February 18, 2009

The Attack of the Superbugs

Stuart Levy has been warning about the rise of antibiotic resistance for years, and even though the battle is getting tougher, there is cause for optimism

By Taylor McNeil

If you had developed a bronchial infection before 1930, most likely you would have been in serious trouble. That infection could have led to greater complications, and possibly even death. But after the discovery of antibiotics, and especially penicillin in the early 1940s, treating an infection was simple: take a course of antibiotics, and poof, you’re cured.

“If you use the drugs judiciously, and you create new drugs,” Stuart Levy says, “mankind can stay ahead of infectious disease agents.” Photo: Alonso Nichols

But that same approach—antibiotics for pretty much every infection that arises—has a big downside. The more antibiotics are used, and especially used inappropriately, the more bacteria become resistant to the drugs. Now the bacteria are fighting back, in a sense, becoming immune not to just one or two kinds of antibiotics, but whole groups of the medication. In hospitals and increasingly in the world at large, new “superbugs” are coming into being that are resistant to multiple antibiotics and increasingly hard to kill off. But they are not alone: even common infections are getting harder to defeat easily.

For the last 30 years, Stuart Levy has been leading the effort to bring this increasingly serious problem to the attention of the medical community and the public. A longtime professor of molecular biology and microbiology and of medicine at the School of Medicine and a leading researcher in the basic and applied science of antibiotic resistance, he gladly tells anyone who will listen why these antibiotic-resistant infectious bugs are here, and what we all need to do to stop them. The trouble is that for many years few people heeded the message.

He’s doing more than just talking, of course. In addition to his work at Tufts, where he’s also director of the Center for Adaptation Genetics and Drug Resistance, Levy is co-founder and president of the Alliance for the Prudent Use of Antibiotics, which works with APUA chapters in more than 60 countries to promote effective antibiotic use. He is also chief scientific officer and co-founder of Paratek Pharmaceuticals, which is developing new antibiotics to combat the growing resistance to currently available drugs.

Persistent Enemies

“Bacteria are resilient,” Levy says, with a trace of admiration. “They have certain traits they can turn on to protect themselves, and they can acquire other traits they need from other bacteria in the environment.”

For example, one bacterium might have resistance to drug A, another to drug B, and a third to C, “and suddenly you see one that has resistance to A, B and C, because it’s picked up all those resistances. It’s not a question of just one resistance. It’s multiple,” he says. “This is almost science fiction kind of biology, where resistance genes jump back and forth like trading cards—it’s quite fascinating. No one would have imagined this kind of gene exchange.”

These things don’t happen purposefully—it’s all random. That said, if a physician prescribes the right antibiotics, the invading organisms usually can be defeated. But that seems to be happening less and less, as bacterial organisms have gained more ability to fight back against antibiotics.

That’s made possible, in no small part, because “there is an unfortunate over-use and misuse of antibiotics,” says Levy.

And then there’s the other factor: the lack of new drugs. “The pipeline for new antibiotics is almost dry,” Levy says, especially for those dealing with the toughest bacteria, the so-called gram-negatives like Pseudomonas. These organisms have an extra cell wall, which helps keep out the antibiotics. They also have more efflux pumps, mechanisms that Levy and Laura McMurry, a research associate in microbiology, were the first to identify in the late 1970s, that use energy in a cell to actively pump out the antibiotic before it can neutralize the bacteria. Other bacteria have become common threats, such as MRSA (methicillin-resistant Staphylococcus aureus, also known as multi-drug-resistant Staphylococcus aureus), which is one of the so-called “superbugs” that can be resistant to all but one antibiotic.

Town Crier on the Antibiotic Front

Sounding the alarm about growing antibiotic resistance has been a core part of Levy’s mission for the last three decades. It’s landed him in the likes of the New York Times, Science, Time and most recently the New Yorker, but it’s also landed him in hot water. In the late 1990s, when he began criticizing the use of antibacterials in hand soaps and household cleaners, such as those containing triclosan, and arguing that these products would lead to more antibiotic resistance, industry groups fired back. They posted a whole Web page devoted to criticizing him for questioning their products.

“I didn’t mind it, because I feel very strongly about the issue,” Levy says. “We’re right—you shouldn’t be using antibacterials in ‘healthy’ households. We proved that triclosan was like an antibiotic, that it has a target, and bacteria can become resistant to it.”

He also uses his position at the Alliance for the Prudent Use of Antibiotics (APUA) as a bully pulpit, arguing that the greatest cause of antibiotic resistance is the drugs’ use in humans, and that not just doctors but the general public need to understand the threat. That’s not to downplay the importance of antibiotic use in animal feed—low levels of antibiotics are routinely fed to cattle and pigs because it has been found to speed their growth—and in certain crops, where they are used as pesticides. Those uses play a role in resistance, too.

But it’s human consumption of antibiotics that really fuels the growth of resistance, he says. It’s easy to tell the difference that attitudes toward antibiotics make. Compare the level of antibiotic resistance in two neighboring countries, the Netherlands and Belgium, and you’ll see a striking difference. The Netherlands has a very low level of resistance, and Belgium a high one. Why? “The Dutch are very careful how they use antibiotics,” Levy says. If a bad bug develops there, it will simply get out-competed and vanish. In countries such as Belgium, Italy or Greece, “with lots of antibiotic use,” resistant bacteria thrive. The United States, unfortunately, falls on the wrong side of that equation, too.

The APUA is addressing the problem around the globe. Its researchers recently began work on a two-year, $1.37 million project funded by the Gates Foundation that is examining antibiotic use and resistance in Zambia and Uganda. Drugs that require a prescription in the U.S. are often available on the street in developing countries. Add to that frequently poor communication about how long the drugs should be taken and the effects of stopping a course of treatment before the full measure of antibiotics have been taken, and it’s a recipe for trouble—and growing resistance.

“A lot of this work is documenting in a concise, well-controlled way the whole issue of how antibiotics are acquired and consumed and what kinds of resistance exists in which organisms,” Levy says. The Gates-funded research is a “total evaluation of the antibiotic usage and resistance patterns in these two countries, as a first step toward implementation of changes to reduce resistance and improve antibiotic access.”

A 21st-Century Antibiotic

As resistance to antibiotics has grown and the number of antibiotics that can be used to combat deadly infectious diseases has declined, the situation has been aggravated by big pharmaceutical companies largely abandoning this area of drug development. That’s because there are fewer drug companies after waves of mergers and consolidations, and because the potential rewards are lower. “The return on the investment is not as good as that found for a cholesterol-lowering agent or agents for cardiac problems or sexual impotency,” Levy says. “There’s more profit for drugs in those areas.”

That leaves smaller start-ups carrying the load. One is Paratek, the company that Levy co-founded in 1996 with Walter Gilbert, a Nobel-prize winning professor at Harvard who co-founded Biogen. Paratek has licensed technologies developed by Levy’s lab at Tufts, and recently completed Phase 2 clinical trials for a promising new derivative of tetracycline, called PTK 0796. It can be taken orally or intravenously and is not affected by resistance to existing tetracyclines or other drug families. Now, having shown it is as good as the currently used drug, Zyvox, with no adverse effects, PTK 0796 is heading into final Phase 3 trials before it can be approved for clinical use.

“We’ve got a fabulous drug, and while in the old days there could be a line of pharmaceutical companies wanting to license it, with fewer large pharmaceutical companies in the antibiotic business, the line is shorter, but the need and interest are there,” Levy says.

He’s optimistic about PTK 0796 and other drugs in the Paratek pipeline, including an antibiotic that narrowly targets acne and enhances an anti-inflammatory property of tetracycline that has been mostly ignored.

With all that on his plate, you’d think Levy would have enough, but he’s got many other projects going on, mostly centered on understanding the basic science of antibiotic resistance. In his lab on the eighth floor of the M&V Building at 136 Harrison Ave., Levy has several research projects underway. One is working to better understand multiple drug resistance among various bacterial pathogens. Another seeks to use soil bacteria instead of chemicals to clean up the environment.

Even though he quotes a saying that’s making the rounds in infectious disease circles—“bad bugs, no drugs”—he’s not pessimistic. “If you use the drugs judiciously, and you create new drugs,” he says, “mankind can stay ahead of infectious disease agents.”

Taylor McNeil can be reached at taylor.mcneil@tufts.edu.

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