Infectious trend: Drug-resistant staph

This is a story about otherwise healthy children confronting life-or-death circumstances after small wound infections spread to lungs, bones and joints. It's about pneumonia that has gone out of control and about entire athletic teams being benched because of rampant, angry abscesses.

On one level, these topics might seem disparate. But there is a unifying theme, because the overall story is about community-associated methicillin-resistant Staphylococcus aureus, a brand of staph that is increasingly viewed as a public health epidemic. With more and more cases occurring across the country, primary care physicians are being urged to rethink how they treat it when they see it.

"This raises the bar for doctors," says Robert Harrison MD, PhD, MPH, infectious disease pediatrician and hospital epidemiologist at Children's Healthcare of Atlanta. "We have to change our thinking about staph, about how we use antibiotics and about how worried we should be when we see staph."

Methicillin-resistant staph long has been associated with hospitals and the seriously ill. But in the late 1990s, doctors began seeing unusual patterns of MRSA, particularly among healthy patients without traditional risk factors.

"We began to see children from the community with MRSA," says Robert S. Daum, MD, professor of pediatrics and microbiology at the University of Chicago. Dr. Daum, who is heading several CA-MRSA studies, including one funded by the Centers for Disease Control and Prevention, says the community isolates are very different from the hospital-acquired type. Genetically distinct, CA-MRSA causes a different spectrum of illness, including skin and soft tissue infections that could be severe and have different antibiotic susceptibility.

Often misdiagnosed, CA-MRSA is spreading at an alarming rate, experts say. With outbreaks occurring from Hawaii to New England, public health officials are warning doctors about its prevalence. The University of Chicago has seen 25 times the number of cases it did in 1998. "State health departments and the CDC woke up to this rather slowly," Dr. Daum says. But health officials are now formulating what messages need to be conveyed to primary care doctors. "The implications for this are huge."

Tales from across the country echo the problem that Dr. Daum describes. At the Texas Children's Hospital emergency department in Houston, for instance, cases doubled from 800 to 1,600 in just two years. CA-MRSA accounts for 95% of skin infections and abscesses at this facility.

"Sixty percent of these kids get admitted. We've had several deaths, a number of kids on ventilators and right now we've got a child with four or five bones and joints involved," says Sheldon Kaplan, MD, TCH's chief of infectious disease. "This is not a simple skin infection and it's not just in Houston. It's in Corpus Christi, Dallas, Chicago, Atlanta, Los Angeles."

Diagnosing and treating

Crowded conditions, close quarters, poor hygiene, contact with contaminated surfaces and shared items including towels, razors and toothbrushes all have been associated with the spread of CA-MRSA. Broken skin also increases vulnerability.

Those at greatest risk include children who attend day care centers and their families, military personnel, homeless people, prison inmates and athletes from football and other contact sports.

"MRSA is prevalent in sports because of the intense skin-to-skin contact," says Brian B. Adams, MD, MPH, associate professor of dermatology and director of the Sports Dermatology Clinic at the University of Cincinnati. "Sweating supersaturates the upper layer of the skin and makes it easier for microorganisms to pass through."

Often manifesting as pimples, boils, cellulitis, folliculitis, impetigo or a raised, reddened area that looks like a spider bite, the infection site should be cultured, the CDC recommends:

Skin infection. Obtain either a small biopsy of skin or drainage from the site. A culture of a skin lesion is especially useful in recurrent or persistent cases , in cases of antibiotic failure and in advanced or aggressive infections.

Pneumonia. Obtain a sputum culture.

Bloodstream and urinary infection. Obtain using aseptic techniques.

Meanwhile, the evolving understanding of this persistent pathogen also underscores the need for physicians to think locally. "Basically, we need to be aware of the prevalence and pathogens in our own community so we can tailor the therapy better," says Bar-Meir Maskit, MD, an infectious disease fellow at Children's Memorial Hospital in Chicago who is involved in an upcoming study examining specific characteristics of patients and the disease.

The upside to the community-acquired bacterium is its susceptibility to several antibiotics. "HA-MRSA is multidrug resistant," Dr. Maskit says. "CA-MRSA is still susceptible to many drugs. We still have drugs we can treat with."

Previously, frontline staph infection treatment included methicillin and other beta-lactams. But doctors can no longer rely on these, Dr. Daum says. "Those days are now over. We see the failures, the kids who went to their primary care doctor and got the standard therapy for staph and it has failed. Sometimes the infection is out of control. Primary care doctors need to change their practices. They must treat as if it's CA-MRSA."

Oral clindamycin is the frontline empiric therapy in patients with skin and soft-tissue infection. Vancomycin, although it is the antibiotic of last resort, should be used for severe infection. Linezolid, a new oxazolidinone antibiotic, might offer an alternative, but it costs about $2,000 for about a 10-day supply.

The first steps are to get a culture and prescribe the antibiotic regimen effective against CA-MRSA, Dr. Harrison says. "If the culture shows it's not [CA-MRSA], you can switch to an easier antibiotic. If it is, you haven't lost days. Say you've got a kid with staph pneumonia and you give the wrong antibiotic for five days," Dr. Harrison says. "Five days later, the patient has a big lung abscess."

A bug of many, virulent colors

Both HA-MRSA and CA-MRSA contain mec A, the gene that encodes protein and allows cell wall synthesis to go on. Japanese researchers identified three hospital MRSA isolates -- mec 1, mec 2 and mec 3 -- which are big and clunky.

"We approached these researchers about collaborating with us in sequencing the staphylococcal cassette chromosome methicillin-resistance determinant elements in our community-acquired strains," Dr. Daum says.

This collaboration led to the discovery of mec 4, a much smaller staphylococcal cassette. Dr. Daum says it is the culprit that has fueled the explosive increase in CA-MRSA. "As soon as I saw it, I knew the rate would nudge up to 100%," he says. "In our ER, 84% of staph is MRSA. Ten years ago it was less than 10%."

Genomic studies show that CA-MRSA strains carry a range of virulence genes and are more likely to encode for Panton-Valentine leukocidin, a virulence factor associated with severe necrotizing pneumonia and serious skin and soft-tissue infections such as dermo-necrotic skin lesions that look like spider bites.

The PVL gene inserts at a specific site in the genome and is present in the vast majority of CA-MRSA strains, Dr. Daum says. "It is a fit pathogen."

Most recently, researchers have seen CA-MRSA fulminating infectious syndrome. It looks exactly like meningococcemia, Dr. Daum says, but little is known about what the organism is doing to cause this fatal syndrome.

"We've had eight or nine [people] die ... despite being given vancomycin promptly in our ER," he says. "This is the tip of the iceberg with this syndrome. It doesn't respond to antibiotics at all, and we lose [the patients]."

In the pipeline

The research community is offering some positive signals.

A polysaccharide conjugate staph vaccine -- StaphVAX by Nabi Biopharmaceuticals -- is in Phase III trials and shows promise even though these trials have included only HA-MRSA patients. "There is no reason to believe it will not work on CA-MRSA," says Henrik Rasmussen, MD, PhD, senior vice president of clinical research and regulatory affairs for Nabi. "But it hasn't been tested."

Both CA- and HA-MRSA bacteria avoid detection by creating a capsule or cloaking devise not detected by the immune system. StaphVAX creators extracted antigens from this capsule, linked it to a genetically modified carrier that overcomes the cloaking and creates a potent immune response. The treatment is under review in Europe. The Food and Drug Administration has asked the manufacturer for a second confirmatory trial. "We anticipate this data will provide the basis for license in the United States," Dr. Rasmussen says.

Meanwhile, there is much more work being done. In 2003, the CDC awarded $3 million to four universities -- Columbia University; Harbor-UCLA Research and Education Institute; the University of California, San Francisco; and the University of Chicago -- for research into CA-MRSA. Investigators will examine the bacteria's genetic characteristics, characteristics of patients' illnesses and outcomes, and the mechanisms of infection and disease.

At the University of Chicago, for instance, research initiatives include examining household spread; what's fueling the reservoir of staph organisms; understanding outbreaks in jails; global collaborations and laboratory investigations at the molecular level to better understand how the strains evolved.

"Epidemiologic data about the scope and extent of staphylococcal infections are surprisingly few, and urgently needed," Dr. Daum says. "This is an epidemic. We are all rethinking how we avoid staph and how we treat it."