World travelers

In late June, the Centers for Disease Control and Prevention's Morbidity and Mortality Weekly Report published brief findings about cases of superbugs found at three U.S. hospitals between January and June 2010.

Less than a page long, the report warned clinicians of a gene that attaches to bacteria and renders even the most powerful antibiotics useless. The CDC report went largely unnoticed until this past September when the British medical journal Lancet Infectious Diseases published a study about the growing global threat of the gene, called New Delhi metallo-beta-lactamase-1, or NDM-1.

According to the Lancet study, NDM-1 bonds to a variety of bacteria, including E. coli and Klebsiella pneumoniae, turning normally treatable bugs into superbugs with the ability to eat up broad-spectrum antibiotics called carbapenems. Such antimicrobials typically are drugs of last resort when treating life-threatening bacterial infections. The list includes meropenem, marketed under the name Merrem, and ertapenum, marketed under the name Invanz.

Bacteria with the NDM-1 gene were found in more than 180 patients in India, Pakistan and the United Kingdom between 2003 and 2009, according to the Lancet study. Cases of bacteria made resistant by NDM-1 also have been reported in Australia, Bangladesh, Canada, Japan, the Netherlands and several other countries.

In the U.S., the drug-resistant mechanism—which infectious disease experts believe originated in India—was found in three patients: one hospitalized at Boston's Massachusetts General Hospital and the others at unidentified hospitals in California and Illinois. All three U.S. patients had, at some point, received care at hospitals in India.

While concern over NDM-1 is significant and growing, infectious-disease specialists and clinicians are quick to point out that NDM-1-enabled bacteria have a number of dangerous predecessors—most of which are more widespread in U.S. hospitals. They include Klebsiella pneumoniae Carbapenemase—bacteria made resistant by the carbapenemase gene—as well as Methicillin-resistant Staphylococcus aureus, or MRSA, and clostridium difficile, or “C. diff.”

Still, experts also acknowledge the appearance of NDM-1 in hospitals around the world highlights the broadening global nature of healthcare-associated infections, as well as growing concern over antibiotic resistance. Tackling the problem demands a coordinated global campaign and locally adapted tactics for antibiotic stewardship, as well as effective disease surveillance, global health experts say.

“We're now at a point where we are sharing everything in the healthcare space including patients and infection,” says Rick van Pelt, director of global programs at Partners Harvard Medical International. Van Pelt argues that healthcare systems and other stakeholders will have to adopt a corporate-like mentality to gain control over the development and spread of superbugs. That means, he says, creating an expansive effort around infection-control knowledge transfer that addresses not only providers and public health experts, but also communities where inappropriate access to and use of antibiotics can fuel the development and spread of superbugs. Such an effort also will require ownership of the problem by all stakeholders beyond the knowledge-transfer process, he says.

“The conventional approach has been to use a consultation model to transfer information about infection control,” van Pelt says. “But now we are increasingly sending patients overseas for care, so they are increasingly bringing their problems with them,” he adds. “We're using consultants to transfer quality-of-care information to places like India, but if their infection-control efforts aren't up to standard, the patient will bring the bugs back with them.”

That reality, van Pelt says, necessitates the development and enforcement of rigorous infection-control protocols by international standards organizations and ministries of health, as well as ongoing partnerships between providers in countries with successful infection-prevention programs and those in countries with problems.

The problem also demands greater attention from global health organizations, public health experts say. “The World Health Organization's international regulations are written so that drug resistance that is considered an international threat is a reportable event, but there hasn't been much serious application of that requirement,” says Rachel Nugent, deputy director of global health for the Washington-based Center for Global Development. “There has been some debate over what kind of drug resistance is of enough significance to require reporting.”

Nugent says, however, that in recent years, world health officials have recognized that the lack of attention to proliferating antimicrobial resistance has allowed the problem to develop unchecked. As a result, WHO plans to make the issue the focal point of its 2011 World Health Day on April 7. The day of recognition will coincide with the release of updated technological guidelines for preventing the development of drug-resistant bacteria.

But while global partnerships and guidelines can be key to tackling the problem of antibiotic-resistant bacteria, infectious-disease experts acknowledge that such programs have their limits, largely because of differences in healthcare system resources and the culture of care.

Chan Harjivan, partner and head of the public health practice for the management consulting firm PRTM, notes, for example, that antibiotics often are sold over the counter in countries where people have problems accessing physicians or other qualified providers who can prescribe appropriate care for infections.

Facilities in many low-resource countries also aren't equipped to test for and accurately diagnose infections. As a consequence, patients can end up taking the wrong drugs and, subsequently, developing drug-resistant bacterial infections. Some countries also are struggling with a system of care where doctors are offered financial incentives to write prescriptions and patients are oriented to expect pills to treat their illnesses, Harjivan says.

While antibiotic resistance is unquestionably a global problem, stakeholders also agree that localized responses will provide the solution for tamping down the development of superbugs.

Belinda Ostrowsky, director of the antimicrobial stewardship program at Montefiore Medical Center and Albert Einstein College of Medicine in New York, believes providers can most effectively address the global issue of drug-resistant bugs by focusing on local problems.

“I don't have control over what happens outside of here, and I can't say whether some of these bugs we're seeing did or didn't come from somewhere else,” she says. “But now they're here and they're spreading,” she adds. “Locally, you need to address that.”

To that end, providers and public health departments in the U.S. are launching efforts to gain control of the problem. In California, where one of the three cases of NDM-1 bacteria was detected, legislators passed the Hospital Infectious Disease Control Program bill in 2006. Included in the law was a mandate for the state public health department to help hospitals institute disease-surveillance plans and antibiotic stewardship programs by 2010.

“Right now, we're trying to assess what's going on at hospitals, and once we know that, we can make their antibiotic use more appropriate,” says Kavita Trivedi, chief of the epidemiology unit for the California Public Health Department's healthcare-associated infections program. “But we know that 50% of antibiotics used in inpatient settings are considered inappropriate and unnecessary. There are many, many studies showing that,” she adds.

The California programs are still in their early stages, Trivedi says, and state health officials are working with small and large hospitals and long-term-care facilities throughout the state to determine their rates of healthcare-associated infections. They also are looking at what types of prevention efforts and antibiotic stewardship actions work best for a particular provider type and community setting. “We're trying to make sure that a stewardship program is in place for even the smallest community or rural hospital,” Trivedi says. “These are places where they have problems even getting surveillance and diagnostic testing done at all.”

New York state public health officials and providers also are instituting a stewardship initiative in an effort to tackle the growing problem of antibiotic-resistant bugs. In October 2009, the New York State Health Department, United Hospital Fund and the Greater New York Hospital Association launched a six-month pilot program that was used to develop an antimicrobial stewardship “tool kit,” which will soon be made available to hospitals through a website. The tool kit will help providers assess their current antibiotic usage practices, establish a stewardship team, develop and implement a stewardship plan and determine the outcomes of the effort.

The pilot project partnered three hospitals with three long-term-care facilities in an effort to reduce the transmission of HAIs between facilities and into the surrounding communities. While the project was too short to allow for rigorous data collection and published outcomes, Maria Woods, vice president of legal, regulatory and professional affairs for the Greater New York Hospital Association, says participants garnered significant knowledge about what makes for a successful stewardship program.

“We really learned that you need the C-suite to be on board with this,” Woods says. “It's both an operational and clinical issue,” adds Woods, who says that experience holds true for both the large, well-equipped and small, modestly equipped facilities.

Beyond stewardship and improved surveillance, public health experts say globally we've reached a point where many superbugs have made their way out of healthcare settings and into the community. Since there is no putting the genie back into the bottle, the development of new, more effective antibiotics is necessary.

“In 30 years, only two new classes of antibiotics have entered the market, and many companies have pulled out of antibiotic development,” says Allan Coukell, director of the Pew Health Group's medical safety portfolio. Coukell says the reasons for the lack of new antibiotic development include the challenge of finding new and effective molecules that are successful at treating the most resistant types of bacteria, the expense and challenge of the regulatory approval process, and the fact that limited, appropriate use of antibiotics means companies have limited earning opportunities attached to even the most successful and widely used antimicrobials.

“To give you an example, the antibiotic used to treat MRSA earns about a half-billion a year—far below what a mid-level antipsychotic drug will earn,” Coukell told attendees at a recent meeting of the Trans-Atlantic Task Force on Antimicrobial Resistance at the National Institutes of Health campus in Bethesda, Md. “Policymakers must consider incentives that will defray costs, including grants and tax credits.”