COVER

Doctors are struggling to control drug-resistant bacteria

MARK NICHOLS September 9 1996
COVER

Doctors are struggling to control drug-resistant bacteria

MARK NICHOLS September 9 1996

Doctors are struggling to control drug-resistant bacteria

COVER

OUTBRAK

MARK NICHOLS

Medical staff and visitors entering the area wear gloves and full-length gowns. When leave, they take off the protective clothing for washing, and scrub their hands carefully. The reason for the precautions last week on the fifth floor of Saskatoon’s St. Paul’s Hospital: an outbreak of a mutant microbe called VRE that is resistant to just about every commonly used antibiotic. Since June, 21 patients with a mix of medical problems—some with kidney failure, others recovering from surgery of one kind or another—were kept in strict isolation from other patients in the 130-bed hospital. Most of them were merely carrying VRE; only one was mildly infected with the potentially deadly bug, and doctors thought that it would clear up by itself. But VRE is a frightening example of a rapidly growing trend: many common infectious agents are becoming resistant to antibiotics. The epidemic of drug-resistant bacteria, warns Dr. Julian Davies, head of microbiology and immunology at the University of British Columbia in Vancouver, “should be recognized as a crisis, because unless we do something now it’s going to get worse.”

How bad could it get? Terrifyingly bad, if the rapidly reproducing and mutating microbes continue to find ways of outfoxing medicine’s battery of antibiotics. There would be nothing to stop some children’s ear infections, for instance, from turning into life-threatening meningitis, and cases of pneumonia that are now routinely treated could instead become routinely fatal. Already, drug resistance is plaguing North American hospitals and the new bugs are making it harder for doctors to treat once easy-to-cure infections. Globally, drug resistance has aided the resurgence of such diseases as dysentery and gonorrhea—and helped turn tuberculosis into the world’s biggest bacterial killer (page 45). If the number and variety of drug-resistant bacteria continue to proliferate, warns Dr. Stephen Vas, a University of Toronto microbiologist, “running out of antibiotics could become a real possibility.”

As the mutants have gained ground, outbreaks of the socalled superbug VRE and of MRSA, a drug-resistant form of

a bacterium called staphylococcus aureus, have become almost endemic in some American hospitals—and the mutant bugs increasingly are infiltrating Canadian institutions. Over the past five years, hospitals in almost every part of the country have confronted outbreaks of drug-resistant bacteria. In Ontario, which appears to be more severely affected than the rest of the country, the number of hospitalbased MRSA cases has more than tripled since 1993—to 1,112 known cases last year. “This problem is like a grass fire,” says Dr. Donald Low, the Toronto microbiologist who is one of Canada’s leading authorities on bacterial problems. “It’s popping up everywhere.”

Drug-resistant bacteria are already killing people, though precise figures are hard to come by. In Ottawa, federal officials are currently carrying out their first study of VRE and MRSA, but the results will not be available until next year. As it is, Dr. Andrew Simor, head of microbiology at Toronto’s Sunnybrook Health Science Centre, says that he is aware of five or six deaths in Canada during the past decade that were caused by drug-resistant bugs. In the United States—where hospital-based drug-resistance problems have made far heavier inroads than in Canada—officials at the Centres for Disease Control and Prevention in Atlanta say that at least 10,000 hospital patients probably die each year while infected with drug-resistant bacteria. “The problem is that people with VRE or MRSA infections are usually seriously ill to begin with,” says Dr. Wendy Johnson, chief of Health Canada’s national bacteriology laboratory. “So it’s often difficult to decide what exactly caused death.”

The invasion of the world by bacteria that can outsmart antibiotics has resulted from a combination of factors. Confident in the 1980s that sophisticated antibacterial drugs had all but won the war on microbes, many of the big multinational drug companies shelved costly research that could have produced new classes of antibiotics. In the meantime, profligate use of antibiotics has created an environment that gives the versatile microbes constant opportunities to come up with drug-resistant mutations.

In North America, drug resistance is showing up with alarming frequency in the form of middle-ear infections in young children. The problem can often be traced to day

Low examining bacteria: bugs that can outfox antibiotics

care centres, where kids pick up viruses that cause colds and flu. Those viral illnesses can, in turn, set the stage for bacterial ear infections, usually involving a bug called streptococcus pneumoniae, which is becoming increasingly resistant to penicillin. Because of that, doctors are often forced to turn to expensive drugs like cefaclor, which costs $1.02 per capsule, compared with amoxicillin, a form of penicillin, which costs only about 10 cents per capsule. The same bug is a common cause of pneumonia. If drug resistance continues to grow, says Dr. Kelly S. MacDonald, associate microbiologist at Toronto’s Mount Sinai Hospital, paying for costly alternatives to penicillin-type drugs “will break hospital antibiotic budgets. And a whole generation of general practitioners will need training in which antibiotics to use. It’s a really difficult situation.”

Some experts think that the growing microbial menace is part of a broader phenomenon, in which humanity’s bruising collision with the natural world is creating new dangers, including those posed by viruses, a class of microbes that are fundamentally different from bacteria—but no less threatening. The so-called emerging viruses, including Africa’s deadly Ebola virus, are believed to have been unleashed as a result of industrial development in the Third World and whisked to the industrialized nations by jet-borne travellers. In the same way, a mutated bacterium that emerges anywhere in the interconnected modern world can soon be infecting victims thousands of miles away.

Unlike viruses, drug-resistant bacteria do not normally pose a threat to healthy people. But when the mutant strains infiltrate the elderly or chronically ill and cause an infection, they can kill. And drug-resistant bacteria thrive in hospital settings, where—despite

routine hand-washing and hygiene practices—the microbes often find ways of jumping from one patient to another. In July, a woman in her 70s who underwent successful open-heart surgery at Toronto’s Sunnybrook suffered an MRSA-induced infection in her left leg, where surgeons had removed veins to replace blocked blood vessels leading to her heart. The infection caused severe pain and a fever—and left untreated could have been fatal. Doctors turned to vancomycin—the so-called drug of last resort—and the infection eventually cleared up. But even vancomycin, the only readily available drug that can almost always defeat MRSA, is not infallible. And if vancomycin and a few possible alternatives had not worked, says Sunnybrook’s Simor, “we might have had to consider trying an experimental drug.”

Doctors dread the day when events in the microbial world could create a kind of doomsday bug. Bacteria are sexually promiscuous, reproduce rapidly—and they can swap genes with ease. Experts predict that, eventually, VRE, which is already immune to the effects of vancomycin, will pass on its resistance skills to MRSA— making another large class of bacteria resistant to it. “If we don’t get control of this problem,” says Stuart Levy, a physician who heads the Boston-based Alliance for the Prudent Use of Antibiotics, which seeks to reduce medical reliance on antibacterial drugs, “we’re going to see people dying of infections—especially people with cancer or AIDS and others whose immune systems have been compromised.”

What is clear is that widespread overuse of antibiotics provides an ideal breeding ground for mutant bacteria that can threaten human life: the more antibiotics are used, the more opportunity the

bacteria have to develop invulnerabilityemdash;and pass that talent on to other bugs. Boston’s Levy cites a widely accepted estimate that “more than half of the prescriptions written for antibiotics in the United States are either not needed, or are for the wrong drug.” Adds UBC’s Davies: “Patients say, ‘Give me an antibiotic, Doc.’ And if you don’t, they go somewhere else and get one.” Experts say that prescribing antibiotics has become so automatic that many doctors do not even bother to determine first if an illness is viralemdash;in which case antibiotics are ineffectiveemdash;or bacterial in origin. Last year, doctors in Canada alone wrote more than 26 million prescriptions for oral antibiotics.

The thinking in North America, says Toronto’s Low, is, “ “Well, it can’t do any harmemdash;might as well start them on antibiotics.’ Now, we’re seeing the consequences of this.” Mississauga, Ont., pediatrician Peter Strachan says that about 70 per cent of childhood ear infections will clear up without antibiotic treatment. In some European countries, drugs are used “only on the most severe ear infections,” he notes. ‘That is probably better than our ap-

proach, which is to use antibiotics for almost any ear infection.”

Today’s crisis over drug resistance is the product of a competition that has raged for the past half-century between disease-causing bacteria and the modern, manmade agents designed to combat them. It began with the birth of the antibiotic era in the early 1940s, when British doctors first treated patients with a drug based on a naturally occurring mould called penicillin. The new drug had a remarkable ability to tame infection-causing bacteria. But within a few years, penicillin-resistant forms of staphylococcusemdash;the drug’s principal targetemdash;had begun to appear. Over the years, the process has been repeated with the introduction of almost every new antibioticemdash;methicillin (a semi-synthetic form of penicillin introduced in the early 1960s), the cephalosporins (a family of penicillin-like drugs), ampicillin, amoxicillin, tetracycline, and vancomycin, a drug first introduced 38 years ago and increasingly used today when other drugs fail.

What enables bacteria to gain the upper hand is their ability to spawn a new generation every 15 or 20 minutesemdash;a rate conducive

to a relatively rapid appearance of mutations. Sooner or later, one of those mutants will have characteristics that enable it to thumb its nose at the latest antibiotic. What follows is a classic example of the Darwinian law of the survival of the fittest: as an antibiotic in a patient’s body wipes out one strain of bacteria, the drug-resistant version thrives, with successive generations of the bug producing millions of offspring a day.

Moreover, bacteria have a remarkable ability to hand on their most useful genes to other bugs—so that drug resistance developed by one microbe can easily be bestowed on others. Just how the microbes manage this feat can baffle even the experts. Biochemist Gerry Wright of McMaster University in Hamilton cites the case of enterococcus, a bowel-inhabiting bacterium that became resistant to vancomycin by somehow acquiring five new genes. It was “a very sophisticated process,” says Wright, which allowed the enterococcus to alter its cell wall so that vancomycin could no longer bind to it and kill the bug. Where did the five genes come from? One possibility, says Wright, is the original source of vancomycin itself—a family of soil bacteria called actinomycètes. Those bacteria secrete a vancomycin-like substance, which is toxic to other microbes—and possesses genes that protect it from its own deadly secretions. “Somehow,” says Wright, “the enterococcus bacterium may have acquired those genes.”

For a number of reasons, drug resistance in Canada is less of a problem—so far—than in the United States. That

Ohio’s 1,000-bed Cleveland Clinic Foundation. There, more than 30 per cent of staphylococcus aureus cultures analyzed are resistant to penicillin-type drugs, while five per cent of enterococcus cases are resistant to vancomycin—rates unheard-of in Canadian institutions. According to Dr. John Washington, the hospital’s head of microbiology, MRSA cases are no longer routinely isolated as they are in Canadian hospitals. “I think our philosophy here is that we have all kinds of drug-resistant bacteria these days and I don’t know that MRSA is any worse a problem than any of the others.” Washington does not think that drug-resistance problems are going to be easily solved. “The bacteria have been around for four billion years or so,” he says, “and they have survived very nicely, thank you, no matter what antibiotics we throw at them.”

Still, despite overprescribing and growing drug resistance, doctors can often find a drug that will work against even the most stubborn bugs. Vancomycin-resistant strains can sometimes be killed by a drug called synerid, and when that fails doctors can try teicoplanin, a British antibiotic that has yet to be approved for use in North America but can be prescribed by doctors in emergencies. And now, after backing away from antibiotic research for over a decade, many of the biggest U.S. and European pharmaceutical firms are once again searching for new and better microbe killers. New drugs are already in the pipeline. Indianapolis-based Eli Lilly and Co. for one,

'This problem is like a grass fire. It's popping up everywhere.'

is partly due to differences between the U.S. and Canadian health-care systems. Because most medical services in Canada are publicly funded, hospitals, and to a lesser extent community-based physicians, face more stringent limitations than many of their American counterparts in prescribing expensive antibiotics. Moreover, experts say that since significant drug-resistance problems first surfaced during the 1980s, Canadian hospitals have routinely taken tougher action to contain outbreaks than American institutions. “Canadian hospitals took drug resistance very seriously from the start,” says Sunnybrook’s Simor. “I don’t believe infection-control measures in many U.S. hospitals are nearly as stringent.”

Certainly, drug resistance is at fairly high levels in

which introduced vancomycin in 1958, is working on a compound that may be able to overcome resistance problems. Company officials say that the drug, aimed at killing a wide range of bacteria, should begin undergoing smallscale human trials towards the end of this year. But some of the most innovative approaches to treating bacterial disease are happening in independent biotechnology companies, including a cluster of Canadian firms concentrated in the West. Among the ideas being investigated: • Scientists at Micrologix Biotech Inc. in Vancouver are working with substances called peptides that, among other functions, help protect plants, insects and animals from dangerous bacteria. Using re-engineered versions of naturally occurring peptides, they hope to create agents capa-

'We could run out of antibiotics'

ble of disarming drug-resistant bacteria so that existing antibiotics will be able to function again. The company is also working on a class of peptide-based antibiotics that would attack and kill dangerous bacteria: the peptides developed by the firm have the ability to punch lethal holes in bacteria. When one of those compounds was injected into mice infected with staphylococcus aureus, the peptide proved effective. One of the next steps, says biochemist Robert Cory, the company’s manager of business development, will be to determine whether the peptide works as well against drug-resistant forms of the bug.

• Researchers at Victoria’s StressGen Biotechnologies Corp. are trying to develop vaccines that would immu>. nize people against potentially danger¿ ous infections. StressGen’s approach, « says Lee Mizzen, the company’s re| search director, is based on sub“ stances called stress proteins that bacteria produce as they invade another organism. The human immune system is alerted by the alien proteins, but often fails to go on the defensive quickly, or strongly, enough. StressGen’s idea is to combine a genetically engineered stress protein with carbohydrates or some other component from potentially dangerous bacteria. The result: a vaccine that would, in effect, train the immune system to attack dangerous disease-causing invaders. The company’s top priority is a vaccine aimed at the increasingly drug-resistant streptococcus pneumoniae bacterium. “It’s not pie in the sky,” says Mizzen. “Our pre-clinical research is very encouraging.”

• According to scientists at Vancouver’s Inex Pharmaceuticals Corp., many drug-resistance problems can be beaten by using a system that delivers existing antibiotics with pinpoint accuracy to the site of infections—and then gets them inside the affected cells. To do this, antibiotics would be packaged in an envelope studded with molecules designed to lock on to receptors that act as biological gateways into cells. The effect, says Inex president James Miller, would be to “swamp the bacteria’s resistance mechanism—you would simply overpower it.” Another advantage of the system, adds Miller, is that by precisely targeting the infected area, smaller amounts of antibiotics could be used than at present, reducing costs and eliminating

some of the side-effects of powerful antibacterial drugs. Miller said that his company hopes to begin human trials aimed at delivering drugs to the site of lung infections in about a year.

But it could be several more years before any new drugs or delivery systems start arriving on pharmacists’ shelves. As drug resistance grows, Canadian hospitals have stepped up screening procedures to spot patients carrying the mutant bugs. And many have taken steps to intensify hand-washing and other hygiene procedures to keep the bugs from spreading. lt;rWe’re constantly harping at our people to wash your hands, wash your hands,” says Ethel Kagan, Montreal General Hospital’s infection control officer.

But some experts think more decisive steps are needed, including controls on the widespread use of antibiotics to prevent disease and promote growth in Canadian farm animals. Many doctors believe that practice gives bacteria added opportunities to develop mutations that can make people sick. Equally pressing, they say, is the need to reduce the use of antibiotics in humans. That is already happening in hospitals, where budgetary pressures and more stringent policing by hospital authorities are placing tighter restrictions on the use of antibiotics. But what about doctors outside hospitals? “That is something we need to look at,” says Simor. “Do we need to put some kind of controls on what doctors can prescribe?” That would be something that doctors, and their patients, would be certain to resent. But it could be just one of the measures up for consideration if the microbial world continues to make progress in its relentless war with modern medicine. □