Superbugs

Back in the late 1980s, as Jan was beginning her nursing career in the intensive care unit (ICU) of a Toronto-area hospital, most patients who acquired a bacterial infection would receive antibiotics and – presto! – the infection would vanish. Today, Jan sees a very different picture. She now deals on a daily basis with stubborn, hard-to-treat and sometimes fatal infections that have become immune to, or have even resulted from, the very antibiotics that used to work so beautifully.

“In our 13-bed intensive care unit, we always have at least three or four patients fighting off superbugs,” Jan says. She and her colleagues keep these patients in isolation, don new disposable gowns, gloves, masks and protective eyewear each time they enter the room, and wash their hands dozens of times a day. But the patients, who must undergo complex treatment and endure long hospital stays, have a higher risk of long-term disability, and some die. “Figuring out how to work the new reality is a huge issue,” says Jan. She won’t use her last name because her hospital doesn’t want to publicize its problem with antimicrobial-resistant infections, even though growing evidence suggests that all hospitals are in the same boat. A 2013 survey of 176 acute-care hospitals across Canada found that one in 12 adult patients is either infected or colonized with the three most common superbugs (see “The Superbug Hitlist“). If they’re infected, they’re already sick with it. If they’re colonized, they may become sick or pass it to others.

The problem of antimicrobial resistance goes far beyond hospitals. It’s an important, pervasive and global issue, says microbiologist Dr. Allison McGeer, director of infection control at Toronto’s Mount Sinai Hospital and a professor of laboratory medicine and pathobiology at U of T. “There isn’t anywhere you can look where resistance isn’t an issue,” says McGeer. “In hospitals, out in the community, foodborne illnesses, sexually transmitted infections, tuberculosis, malaria – resistance is everywhere.”

Counting the Cost of Superbugs

Conservative estimates suggest that more than two million people in North America get sick every year with infections resistant to antimicrobial drugs, which include mostly antibiotics but also antiparasitics, antivirals and antifungals. About 25,000 die from these infections, and many more die from conditions complicated by such an infection. More than a quarter of Canadian cases of salmonella, caused from eating contaminated food, are resistant to one or more antibiotics. About one in five urinary tract infections is now resistant to the sulfa drugs that were once a reliable cure. While gonorrhoea was once easily treated, now as many as 60 per cent of cases worldwide may be caused by multi-drug-resistant strains. Globally, there are 630,000 cases of multi-drug resistant tuberculosis in 84 countries, including Canada.

Antimicrobial-resistant infections can still be treated, but when first-line drugs – the most narrowly targeted ones with the fewest side effects – don’t work, doctors must turn to more broad-spectrum second-line drugs, which may be less effective, cost more and have worse side effects. If those fail, doctors try even harsher third-line drugs. The costs, both human and financial, are enormous; the U.S. Centers for Disease Control and Prevention estimates that antibiotic resistance costs that country’s economy up to $55 billion a year due to increased health-care costs and lost productivity. It’s one of the most important public health concerns of the 21^st century, especially with health-care systems already heavily burdened with non-communicable illnesses such as heart disease, diabetes and cancer, says epidemiologist Dr. Keiji Fukuda of the World Health Organization (WHO). In August 2013 he warned, “If we begin to add on top of that a lot of untreatable or difficult-to-treat infections, we really are going to begin bringing some of these health systems to the brink.”

In Canada, an estimated 250,000 patients each year develop difficult infections, costing our health-care system an extra $1 billion annually. And despite their treatment, several thousand of these patients will die. “With these superbugs, we’ve now reached an age where some patients’ infections are resistant to all antibiotics,” says Tony Mazzulli, interim microbiologist-in-chief at Toronto’s University Health Network and Mount Sinai Hospital, and a U of T professor in laboratory medicine and pathobiology. “For those patients, we have no usable antibiotics left.”

How Antibiotics Stopped Working

During much of the 20th century, antibiotics were considered wonder drugs that would rid the world of all infections. What happened? Why have many of them stopped working? There are several reasons, starting with the bacteria themselves. These creatures, which have been around for billions of years longer than humans, are perfect examples of evolution in action. They evolve quickly to survive any threat, including a drug designed to kill them. There are so many bacteria – billions – that new mutations arise often. For instance, if some bacteria develop membranes that drugs can’t get through, those will survive drug treatment and proliferate. Others may produce potent enzymes that inactivate the antibiotic. Still others may acquire resistance genes from different bacteria or even different species such as viruses. It’s not that you become resistant to an antibiotic; it’s that the bacteria do. It’s nature’s inevitable defence strategy: survival of the fittest.

Humans have unwittingly sped up this natural selection process through our overuse of antibiotics. (Roughly speaking, the more we take antibiotics, the more quickly bacteria evolve.) Antibiotics are among the most commonly prescribed drugs worldwide. The latest figures from the 2013 report on the state of public health in Canada show that for every 1,000 Canadians, there are 670 prescriptions for oral antimicrobials filled every year. Yet the U.S. Centers for Disease Control and Prevention estimates that up to 50 per cent of all antibiotics prescribed are unnecessary (in many cases, we’d get better without them) or not optimally effective as prescribed.

And that’s just in people. More than three-quarters of antimicrobials in Canada are given to food animals such as cattle, pigs, chickens and fish. Ninety per cent of the time the drugs are given to healthy animals to help prevent infection or promote growth. (For reasons not well understood, antibiotics help animals grow faster on less food and make them market-ready sooner.) But sometimes antibiotics for animals are the same ones used in people, and resistant bacteria can travel from animals to humans. The WHO says when healthy chickens receive tetracycline, within 36 hours their excrement contains resistant E. coli, a common cause of infection in people. A 2013 Mount Sinai study in Ontario and Alberta found that the risk of resistant E. coli was highest near properties housing livestock. Resistant bacteria are even turning up in bottled mineral water.

The European Union banned the use of antibiotics as growth promoters in animals in 2006, and the U.S. Food and Drug Administration began implementing a voluntary plan with the American agricultural industry in late 2013. But in Canada, not only do we lack any official guidelines or policies to manage antimicrobial use in animals, but we’re one of the few industrialized countries where farmers can buy over-the- counter antibiotics simply to promote growth in animals, without a veterinarian’s prescription. In 2013 the Ontario Medical Association called on federal and provincial governments to crack down on antibiotic overuse in farming, with no results yet.

At U of T, Ziana Ahmed, a graduate student pursuing a master’s in economics, has proposed a novel approach to this problem: user fees.

In a paper she wrote with Aidan Hollis (MA 1990, PhD 1996), now a professor of economics at the University of Calgary, Ahmed argues that user fees have several advantages over an outright ban: they are easier to administer, they deter low value uses of antibiotics, they generate revenues that can be used to boost development of new antibiotics and they can be applied on an international scale. Ahmed says the higher costs of antibiotics will encourage farmers to improve animal management methods and adopt substitutes for drugs, such as vaccinations. The paper, “Preserving Antibiotics, Rationally,” was recently published in the New England Journal of Medicine and generated headlines throughout North America and Europe.

While overuse of antimicrobials is a danger, so is under-dosing. Scientists have known for decades that using too little of an antibiotic can hasten resistance. As long ago as 1945, Alexander Fleming, who discovered penicillin, said in his Nobel lecture, “I would like to sound one note of warning . . . It is not difficult to make microbes resistant to penicillin in the laboratory by exposing them to concentrations not sufficient to kill them.”

If you take too low a dose of an antibiotic or stop it too soon, you may kill off many of the bacteria that are causing the infection but leave stragglers that may be slightly resistant. These can survive, multiply, increase their resistance with each new generation, eventually outnumber the non-resistant bacteria, and be passed to another person. So the same antibiotic may not work the next time you or a family member needs it. Patients need more information about this, but physicians need to be reminded as well. Says Mazzulli: “I give talks to groups of family physicians and community doctors all across Canada to educate them about the importance of this issue.”

What Are the Solutions?

Resistance is a serious situation, to be sure, but certainly not a hopeless one. “We’re by no means at an antimicrobial apocalypse,” says Nick Daneman, a clinician-scientist in infectious diseases and clinical epidemiology at Sunnybrook Health Sciences Centre in Toronto and a professor of medicine at U of T. “But it’s kind of like global warming. It’s not an immediate catastrophe, but it could become one if we don’t do something soon.”

As with the issue of climate change, there’s no single solution to the problem of antimicrobial resistance. Researchers around the world, including several at U of T, are pursuing a variety of strategies. One of them involves antimicrobial stewardship programs. Now mandatory in all Ontario acute care hospitals, these programs aim to optimize antibiotic use to maximize their effects and minimize their harm. They generally involve surveillance screening of all patients for infection, regardless of why they come to hospital, and monitoring all antibiotic use. At Sunnybrook, for example, only infectious disease specialists can approve certain broad-spectrum antibiotics.

“The neat part of antimicrobial stewardship programs is they improve quality [of care] and value,” says Daneman. In Sunnybrook’s first year of the program, in 2009, broad spectrum antibiotic use in the ICU dropped 21 per cent. In the same year, rates of C. difficile, a common infection, fell 30 per cent, and the hospital saved $95,000. Daneman is now co-leading a research program comparing shorter- and longer-course antibiotic therapies, since emerging evidence suggests that shorter courses – but not too short – can safely treat certain mild to moderate bacterial infections without increasing resistance. Shorter treatment periods also reduce the side effects and the cost.

Another way researchers are tackling transmission of infection is by prioritizing prevention. “Probably the main route of transfer of infection is on the hands of health-care workers,” says Mazzulli. Improving cleaning methods and increasing hand washing are essential, but they can cause their own problems.

“We wash our hands so much – sometimes four or five times during one interaction with one patient – that our hands dry out, they crack, they bleed, they’re open to infection, and then we’re told we can’t work,” says Jan, the ICU nurse. Sinks in hospital rooms can actually increase infections because bacteria like moisture. Alcohol-based hand sanitizers are effective (and, for complex reasons, don’t contribute to microbial resistance, unlike other antibacterial cleansers), but they do dry out hands. Because of all the things a doctor, nurse or technician has to touch – doors, beds, switches, equipment, pens, wheelchairs, computer keyboards and patients – it’s impossible to keep hands constantly clean. Industrial antibacterial cleansers and detergents, for cleaning rooms, don’t significantly reduce infections and may even contribute to antimicrobial resistance, says the Public Health Agency of Canada.

Novel Approaches Hold Promise

The newest initiatives are focusing in other directions: sanitizing mists, robots emitting bacteria-killing ultraviolet light, and even antimicrobial building materials such as copper. It’s been known since ancient times that copper and its alloys kill bacteria, but building hospital furniture out of solid copper would be horrendously expensive.

A U of T team, however, has developed a cost-effective method of spray-painting molten copper and its alloys onto almost any surface, such as wood, plastic or metal. “The coating is toxic to bacteria, it doesn’t degrade, and the beauty is it can come in different colours, to look like bronze, brass, copper or stainless steel,” says Javad Mostaghimi, a professor of plasma engineering in the department of mechanical and industrial engineering and the holder of a Distinguished Professor award. He is also founding director of U of T’s Centre for Advanced Coating Technologies.

Mostaghimi won a $100,000 grant from Grand Challenges Canada, funded by the federal government, to further this research. In February, with colleagues Maurice Ringuette, a professor in cell and systems biology, and centre director Larry Pershin, Mostaghimi was to begin to copper-coat ICU rooms in Mount Sinai Hospital and a hospital in Lima, Peru, covering bedrails, sinks, tables, cabinet handles, countertops and push plates on doors. The researchers will compare bacteria counts and infection rates with non-coated ICU rooms.

Faster, easier and cheaper diagnostic tests are also an urgent need, not just in hospital settings but in the community, especially in rural areas where people have no access to high-tech facilities. Shana Kelley, a professor of pharmacy and biomedical engineering, leads a team that has developed a portable diagnostic technology using tiny 3-D sensors patterned on the surface of an electronic chip. The sensors can detect and analyze molecules from a blood sample. Instead of traditional diagnostic methods, which involve waiting days for bacteria to grow, this method gives easy-to interpret results in 20 minutes. “This can show almost instantly what kind of bacteria are present and with what resistance, so the patient can get exactly the right drug sooner,” says Kelley, who won a Grand Challenges Canada grant to focus the technology on malaria in Tanzania and urinary and blood infections in Toronto. She predicts the unit will be commercially available within two years for less than $50.

Chip-based diagnostic testing is also under development for multi-drug-resistant tuberculosis, which is a huge problem in developing countries and, because of international travel, trade and immigration, a rapidly growing issue in North America. Edmond Young, a professor in mechanical and industrial engineering and also a Grand Challenges Canada grant recipient, has developed a technology combining microchips and microfluidics. With colleagues in Thailand and the U.S., he’s designing a kit, using Lego-like plastic bases with snap-on lids, for quick assessment of mucus samples for multi-drug-resistant tuberculosis. “It’s cheap, portable, easy to use and doesn’t require any expensive machinery or extensive training,” says Young, who hopes to begin testing the kits soon in hospitals and clinics in Thailand.

With resistance such a global challenge, why don’t we just create new antibiotics? We could, but bringing a new drug to market can take more than 10 years and cost a billion dollars. Pharmaceutical companies, who must answer to shareholders, are more inclined to invest in developing a drug that people take daily – such as for high blood pressure, high cholesterol or arthritis – than an antibiotic that people take as rarely as possible. So scientists are looking at tweaking some of the old antibiotics. Peter Stogios, a research associate in chemical engineering and applied chemistry, is studying, among other things, aminoglycosides, a class of antibiotics that lost their effectiveness in the 1970s. Stogios is testing various chemical compounds, some of them donated by pharmaceutical companies, to try to restore the old drugs’ effectiveness so they block the resistant enzymes that the bacteria have developed. “In the lab we can kill these resistant bacteria,” says Stogios, adding that his research is still in the early stages.

It may take constant vigilance on all fronts, but the fight against antibiotic resistance is showing signs of success. Microbiologist McGeer says, “Five or six years ago, I thought we were probably going to have to accept methicillin-resistant Staphylococcus aureus (MRSA) as endemic in hospitals. I was dead wrong.” She says in places that have aggressively tackled the problem, such as the U.K., MRSA rates have dropped significantly, and in Ontario they’ve begun to stabilize. “And that’s absolutely brilliant.”