Evolution at Work: Watching Bacteria Grow Drug Resistant

Day by day, the doctors unwittingly helped the bacteria infecting their young heart patient to evolve. The more intensively they treated his affliction with antibiotics, the more the microbes resisted the therapy.

In a strict medical sense, the young man, identified only as Patient X, died of complications from a congenital heart ailment and a Staphylococcus aureus infection.

More broadly, evolution killed him.

The life-and-death struggle inside his infected heart was driven by the same evolutionary forces of natural selection and adaptation that are causing a pandemic of drug-resistant diseases world-wide. The emergence of such immunity among infectious diseases is one of the most well-documented problems in modern public health. Until now, however, researchers knew little about how bacteria multiplying inside the human body overcome the drugs designed to control them.

Patient X died in October 2000 after a 12-week hospital stay. His case comes to light now because researchers only recently developed the computational techniques needed to sequence generations of bacteria. The hospital, which also wasn't identified, gave the patient's Staph samples to the Rockefeller team for research purposes. The techniques still are too slow and expensive for clinical use.

When Patient X was admitted to the hospital, he was already suffering from a Staphylococcus aureus infection, but it was still vulnerable to antibiotics. During treatment, however, the bacteria quickly developed stronger resistance to four antibiotics, including vancomycin, the drug of last resort for intractable infections, the scientists reported. As living bacteria, the Staph were driven to survive.

Every time the patient took his medicine, the antibiotics killed the weakest bacteria in his bloodstream. Any cell that had developed a protective mutation to defend itself against the drug survived, passing on its special trait to descendants. With every round of treatment, the cells refined their defenses through the trial and error of survival. "It means that during a normal course of treatment there is an evolutionary revolution going on in your body," said Stanford University biologist Stephen Plaumbi, author of "The Evolution Explosion: How Humans Cause Rapid Evolutionary Change."

These resistant microbes, all disease-producing organisms spawned by the original infection, quickly accumulated 35 useful mutations. Each one altered a molecular sensor or production of a protein.

Researchers then matched these gradual genetic changes to increasing levels of drug resistance, shocked that it took so little to undermine the foundation of modern infectious-disease control. "We have now really looked into the belly of the beast and seen the mechanism," said Rockefeller microbiologist Alexander Tomasz.

Nearly two million people catch bacterial infections in U.S. hospitals every year and 90,000 of them die -- seven times as high as a decade ago as germs become immune to almost every antibiotic developed during the past 60 years. The most common is the Staphylococcus bacteria. World-wide, some two billion people carry these bacteria; up to 53 million people are thought to harbor antibiotic-resistant forms.

On average, people who contract Staph infections stay in the hospital three times as long and face five times the risk of dying. But these infections are becoming more prevalent outside hospitals. Antibiotic-resistant Staph infections increased almost sevenfold from 2001 to 2005, researchers reported last week in the Archives of Internal Medicine. Contagions such as tuberculosis, pneumonia and bubonic plague also are becoming immune to the drugs that once kept them at bay.

The death of Patient X highlights the speed of natural selection in fostering antibiotic resistance. "When you talk about the evolution of an arm or an eye or a species, you might be talking about millions of years. You can get bacteria resistant in a week," Dr. Mwangi said.

The Rockefeller researchers believe that a better understanding of evolution will lead to better antibiotic treatments. They want to disable the genes that allow these disease bacteria to mutate and adapt. The Staph bacteria that evolved inside Patient X now have such strong defenses that, in recent tests, they easily withstood even the next generation of clinical antibiotics. For the time being, the microbes are keeping one step ahead.