The New Attack Of The Multi-Drug Resistant Organisms

Warren S. Joseph DPM FIDSA

I recently returned from the Diabetic Foot Global Conference (DFCon) in Los Angeles. This is always my favorite scientific conference of the year. (I have blogged about it previously

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, 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 Los Angeles hotel polishing up my lecture for later in the afternoon of March 25, I had Good Morning America 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, there was a report on an outbreak of carbapenem resistant Klebsiella pneumoniae (CRKP) in 350 patients right there in southern California. Needless to say, I immediately added it 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 e-mail from a friend/colleague asking about CRKP since the news headline also hit our local all-news radio station. Although I speak about multi-drug resistant organisms frequently at lectures, I realized 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 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 organisms 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 organisms resistant to most commonly used antibiotics and only susceptible to the traditional “big guns” such as carbapenems and tigecycline (Tygacil, Pfizer). Do not think these isolates 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.1 In severe, life-threatening infections caused by KPC containing organisms, 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.2 This leaves essentially no good treatment for KPC-containing organisms. This is why the physician interviewed for the Good Morning America story reported a 40 percent-plus mortality rate related to this organism. To date, the vast majority of these cases are occurring in debilitated hospitalized patients. However, the very first KPC in our hospital occurred in a patient I was seeing with a diabetic foot infection.

A Closer Look At The Spread Of NDM-1

The “multi-drug resistant organism of multi-drug resistant organisms” has to be the organism containing the NDM-1 gene. This gene was first reported in 2009 in Sweden in a patient who had been hospitalized in India and the gene reportedly has a greater ability to spread rapidly to other bacteria in comparison to KPC.3 This has become a huge issue in Asia and Europe, but has now also spread to the United States with, I believe, four reported cases at last count.4-6 All patients had some relationship to the Indian subcontinent, either having lived 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?”7 To 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.8

Unfortunately, there is not a lot of promise for new antibiotic development to fight these multi-drug resistant organisms. 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, gastroesophageal reflux disease (GERD) and cholesterol.

To this end, the Infectious Diseases Society of America (IDSA) has developed the “Bad Bugs Need Drugs, 10 by 20” campaign.9 This is a collaboration among the IDSA, industry and the government to develop 10 new antibiotics by 2020. I urge all of the readership to check out this Web site and others to educate yourselves on the risks and dangers these new organisms cause.

Editor’s note: This blog was originally published at and has been adapted with permission from Warren Joseph, DPM, FIDSA, and Data Trace Publishing Company. For more information about the Handbook of Lower Extremity Infections, visit .


1. Livermore DM, Warner M, Mushtaq S, et al. What remains against carbapenem-resistant Enterobacteriaceae? Evaluation of chloramphenicol, ciprofloxacin, colistin, fosfomycin, minocycline, nitrofurantoin, temocillin and tigecycline. Int J Antimicrob Agents. 2011 March 21. Epub ahead of print.

2. Chan-Tompkins NH. Multi-resistant gram negative infections. Crit Care Nurse Q. 2011; 34(2):87-100.

3. Yong D, Toleman MA, Giske CG, et al. Characterization of a new metallo-beta-lactamase gene, bla(NDM-1), and a novel erythromycin esterase gene carried on a unique genetic structure in Klebsiella pneumoniae sequence type 14 from India. Antimicrob Agents Chemother. 2009; 53(12):5046-54.

4. Kant S, Haldar P. Is NDM-1 actually being imported to UK from India? Indian J Public Health. 2010; 54(3):151-4.

5. Mulvey MR, Grant JM, Plewes K, et al. New Delhi metallo-β-lactamase in Klebsiella pneumoniae and Escherichia coli, Canada. Emerg Infect Dis. 2011; 17(1):103-6.

6. Centers for Disease Control and Prevention. Detection of Enterobacteriaceae isolates carrying metallo-beta-lactamase - United States, 2010. Morb Mortal Wkly Rep. 2010; 59(24):750.

7. Bonomo RA. New Delhi metallo-β-lactamase and multidrug resistance: a global SOS? Clin Infect Dis. 2011; 52(4):485-7.

8. Kaase M, Nordmann P, Wichelhaus TA, et al. NDM-2 carbapenemase in Acinetobacter baumannii from Egypt. J Antimicrob Chemother. 2011 March 21; Epub ahead of print.

9. Available at×20.htm .

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