The Nearly Unstoppable Superbugs

A particularly virulent type of bacteria called CREs, which include E. coli and Salmonella, is gaining in strength. Can we develop better antibiotics to fight them off?

CRE superbugs like E. coli and Salmonella are becoming especially hard to treat.

Superbugs, including Escherichia coli (E. coli), Salmonella, Yersinia pestis (plague), and Klebsiella, are becoming resistant to many antibiotics, sometimes leaving doctors with few or no options for treating patients with serious infections.

The Disease Daily is a publication from HealthMap at Boston Children's Hospital.

Just a few weeks ago, the director of the Centers for Disease Control and Prevention (CDC) declared the superbugs carbapenem-resistant enterobacteriaceae (CREs) nothing less than a “nightmare.” When the federal agency whose mission is to protect us from infectious diseases gets serious enough to use that word, we should all pay attention.

The statement came after the CDC released a Morbidity and Mortality Weekly Report in which researchers looked at CREs in the U.S. The report found two things: The presence of bacteria that are resistant to carbapenem antibiotics has grown in the last decade, and that most infections with CREs happen when people are in healthcare facilities like hospitals and clinics.

Add this news to stories about the new bird flu, H7N9, and the novel coronavirus that's killed people in the Middle East and sickened some in Europe (sometimes dubbed “the next SARS”), and it may feel like there are meddlesome microbes everywhere you look. The real danger may be that the frequency of these warnings may numb our sensitivity to CREs, which are actually a hugely significant and complex problem. (Remember, the CDC called them a nightmare.)

So let’s break down CREs so we can understand them a bit better: “Enterobacteriaceae” may not be a household name, but you’re already familiar with some of the bacteria in the CRE family, which include Escherichia coli (E. coli), Salmonella, Yersinia pestis (plague), and Klebsiella.

Enterobacteriaceae are what are called “gram-negative” bacteria. Hans Christian Gram, a 19th-century scientist, is the namesake for this bacteria classification. Through a method known as gram-staining, he discovered that some bacteria had a single cell lining; these are called “gram-positive” bacteria. Others have a double cell lining and these are the gram-negative kind. The double lining is simultaneously what can cause illness in people and also allows these bacteria to more effectively fight off the human immune system, making them the more dangerous of the two bacteria.

Many antibiotics are designed to kill bacteria by destroying a single cell lining. Carbapenems are part of the smaller class of antibiotics that was designed to fight through both linings. Carbapenems are similar to penicillins, but have a slightly different structure. Some of the antibiotics in this class are doripenem (brand name: Finipax), meropenem (brand name: Meronem or Monam), and ertapenem (brand name: Invanz).

Carbapenems are effective against a range of bacteria but are actually often seen as a “last-resort” antibiotic because of their potency; these antibiotics are unaffected by some of the mechanisms that double-cell-lining bacteria use to survive. In other words, bacteria are typically vulnerable or susceptible to carbapenem antibiotics. That said, this is a good time to remember your Antibiotics 101: The more we expose bacteria to antibiotics, the more chances the superbug germs have to develop resistance against these same drugs. Because carbapenem drugs work against so many bacteria, the idea is to use them only when necessary to avoid the development of drug resistance.

In 2001, carbapenem antibiotics met their match. A study in Antimicrobial Agents and Chemotherapy described a Klebsiella pneumoniae infection in a North Carolina hospital that was able to fend off multiple antibiotics, including carbapenems. What the study found was the presence of an enzyme, Klebsiella pneumoniae carbapenemase-1 (or KPC, and yes, that sounds frustratingly similar to carbapenem, the name of the antibiotic) that degraded carbapenems, penicillins, and cephalosporins—in other words, all the antibiotics that the doctors threw at the infection. So while we talk about bacteria that are resistant to a drug, what's actually causing the nightmare is an enzyme that destroys the antibiotic, rendering enterobacteriaceae drug-resistant.

The Klebsiella bacteria in that North Carolina hospital basically picked up a shield, almost as if it had “powered up.” Think of a role-play video game in which your character can collect items and skills to get stronger. If this Klebsiella pneumoniae bacteria were in your game, it just picked up a super-advanced weapon and a level-10 shield.

Unfortunately, KPC isn’t the only enzyme we know of that can defeat carbapenems. In 2008, in another landmark study published in Antimicrobial Agents and Chemotherapy, authors described the case of a man hospitalized in India with a not-so-uncommon urinary tract infection caused by a not-so-uncommon bacteria: Klebsiella pneumoniae. The uncommon factor was that the man's Klebsiella was disturbingly resistant to antibiotics. And thus a new enzyme—New Delhi metallo-beta-lactamase-1, or NDM-1—was discovered. In both these examples, Klebsiella pneumoniae was the resistant bacteria. However, other commonly found bacteria, such as E. coli, can produce KPC and NDM-1 enzymes and become resistant, too.

Perhaps the best-known outbreak of carbapenem-resistant Klebsiella pneumoniae in the U.S. was at a National Institutes of Health (NIH) hospital. In June 2011 a woman infected with carbapenem-resistant Klebsiella pneumoniae was admitted to the Clinical Center of the NIH. Despite precautionary measures taken by hospital staff, 17 other patients became sick and 11 died. Then, in 2012, there were four cases of CREs with NDM-1 enzymes reported to the CDC, two in Colorado and two in Rhode Island. There have also been reports of the enzyme in a military hospital in Afghanistan. In the Wired science blog, Superbug, Maryn McKenna reports NDM-1 even being found in a domestic cat in the U.S. CREs aren't just happening here, either; common gram-negative bacteria with resistance to carbapenems are popping up all over the world.

So what puts someone at risk for an infection with CREs? Exposure to antibiotics and healthcare facilities are the two big risk factors. A long hospital stay, catheter use, organ or stem cell transplants, and mechanical ventilation all put people at a higher risk of CRE infection. So if you steer clear of those things, you'll be doing yourself a favor. But not everyone can do that, of course. Dr. Eli Perencevich of the University of Iowa is concerned about our lack of response to these infections and how they will negatively affect the types of surgeries and procedures we're able to perform. In an interview with USA Today Perencevich suggests that we're entering the “post-antibiotic era.”

It is a terrifying fact that there are so few drugs that work against superbug CREs. Some are old and have been shelved because of their high toxicity. Then there are other of these bacteria for which we have no method of treatment. The most important thing we can do is to make sure the infection doesn’t spread. Healthcare professionals need to take extreme cautions and infected patients may even need to be isolated. In an interview with NPR, Perencevich suggested that hospitals and other healthcare facilities must get better at detecting resistant bacteria; the sooner we know they're around, the faster we can work to contain them. The CDC recommends improved communication between healthcare facilities, so if one facility detects a CRE, it should alert others. The agency also advises healthcare administrators to ask patients if they've received care in other facilities. And of course appropriate use of antibiotics is necessary; in short, people shouldn't be prescribed the drugs for viruses and other ailments that antibiotics can't treat.

If there's one message that bears repeating, it's that CREs, like all superbugs, should never be underestimated.

--By Anna Tomasulo

Are you afraid of superbugs? Do you know of anyone who's been infected with CREs or another kind of superbug?

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