JAMES MAY

The Bugs Stop Here

More and more bacteria are resisting our strongest drugs. An Alberta superlab finds out why.

By Paul Webster

It’s a dark room about the size of a cargo van. The walls are made of enamel-coated steel. There’s a deep electronic purr, and a slightly acrid odour that quietly catches in the throat. The temperature is exactly the same as human blood—380C. At all hours of the day and night, technicians pass in and out through airtight doors depositing stacks of saucer-sized glass discs on stainless-steel shelves. Inside these discs, killers from all corners of the earth silently come alive in the dark. They multiply rapidly, emitting the sickly-sweet smell of disease and death. It was here, in the incubation room in the centre of a Calgary laboratory crammed with high-tech diagnostic equipment, that Dr. Johann Pitout’s career went viral.

Research Road looks much like any other two-lane ribbon in the University of Calgary’s sprawling tangle of asphalt and parking lots. The buildings here, which include the Calgary Laboratory Services (CLS) facility, which serves as Alberta Health Services’ main diagnostic lab in the region, are as utilitarian as the name chosen for the corridor that serves them. But the bland texture of this place belies its importance: in recent years, this stretch of tarmac has come to serve as one of the world’s main medical research superhighways. Medical testing for all of the Calgary region’s 1.2 million people was centralized about a decade ago. Ever since, as many as 1,000 blood, urine and stool samples a day have been dispatched for testing at CLS. Currently, more than 18 million tests are conducted in the lab annually, making it one of the busiest and most important in the world.

Investigations of drug-resistant diseases have helped put Calgary on the global science map.

This flood of samples—all of which are minutely examined by teams of technicians and specialists—explains why Johann Pitout, the facility’s senior medical microbiologist, chose to set up shop here in 2002. As Pitout knew when he arrived from a previous posting in the Middle East, Calgary’s unusually high-volume lab offered him unrivalled professional possibilities. But what Pitout didn’t know when he arrived for work at CLS was that the lab harbours a uniquely rich lode of clues that are proving crucial to one of the most important investigations now under way in medical research. 

Within days of his arrival, Pitout realized he’d stumbled upon the raw materials for a scientific breakthrough. “I thought it was just the cold temperature affecting my brain,” quips Pitout about his first encounter with the biological evidence he found frozen within the lab’s deep storage facilities. Within weeks, Pitout and his new colleagues at CLS plunged into a series of investigations that have broken important new ground in understanding how infection-causing bacteria gather power to resist drugs and kill huge numbers of people while travelling through communities, cities, countries and continents. Those investigations, which are helping scientists map the global transmission of drug-resistant diseases, have also helped put Calgary on the global science map. 

These achievements—which Pitout is quick to credit to teamwork among an extensive group of research collaborators in the lab, at the U of C and across Canada—result largely from Pitout’s success in quietly harnessing the entire city of Calgary itself to the global search for clues in infection control. It’s all been a matter of luck, says Pitout: “I don’t consider myself just a scientist,” he explains with characteristic understatement. “I consider myself someone who got incredibly lucky in the right time and place.”  

Visitors looking for clues to what drives Johann Pitout won’t find his office especially yielding. There are no personal trophies, no icons, no art—not even a potted plant. The label slots on the filing cabinets facing his desk are empty. The lack of personal statements here is, perhaps, a statement in itself. But any scientist anywhere on the planet would find the roadmap to Pitout’s professional soul—and a beacon that reveals his considerable ambition—soon enough: it’s all there in black and red ink on a huge whiteboard above his desk where the word “accepted” is flagged in red next to 14 manuscript titles scrawled in erasable black ink.

In science, where careers are built on the basis of getting studies accepted for publication by journals that serve as the information gateway not just for other scientists, but ultimately for government policy-makers and the mass media, Pitout’s whiteboard comes as close to boasting as good manners will allow.

A closer look reveals more. Contained within each of the 14 titles scrawled across the wall are the letters “ESBL.” Those four letters stand for a type of bacteria forbiddingly named Extended Spectrum Beta Lactamase—a central concern for public health officials across Canada and in many other countries as well. An earlier type of antibiotic-resistant bacteria known as MSRA is now estimated to kill tens of thousands annually across North America. Now, partly due to Pitout’s work, an understanding is growing that ESBLs can be expected to do even more damage. 

The molecular unidirectional flow chamber of CLS.

The molecular unidirectional flow chamber of CLS. (Photo courtesy of Dr. Johann Pitout)

“Pitout and his group are major players in the field,” confirms David Livermore, director of the Antibiotic Resistance Monitoring & Reference Library at the UK Health Protection Authority in London. “He’s been at the front of the pack in focusing our attention on what is undoubtedly going to be a major problem in international medicine.”

Public preoccupation with controlling the spread of bacteria can be measured in many ways, but perhaps the simplest measure is the amazing growth in sales of hand sanitizers. In 2005 alone, US sales of these products doubled—and double digit growth has followed every year since. They’ve become ubiquitous in airports, hospitals, even hotels and car rental outlets. The problems posed by bacteria are now so widely understood that children learn in kindergarten that we all live amid a sea of living bacterial organisms. 

Along with the massive expansion of public demand for bacteria-killers such as hand sanitizers, medical demand for bacteria-killing antibiotic drugs is also booming. Sales of 12 of the world’s top 15 bestselling antibiotics more than doubled in 2008 alone. 

Antibiotic drugs—which were discovered in 1920, almost three centuries after bacteria were discovered to be alive in our bodies—are the hottest success story in the history of human medicine. They are also one of the biggest stories in agricultural history, thanks to their spectacular popularity in poultry, pork, beef and fish farming. 

Antibiotic use in medicine has saved innumerable lives and raised standards of living in every country of the world, including those in the many poor countries of Asia, Africa and Latin America where public hygiene remains dangerously primitive. Their use on farms, where animals consume an estimated 80 per cent of all antibiotics produced worldwide (mostly in order to increase growth rates rather than to treat animal illnesses), has hugely increased food production while driving costs down for meat and poultry producers and consumers. 

The scores of different types of antibiotics available to physicians have emboldened humans enormously—not least in providing us with the assurance that no matter where we go on the planet and no matter what sort of bacteria we encounter, the illnesses they cause will always be treatable with a routine course in relatively cheap, highly effective pills. 

The only trouble with antibiotics, unfortunately, is that like so many silver bullets in science, they contain the seeds of their own destruction—a problem that has come to be widely known in medicine as “the antibiotic paradox.”

The trouble with these drugs is that they contain the seeds of their own destructionthe “antibiotic paradox.”

Less than five years after the first major type of commercial antibiotic—penicillin—was introduced into mass production in the 1940s, researchers began to notice that bacteria treated with this antimicrobial compound rapidly acquired the ability to repulse the drug. The bacteria were able to do this, they learned, due to their ability to very quickly mutate in a rapid evolutionary process of natural selection in which genetic resistance to drugs was quickly acquired by bacteria such as E. coli and salmonella. 

Ever since that discovery, antibiotic use has been guided by a central problem: the more often they are used, the less they work.

Within a few years of the introduction of widespread penicillin use, physicians began noting that it failed to work for patients who had been previously treated with the drug. Drug researchers responded by developing a series of new types of antibiotics with greater power to kill bacteria. But the paradox persisted with every new type of drug invented. In fact, the paradox intensified: the more powerful the drug’s effect in killing bacteria, the more powerful became the backlash that allowed bacteria to defeat it. 

Even more discouragingly for the future prospects of antibiotics, over the past 20 years, scientists have begun tracking the emergence of so-called “superbugs”—bacteria which are able to resist not just one class of antibiotics, but many. Among the very most powerful such bugs are the ESBLs—which are resistant to almost all the major classes of antibiotics in current use. 

The fact that we know as much as we do about these drugs is largely due to the work of Pitout, and to his success in turning the city of Calgary itself into one of the world’s largest antibiotic laboratories.

Johann Pitout’s journey into the ceaselessly teeming microcosmos of drug-resistant bacteria began in a newborn children’s unit in a hospital in Cape Town, South Africa, in 1992. That was the year an outbreak of salmonella in the hospital unit where Pitout was completing his medical studies proved untreatable with antibiotics. “It killed a lot of kids,” Pitout says bluntly. “At least five babies died.” 

That first experience with drug-resistant bacteria set Pitout’s career as a medical microbiologist—a physician with advanced training in microbiology—on course. He soon moved to a lab in Omaha specializing in the bugs of the sort that killed the Cape Town babies. By that time these bugs, which were resistant to a broader array of antibiotics than any ever seen before, had been dubbed ESBLs, and were starting to attract limited attention among scientists. In 1992, the year of the Cape Town outbreak, just two serious scientific papers were published on ESBLs. In 1994, five such studies were published, and in 1996 there were 15. By 2000, there were 57. Last year, 280 studies were published. The deaths Pitout encountered in Cape Town projected him onto scientific terrain that has now become the hottest field in medical microbiology.

Calgarians show higher levels of ESBL bacteria than people in any other city in the world.

When Pitout first signed in for duty at CLS in 2002 (the job came with an academic posting at the U of C, where Pitout is a professor of pathology and laboratory medicine) there were no scientists in western Canada working on ESBL-related research. But the lab’s director of microbiology, Deirdre Church, was well aware of the significance of ESBLs. Shortly after the Calgary superlab opened in 1997, Church decided to begin testing every specimen arriving in the lab for ESBLs—an early step that almost no other lab in the world had yet taken. Church also decided that all samples containing ESBLs should be stored for later investigation. The next step in Church’s strategy was to find an investigator capable of putting these samples to use. And according to Pitout, that’s why Church hired him.

“They told me about their ESBL samples to try to lure me here,” Pitout recalled on a summer morning earlier this year. “They didn’t need to do that—I was keen to come.” The morning was a busy one for Pitout, who was on call at the lab, fielding phone calls from any number of the more than 2,000 physicians across the Calgary region that rely on the lab for testing. When a doctor from a travel clinic phoned looking for information about a patient worried about malaria, Pitout told her he’d get back to her. “If you don’t hear back from me, everything’s hunky dory,” he reassured her in an accent gently inflected with Afrikaans. Then, before continuing with his narrative about ESBLs, Pitout chased down the malaria test results and phoned the physician back, only to discover that he’d written down her phone number incorrectly. “If it weren’t for the research I get to do,” Pitout laughed, “I’d go nuts.”

Within days of setting up shop on Research Road in 2002, Pitout began crafting a strategy to use Calgary’s supersized lab for significant research. “That’s what I was brought out here to do,” he figures.

But even though he knew the resources Calgary had to offer were superb, he was still astonished by what he almost immediately found. Within two weeks of his arrival, Pitout had established that an unprecedented number of urine samples arriving in the lab contained ESBLs—suggesting that bacteria resistant to almost all antibiotics were disturbingly common in the Calgary community.

That finding jarred Pitout, because even today ESBLs are mostly considered to be a problem within hospitals and among patients who either visit hospitals frequently or live in places like seniors homes, where intensive antibiotic usage nourishes high levels of drug-resistant bacteria. 

The discovery that Calgary’s 1.2 million people showed higher levels of ESBLs than documented in any other city in the world at first struck Pitout as simply incredible: “When you come to a new country and you see something like this you think ‘it can’t be true’, ” he recalls. “To see this in Calgary was very strange. It was bizarre. Yes, I can use that word.” 

But Pitout was not alone in the discovery that ESBLs have migrated from being a very contained healthcare issue of concern only in hospitals and long-term care facilities for the elderly and chonically ill to being a looming health crisis for the general public. Halfway around the world, in Seville, Spain, another team of researchers was racing ahead on a very similar investigation into ESBLs in Spanish cities. The two teams were tackling the investigations in very different ways, however. In Calgary, Pitout and his team were using data gathered from across the city as a whole to mount what is known as a population-based study that gave what Pitout calls a “real-life” overview of actual conditions on the ground. In Seville, the Spanish team was conducting a study that probed a group of patients known to have not been hospitalized. Their study—known as a “case controlled” approach—established ESBL contamination levels high enough among these patients to indicate the existence of a community-wide problem.  

By late 2004 both teams were racing toward publishing a paper. In reviews published later, some observers gave Pitout the edge over the Spanish, while others suggest the Spanish bested Pitout. In a bulletin circulated among CLS staff in 2005, Pitout and Church graciously gave the Spanish researchers first mention—but an independent external review by the staff at the UK Health Authority put Pitout first. “We got to the head of the pack together,” shrugs Pitout. 

What matters most, says Pitout, is not who first found out that ESBLs are spreading through cities such as Calgary and Seville. The point, he emphasizes, is that the genie is out of the bottle: ESBLs are now a community-based problem “and once it’s out in the community, you can’t control it.” 

If previous experience is anything to go by, says Pitout, ESBLs will become increasingly common and will within a few years be responsible for huge numbers of deaths. The findings at CLS sent a clear warning signal to the world. The spread of powerfully drug resistant ESBL-producing bacteria, says Pitout, “is a serious medical problem that is now gaining speed and taking us to the point where we’ll have a tough time finding drugs to treat large numbers of people.”

Pitout warns that drug costs could increase tenfold. And in many cases, drugs may simply be unavailable.

Like most findings in science that are later recognized to be notable, Pitout’s finding made a very small splash. But as is again often the case with such findings, the ripples that radiated from this small splash have not receded. Instead, they continue to grow larger. 

At a recent conference of more than 1,000 medical microbiologists from 20 countries in Toronto, over and over again, researchers touched on Pitout’s findings in Calgary. Among global bug-hunters tasked with tracking and foiling the spread of drug-resistant bacteria before it overtakes medical defences, the finding that ESBL contamination jumped from 1 per cent to 4 per cent of samples taken in places such as Calgary between 2000 and 2007 has changed the landscape entirely. 

“ESBLs are resistant to a lot of antibiotics, but most importantly they’re resistant to a class of drugs known as cephalosporins,” explains George Zhanel, a University of Manitoba medical microbiologist who recently conducted an intensive survey of antibiotic resistance in Canadian hospitals. About 10 per cent of all antibiotic prescriptions written by Canadian doctors are for cephalosporins, says Zhanel. “These are very, very important drugs.” 

Cephalosporins were first marketed decades back, but doctors have come to rely increasingly on newer, more powerful generations of these drugs in recent years as bacterial resistance to other heavily used types of antibiotics such as penicillin and tetracycline has grown. Although they were long considered a last-resort drug to be used only in rare situations when other drugs failed, third, fourth and fifth generation cephalosporins are now becoming first resort when patients need antibiotics, says Zhanel. “These are Cadillac drugs,” he says.

The development of increasingly widespread resistance to these drugs due to the spread of ESBLs in Canadian communities represents “a crisis,” says Zhanel, who credits Pitout for bringing the issue into focus not just in Calgary but across Canada. “Now that the ESBLs are out in the community, it’s very hard to stop them. My prediction is that we will see the spread of ESBL-producing bacteria grow steadily. It’s just a matter of years before they knock out cephalosporins as a reliable category of drugs.”

Over the past decade, resistance to cephalosporin antibiotics has increased dramatically in North America, Europe and Asia, leading experts such as Robert Moellering of Harvard Medical School to warn that “we are perilously close” to not having drugs to treat tough-to-beat infections such as gonorrhea. “There are very few situations where we have no therapeutic options, but we are getting close,” says Moellering after noting a recent crisis in which eight patients in New York City died when cephalosporins and every other antibiotic available failed. 

“Once cephalosporins have been eclipsed by drug-resistant bacteria, physicians will face limited options,” says Pitout, who warns that drug costs could increase tenfold for many treatments. And in many cases, antibiotics may simply be unavailable: the last remaining major category of antibiotics, a class known as carbapenums, is already succumbing to antibiotic-resistant bacteria in places such as the US northeast, notes Zhanel. “The carbapenums are the last drug we have,” he warns. “It’s a race, and we are on the losing side of it.”

If there is any good news in all of this, it’s that the alarm raised by Pitout and others is being heard. “We have reached a period in which antimicrobial resistance is finally receiving the close attention it merits,” says Stuart Levy, a US researcher widely credited with being the first to sound the alarm in his 1992 book The Antibiotic Paradox. In Canada, the federal government has established national antibiotic resistance surveillance networks, following demands from activist physicians such as John Conly, a U of C professor who has long pushed for government action to protect antibiotics against misuse in medicine and agriculture.  

The rapid decline in efficacy of numerous categories of antibiotics, including those considered to be drugs of last resort—such as the cephalosporins revealed by Johann Pitout to be potentially doomed—alarms physicians. And it puzzles them, too, because these drugs have been quite carefully protected against misuse in Canada: even though they are used fairly often, they are almost always used only in closely monitored settings like hospital wards and long-term care facilities, so widespread resistance such as that identified in Calgary should not be occurring. Cephalosporins were supposed to endure. Calgary’s city-wide ESBL problem shows this is not the case.

Finding answers to why this is happening is now one of the most important areas of investigation in public health research, say scientists such as George Zhanel and David Livermore. Driven by news that ESBLs are circulating in Calgary and other cities, public health agencies in North America, Europe and Asia have plunged into investigating where these devastatingly hard to kill bugs are coming from. 

Michael Mulvey, the Public Health Agency of Canada’s top ESBL investigator, has moved from studying ESBLs solely in hospitals to tracking them in farmyard animals used in meat production as well as drinking water and food. In probing whether agricultural use of cephalosporins is contributing to their demise along with medical use, says Mulvey: “We’re trying to tie it all together.” 

Working with Pitout, Mulvey helped reveal that ESBLs circulating in Calgary are unlike those usually found in Canadian hospitals. Oddly, the type of ESBLs they found to predominate in Calgary are most often found in places like India and Pakistan. Mulvey credits this finding to the power of the CLS facility. “He’s in a fairly unique situation,” Mulvey says of Pitout, “where he is able to capture all ESBLs identified in the entire health region. This is because there is one centralized lab which generates the microbiology data that is linked with all of the patient information in that region. This enables him to do true population-based studies which generate very robust data.”  

Last year, Pitout, Church and other colleagues revealed a key clue to why the ESBL problem has internationalized so rapidly. In a study that attracted strong praise among researchers, Pitout established that among the people in Calgary who sent ESBL-bearing specimens to the lab, international travel was a common risk pattern, especially for travellers to India and Pakistan. 

That finding was matched with a map of the areas of Calgary where people providing ESBL specimens were located. Neighbourhoods with high percentages of people who travel to India and Pakistan were found to be hot spots for ESBLs.

The finding makes sense given that the misuse of antibiotics in India—with its huge population and inadequate healthcare system—is notorious, says Livermore. Cephalosporin resistance in much of the subcontinent, including India, Pakistan and Bangladesh, has become common. But once again, Calgary has yielded a key, entirely unexpected insight in the revelation that antibiotic-resistant bacteria are jumping from continent to continent at the speed of travel. “We thought the risk factors might be water or food. I even thought it could be pets,” says Pitout. “But we didn’t think travel would stand out as a risk for ESBLs.” 

And once again, the work of Pitout and his group at CLS is of international significance. Pitout credits the city of Calgary itself for having a lab he now fondly describes—in a version of the “tip of the iceberg” metaphor that only a transplanted African could use—as “the eyes of the hippopotamus.” 

Paul Webster is a Toronto-based writer and film director who specializes in reporting on business, science, medicine and nature.

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