S.F. General researchers follow strain of drug-resistant bacteria

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S.F. General researchers follow strain of drug-resistant bacteria
Sabin Russell, Chronicle Medical Writer

Tuesday, January 15, 2008


San Francisco General Hospital researchers have been chasing the rogue strain of drug-resistant staph called USA300 since they first isolated it from a patient specimen seven years ago.

With every turn, the aggressive and persistent bug keeps getting worse.

Now, a new variant of that strain, resistant to six major kinds of antibiotics, is spreading among gay men in San Francisco, Boston, New York and Los Angeles.

City doctors first spotted the original USA300 during tests for patients treated at a walk-in clinic for skin infections in 2001. Since then, they have watched it morph from laboratory curiosity into the dominant form of staph infection in much of the United States.

\"It stormed into town and just took over, displacing everything else,\" said Dr. Chip Chambers, infectious disease chief for the renowned hospital.

At first, USA300 hit the down-and-out: injection-drug users, jail inmates, homeless men and women. Today it is also infecting suburban moms, executives, doctors, athletes and children. It has turned up in tattoo parlors and newborn nurseries. People with HIV infection seem especially prone to it, but it also strikes patients, gay and straight, who have no previous health problems.

Staph infections are usually treatable but can be lethal. USA300 is as dangerous as they come - it can attack organs throughout the body, forcing doctors to amputate fingers, toes and limbs. Its most disturbing trait, however, is just how easily it gets around.

\"USA300 has a tremendous ability to spread,\" said Francoise Perdreau-Remington, director of the molecular epidemiology lab at San Francisco General, where the strain was first identified. \"It has been described in at least 44 states and is now spreading in European countries.\"

USA300 is one of a dozen distinct varieties of MRSA, or methicillin-resistant Staphylococcus aureus, now circulating. The first MRSA strain, resistant to the penicillin substitute methicillin, was discovered in 1961. It continues to evolve. More than 200 families of the strain have come and gone since. USA300 is shaping up as the worst of the lot.

The various MRSA families have been gaining strength as a public health menace for years.

MRSA infections used to be confined to hospitalized patients. But in the late 1990s, people began contracting them in community settings - in gyms, jails, schools and even at home. The federal Centers for Disease Control and Prevention calculated last fall that drug-resistant staph was killing 19,000 Americans a year - more than are dying of AIDS.

Tracking down new disease threats is Perdreau-Remington's specialty. The French-born microbiologist was recruited to San Francisco General in 1995 to create the lab because of her expertise in disease detective work at the University of Cologne in Germany. A key to her microbe hunting is the ability to compare new strains to old ones. Her lab at the San Francisco hospital stores a frozen cache of 16,000 germs taken from patients in the hospital and health clinics.

In 2000, San Francisco General had set up a special walk-in clinic catering to drug users and street people to handle the growing volume of skin and soft-tissue infections that were driving up costs in its emergency room.

Perdreau-Remington began running tests to find out what was causing so many infections. Her lab analyzed bacterial specimens to produce genetic fingerprints that look like strips of bar code. It was during that screening program, using samples from the clinic, that she found the genetic fingerprint of what would be called USA300.

The unique signature showed up on March 1, 2001. At first, it represented just one of 15 specimens on a standard computer readout, known as a \"gel.\" When the same new fingerprint showed up in three of 15 specimens three months later, Perdreau-Remington remembers thinking: \"Uh-oh, we have a problem.\"

She labeled the new strain the \"S-clone.\"

By February 2002, six of 15 samples displayed the S-clone's signature. Among patients at the clinic, the new bug shortly thereafter outnumbered all others by a 2-to-1 ratio.

Perdreau-Remington soon learned that the bug had been lurking elsewhere. She began collaborating with her counterparts in Los Angeles County, where inmates of the largest jail system in the United States had been complaining of \"spider bites.\" Samples of the skin sores yielded the same S-clone fingerprints.

Throughout the United States, other researchers were independently finding the same bug.

Fred Tenover, director of laboratory science at the CDC, remembers running a test that pooled drug-resistant staph samples from 12 states, including ones from prisons in Georgia, Texas and California and from a football team in Pennsylvania. \"The patterns were indistinguishable,\" he said. \"I looked at the gel and said, 'This can't be.' So we went back and retested them. It was amazing.\"

The fingerprints were identical to those of Perdreau-Remington's S-clone.

Tenover, who was developing for the CDC a uniform system for describing a dozen distinctive types of drug-resistant staph, named the emerging bug USA300.

Perdreau-Remington's early isolation of USA300 has made her lab at San Francisco General a world leader for the study of it. Once it became clear that a new strain of drug-resistant staph was loose, she set out to discover where it came from. She went back to her freezers and screened hundreds of samples of staph taken since 1996.

Her survey unearthed the earliest known sample of USA300. Its fingerprints were spotted in a frozen specimen taken from a man who visited the newly opened walk-in clinic at San Francisco General on Sept. 25, 2000.

Ominously, the strain that first appeared outside the hospital began to infect vulnerable patients inside as well. By 2002, USA300 accounted for 14 percent of staph infections acquired at San Francisco General, and the numbers keep rising.

\"Now, more than 80 percent of MRSA infections in this hospital are caused by USA300,\" Perdreau-Remington said.

Under a powerful microscope, USA300 resembles a cluster of faintly yellow BBs - indistinguishable from other strains of drug-resistant staph. Like a fancier brand of automobile, however, this one is packed with options that make it potentially more deadly and easier to spread.

Toxic proteins carried by USA300 have been implicated in infections that destroy fingers and toes or cause the rare but frighteningly fast skin- and muscle-tissue destruction attributed popularly to \"flesh-eating bacteria\" - a condition known as necrotizing fasciitis.

Until recently, flesh-eating infections were thought to be caused by other bugs, such as Streptococcus. A study published in the New England Journal of Medicine in 2005 changed all that. Doctors at UCLA-Harbor Medical Center reviewed 14 cases of the frightening skin disease. All 14 had drug-resistant staph cultured from their wounds. Five samples were tested at Perdreau-Remington's San Francisco lab for strain type. They all turned up USA300.

When drug-resistant staph invades the lungs, it can cause a pneumonia that destroys lung tissue and kills a patient within hours. Last winter, the CDC implicated USA300 in outbreaks of severe pneumonia such as the one that killed six of 10 flu patients in Louisiana and Georgia last winter. Four of the dead were children.

Concern over USA300 is so great that Perdreau-Remington won funding to map the complete genome of the germ, identifying the entire coded sequence of genetic instructions that tell this particular strain of staph bacteria how to make copies of itself.

She chose a sample taken in 2003 from a wrist abscess on a 36-year-old patient who was also being treated for AIDS at San Francisco General. She picked that specimen because it seemed unusually resistant to treatment. It was labeled USA300 FPR3757 - using Perdreau-Remington's initials.

The gene map, published in the British medical journal the Lancet in February 2006, has yielded clues to why this strain spreads so quickly. The bug appears to have swapped genes from Staphylococcus epidermidis, a usually harmless staph species that is commonly found on human skin. Researchers theorize that, by stealing a trick from the milder staph bug, the malevolent USA300 may colonize on human skin more easily than other varieties of MRSA.

Further along the gene map are sections that produce resistance to the antibiotics tetracycline, erythromycin, clindamycin, Cipro and mupirocin, a topical ointment often used to kill MRSA colonies living in people's noses.

Perdreau-Remington did not know it at the time, but the sample she took - FPR3757 - was among the very first isolates found of the highly drug-resistant USA300 variant now spreading readily through San Francisco's gay community. The new bug virtually has her name on it.

USA300 - even the new variant - is treatable with some antibiotics. Perhaps the most important of these is vancomycin, an antibiotic reserved for the most serious staph infections. But FPR3757 is just a short step away from acquiring resistance to that drug as well.

Dangerous intestinal bacteria have already evolved resistance to vancomycin. Known as vancomycin-resistant enterococcus, or VRE, the bugs carry a \"cassette\" of genes containing all the instructions needed for bacteria to sidestep the antibiotic.

Perdreau-Remington's team has spotted on the USA300 genome a region that is primed to accept this vancomycin-resistance cassette. It could snap into place like a Lego block.

Drug-resistant bacterial strains have been labeled \"superbugs,\" but most infectious disease specialists recognize that these bacteria are not doing anything remarkable. They are performing as they have for millions of years, using their enormous capacity to mutate and multiply to outmaneuver whatever biological or environmental threats they face.

Because both VRE and USA300 are circulating in hospital environments, some patients are probably battling both bugs at the same time. Given the propensity of staph germs to swap genes, these patients provide fertile ground for the evolution of an even more dangerous bug.

If USA300 were to acquire vancomycin resistance from VRE, the result would be a virulent new form of staph, which would spread readily outside the medical setting and be nearly impossible to treat.

Perdreau-Remington believes there's an urgent need for new drugs to combat such a monster.

\"This is the horror scenario,\" she said. \"We have very little time left.\"

E-mail Sabin Russell at srussell@sfchronicle.com.

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