deborah C. Molrine of MassBiologics at the University of Massachusetts Medical School and their colleagues demonstrated that monoclonal antibodies created to attack the C. diff. toxins reduced the risk of a recurrence to 7 percent from 25 percent. This, too, is a stopgap measure designed to provide time for the restoration of normal gut microbiota.
A more permanent solution now under study involves an injectable antitoxin vaccine. Because it can take weeks to months for vaccine protection to take effect, one of the temporary measures could be used in the interim, Dr. Gerding said.
Well-publicized treatments using fecal transplants from healthy individuals are reserved for patients who have experienced multiple recurrences of C. diff. Researchers are trying to isolate the organisms in feces from healthy people that are most effective, with the hope of incorporating them into a capsule that could be taken orally as a treatment or preventive.
Dr. Gerding foresees the possibility that people taking an antibiotic might simultaneously receive a dose of live therapeutic bacteria that can prevent colonization by hazardous organisms. “If this works, it will be huge in preventing transmission of C. diff.,” he said.
