How nightmare microbes could spell the end of the world’s ‘antibiotic miracle’

From The Ottawa Citizen, November 15, 2013

Ronald Hale was admitted to Edmonton’s Royal Alexandra Hospital with complications following lung surgery. The 74-year-old retired mine manager died days later, his body overwhelmed by a nightmarish bacterium from half a world away.

An Alberta woman, who had been in a rickshaw accident in India, had carried the microbe home and it got loose in the Royal Alex. Hale became infected and died when he could not fight off the microbe, which has acquired the biochemical machinery to evade nearly all antibiotics on the shelf.

While still rare in Canada, Britain and the U.S. are both struggling to contain these alarming microbes, which could spell the end of the antibiotic miracle.

Leading health officials are warning of a “catastrophic” threat, and Canadian doctors are calling for action to prevent the organisms from taking hold here.

“Every hospital and health region is going to have to face it one way or the other,” says Dr. Mark Joffe, senior medical director of infection prevention and control for Alberta Health Services. He helped the Royal Alex revamp its procedures after the rickshaw outbreak.

“It should be a wake-up call for all of us,” says Joffe, who is also president of the Association of Medical Microbiology and Infectious Disease Canada, representing physicians, clinical microbiologists and researchers.

The Edmonton outbreak that killed Hale involved a resistant strain of Acinetobacter baumannii, as well as two strains of Klebsiella pneumoniae and Escherichia coli (E. coli). They belong to a worrisome new class of bacteria known as carbapenem-resistant Enterobacteriaceae (CRE).

Dr. Thomas Frieden, director of the U.S. Centers for Disease Control and Prevention, didn’t mince words this spring when he called CRE “nightmare bacteria.”

They pose a triple threat, he said: They are resistant to all or nearly all antibiotics; they kill up to half of people who get serious infections with them; and they can spread their resistance to other common bacteria.

Sally Davies, England’s chief medical officer, had a similar message, saying antibiotic-resistant bacteria pose “a catastrophic threat” that warrants urgent action worldwide.

“If we don’t act now, any one of us could go into hospital in 20 years for minor surgery and die because of an ordinary infection that can’t be treated by antibiotics,” Davies said. “And routine operations like hip replacements or organ transplants could be deadly because of the risk of infection.

“That’s why governments and organizations across the world, including the World Health Organization and G8, need to take this seriously.”

Michael Mulvey, chief of antimicrobial resistance and nosocomial (hospital acquired) infections at Canada’s National Microbiology Laboratory in Winnipeg, is not given to bold public pronouncements. But he is worried.

“My biggest concern is the CRE organisms,” Mulvey said in a recent interview at the Winnipeg lab where his team uses powerful microscopes and gene-sequencing machines to get a read on microbes circulating and arriving in Canada. The scientists have taken a close look at 359 samples of CRE sent to the laboratory by hospitals across Canada since 2008. And Mulvey doesn’t like what he sees.

Most antibiotics, including carbapenems – “one of last drugs on the shelf” – do not kill CRE organisms, says Mulvey. The bacteria, which are relatives of many common gut-dwelling microbes, are also “highly promiscuous,” he says.

CRE carry their genes for drug resistance on mobile elements, called plasmids, and readily share them with other microbes. And when a neighbouring E. coli or salmonella picks up one of the plasmids, Mulvey says, it becomes “instantly multi-drug resistant.”

One of the most worrisome types of CRE has an enzyme known as KPC, short for Klebsiella carbapenemase, that breaks down carbapenem antibiotics. KPC organisms, which emerged in the U.S. more than a decade ago, are now widespread in New York City hospitals and have spread to Israel and Europe where thousands of patients have been infected.

Another type of CRE has acquired an enzyme called New Delhi metallo-beta-lactamase, or NDM-1, that also allows bacteria to evade carbapenems. NDM-1, first seen in 2008, emerged from the Indian subcontinent where it circulates in hospitals and has also been found in wastewater from pharmaceutical plants.

Canada has so far avoided the problems seen in Britain and the U.S., where CRE have caused thousands of infections and deaths.

The U.S. Centers for Disease Control and Prevention estimates CRE now cause about 9,300 health-care-associated infections a year in the U.S. and 600 people die of the infections. In September, the agency declared CRE an “immediate public health threat that requires urgent and aggressive action.”

Canadian health officials are not sounding an alarm, but the Public Health Agency of Canada says CRE are “a serious concern.”

Comprehensive numbers on Canadian infections are not available, but Mulvey’s team collected 359 CRE samples from across the country between 2008 and 2012. And a national surveillance system involving more than 50 large hospitals across Canada reports 154 patients were either colonized or infected by CRE between 2010 and 2012

That may not sound like many, but doctors say every case is cause for serious concern.

“CRE spread very, very easily,” says Dr. Mark Miller, an infectious diseases expert who does research at McGill University and the Jewish General Hospital in Montreal.

A KPC-carrying microbe got loose in an intensive care unit in a Montreal hospital in 2010 and spread to nine patients, four of whom later died, though the deaths could not be “attributed entirely” to the infections, according to a report on the outbreak.

In another Montreal outbreak, 16 patients picked up KPC-carrying organisms which resulted in pneumonia, urinary tract and wound infections.

Montreal hospital are bracing for more CRE outbreaks. New York “is full of them,” says Miller, who would like Canada to improve its surveillance by making it mandatory for doctors and health care facilities to report CRE cases.

“Things should be done proactively, and not in a crisis,” says Miller.

The Public Health Agency of Canada says the provinces and territories have responsibility for establishing mandatory reporting of diseases.

CRE have also turned up in Ontario hospitals. In one case, a 71-year-old woman acquired an NDM-1-producing organism when she travelled to India for an experimental medical treatment for multiple sclerosis.

And five patients picked up NDM-1 bacteria in a 2011 outbreak at hospital in Brampton, Ontario. An analysis of the microbes revealed how one of the organisms shared its resistance genes with other bacterium in one of the patients.

CRE have also touched down in British Columbia. A 76-year-old woman returned to Vancouver from India carrying E. Coli and Klebsiella pneumoniae with NDM-1 in early 2010. The woman had been hospitalized while visiting India. She died soon after returning to Canada from what doctors believe were complications from an overwhelming immune response to infection.

In a bid to keep the bugs at bay, some Canadian hospitals isolate patients who have been hospitalized outside the country until they can be checked for CRE – a time-consuming precaution that requires people to be isolated for up to three days while the tests are completed.

The practice is controversial, and it is not failsafe – as the Royal Alex learned last year when the woman who had been in the rickshaw accident was wheeled into the Edmonton hospital.

The 62-year-old Albertan, who has not been identified, underwent surgery in India after her thigh bone was fractured in the accident. Her leg wound developed an infection that did not respond to treatment in the Indian hospital. “Eventually, she discharged herself and flew back to Edmonton,” Joffe and his colleagues say in a recent report on the outbreak.

Doctors at the Royal Alex wasted no time booking the woman for surgery. They carved away the inflamed tissue, saving her life and her limb.

But the staff missed a key step when she was admitted. They placed the woman in a room on a surgical ward with three other patients, violating the Royal Alex’s policy of isolating and screening patients who have recently been treated in medical facilities outside Canada.

“She should have been isolated; that was the step that was missed,” says Joffe.

It wasn’t until the woman had surgery that Royal Alex’s infection control team became aware of the threat and she was isolated in a private room. By then, three antibiotic resistant microbes she’d carried home were on the move, triggering an outbreak in the hospital that lasted almost two months.

One of her roommates, an 83-year-old woman in hospital with a broken ankle, picked up the resistant Klebsiella pneumoniae. A second roommate, a 69-year-old woman in hospital for an infected thigh incision, was colonized by the resistant Acinetobacter baumannii. Neither woman became ill but they carried the microbes when they were moved to other parts of in the hospital.

In the end, the resistant microbes spread to five patients.

Ron Hale was one of them. The Camrose resident was in hospital for surgery after developing complications from a previous lung operation. He picked up the drug-resistant A. baumannii and his body was soon overwhelmed by the bacteria known for causing pneumonia and bloodstream infections in critically ill patients.

Drugs were of little help as the bacteria were resistant to a long list of antibiotics including carbapenems. And Hale could not fight off the bacteria on his own.

He “developed septic shock and organ failure, was transferred to the intensive care unit and died a few hours later,” Joffe and his colleagues report. They say the case is believed to be the first in which a Canadian died from a carbapenem-resistant bacteria someone brought home from a foreign hospital.

The outbreak caused a major disruption at the Royal Alex. Several units were closed to new admissions until infection control teams sterilized equipment and ensured the bacteria were contained. More than 400 patients were screened to see if they had picked up one of the organisms.

Joffe says the bacteria were likely “spread on unclean hands or possibly on a shared piece of equipment that was not cleaned between one person and the next.”

“These bacteria don’t fly, they don’t jump, they don’t hop,” says Joffe. “So to get from one person to another they have to be carried there.”

The fallout from the outbreak went on for “many months, and in reality is still going on,” says Joffe.

He says ongoing staff education continues to hammer home the importance of hand hygiene and infection control. And the Royal Alex has revamped its admission policy to try to ensure its isolation strategy is not violated in future.

Isolating patients who have been in hospital abroad is costly and controversial. Health researchers in Calgary recently concluded “pre-emptive isolation” for CRE is “not practical at this time” given the number of people travelling, and cost of isolating and screening patients.

Ontario doctors report that the Brampton outbreak involving five patients had no obvious link to travel in regions where CRE are common. “The greater threat may be the eventual dissemination” of CRE organisms in communities where the organisms can move silently between carriers, they report. There has already been a report from Ontario of one 86-year-old man who “locally acquired” an NDM-1 bacterium.

CRE, like many antibiotic resistant microbes, can take up residence in the gut of individuals who then become carriers and can pass the bacteria on to more vulnerable people. While the carriers show no symptoms of infection, the bacteria do put them at risk. “You’re colonized so the potential risk of getting a urinary infection that is very drug-resistant can be higher,” says Mulvey.

And if an individual carrying a CRE needs surgery, “the risk of getting an infection from a surgical site is higher, because you’re colonized, you’re a carrier,” says Mulvey, who stresses the need for people to be vigilant about washing their hands to prevent microbes from spreading.

Joffe expects the CRE seen in Canada are “just the beginning” and stresses the need for surveillance and stringent infection control: “Bacteria don’t respect national and international borders.”

– Research for this story was funded in part by a journalism award from the Canadian Institutes of Health Research.

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