Superbug breakout: They're harder to beat -- and recognize

Developments regarding certain types of drug-resistant bacteria underscore why such infections are a public health imperative.

By Kathleen Phalen Tomaselli amednews correspondent — Posted Feb. 5, 2007

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At first Patricia Raymond, MD, thought it was just an atypical flare-up of a patient's long-standing ulcerative colitis, but it turned out to be community-acquired Clostridium difficile. Perhaps most surprising to the Chesapeake, Va., gastroenterologist was that the patient had no recent antibiotic history, the traditional precursor to C. diff.

Meanwhile, in Portland, Ore., an otherwise healthy young woman was diagnosed with community-associated methicillin-resistant Staphylococcus aureus. She succumbed to the microbial assault in 18 hours. "She was making two toxic shock toxins," says David Gilbert, MD, chief of infectious diseases at Providence Portland Medical Center.

And this year, in KwaZulu-Natal, South Africa, 53 tuberculosis patients were infected with an extensively drug-resistant -- XDR -- strain. Fifty-two died in less than a month.

Such grim tales have become all too familiar: virulent, refractory bugs; unusual microbial behaviors; more toxins; less treatments; and increasing antibiotic resistance.

"It knows no boundaries," says L. Clifford McDonald, MD, a Centers for Disease Control and Prevention medical epidemiologist. "Another factor, at least in cities, may be increased crowding, increased population and increased use of ."

In the past decade new and re-emerging microbial threats have continued to be a worldwide public health challenge. Most troublesome to scientists and physicians is the recent rise of resistant bacteria, particularly among the Big three: C. diff, CA-MRSA and XDR TB.

"This is the complexity of life. We are discovering more and more mechanisms in which organisms can become resistant. They are set up to survive, and we should have known this. It is an inevitable development," says Tawanda Gumbo, MD, assistant professor of internal medicine and infectious disease at the University of Texas Southwestern Medical Center in Dallas. "It's a humbling thing. They will develop resistance to drugs, and we need to keep a step ahead."

C. diff. developments

The garden variety C. diff Dr. Raymond learned about in medical school resulted from altering colonic flora with powerful broad-spectrum antibiotics or being hospitalized with severe illness. "This new event C. diff in well people in the community commonly occurs in the absence of antibiotic exposure or hospitalization," says Dr. Raymond, associate professor of clinical internal medicine at Eastern Virginia Medical School. "In studies, 45% had not taken an antibiotic in the three months prior to symptoms, and 70% had not been hospitalized."

Long associated with hospital-administered broad-spectrum antibiotics, this illness causes abdominal pain, and diarrhea with mucous and blood. C. diff infections are responsible for 3 million cases of diarrhea and colitis in the United States each year, according to the American Academy of Family Physicians.

Caught in a "Catch-22" cycle, the more common strain is caused and cured by antibiotics, thus leading to recurrent bouts in about a quarter of patients. "Most infections were commonly called health care-associated antibiotic diarrhea," says the CDC's Dr. McDonald. "It was the status quo in hospitals, and patients rarely died because of [it] -- only about 2%."

But in its migration into the community, C. diff has become more frequent, severe, refractory to standard therapy and more likely to relapse. In recent years, several deadly outbreaks have occurred in the U.S., Canada and the United Kingdom. "We are seeing about one-fifth of the cases in the community," Dr. McDonald says.

Of grave concern is a new strain, NAP1/027, which is also known as ribotype 027. This supercharged version produces as many as 23 times more toxins than previous strains and does not discriminate victims -- leaving even the healthiest at risk. "This strain has been around for 20 or 30 years, but there were only 14 unique patient isolates in the database; now it's an epidemic strain," Dr. McDonald says. "We think the machinery of the bug is the same, but it is more resistant to fluoroquinolones. The strain may have gotten the upper leg."

In the first six months of 2006, four women -- three pregnant and one immediately postpartum -- were hospitalized in Philadelphia with similar symptoms. All of their infections matched the NAP1 strain, leaving experts to suggest that gynecologists and obstetricians consider C. diff in cases of severe, ongoing diarrhea.

Last fall, reports of clusters of neonates developing C. diff-related illness also surfaced. While the infection is not reportable, the CDC is calling upon physicians to contact the agency with information about clusters or an increase in children younger than 2 who test positive for the infection.

More information on XDR TB

Last year, XDR TB has been seen in increasing numbers and has proven to be virtually untreatable with available drugs. "The bacteria are spreading in large clusters," says Carol Hamilton, MD, associate professor of medicine at Duke University Medical Center in Durham, N.C. "There are cases in every country in the world."

Nonetheless, Dr. Hamilton points out, the numbers are still small -- about 4% in the United States -- and the vast majority of TB is still susceptible to treatment.

But patients who do contract XDR TB are resistant to both of the first-line antibiotics used to treat TB such as rifampicin and isoniazid, and certain second-line drugs (at least one, fluoroquinolone, and one of the three injectable drugs kanamycin, amikacin or capreomycin). But what sets XDR TB apart from CA-MRSA and C. diff is that it is not more virulent, just more resistant.

Particularly troubling is that anyone can get this strain, even if not previously infected with TB. Say a patient's friend gets XDR TB on a Nepali trekking expedition. After returning, the friend coughs while they are in the same room. Even with no risk factors, the patient could get the infection. "The message here is over 50% of the cases are in people who have emigrated from other countries," Dr. Hamilton says. "If they come in coughing, remember this may be TB."

Treatment compliance has been at the core of resistance, with patients often stopping lengthy antibiotic regimens early, which led public health officials to require directly observed therapy. Still, Dr. Gumbo says research must look at dosing. "Dosing could actually increase resistance. We haven't done well. Right now we go for the kill with the maximum dose."

In addition, length of time until diagnosis has been particularly worrisome, usually about three weeks. A new, inexpensive method presented by a team of international scientists in the Oct. 12 issue of the New England Journal of Medicine cuts that time in half. This method, the microscopic observation drug susceptibility model, or MODS, involves a single MODS culture of a sputum sample. The researchers say it offers more rapid and sensitive detection of TB and multidrug-resistant TB than the existing gold standard methods.

CA-MRSA on the move

Community-associated MRSA has been known to wreak havoc, and the latest circulating strains appear to be hypervirulent. "This bacteria adapts to its environment and finds ways to survive," Dr. Gilbert says. "What's disturbing is it's clear that this staph can make a whole family of toxins. Now CA-MRSA is making toxic shock toxins."

While usually associated with hospital isolation rooms, MRSA found a path outside hospitals a decade ago, and isolated clusters appeared in prisons, health clubs and day care centers.

Recently, the bacteria has gotten nastier and no longer isolated. "We're seeing it in all kinds of places. Now almost every skin infection is MRSA, and we assume every one is when we treat," says R. Doug Hardy, MD, assistant professor of internal medicine and infectious diseases at UT Southwestern Medical Center in Dallas. "We changed our empiric skin infection treatment. But we are seeing resistance even among the drugs we use for MRSA like clindamycin."

So rampant is the spread of CA-MRSA that it is finding its way into newborn nurseries. And children are at risk for such clinical expressions as pelvic syndrome, septic arthritis, pelvic abscess, pelvic osteomyelitis and septic thrombophlebitis.

One of its most troubling aspects is its virulence and the increase of diffuse, disseminated, multi-organ infections. "Patients come in with multifocal MRSA -- lungs, bones, heart," Dr. Hardy says. "There's an increase in CA-MRSA pediatric pneumonia. We're seeing an increase among the young and old."

Of particular note is the Panton-Valentine leukocidin (PVL) gene, which has a virulence factor associated with severe necrotizing pneumonia and serious skin and soft tissue infections. While it is present in less than 5% of health care associated isolates, it has been identified in more than 77% of CA-MRSA isolates.

It's critical that primary care doctors culture skin infections, Dr. Gilbert says. "You can't empirically throw an antibiotic at the patient," he says. "You must culture it. None of the antibiotics are incredibly effective, but vancomycin -- we've had it for 50 years -- kills it slowly. None of the new drugs have proven superior to vancomycin."

Dr. Gilbert points out that everyone who develops influenza is at risk of secondary Staphylococcus aureus. "Staph pneumonia can be a serious complication. Last year we had spotty outbreaks of secondary CA-MRSA with high mortality rates. Here, we're gram-staining the sputum of all hospitalized patients with pneumonia."

Primary care role

These bugs are smart and sophisticated, making treatment challenging, especially since commonly used empiric therapies are not effective. Experts such as Dr. McDonald say doctors could be forced to change comfortable treatment regimens.

These bugs must be at the top of doctors' minds: If there's an angry abscess, suspect CA-MRSA; ongoing diarrhea, C. difficile; persistent cough, TB. "There is a need for a high index of suspicion," says the University of Texas' Dr. Gumbo. "Be aware what looks like pneumonia could be TB."

The CDC recommends strict infection control measures and hand washing with soap and water instead of alcohol-based waterless hand sanitizers during outbreaks, especially since alcohol does not kill C. diff spores. "The role of the family doctor? It's all more important to follow the basic rule of infection control," Dr. Gilbert says.

For now, though, Dr. McDonald says it's critical to treat antibiotics with more respect. "Everyone knows about avoiding unnecessary antibiotic use, but now we're talking about infections caused by antibiotics -- antibiotics designed to heal can actually kill you."

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Specialists' views on resistant infections

Antidiarrhea agents are one of the worst treatment paths for Clostridium difficile. "It's not nice to fool Mother Nature," says Patricia Raymond, MD, a gastroenterologist in Chesapeake, Va.

"After diagnosis, the first round of therapy is the ubiquitous metronidazole or more expensive vancomycin, along with a warning to your patient that in 24% of patients, a recurrence of symptoms might be expected," she adds. For recurring problems, she recommends concomitant therapy with Saccharomyces boulardii, a non-pathogenic yeast available as Florastor.

"Stand strong against using unnecessary antibiotics for viral syndromes, no matter how persuasive the patient requests," she says. "Doctors must tell the tale of helpful symbiotic bacteria and scientific basis for the use of probiotic rather than antibiotic therapy."

A related theme is echoed in regard to the other superbugs.

Regarding community-associated methicillin-resistant Staphylococcus aureus, "We have to quit using old drugs like Keflex and cephalexin. They're just not useful," explains R. Doug Hardy, MD, assistant professor of internal medicine and infectious diseases at UT Southwestern Medical Center in Dallas.

A 10-day course of Zyvox (linezolid) works but comes with a hefty price tag -- between $1,000 and $1,300. That's why he says many physicians are opting for inexpensive drugs such as Bactrim at $3. "Bactrim works. The problem with this [is] these drugs have never been studied. We need good studies on cheap drugs."

Meanwhile, treating extensively drug-resistant tuberculosis means creating a piecemeal plan, says Carol Hamilton, MD, assistant professor of medicine at Duke University Medical Center in Durham, N.C.

"It is essentially untreatable, since the bacteria have resistance to first-line and each of the classes of second-line drugs," she says. "But you could put together two or three of the pretty weak drugs that might work. You could cut out the infected piece of lung. You might be able to cobble together a treatment that may help."

Dr. Hamilton tells of times a decade ago when TB treatments were pieced together. "We got them healthy," she says. To quell its spread, she adds, wash hands, wear a mask, and, if a patient has had a cough for a couple weeks, suspect TB.

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External links

"Management of Management of Multidrug-Resistant Organisms In Healthcare Settings, 2006," Centers for Disease Control and Prevention, in pdf (link)

"Severe Community-acquired Pneumonia Due to Staphylococcus aureus, 2003-04 Influenza Season," Emerging Infectious Diseases, June 2006 (link)

American Medical Association on antibiotics and antimicrobials (link)

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