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Arms Race With a Superbug

Arms Race With a Superbug

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Getting a bacterial infection is no big deal, right? Your doctor prescribes an antibiotic and you get well. Not so fast. Some bacteria—like Acetinobacter, aka Iraqibacter—have become resistant to commonly used antibiotics; some "superbugs" can withstand a host of different medications. A sobering case in point is Staphylococcus aureus. As this time line shows, strains of Staph aureus have gotten the better of every antibiotic we've developed, often within just a year or two of a new agent's introduction. Follow this ongoing arms race and learn about its unsettling implications below.—Ron Lubelchek

Arms race printable graphic

Penicillin resistance reported (1942)
Only a year after an English constable named Albert Alexander became the first patient to receive penicillin, experts identified strains of Staph aureus that showed resistance to the "miracle" drug. (Ironically, the original culture dish upon which the Scottish biologist Alexander Fleming had first observed the antibiotic properties of the penicillium mold in 1928 was growing colonies of Staph aureus.) Experts now know that, without controls, a single-celled bacterium like Staph aureus can give rise to five billion trillion new cells in a day. With such exponential growth, the chance for natural mutations that might confer resistance is robust. Currently, over 90 percent of Staph aureus strains are essentially immune to penicillin.


Methicillin resistance reported (1961)
As with penicillin, only a year passed after this semi-synthetic penicillin was released before methicillin-resistant Staph aureus (MRSA) was reported. Initially, MRSA only appeared in hospitals and nursing homes, but in the past decade it has become a major public health problem, sickening otherwise healthy people in the community. Often it lurks in schools, gyms, and other places where people come in close contact with one another. Most cases involve only a minor skin infection, such as a boil, but some prove deadly. A 2007 Centers for Disease Control study reported that serious Staph aureus infections struck over 94,000 people in the U.S. in 2005, contributing to the deaths of 18,650 of them, more than died of AIDS that year.


Staph aureus gains vancomycin-resistant gene
from Enterococci bacteria
(1992)
In the laboratory, scientists documented Enterococci, a strep-like bacteria, transferring a vancomycin-resistant gene known as vanA into Staph aureus. Such "horizontal gene transfer" has been observed in many bacterial species, including Iraqibacter. (We humans can only do "vertical" transfer, from parents to their offspring.) With this ability, microbes don't need to evolve resistance themselves but simply appropriate it from other pathogens that already have. Experts knew after this study, if not before, that it would only be a matter of time before Staph aureus gained resistance against vancomycin in the outside world.

Partial Vancomycin resistance was reported five years later.


Partial vancomycin resistance reported (1997)
Vancomycin, originally derived from a soil bacterium scooped from the rain forests of Borneo, demonstrated more tenacity against the ever-evolving staph than any other antibiotic. But eventually its defenses weakened. In 1997, the first strains of so-called vancomycin-intermediate Staph aureus, or VISA, were reported. VISA strains, by definition, require a minimum of 4 to 8 micrograms per milliliter of vancomycin to inhibit bacterial growth in a test tube. Again, experts knew all too well that full vancomycin resistance would eventually appear.

Full Vancomycin resistance was reported in 2002.


Quinupristin/dalfopristin resistance reported (2000)
In the laboratory, this one-two punch initially showed activity against methicillin-resistant Staph aureus. But like all antibiotics that came before it, it quickly lost its immunity. In the United States, certain strains of Staph aureus had acquired resistance within a year after this pair was approved for use. With each weakened antibiotic, bacterial infections are becoming more severe, require longer and more complex treatments, and are more expensive to diagnose and treat.


Linezolid resistance reported (2001)
Linezolid, a broad-spectrum antibiotic, fared no better than its predecessors in, well, resisting resistance. Introduced to the market in April 2000, its standing was shaken by the following July, when the first resistant strain was reported; other resistant strains appeared in 2003 and 2004. To date, bacteria have discovered resistance to all classes of antibiotics. The molecular mechanisms by which they have done so remain diverse and complex, stymieing easy explanation.


Full vancomycin resistance reported (2002)
In 2002, specialists reported the first full vancomycin-resistant strain of Staph aureus. By definition, such strains require a dose of vancomycin greater than or equal to 16 micrograms per milliliter to inhibit the microbe's growth in the test tube. Neither raising the dose nor using vancomycin in combination with other antibiotics has helped to any degree. As one researcher put it bluntly, "S. aureus has evolved; vancomycin has not." Fortunately, outright resistance to vancomycin remains vanishingly rare, though partial resistance is becoming increasingly frequent.


Daptomycin resistance reported (2005)
Daptomycin binds to the membrane of the Staph aureus cell, disrupting the membrane's function. But some strains, predictably, got around this, developing resistance to Daptomycin within two years of its release. Staph aureus's ever-evolving resistance casts a more ominous shadow when one considers the range of severe infections it can cause, including pneumonia as well as bloodstream and surgical-wound infections. Characterized by the death of tissue, hence the colloquial term "flesh-eating bacteria," these severe infections have killed both adults and children.


Tigecycline resistance reported (???)
Approved in 2005, Tigecycline has shown activity against multidrug-resistant Staph aureus. Resistance to this new agent has yet to be documented in clinical isolates—that is, strains from individual patients studied in the lab. But judging from past history, it will happen soon enough. And so the arms race continues, with fears of a post-antibiotic era rising with each new hardy strain. Several things need to happen, experts say: Wanton overuse of antibiotics in medicine and agriculture must be curbed. Hospitals need to improve basic hygiene. Pharmaceutical companies, large universities, and the government need to step up their currently anemic R&D of the next generation of antibiotics. And a vaccine against Staph aureus is essential. Several vaccines are in early stages of development, but none will be available soon. Meanwhile, Staph aureus lies in wait, ready to adapt once again.


Dr. Ronald Jay Lubelchek is an infectious-diseases specialist at Stroger (Cook County) Hospital and assistant professor of medicine at Rush University Medical Center, both in Chicago. He is coauthor, with Robert Weinstein, of "Antibiotic Resistance and Hospital-acquired Infections," a chapter in The Social Ecology of Infectious Diseases (Academic Press, 2008), from which this time line was adapted with permission.

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