CHARLOTTESVILLE, VA - The doctors tried one antibiotic after another, racing to stop the infection as it tore through the man's body, but nothing worked.
In a matter of days after the middle-aged patient arrived at University of Virginia Medical Center, the stubborn bacteria in his blood had fought off even what doctors consider "drugs of last resort."
"It was very alarming; it was the first time we'd seen that kind of resistance," says Amy Mathers, one of the hospital's infectious-disease specialists. "We didn't know what to offer the patient."
The man died three months later, but the bacteria wasn't done. In the months that followed, it struck again and again in the same hospital, in various forms, as doctors raced to decipher the secret to its spread.
GRAPHIC: Deadly bacteria that defy drugs of last resort
The superbug that hit UVA four years ago -- and remains a threat -- belongs to a once-obscure family of drug-resistant bacteria that has stalked U.S. hospitals and nursing homes for over a decade. Now, it's attacking in hundreds of those institutions, a USA TODAY examination shows, and it's a fight the medical community is not well positioned to win.
The bacteria, known as Carbapenem-Resistant Enterobacteriaceae, or CRE, are named for their ability to fight off carbapenem antibiotics -- the last line of defense in the medical toolbox. And so far, they've emerged almost exclusively in health care facilities, picking off the weakest of patients.
The bacteria made headlines this summer after a CRE strain of Klebsiella pneumoniae battered the National Institutes of Health Clinical Center outside Washington, D.C. Seven died, including a 16-year-old boy. (Hospitals don't reveal victims' names in keeping with medical privacy rules.) But that case was neither the first nor the worst of the CRE attacks
USA TODAY's research shows there have been thousands of CRE cases throughout the country in recent years -- they show up as everything from pneumonia to intestinal and urinary tract infections. Yet even larger outbreaks like the UVA episode, in which seven patients also died, have received little or no national attention until now.
The bacteria's ability to defeat even the most potent antibiotics has conjured fears of illnesses that can't be stopped. Death rates among patients with CRE infections can be about 40%, far worse than other, better-known health care infections such as MRSA or C-Diff, which have plagued hospitals and nursing homes for decades. And there are growing concerns that CRE could make its way beyond health facilities and into the general community.
"From the perspective of drug-resistant organisms, (CRE) is the most serious threat, the most serious challenge we face to patient safety," says Arjun Srinivasan, associate director for prevention of health care-associated infections at the Centers for Disease Control and Prevention.
Since the first known case, at a North Carolina hospital, was reported in 2001, CREs have spread to at least 41 other states, according to the CDC. And many cases still go unrecognized, because it can be tough to do the proper laboratory analysis, particularly at smaller hospitals or nursing homes.
To assess the threat and what's being done to stop it, USA TODAY interviewed dozens of health care authorities and reviewed hundreds of pages of journal articles, clinical reports, and state and federal health care data. The examination shows:
• CRE infections already are endemic in several major U.S. population centers, including New York, Los Angeles and Chicago, which account for hundreds of confirmed cases. Smaller pockets of cases have been reported across much of the country, including Oregon, Wisconsin, Minnesota, Pennsylvania, Maryland, Virginia and South Carolina.
• There is no reliable national data on the scope of the CRE problem. The CDC has urged states to track cases, but only a handful do so -- and they're just getting going. "We don't have enough ... data to tell what the trend looks like," says Stephen Ostroff, director of epidemiology at the Pennsylvania Department of Health. "All we know is that it is here."
• There is little chance that an effective drug to kill CRE bacteria will be produced in the coming years. Manufacturers have no new antibiotics in development that show promise, according to federal officials and industry experts, and there's little financial incentive because the bacteria adapt quickly to resist new drugs.
• Many hospitals -- and an even greater percentage of nursing homes -- lack the capacity, such as lab capability, to identify CRE, or the resources to effectively screen and isolate patients carrying the bacteria. And even when screening is possible, there's a lack of consensus on whom to target.
"We're working with state health departments to try to figure out how big a problem this is," says the CDC's Srinivasan, noting that his agency can pool whatever incidence data states collect. "We're still at a point where we can stop this thing. You can never eradicate CRE, but we can prevent the spread. ... It's a matter of summoning the will."
Other experts are less optimistic.
"My concern is that there aren't a lot of methods in our tool kit that are significantly effective in curbing the spread of these infections," says Eli Perencevich, a professor and infectious-disease doctor at the University of Iowa's Carver College of Medicine.
The spread of CRE threatens to change the face of health care, crippling hospital units that specialize in treatments such as organ transplants and chemotherapy, which rely on the ability to control infections in patients with weak immune systems.
If unchecked, "these (bacteria) are going to greatly impact the kind of surgeries (and) treatments we can have," Perencevich says. "We're entering the post-antibiotic era; that's a very big problem."
Tracking an elusive killer
The UVA epidemiologists knew their CRE outbreak would be tough to contain -- they'd read about other cases in medical literature and knew that the bacteria spread fast, with frighteningly high death rates.
But it quickly became clear that this case would be even more difficult than most.
When the doctors began analyzing the bacteria in their first patient, who'd transferred from a hospital in Pennsylvania, they found not one, but two different strains of CRE bacteria. And as more patients turned up sick, lab tests showed that some carried yet another.
"We were really frustrated; we hadn't seen anything like this in the literature," says Costi Sifri, the hospital epidemiologist. "The fact that we had different bacteria told us these cases were not related, but the shoe leather epidemiology suggested to us that all these (infections) came from the same patient. ... We realized we might be seeing a mobile genetic event."
In other words, it looked like a single resistance gene was jumping among different bacteria from the Enterobacteriaceae family, creating new bugs before their eyes.
The doctors went back to the lab with even more urgency. It was January 2008, five months after the first case turned up, and they'd identified five patients harboring three distinct species of CRE.
Three of those patients already were dead.
Mobile patients; mobile bugs
There are many challenges to containing the spread of CRE, but one of the most daunting -- and immediate -- is figuring out where it's showing up.
There is no billing code for CRE infections under Medicare or Medicaid, the health care programs for the elderly, poor and disabled, and there's no federal reporting requirement for the infections. So getting a reliable national picture of prevalence or where cases are concentrated is a challenge.
Based on academic studies and data from the handful of states and counties that require at least some reporting, it's clear that CRE is spreading fast. USA TODAY surveyed those states and counties, and every one of them has found cases.
In Los Angeles County alone, a year of surveillance through mid-2011 turned up 675 cases at hospitals, nursing homes and clinics. In Maryland, a 2011 survey by the state health department identified 269 patients carrying CRE and estimated that up to 80% of the state's hospitals had seen at least one case during the year.
But the data are so isolated, and the reporting methodologies so varied, that the reports are of little practical use.
"If we don't know the scope and we don't know the distribution -- how big is the problem and where is the problem -- it's hard to know the next piece, which is what (prevention strategies) are you going to implement and where?" says Claudia Steiner, a physician and research officer at the U.S. Agency for Healthcare Research and Quality.
It's especially important to know where CRE bacteria are emerging because they spread among patients who bounce between or among clinics, surgical centers, rehabilitation facilities, nursing homes and, of course, hospitals.
In the Chicago area, where scores of CRE infections have been found since 2008, studies show that about 3% of hospital patients in intensive care carry the bacteria, says Mary Hayden, director of clinical microbiology and an infectious-disease doctor at Rush University Medical Center. Those same studies have found CREs being carried by about 30% of patients in long-term care facilities.
Not all of those patients are symptomatic: The bacteria can lurk, unseen, until a carrier's immune system is compromised or until the bug finds a path into the body and infection sets in. And as those patients move from one facility to another, the bacteria move with them, often clinging to caregivers' hands -- and moving to new victims.
"We have to think about a new approach, a regional approach, to controlling these organisms, because ... no facility is an island," Hayden says. If a nursing home patient is carrying CRE and gets sick in the night, "the staff there just want to get him to a hospital," she adds. "They may not know much about his (history), so that information doesn't come with him."
But the bacteria do.
The problem underscores the need for some sort of universal patient record system that can allow clinicians to see key aspects of a patient's medical history as that person moves among facilities, Hayden says. The technical hurdles and privacy concerns are challenging, she adds, but some Chicago-area hospitals are working with public health agencies to develop a model.
Meanwhile, the bacteria cycle from one facility to the next -- and back.
"It is continually reintroduced; I don't think it is going away," says David Landman, an infectious-disease doctor at the State University of New York's Downstate Medical Center in Brooklyn. "You need extreme control efforts."
A new tracking plan
Back at UVA, the doctors' theory was proving correct: They identified a common resistance gene among the different CRE bacteria attacking the hospital, and it matched what they found in the initial patient from Pennsylvania. The gene was jumping, one by one, to other species of Enterobacteriaceae bacteria, creating new carbapenem-defying bugs.
The doctors were seeing, in real time, a phenomenon that had worried researchers for years: the ability of CRE to share resistance genes across different members of the Enterobacteriaceae family.
The big fear is that the genes may start to convey resistance to more common strains of the bacteria, turning routine illnesses, such as urinary tract infections, into untreatable nightmares. Worst-case scenario: Resistance could move to bacteria outside of health care, so people could pick it up in the community through something as simple as a handshake.
The UVA doctors were in uncharted waters. Medical literature on CREs said to look for resistance in certain types of Enterobacteriaceae bacteria, "but we were seeing it in all kinds of bacteria," says Mathers, the infectious disease specialist.
The doctors sent out an urgent set of new instructions: Patients sickened with any form of Enterobacteriaceae bacteria should be checked immediately to see whether it is carbapenem-resistant, even if it's a strain not normally associated with CRE infections.
"We told the lab to look at anything that has a possible link with this (resistance) gene" that the hospital had identified, Mathers says. "Any hint of resistance, then we need to know about it."
Stopping the untreatable
There's not much hope for a new treatment of CRE infections.
A few drugs show marginal effectiveness, including an old antibiotic shelved decades ago because of high toxicity. And there's little incentive for drug companies to invest in developing alternatives. Effective medications would be taken only until a patient recovered, making them far less profitable than life-long drugs for chronic illnesses. Plus, CREs develop new resistance quickly, so any new antibiotic isn't likely to last.
"If you look at the current pipeline of antibiotics (in development) ... none of them really is going to be active against these bacteria," says Gary Roselle, director of the Infectious Diseases Service for the Department of Veterans Affairs health care system.
"The reality is, (CRE infections) are remarkably difficult to treat, they often have bad outcomes ... and they're increasing nationally," adds Roselle, a doctor who oversees infection control for the VA's hundreds of hospitals, clinics and nursing homes. "I'm assuming this is going to get worse, and there likely won't be new antibiotics to treat it in the near future, so the focus has to be on prevention."
CDC guidance for controlling CRE rests on traditional infection control strategy: rigorous hand cleaning by staff and visitors; isolating infected patients and requiring gowns and gloves for anyone contacting them; cutting antibiotic use to slow the development of resistant bacteria; and limiting use of invasive medical devices, such as catheters, that give bacteria a path into the body.
But the measure that may hold the most promise is contentious: screening patients for the bacteria so carriers can be isolated. There's disparate opinion over who should be screened. Every patient? Only those whose history puts them at high risk for infection? Only those showing symptoms?
Because many hospitals and nursing homes lack the resources to do much screening, some patient advocates say the priority should be looking for more common bugs, such as MRSA (Methicillin-resistant Staphylococcus aureus), which is more treatable than CRE.
"Why cause hospitals to use resources for a pathogen with unknown (prevalence)?" says Michael Bennett, president of the Coalition for Patients' Rights. "Doesn't it make sense to attack the biggest problem?"
But screening has proved effective at facilities that have cut high CRE rates.
In New York City, where CRE cases are endemic at many facilities, Bronx-based Montefiore Medical Center cut prevalence rates in half across its nine intensive care units with a program that relied heavily on screening. The initiative tested all intensive-care patients using an experimental, high-speed assay for the bacteria, and carriers were isolated immediately.
The initiative, which grew to include sampling of patients across all units of Montefiore's three-hospital network, revealed that 40% of Montefiore's CRE cases involved patients who had arrived with the bacteria when transferred from nursing homes and other institutions.
"So even if I had a perfect program to stop all patient-to-patient transmission in the hospital, the maximum impact I could have would be a 60% reduction in prevalence," says Brian Currie, the hospital's vice president for research and an assistant dean at the affiliated Albert Einstein College of Medicine.
Currie sees the cut in Montefiore's CRE rates as "a significant achievement," but he notes that the initiative also underscored the trials ahead. The doctor and his staff identified 11 nursing homes and several hospitals that regularly -- and unwittingly -- send CRE-infected patients to his facility.
"It's amazing how little awareness many of the providers have," he says.
The challenge at nursing homes, which typically have no labs and limited ability to test patients for infectious bacteria, is even more daunting.
"Personnel working in long-term care facilities may be unaware of 'new' resistance (bacteria)," researchers concluded in a 2008 study of CRE infections in New York nursing homes, published in Clinical Infectious Diseases. The risk of CRE in nursing home patients "should be of great concern."
New tools in the fight
Once the UVA doctors figured out that a single gene was driving the spread of CRE through the hospital, they still needed to figure out a way to find it -- and stop it. And the clock was ticking.
By April 2008, eight months after they'd identified their first infection, 13 additional patients had been infected with related strains of the bacteria. Seven were dead.
Back in the lab, the doctors figured out that the gene was hitching a ride among bacteria on mobile pieces of DNA, called plasmids, that can move from one cell to another. With more work, they developed a genetic test that could identify those plasmids -- and the bacteria they'd affected -- in days.
Traditional tests to identify the resistance-carrying plasmids can take months.
"Half the story is the outbreak and half the story is how we figured it out," says Sifri, the epidemiologist. "We had to understand what was happening before we could attack the problem."
The lessons learned at UVA have helped them target CRE screening of at-risk patients across the hospital, as well as those checking in. And with rapid identification and isolation of carriers, heavy vigilance on hand washing, and other infection-control measures, the hospital has been able to control its outbreak, Sifri says.
But the bacteria are there to stay, lurking somewhere, invisible and always a threat.
"We have continued to have patients with CREs that are related to this (first) event," Sifri says. "We haven't been able to close the door on this. ... I'm not sure you ever can."
By Peter Eisler