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In the fight to stay alive, many bacteria, such as MRSA, have developed resistance to commonly used antibiotics. But other bacteria are using a more insidious type of resistance: that imbued by transferable genes, which can spread among commonly circulating strains.
One of these genetic elements, NDM-1 (New Delhi metallo-beta-lactamase 1), is an enzyme-based defense that renders a bacterium immune to beta-lactam-based antibiotics, which include penicillin, as well as carbapenems (often used as a last resort antibiotic against Escherichia coli infections), cephems (such as cephalosporins and cephamycins) and monobactams, making treatment extremely difficult. The trait was first identified in 2008 (in a patient with Klebsiella pneumoniae), and instances of NDM-1–positive infections are now not uncommon in India, Pakistan and Bangladesh. Cases also have been documented in Brazil, Canada, Japan, the U.K. and the U.S.
A new essay published in the December 16 issue of The New England Journal of Medicine revisits the issue, highlighting the potential that NDM-1 and other antibiotic-busting genes have to disable much of our current pharmaceutical arsenal.
"The spread of these organisms has prompted widespread concern because some of them are resistant to all antimicrobial agents except the polymyzins," Robert Moellering, of Harvard Medical School and Beth Israel Deaconess Medical Center, wrote in the perspective piece.
Initial cases of NDM-1 seemed to be only found among patients who had received medical care in India, where antibiotic use is less regulated. But more recent findings have suggested some NDM-1–positive patients in the U.K. might have picked up a resistant strain without traveling abroad.
These genes do not need an exotic infection to wreak havoc in a patient. They can be picked up by "all sorts of bugs we're all walking around with in our guts," says Brandi Limbago, of the Division of Healthcare Quality Promotion at the U.S. Centers for Disease Control and Prevention. But once the resistant genetic material enters the bacterium, "it produces an enzyme that attacks the antibiotic and makes it nonfunctional—they basically chew it up," she explains. These infections are not always deadly, but "in the right host," such as one with a weakened immune system or inserted medical equipment (including catheters), "those patients become infected with these organisms," Limbago says. "And if you don't have the right tools to treat them, that's when you run into trouble."
Newer antibiotics, such as cephalosporins and carbapenems as well as beta-lactamase inhibitors, seemed like an effective strategy against these bacterial tactics. But these have "simply been met with the evolution of new beta-lactamases, often through mutations, that inactivate these antibiotics," Moellering wrote. Currently, there are some 890 such known enzymes, "far more than the antibiotics developed to combat them."
Indeed, Limbago warns, "all carbapenem-resistant Enterobacteriaceae [CRE] are bad—it's not just NDM-1 that should have us worried." And although NDM-1 might be grabbing more headlines globally, Limbago explains that here in the U.S., another enzyme, Klebsiella pneumoniae carbapenemase (KPC), has been a much bigger concern. And, as Moellering noted in his essay, another class, known as CTX beta-lactamases, "at the very least will compromise our ability to use beta-lactam antibiotics to treat community-acquired urinary tract infections."
Misuse of antibiotics has been a major driver of resistance—both in strain-specific bacteria and gene-based resistance. "Prudent antibiotic use should always be the goal," Limbago says. But "once the gene is there, it's there. And at that point, the genie's out of the bottle."
After resistance has started circulating, surveillance and infection control become the key tools to fight further spread. The U.S. does not have KPC- or NDM-1–specific strategies, but offers recommendations for all CRE-positive infections. The government also does not require hospitals to report CRE cases, but even so, infections have been confirmed in at least 35 states. Rather than being cautious about the growing concern over NDM-1 and other resistance genes, Limbago suggests that, "in some places in the U.S. people are not getting as excited about this as they should."