Our best hope against drug resistance isn't better antibiotics. It's better tactics.

Health and medicine explained.
Dec. 2 2009 12:17 PM

Stop Whining About Antibiotic Abuse

We can win our battle against bacteria. Here's how.

Pills.
Our best hope against drug resistance isn't better antibiotics. It's better tactics.

Ever felt personally responsible for drug-resistant diseases? It's no wonder. Virtually everyone—permissive doctors, nagging patients, hospital administrators, government bureaucrats, and snotty kids—has been blamed for the problem. It's true: Bacteria are conquering our antibiotics much faster then we're developing them. It's scary, too. When a passenger carrying an extremely drug-resistant strain of tuberculosis boarded two flights in May 2007, hysteria ensued. Panicked schools across the country have closed their doors and undergone thorough scrubbings after detecting MRSA.

It's more than a little embarrassing to be decisively losing a battle of wits to unicellular organisms. At least the bacteria are smart enough to develop new strategies every now and then. We plodding humans have been fighting antibiotic resistance the same way for decades: by restricting access to antibiotics and developing new drugs to kill off problem bugs. It hasn't worked, and it's never going to. Until we make a tactical shift, resistance is going to become more common and more dangerous. But these seemingly indomitable microbes have a soft underbelly. To recognize it, you have to understand how bugs develop drug resistance in the first place.

Antibiotic resistance is often described as a simple evolutionary response to environmental pressures—when a bacterial colony is exposed to drugs, the cells that develop defenses will survive and multiply. If it were this simple, bacteria would rarely survive an antibiotic attack. The few cells that mutated to defeat the drug would be killed off by your immune system before they could flourish. But bacteria can transfer genes to one another. When one cell "solves" a drug, it can package up the genetic recipe and transfer it to other bacteria. An entire colony of bacteria can develop antibiotic resistance with a single lucky mutation. And your body, which graciously hosts about 2 quadrillion bacterial cells—20 times your total number of human cells—is one enormous genetic swap meet. Most of your resident bacteria are either helpful or harmless. But some of them have been in our guts long enough to have seen our full menu of antibiotics. So even the so-called "normal flora" can archive antibiotic resistance and either go rogue themselves or spread it to more virulent invaders.

Klebsiella pneumoniae is one such bacterium. It has resided in the human gastrointestinal tract for as long as we have been able to identify microbes. Each time someone is treated for strep throat, syphilis, Lyme disease, or any other bacterial illness, it learns a little more about our medical arsenal. In 1996, doctors identified a strain of Klebsiella that produced an enzyme called KPC, which has the ability to destroy virtually all modern antibiotics.

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The mutant Klebsiella is harmless in the G.I. tract, but if it escapes to another part of the body—because of poor hygiene or any number of other minor slip-ups—it can turn a routine urinary-tract infection into a life-and-death struggle. To make matters worse, Klebsiella has transferred the genetic recipe for KPC to other—sometimes more dangerous—pathogens. Doctors are now seeing strains of E. coli and Pseudomonas that can produce KPC. To combat the bugs, doctors can either throw a cocktail of antibiotics at the infection or dig up classes of antibiotics that were abandoned decades ago because of their intolerable toxicity.

Mutant Klebsiella is now spreading around the world, jumping from person to person. It is a particular problem in New York City, where hospital studies have shown that as many as 60 percent of Klebsiella cells can produce KPC. When these bacteria cause an infection, more than one-third of the victims die.

So far, researchers have responded to this outbreak using the traditional strategies of blame and drug development. The former is useless: Tightening antibiotic controls might help prevent the next emergency, but relying on it to solve the problems we've already created is a bit like slamming shut the city gates after the plague has entered. The latter is short-sighted: Drug development has slowed to a near standstill—down by about 75 percent since the 1980s.

A little creativity might end this game of microbial Whac-A-Mole. Some underfunded, underappreciated researchers have dreamed up truly innovative strategies for stopping genetic transfer—even turning the phenomenon against our enemies. In vitro studies have shown that chemicals like ascorbic acid shut down the movement of antibiotic resistance between cells. (Right now it's effective only at concentrations that a person couldn't tolerate, but it's a start.) Because almost all antibiotic resistance relies on genetic transfer, this technique might be the solution we've been seeking since the very first colony of bacteria solved penicillin in 1944. In the best-case scenario, coupling antibiotics with anti-genetic transfer agents could eliminate the need to ration antibiotics.

Others studies have suggested that we can "infect" bacteria with genetic instructions that cause them to waste their resources copying useless genes, leaving them no time to eat and reproduce. Another possibility is to train bacteria genetically to coexist with us peacefully. For example, some bacteria survive by releasing a toxin that helps them consume our intestinal material, causing disease. If we can develop a gene that enables these strains to eat our food instead of our flesh, they'll have been effectively disarmed. Antibiotic resistance wouldn't even be a concern.

The objection to these strategies isn't scientific; it's financial. Developing a new drug costs between $800 million and $1.7 billion, depending on whether you include the cost of failures, so drug makers believe that only blockbusters can be profitable. Initial research suggests that the smarter, genetically based strategies—much like influenza vaccines—will have to be narrowly targeted at specific outbreaks, because the genetic recipe that works on one strain of bacteria may not work on even closely related pathogens. The chemicals that inhibit the transfer of antibiotic resistance might not be patentable.

Nevertheless, unlike conventional drug development, this research has the potential to open new avenues for countless treatments. It's a completely new way of thinking about fighting disease. And the cost of antibiotic resistance is difficult to ignore. Treating a patient who has garden-variety TB costs $12,000; treating one with a drug-resistant strain costs $180,000. The annual cost of antibiotic resistance may be as high as $30 billion annually. It's time to learn something from the bacteria: adapt to survive.

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