Drugs vs. Bugs
As antibiotics make germs ever deadlier, researchers race to make hospitals safer for patients.
By Dale Keiger
Sometime around Valentine's Day 2005, bacteria entered James Fauerbach. They were a strain with the imposing name methicillin-resistant Staphylococcus aureus, or MRSA: common staph germs that had mutated to become much less vulnerable to the methicillin class of antibiotics, for years the standard treatment for staph. The variant of MRSA that found its way into Fauerbach also packed a toxin called Panton-Valentine leukocidin, or PVL. The combination of drug resistance and this toxin made the pathogen unusually dangerous. The germs colonized his body and waited for an opportunity.
An associate professor of psychiatry and chief psychologist at the Johns Hopkins Burn Center, on the Bayview campus, Fauerbach recalls first feeling sick around February 14 or 15. A few days later, he went to a doctor who, based on his symptoms, diagnosed influenza. The next day, he had trouble breathing and felt as tired as he'd ever felt in his life. When he tried to stand, he was so woozy from oxygen deprivation that he fell, knocking over furniture. His alarmed wife, Lynn Fauerbach, made him go to an outpatient clinic, where he began to cough up blood. The clinic transferred him to Upper Chesapeake Medical Center in Belair, Maryland, where he was placed on a ventilator. He was deteriorating fast.
Fauerbach knew he was in trouble. Before doctors intubated him, he tried to write a note to his children, Anna and Adam, but all he could manage was an illegible scrawl. His condition worsened when the air sacs of his lungs could not tolerate the forceful puffs of air generated by the ventilator. Lynn, a nurse with critical care experience, knew he needed a more sophisticated vent, known as an oscillator, that would be easier on his lungs. She called colleagues of her husband and finally found an intensive care bed and an oscillator for him at Bayview. It was nearly too late. Fauerbach spent the next 11 days intubated and in a medically induced coma as doctors fought to keep him alive through a powerful antibiotic called vancomycin.
Hopkins infectious disease specialist Jonathan Zenilman and pulmonologist Jonathan Sevransky made the diagnosis: a rare disease called necrotizing pneumonia. Not only were Fauerbach's lungs filling with fluid, the lung tissue itself was dying, attacked by the PVL toxin. Influenza had caused inflammation of his respiratory tract, and the PVL-MRSA already in his system had then seized its chance to begin destroying his lungs.
After 11 days, the Bayview physicians thought Fauerbach was well enough to be taken off the ventilator. Doctors and nurses who had cared for him stood by his bed as he was extubated, and when they saw him breathe on his own they broke into applause. Remembering this, Fauerbach pauses to fight back tears. During his illness, he lost 30 pounds, mostly muscle mass, and a few days after his release, a rare allergic reaction to the vancomycin put him back in the hospital. His recovery was long. Restoring his lungs to nearly full function took months. For almost a year he had trouble concentrating. He recalls sitting in his Bayview office two or three months after his release from the hospital, trying to reply to a simple e-mail; it took him 90 minutes. "The weirdest things would happen," he says. "I would try to type 'dog' and 'bear' would come out. It was really a strange thing."
No sooner did science develop penicillin, the first antibiotic, 60 years ago than bacteria began demonstrating resistance to it. MRSA, the germ that nearly killed Fauerbach, is but one of several dangerous drug-resistant (and pronunciation-resistant) pathogens: vancomycin-resistant enterococcus (VRE), a particular problem with transplant patients who have compromised immunity; Clostridium difficile (C. diff), which can induce fatal diarrhea; multi-drug resistant Acinetobacter baumannii; vvancomycin intermediate-resistant Staphylococcus aureus (VISA), currently rare but worrisome. They are germs that can live in many places, but mostly they live in hospitals, where they have become a menace. Last October the Journal of the American Medical Association published a startling study of data from nine U.S. cities and estimated that in 2005, MRSA caused serious invasive infections in 94,360 hospital patients; 18,650 of them died. If the estimates were accurate, that meant MRSA killed, or at least contributed to the deaths of more people in 2005 than HIV/AIDS, Parkinson's disease, or emphysema. In the days following the JAMA report, newspapers quoted epidemiologists saying things like "It is astounding" and "We should be very worried."
Among the worried is Trish Perl. She's paid to be worried, as Johns Hopkins Hospital's director of hospital epidemiology and infection control. She studies the infectious diseases that beleaguer hospitals, designs improved systems for disease surveillance, creates interventions to better contain and eliminate hospital infections, and persuades physicians, nurses, technical staff, and administrators that Hopkins can and needs to do better. Her efforts and those of other infectious disease specialists throughout the Hopkins system have led to improvements in the monitoring, prevention, and treatment of hospital-acquired infections. But they are up against a vexing, shape-shifting opponent that, day by day, makes their task ever more complicated.
go, a bacterium could not be simpler: one cell, no nucleus.
A membrane surrounding cytoplasm, some protein-synthesizing
ribosomes, and a single looping strand of DNA. That's it.
But if you study bacteria, it becomes hard not to think of
them as possessing agency. They are obstinate. They are
insidious. They are ingenious. And, says Karen Carroll,
director of microbiology at Johns Hopkins Hospital, "they
are always one step ahead of us."
Each time researchers developed a new class of antibiotics, pathogens developed resistance. It was as if antibiotics had hit the evolutionary gas pedal.
Through a microscope, Staphylococcus aureus looks
like a bit of flung caviar. The bacterium's name comes from
staphyle (grape cluster) + coccos (berry) +
aureus (golden), and an electron micrograph indeed
reveals clusters of yellow, spherical microbes. It has
tended to colonize the inside of the human nose, and the
skin in warm, moist places like the armpit or groin. Thirty
percent of people walk around with S. aureus in
their noses and suffer no ill effects. But if it gets past
the barrier of the skin through injury or an incision, it
can cause no end of trouble: boils, sties, urinary tract
infections, impetigo, pneumonia, sinusitis, mastitis,
phlebitis, meningitis, osteomyelitis, endocarditis,
septicemia, and toxic shock syndrome. Before the advent of
antibiotics, if S. aureus entered the bloodstream,
the patient had an 80 percent chance of dying.
Antibiotics promised an end to that scourge. But in only a few decades, scientists noticed a distressing pattern: Each time researchers developed a new class of antibiotics, pathogens developed resistance. It was as if antibiotics had hit the evolutionary gas pedal. Physicians turned to methicillin to fight S. aureus resistant to penicillin; two years later, British researchers first isolated strains of S. aureus that were resistant to methicillin, too. In 1964, physicians began using new drugs called cephalosporins, which were effective against many infections, including pneumonia; but E. coli, Klebsiella pneumoniae, and a genus of bacteria called Enterobacter quickly "learned" how to fight them off. Out of pharmaceutical labs came the carbapenem and fluoroquinolone drugs; within a matter of years they began to lose their effectiveness against Acinetobacter species and other microbes.
Bacteria, primitive though they are, have survived more than 3 billion years because they possess a remarkable ability to adapt to their environments. They defend themselves against drugs by a variety of means. One example: Methicillin kills S. aureus by interfering with the bacterium's ability to form a cell wall. But somewhere along the evolutionary fast lane, the staph germ picked up a gene called mecA, and mecA reduced methicillin's ability to interfere with S. aureus' cell wall by a thousandfold. Once the pathogen had mecA, it had transformed itself into MRSA.
No one knows where S. aureus came by its genetic augmentation. Bacteria possess a deadly ability to trade DNA, and not just within their own tribes, so to speak. After enterococci bacteria developed resistance to vancomycin, British researchers in 1992 watched in the lab as the enterococci bugs passed this resistance to S. aureus. Enterococcus to staphylococcus: pathogenic allies. As more and more physicians prescribed more and more antibiotics — sometimes appropriately, sometimes not — resistant pathogens multiplied.
The first recorded case of MRSA in the United States occurred in Boston in 1968. Six years later, 2 percent of all hospital-acquired S. aureus infections were resistant to methicillin. By 2002, 57 percent of ICU staph infections were MRSA, and experts believe it's now 70 percent. Other resistant bugs like Acinetobacter, C. diff, and VRE flourish in hospitals as well. But for now MRSA is the bigger problem. Says Zenilman, "Most VREs are not that virulent. The same thing with Acinetobacter. The bug is there, it's got an antibiotic-resistance profile which looks horrendous — resistant to everything — but the bug really is a wuss. It doesn't do much. It's usually more a colonizer than an invasive kind of bug. MRSA is a different ball of wax because it causes major problems when it gets into the bloodstream and organs."
It's simplistic but not wrong to say that Trish Perl works in a giant Petri dish. Tertiary care hospitals like Hopkins are incubators for resistant pathogens. Hopkins cares for very sick people, plus it does a lot of major surgery. All that illness and all those invasive procedures mean every day Hopkins physicians contend with infections. Infections require application of antibiotics, which inevitably create hothouse conditions for developing more drug-resistant pathogens. And those pathogens get around to counter tops, door knobs, bed rails. They find their way on to patients' skin. They hitch a ride on physicians, surgeons, nurses, medical technicians, custodial staff, and visitors, transported to new surfaces and new people. Finally, they end up in patients' bodies through incisions, intravenous central lines, medical hardware, and catheters.
When Perl came to Hopkins in 1996, the hospital had an infection control program that, she says, met regulatory requirements but did not encourage either preventive action or interventions that targeted specific problems. No sooner had she settled in than the hospital experienced a number of infections among transplant patients from VRE, an intestinal germ or "gut bug." That got her attention and she began to investigate drug-resistant infections in the various hospital units. Perl had come from the University of Iowa School of Medicine, which had few problems of this sort. "I was quite surprised by the burden of disease here," she says. "I was told, 'Well, our patients here are sicker.' But I was a doc, too, and I looked around and I didn't think our transplant patients were any sicker than the transplant patients I'd seen in my previous job." She studied the VRE outbreak and hospital practices at Hopkins and believed she saw ways to decrease incidence of the infection among transplant patients. She worked on another project in the hematologic malignancy service and decreased not only infections but bacterial colonizations. As she began to hear about other interesting pathogens in the hospital, she decided Hopkins needed to do better identifying emerging problems. "It's one thing to just measure, but the most effective infection prevention was doing interventions to actually decrease problems."
Perl and her team, which includes epidemiologists, infection control specialists, and the hospital's director of antibiotic management, invested several years in research to amass evidence of problems at the hospital. Some of the early data came from testing various hospital surfaces. They found drug-resistant germs everywhere. One study of frequently touched surfaces, such as door knobs, found 9 percent colonized by MRSA, 24 percent by VRE, and 37 percent by C. diff. Researchers also checked surfaces that only health care workers, not patients, would touch, and found one-third colonized by MRSA and 36 percent by VRE.
Various surfaces at the hospital were only part of the problem. Nobody knew how many people there at any given time were carrying infectious microbes, including drug-resistant strains. This lack of knowledge was not confined to Hopkins. "There are multiple surveillance systems throughout the world," Perl says. "You get snippets from each one. Some are focused on everything that comes into the microbiology lab. Some are more focused on infections acquired within acute-care hospitals. But they all have limitations. [So] there are various guesstimates of how prevalent these organisms are." The U.S. Centers for Disease Control (CDC) studied hospital-acquired infections, known in the business as nosocomial infections, recorded in 2002. It found 1.7 million, resulting in 98,987 deaths.
To gain more control over health care-associated infections, Hopkins had to do more to identify colonized patients. If someone became ill from an infection, that was recorded, but Perl knew that data based on cultures taken from sick patients significantly underestimated the amount of disease. "A clinical culture is the top part of the iceberg," she says. "We have a huge reservoir [of germs] underneath the water, not seen in clinical cultures because these people are just colonized and it's not causing infection. But the risk of transmission is equal if you're colonized versus infected."
Perl and her colleagues convinced various units of the hospital to enact more stringent surveillance procedures. First they concentrated on the most high-risk units: the surgical ICU, medical ICU, and HIV ward. After their research found problems in other intensive-care units, they broadened surveillance. For example, Aaron Milstone, a Hopkins assistant professor of pediatric infectious diseases, in 2006 repeated a study of the pediatrics ICU that had been done in 2001. He found the rate of children in the PICU colonized by VRE had nearly doubled in five years; colonization by MRSA had gone up fourfold. Hopkins Hospital now swabs the nose of every person admitted to any of its intensive-care units, not just on admission but every seven days. Anyone found to be colonized by a drug-resistant strain is immediately isolated.
By these measures, Hopkins made progress against its infection problem. But MRSA, the deadliest drug-resistant germ, was not at rest. It was evolving new strains, finding new places to reside, and new hosts to colonize and infect.
In 1981, physicians began to notice MRSA infections among intravenous drug users in Detroit. Some, but not all, had been hospitalized recently. Then people who had not been anywhere near a hospital began acquiring staph infections, and when researchers cultured them they found MRSA, but not the same MRSA found in hospitals. These were different strains. For three decades, the problem of drug-resistant pathogens had been almost entirely confined to hospitals. Now the pathogen appeared to be loose in communities. In most cases, the germs caused skin problems like boils — painful but treatable. But there were well-publicized fatalities, first in North Dakota and Minnesota in 1997 and 1999. One day in 2007, Ashton Bonds, a healthy 17-year-old senior at Staunton River High School in Virginia, complained of pain in his side. Twelve days later he was dead from MRSA-induced multi-organ failure that ruined his kidneys, liver, lungs, and heart. That same month, a pre-schooler in New Hampshire, Catherine Bentley, and an 11-year-old, Shae Kiernan of Mississippi, died from MRSA infections. For a week or two last October, it was hard to find a daily newspaper that did not have a front-page story about drug-resistant staph. Reporters dug up earlier reports, less noticed at the time, of staph infection outbreaks among football players at the University of Southern California, and members of the St. Louis Rams of the National Football League and the Boston Celtics of the National Basketball Association. Although fatal infections due to MRSA in otherwise healthy people were extremely rare, media coverage scared parents with the idea that "superbugs" lurked in school locker rooms and who knew where else.
Epidemiologists began gathering and studying data on the new community-acquired infections, called CA-MRSA. They found that congested cities with large populations of urban poor — Detroit, Atlanta, Baltimore, Chicago — recorded high rates of staph infection. Zenilman has seen it at Bayview, where he estimates 25 to 35 percent of the outpatient visits to the infectious diseases clinic are for recurring cellulitis caused by staph infections. "These people are miserable," he says. "You get recurring boils that can be difficult to control. Because it's spread through casual contact, you can have kids, relatives who besides being treated have to change the way they live: no sharing of bath towels, of soap. If you have teenagers in the house, that's not easy to implement."
Jason Farley, a Hopkins nurse practitioner and doctoral candidate specializing in infectious diseases, tested men brought into the Baltimore City prison. He found 40 percent of them colonized by S. aureus and 15.8 percent by MRSA. Prisons, like hospitals, are excellent places for transmission of infectious agents, so it might have seemed likely that Farley would find lots of MRSA colonization there. But among men never previously arrested, a greater percentage (16.4) had been colonized by MRSA, which indicated how many drug-resistant germs were out in the community. Of additional concern, people now were bringing CA-MRSA from the community into the hospital.
Staphylococcus aureus and other bacteria also took
evolutionary advantage of the complex network that is the
U.S. health system. If sick people went into the hospital
and stayed until they were well, pathogens like MRSA, VRE,
or C. diff could possibly be contained there. But a
seriously ill patient might move through four or five
different facilities. Says Perl, "Both MRSA and VRE have
been introduced into more non-traditional health care
settings because of the movement of patients. [First]
they're here in an acute-care setting. Then more and more
we're pushing sicker patients into rehabilitation
facilities. Then they may go into a long-term care
facility, then they may cycle back to acute care." So what
had been a problem mostly for tertiary care hospitals like
Hopkins became a problem for dialysis centers and
outpatient clinics and assisted-living care centers.
For three decades, the problem of drug-resistant pathogens had been almost entirely confined to hospitals. Now the pathogen appeared to be loose in communities.
Perl was senior author on a 2006 study that screened 1,600
newly admitted patients in five Hopkins ICUs. All had been
in a nursing home or long-term care facility sometime
within six months of admission to Hopkins. The data showed
that these patients were 12 times more likely to be
colonized with multi-drug-resistant Acinetobacter. If they
were wheelchair- or bed-bound due to paralysis, they were
22 times more likely to be colonized. Among the patients
carrying Acinetobacter, 62 percent also had been colonized
by MRSA, 77 percent by VRE, and 39 percent by a pathogen
with the jawbreaker name extended-spectrum beta-lactamase
gram-negative bacteria. As a result of the study, Hopkins
plans to begin testing every incoming patient who has been
in a nursing home, and isolating them until the test
results come back from the lab.
Carroll, the hospital's chief microbiologist, says, "The crux of the problem is that we're dealing with a community epidemic that has to be approached from a lot of different ways. We need to stress that people should not self-manipulate lesions. They need to come in at the first signs of infection. They need hand washing — the simple things that people can do. In the hospital, the biggest question is, should we screen everyone who walks through the door for admission? For me, as a microbiologist, that would present a huge burden because that will double, maybe triple, the samples we receive. But if that's what it takes to reduce transmission, we're just going to have to say that we need to do it."
Once an infection like MRSA is found, a patient can be isolated and treated. For the hospital, that's not the hard part. The hard part is containing and eradicating the pathogen. Physicians, nurses, therapists, and technicians carry germs from person to person on their white coats, on instruments like stethoscopes, and especially on their hands. The single most effective method of preventing transmission is also the simplest: hand washing. If only people would do it.
Study after study has found that health care practitioners are lax about observing protocols for washing hands with soap or alcohol-based gels like Purell. In 2006, The New York Times quoted Australian research that first asked physicians about their hand washing; 73 percent of the respondents said they properly followed protocols. Researchers then observed actual practice and found that true compliance was a dismal 9 percent. Perl once sent students from the Bloomberg School of Public Health to discretely observe hand washing in the hospital; they found proper compliance was around 30 percent. A University of Maryland study in 2007 noted that 65 percent of physicians and other practitioners reported not having worn a newly laundered white coat in at least a week; 16 percent had not done so for a month.
Why aren't health care professionals more conscientious? Sometimes the situation — a crashing patient, for example, or a beeping ventilator — demands an instant response with no time for following hygiene protocols. But Perl encounters a surprising number who still do not understand the importance. She says, "There are still people out there who look at me and say, 'Is it really important that I wash my hands?' I say, 'Well of course it is,' and I try to show them the data, but in my mind I'm thinking, and what planet are you on?"
Getting hands clean is a straightforward business. Getting the environment clean is not. No one knows how to decolonize a hospital, or if it even can be done. Cleaning crews face an immense task trying to kill every last microbe on every surface. Especially problematic are high-technology components that no one wants to be responsible for, such as computer keyboards. Says Perl, "Environmental services doesn't want to touch them because they get in trouble if they break anything. The nurses don't consider it their job. The physicians certainly aren't going to clean anything. So who is responsible?"
Perl and technicians from a British company recently tested new machinery that aerosolizes hydrogen peroxide and disperses it throughout a room. "We bombed the SICU," Perl says, referring to the surgical ICU, one of the units where the test took place. "It was so cool." She is waiting for results on the test's effectiveness.
Last November, Johns Hopkins Medicine launched the WIPES campaign to persuade hospital personnel of their role in containing and eradicating infectious agents. WIPES is an acronym for five aspects of the battle against drug-resistant pathogens: washing hands, identifying and isolating infected or colonized patients, precautions taken (like use of gowns, gloves, and masks in isolation rooms), environment cleaned and kept clean, and sharing the commitment to better hygiene. Posters appeared on the hospital walls, each one featuring a hospital employee, including Hopkins Medicine CEO Edward Miller, holding up his or her (presumably just-washed) hand.
"It's hard to change behavior," Perl says. "It was hard to get people to wear seat belts. The hand-hygiene stuff is the same thing. We need to make this so automatic nobody even thinks twice about it."
is making progress on keeping patients healthier. Perl says
that MRSA transmission in the medical intensive care unit
is down 39 percent, and there was only one nosocomial MRSA
bloodstream infection in all ICUs in 2007, down from
approximately three per year before that. "We're seeing
more and more infection coming in, but when we look at our
disease transmission, it's going down, and our infections
are going down. That's a pretty remarkable story to tell.
We can at least modulate what happens to a vulnerable
patient population." Meanwhile, she keeps studying new
interventions. Sara Cosgrove, the hospital's director of
antibiotic management, monitors use in the hospital and
advises physicians on avoiding inappropriate prescriptions
that will only hasten the evolution of new resistant
strains. Carroll in the microbiology lab remains vigilant
for new germs finding their way into the hospital.
Drug-resistant gram-negative bacteria are likely the emerging pathogens of the next 10 to 15 years. "Some of them are extremely scary," says Trish Perl.
Because that will surely happen. Scientists have identified
a new, more lethal strain of C. diff, and a variant
of VRE that resists the drug linezolid. Vancomycin is not
yet exhausted for use when methicillin and others no longer
work. But cases of VRSA (S. aureus resistant to
vancomycin) have turned up — only about 100 so far
and none at Hopkins, but most infectious disease
specialists believe that it's only a matter of time. There
are a couple of new drugs that can be used in those cases,
but for now they are the end of the line. Research and
development of new antibiotics has not been a priority of
pharmaceutical companies for many years now. They are
expensive to develop, require difficult and expensive
clinical trials before they can be brought to market, and
they don't promise the same returns as drugs like Viagra or
medications used by people infected with HIV. Invent an
antibiotic and you have something a patient might need for
two weeks. Create an effective HIV or rheumatoid arthritis
medication and you have a customer for decades.
Even more worrisome for infectious disease researchers are emergent strains of drug-resistant gram-negative bacteria. Microbes are designated gram positive or gram negative depending on how they respond to the gram stains used to examine them in laboratories. That sounds like a benign distinction, but it's not. The resistance mechanisms of gram-negative germs are far more complicated than those of gram-positive bacteria like MRSA; for example, some gram-negative pathogens can produce enzymes that render entire classes of antibiotics ineffective. Some can actually pump an antibiotic back out of a cell. Perl says, "We think these are going to be the emerging pathogens of the next 10 to 15 years, and some of them are extremely scary." Carroll recently found a case of resistant gram-negative infection at Hopkins when she isolated an organism from a liver-transplant patient. The organism was using an enzyme, carbapenemase, to armor itself against all the carbapenum antibiotics. "It was resistant to everything we've tested down here except for one drug, out of 20 agents," she says.
Part of what most scares epidemiologists about drug-resistant gram-negative pathogens is that pharmaceutical companies and other research institutions have done little to develop drugs to fight them. There is nothing in the pipeline. Corporate priorities, research funding, public concern, and health care practice are not yet aligned to face this new threat, and may never be. But everyone knows the new germs are coming. Pathogens like MRSA are implacable — not just single-celled but single-minded. Evolution never rests.
Dale Keiger is the magazine's associate editor.
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