C. diff turns deadly: Mortality spikes with new strain in U.S. and Canada

Spore-forming bug impervious to alcohol hand rubs

A virulent new strain of Clostridium difficile (C. diff) that has been associated with an eightfold increase in mortality in some outbreaks is emerging in the United States and Canada, Hospital Infection Control has learned.

"We have evidence of it in seven hospitals in six states," says L. Clifford McDonald, MD, medical epidemiologist in the division of health care quality promotion at the Centers for Disease Control and Prevention (CDC). "We certainly expect it will be in many more states. We have confirmed that what they are dealing with [in Montreal] is the same strain that we are grappling with here."

The CDC has not identified specific regions and outbreak sites, but the pathogen apparently first appeared in the United States in 2000 or 2001. A recent survey of some 400 infectious disease physicians nationwide found that 30% reported seeing more severe C. diff infections and an overall increase in the pathogen, he says. National discharge data also show increased number of C. diff cases. "There is good evidence in the United States that something is going on," McDonald notes.

A spore-forming, gram-positive anaerobic bacillus, C. diff always has been a troublesome pathogen because of its ability to persist in the hospital environment and spread via equipment and the hands of health care workers. (See handout.) The typical patient symptoms include watery diarrhea, fever, loss of appetite, nausea, and abdominal pain. Yet until this strain emerged, C. diff rarely has been a killer. Now reports indicate some 100 patients have died of C. diff infection in hospitals in Montreal over a period of six months, McDonald says.

"Historically, mortality has been around 1% or so," he says. "They are reporting rates around 8% in Montreal. Some of the [U.S.] hospitals that we have worked with when we have found this strain have not noticed any increase in mortality, but others have. It is a little [inconsistent], and we are not sure why that is; but certainly Montreal, which has the same strain, has had tremendous increases. That is very new. The deaths are probably resulting most often from severe colitis with a septic syndrome."

At least a dozen hospitals in Montreal reportedly are battling the new strain, which previously had not been seen in the area. "It is definitely more virulent," says Leila Ramman-Haddad, BSN, CIC, president of the Montreal chapter of the Community and Hospital Infection Control Association.

"We are seeing higher mortality rates than what we have seen before. The increase in numbers from our initial baseline is really different. Most of the people affected are the elderly and immune-suppressed patients," she explains.

The deadly set-up: Prior use of antibiotics

While investigators still are trying to analyze a host of factors, it appears that prior administration of antibiotics is a clear risk factor for disease. "We know that second- and third-generation cephalosporins and clindamycin are the ones that trigger it, so we have removed them in our antibiotic restriction policies," Ramman-Haddad says.

CDC investigators say an old strain of C. diff, which was a relatively minor disease-causing agent, has mutated to advantage by acquiring resistance to fluoroquinolones. "Not only is it more resistant than its ancestors, but it is generally more resistant than the nonepidemic strains in some of the same hospitals," McDonald says.

That doesn’t necessarily confound treatment options, as metronidazole and vancomycin still are the respective first and second lines of therapy. But the resistance factor appears to be helping the new C. diff strain set up aggressively in the gastrointestinal system after exposure to antibiotics.

"Antibiotic use has always been talked about as a risk factor for antibiotic resistance, but we don’t talk about it as a risk factor for actually causing a disease," McDonald says. "The exception is C. diff. You can be colonized with it, and you never get disease until antibiotics knock down the natural host defenses of the normal bacteria flora."

Of particular concern, many patients in Montreal are not responding well to initial treatment with metronidazole, Ramman-Haddad says.

"Sometimes, the patients are not responding with the first line [therapy]," she says. "This is one of the differences that we have seen from previous C. diff."

A major emphasis is placed on housekeeping in Montreal hospitals because C. diff is notoriously difficult to eradicate from the environment. A solution containing bleach typically is needed because of its protective spore-forming capabilities. Similarly, the recent emphasis on alcohol-based hand rubs translates to little efficacy because traditional soap and water hand washing is needed to remove C. diff.

"We are focusing on three things — all equally important — to stop transmission: antibiotic use, the cleaning of the environment, and hand washing," Ramman-Haddad says. "We have the alcohol gels everywhere in the hospital so we made sure that people are using soap and water with any contact precautions. It was hard in the beginning [getting them to switch]."

C. diff patients are placed in contact isolation, and cohorts typically are used in the Montreal hospitals, she adds. "Compliance is a challenge for us. You see that sometimes people are not using soap and water because it easier to use the gel. But they are being informed in a massive blitz about hand washing."

Indeed, American ICPs fighting C. diff outbreaks have run into the same problem. "Alcohol does not kill C. diff," says Deoine Reed, PhD, infection control coordinator at Ochsner Clinic Foundation in New Orleans. "Only a bleach solution or the mechanics of washing your hands [will eradicate it]. We educated everybody because few of our staff members really knew about C. diff and didn’t know that it wasn’t killed by the alcohol sanitizers."

The fact that the dramatic emergence of C. diff coincides with the new emphasis on alcohol hand rubs has some suspecting there actually is a causal relationship between the two factors. That notion is rejected under current thinking at the CDC.

"Europeans have been using alcohol-based products for years and have not been having problems with C. diff," McDonald says. "Our take right now on this is that it is probably just a bad alignment of two things that are unrelated. At the same time, if you are having an outbreak, it is true that the alcohol-based products do not kill spores. So the hospitals that are having problems should consider reverting to hand washing at least for the care of patients with known C. diff."

An intriguing and disturbing aspect of the new strain is its expressions of heightened virulence in the form of increased morbidity and mortality. The question investigators are pondering is, why? Some of the emerging evidence points to genetic factors. Two toxins, A and B, are found in typical C. diff strains. The new strain has an extra binary toxin that may in part explain its increased virulence.

"As the name suggests, it is made up in two parts," McDonald says. "It is a toxin that is also in Clostridium perfringens. It has been called the iota toxin. At least in C. perfringens, it is a virulence factor. How important it is for C. diff we don’t know."

The iota toxin previously was seen in only about 6% of C. diff strains, but that is rapidly changing. "This outbreak strain is so predominant that in five of seven hospitals where we found it, it was responsible for more than 50% of [C. diff] isolates," he says. The new strain also has a small 18-base pair deletion in an accessory gene to the toxins A and B. "It’s a gene that is thought to down-regulate toxin A and B production, so a deletion in that gene, we hypothesize, could lead to increased production of toxin A and B," adds. McDonald. "So that is another virulence factor."

A genetic ancestor to the emerging epidemic strain had the same combination of binary toxin and the deletion in the regulator gene. "It had both of those factors, and yet the isolate itself was a minor player only causing sporadic disease," he explains. "We have found it in the historic database dating back as far as 1984. So it was out there, but it was never major pathogen. How did it go from being a minor player to such a major player?"

The answer, as it so often is these wavering days of the antibiotic era, appears to be increasing levels of drug resistance. "In the historic isolates, it was occasionally resistant to clindamycin, but now it is more resistant to clindamycin," McDonald notes.

"But what is even more telling is that previously — the isolates before 2000 — were all susceptible to fluoroquinolones. Now this epidemic strain is uniformly resistant to fluoroquinolones. Perhaps, this strain — which was not that major historically — has been selected with the widespread use of fluoroquinolones. It mutated to advantage," he adds.

The perception in Montreal is that the strain was imported — presumably from the United States — but McDonald is not so sure the pathogen didn’t simply emerge there as it did stateside. "This strain was around in the United States in a lot of different geographic locations back to 1984. I don’t think there is any reason to believe it wasn’t also in Canada, but I don’t have proof of that."

Still, the outbreaks have created such shock waves in Canada that officials have renewed discussions of increasing the ratio of ICPs per licensed beds in health care settings. On the heels of the devastating attack of severe acute respiratory syndrome on Toronto, infection control resources are a hot topic.

"[C. diff] is labor-intensive," Ramman-Haddad says. "It made the government look at the ratio of ICPs to beds. They seem to very motivated to help us, but money is always an issue."