Saturday, January 14, 2017

Pan-resistant does not mean "resistant to sauce pans"

Well this is it folks, the end of days is nigh. The Centers for Disease Control and Prevention (CDC) put out a report in the Morbidity and Mortality Weekly Report (MMWR) yesterday. "Notes from the Field: Pan-Resistant New Delhi Metallo-Beta-Lactamase-Producing Klebsiella pneumoniae — Washoe County, Nevada, 2016" tells the tale of a particularly scary kind of bacteria. This is the kind of bacteria that is the impetus for the title of my blog, Death by UTI. New Delhi Metallo-Beta-Lactamase-Producing Klebsiella pneumoniae is a flavor of carbapenem-resistant Enterobacteriaceae. Let's back up a step or two shall we?

Enterobacteriaceae (entero-bact-ear-E-A-C-A) are a large family of bacteria that live in the guts of mammals, including humans. You probably have heard of Escherichia coli, or E. coli right? E. coli is a member of the Enterobacteriaceae family along with K. pneumoniae and a whole host of others. They all live in the gut happily breaking down food components for their use and ours. Sometimes the byproducts of bacterial munching are not so welcome, like gas. But we all fart and that's just the way it is. These bacteria living in our guts are not out to harm us, but occasionally they wind up in areas they shouldn't. Such as the urethra and bladder where the result might be a urinary tract infection. Or the bloodstream where the result might be death. Antibiotics used to be able to readily kill these bacteria, curing infections and allowing us all to live to ripe old ages. But this family of bacteria living in our guts is very good at developing resistance to the antibiotics we throw at it. Resistance means that the bacteria have ways of living in the face of the antibiotics that intend to kill them. It's all very Hunger Games.

Carbapenem-resistant Enterobacteriaceae, or CRE, are those members of the family that are resistant to carbapenem antibiotics. The carbapenem antibiotics were introduced relatively recently for the treatment of infections caused by Enterobacteriaceae that are resistant to a bunch of other antibiotics. CRE have several different ways to resist carbapenems. They change the walls of their cells so that the antibiotic can't get in. Or they turn on pumps that flush the antibiotic back out once it has entered, like a teeny tiny sump pump. They also produce enzymes (macromolecules that accelerate chemical reactions) that break down the structure of the antibiotic rendering it useless. It's these darn enzymes that are such a worry.

A beta-lactamase is a type of enzyme (you can always recognize an enzyme by the -ase at the end of its name) that breaks down beta-lactam antibiotics such as penicillin. Specifically, bacteria release the enzyme into the space around their cells. The enzyme then cleaves the beta-lactam ring in the antibiotic's molecule, its basic structure. Once that ring is cleaved, the antibiotic molecule no longer holds its shape and is not able to bind to the bacterial cell wall. Success! For the bacteria that is. For humans, this is bad news. If the antibiotic doesn't work, the infection is less likely to go away. Your body's natural defenses will do what they can, but it might not be enough. There are many different beta-lactamase enzymes that are active against various beta-lactam antibiotics. Beta-lactamases that are active against carbapenems are called carbapenemases. These enzymes also are active against all of the older beta-lactam antibiotics. As if this weren't bad enough, here comes the super scary part: bacteria share with each other. Friendly little buggers. If one bacterium learns how to make these enzymes (meaning that they have genes that code for them) they can pass that information on to their children through their DNA. What makes these beta-lactamases, particularly the carbapenemases, so terrifying is that the genes that code for them are often located on plasmids. Plasmids are bits of DNA that are free-floating, that is to say that they aren't attached to the DNA strands. They are free to move about and transfer to other bacteria, including those that aren't even the same species. So an E. coli can share its genetic information with a K. pneumoniae or another member of the Enterobacteriaceae family. Beatrice the Biologist (who I adore with my whole heart) shows us just how happily these bacteria share their genetic info.
When you consider the bacterial stew that is the human gut, you begin to understand how troublesome this is. Bacteria are constantly bumping up against one another. Kind of like a crowded dance floor. Remember this.

New Delhi-Metallo-Beta-Lactamase, or NDM, is a kind of carbapenemase that is so-called for two reasons: 1. The first reported case of this enzyme was from an infection in a patient who had received health care in New Delhi, India and 2. This enzyme requires the metal zinc in order to do its job, hence "metallo." The first case was reported in 2009 and since then, NDM has spread across the globe and into the United States. Most of the cases in the U.S. have been patients that have lived in and/or received significant health care in areas where NDM is endemic, such as India, Pakistan, and Bangladesh. However, there have been reports of outbreaks of infection or colonization with NDM-producing CRE that have been associated with medical procedures in the U.S. like in Illinois, Colorado, and others. NDM is of particular concern because the genetic info that codes for the enzyme is located on a promiscuous plasmid, one that quite readily passes from one bacterium to another. Picture that crowded dance floor. One bacterium bumps into another: "Hey man, it's been a long time! So good to see you, how are the kids? Great. Say, you want a resistance gene? It's a good one. Yeah, you'll be resistant to so many antibiotics! Here you go pal!" Or that's how I assume it goes down.

Okay, that was a LOT of information. My apologies, but this is an extremely complicated topic. Thanks for sticking with it. Let's get back to the story at hand.

The report in yesterday's MMWR refers to a patient that developed an infection caused by a strain of NDM-producing K. pneumoniae that was "pan-resistant." That means resistant to ALL available antibiotics. Every. Single. Antibiotic. Even the really old, not-often-used-because-they-are-so-toxic antibiotics. The good news is pan-resistance is exceedingly rare in the U.S. The bad news is that we fear that it will become more common. New antibiotics don't come around often and when they do are frequently just slightly different versions of old antibiotics. For example, we are now up to the 5th generation of a particular group of antibiotics called cephalosporins because bacteria have developed resistance to the 1st, 2nd, 3rd, and 4th generations. You see, bacteria develop resistance to our "new" antibiotics as soon we start using them. It's a war that we are losing. A war that suggests we need to change tactics, but that's a story for another time.

The patient at the heart of yesterday's MMWR unfortunately lost her life. The Center for Infectious Disease Research and Policy (CIDRAP) ran a piece on this case that delves a bit deeper than the MMWR report itself. Now I need you to understand that pan-resistance is a HUGE deal and exceedingly scary. Physicians and pharmacists can attempt to treat an infection caused by such bacteria by combining different antibiotics and using higher doses in the hopes that they will be able to fight off the bacteria. This can and does work, but not always and not without serious consequences. Antibiotics are NOT benign drugs. They are medications that can have major side effects and adverse events like Clostridium difficile diarrheal infection, permanent disabling issues involving tendons, muscles, joints, nerves, and the central nervous system, and neurological problems. This patient had an infection with NDM-producing bacteria and we talked about how promiscuous the plasmid is that carries the genetic information for NDM. Once the hospital was notified of this infection the patient was placed on Contact Precautions and there were studies done to determine if transmission occurred. Had this bacteria spread to any patients that had been roommates of the case or were hospitalized on the same floor prior to Contact Precautions having been implemented? Thankfully, no transmission was found to have happened.

So what can you do?
Be mindful of antibiotics.
1. Don't demand or take antibiotics for viral infections like colds, acute bronchitis, and sore throats. Antibiotics don't work against viruses, all they do is kill off regular bacteria and leave the resistant ones behind to take over.
2. When you do have a bacterial infection and are prescribed antibiotics, take the WHOLE dose. Don't save some for another time and don't share antibiotics with friends and family.

Be aware of the risk factors for infections caused by CRE. This list is not all inclusive.
1. Hospitalizations or surgery in the last year
2. Residing in nursing homes or long-term acute care hospitals in the last year
3. Indwelling devices like urinary catheters (more of a short-term risk, unless you are chronically catheterized)
4. Exposure to antibiotics in the last year
5. Receipt of health care in an area in which CRE is endemic

It is no guarantee that if you have one of the above risk factors you will get an infection with CRE. It just means that you have a higher risk than people who don't have any of the above risk factors.

CRE and other antibiotic-resistant infections are more common in people who have significant health care exposures, but none of us are immune. The thing to remember here is that antibiotics are a shared resource. Use in one person may cause resistance only in that person's bacteria, but when that bacteria spread to someone else it becomes a much bigger problem. We are on the brink of a post-antibiotic era.

Cue the ominous music.

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