The Attack of the MDROs (ESBL, KPC, NDM-1, NDM-2)
I just returned from the DFCON meeting in Los Angeles, always my favorite scientific conferences of the year (I have blogged about it previously http://www.leinfections.com/diabetic-foot/the-olmos-award-and-dfcon-2010/). My topic this year was “Drugs and Bugs 2011”. Since I gave a similar talk last year I had to try to find a few “hot” topics to update the talk. Without a doubt, the most important development in Infectious Diseases over the past year has been the increasing prevalence of multi-drug resistant organisms (MDRO), in particular the gram negative rods harboring extended spectrum beta-lacatamase (ESBL), Klebsiella pneumoniae carbapenemase (KPC) and the New Delhi metallo-beta-lactamases (NDM-1, NDM-2). In fact, as I was in my hotel in L.A. polishing up my lecture for later that afternoon of Friday 3/25, I had Good Morning America (GMA) on the TV in the background. A story was announced on the latest “Superbug”. These fear-mongering sorts of titles always get my attention so I stopped work on the lecture and listened. Sure enough, they were reporting on an outbreak of Carbapenem resistant Kleb pneumo (CRKP) in 350 patients right there in Southern California. Needless to say, it was immediately added to my lecture, although I doubt that Good Morning America would be considered an appropriate peer reviewed, primary reference for a scientific publication! When I arrived home the next day, there was an email from a friend/colleague asking about CRKP since the news headline also hit our local all-news radio station. I realized that, although I speak about them frequently at lectures, I have never written about them here. It is past due.
Although I may give a more complete scientific explanation in a future post, I just wanted to pique your interest so that you can do some reading and exploration on your own about this major threat. In the most basic terms, ESBLs are enzymes that inactivate most current beta-lactam antibiotics including cephalosporins and penicillins. The most common organism in which the ESBLs are found seem to be E. coli and Proteus mirabilis. Many of us of a certain generation remember a time when these organisms were so susceptible to antibiotics that you could pretty much choose any drug with basic gram negative activity and it would be effective. Now, there are isolates of these organism resistant to most commonly used antibiotics and only susceptible to traditionally thought of “big guns” such as carbapenems, and tigecylcine. And, don’t think these are only found in urinary tract infections, bacteremia, pneumonia or other severe hospital based infections, I have seen them in diabetic foot infections on a number of occasions.
As the name implies, KPCs are enzymes that not only inhibit the previously mentioned antibiotics but also one of the remaining choices effective for ESBLs…carbapenems. Needless to say, this makes these organisms extremely difficult to treat. Tigecycline resistance has been reported. In severe, life threatening infections caused by KPC containing organism the “last ditch” treatment has become either polymyxin-B or colistin. These are nasty drugs with rather significant adverse event profiles, mostly renal toxicity. The problem is that, as recently as the past month or two there have been reports of both polymyxin and colistin resistant strains reported in the literature leaving, essentially, no good treatment. This is why the physician interviewed for the GMA story reported 40%+ mortality related to this organism. To date the vast majority of these cases are occurring in debilitated hospitalized patients but, the very first KPC in our hospital occurred in a patient I was seeing with a diabetic foot infection.
The “MDRO of MDROs” has to be those containing the NDM-1 gene. This gene was first reported in 2008 in Sweden in a patient hospitalized in India and has a greater ability to rapidly spread to other bacteria than does KPC. This has become a huge issue in Asia and Europe but has now also spread to the US with, at last count, I believe 4 reported cases. All patients had some relationship to the Indian subcontinent either having come from there or visited as a tourist. These bacteria have a similar antimicrobial susceptibility pattern as the KPCs but tend to develop resistance more rapidly. In the February 2011 issue of Clinical Infectious Diseases an Editorial Commentary says it all just by its’ title “New Delhi Metallo-β-lactamase and Multidrug Resistance: A Global SOS? http://cid.oxfordjournals.org/content/52/4/485.extract. To only make matters worse, as recently as last week I saw the first report of an Acinetobacter with a brand new variant, the NDM-2 gene http://jac.oxfordjournals.org/cgi/content/abstract/dkr135v1.
Unfortunately, there is not a lot of promise for new antibiotic development to fight these MDROs. The Pharma industry does not make its money on new antibiotic development as most of these drugs are only given for a short period of time in contrast to therapies for hypertension, GERD and cholesterol. To this end the Infectious Diseases Society of America has developed the “Bad Bugs Need Drugs, 10 by 20” campaign (http://idsociety.org/10×20.htm) a collaboration between the IDSA, Industry and the Government to developed 10 new antibiotics by 2020. I urge all of the readership to check out this website and others to educate yourselves on the risks and dangers these new organisms cause.