There's a troubling item in this afternoon's issue of the CDC's Morbidity and Mortality Weekly Report or MMWR: The first report in the United States of a novel resistance mechanism that renders gram-negative bacteria extremely drug-resistant and that has been linked to medical care carried out in India or Pakistan.
The short item describes three isolates (E. coli, Klebsiella pneumoniae and Enterobacter cloacae) found in three patients in three states between January and June of this year. All three isolates produced New Delhi metallo-beta-lactamase (NDM-1), which has never been recorded in the US before. Because of that novel mechanism, the three isolates were resistant to the carbapenems usually used on the most serious gram-negative infections, in fact to all beta-lactam antibiotics (penicillins, cephalosporins, carbapenems, monobactams, etc.) except for one monobactam, aztreonam -- and they were also resistant to aztreonam through another mechanism that hasn't been identified yet. All three of the patients found carrying this novel resistance factor had undergone medical care in South Asia recently.
This may be the first finding of this mechanism in the US, but it's been causing alarm in Europe for at least two years.
The first identification of NDM-1 was in 2008, in a 59-year-old resident of Sweden who was of South Asian origin and had returned to India for several months. The man was not well -- he had long-standing type 2 diabetes and had experienced a number of strokes -- and while in India he was hospitalized for an abscess, underwent surgery, developed bedsores and was treated for them as well. He returned to Sweden and was hospitalized there in January 2008, where physicians found him to be suffering from a urinary tract infection caused by a Klebsiella strain carrying this never-seen resistance mechanism.
Last July, the UK's Health Protection Agency put out a national alert about NDM-1, warning that the novel mechanism had gone from never-seen in 2007, to 4 isolates in 2008, to 18 in the first half of 2009. They were not an outbreak, but represented repeated importations: The isolates were clonally diverse and had been collected at 17 different hospitals. They were, instead, a sign that long-standing two-way population movement between England and South Asia --Â augmented by elective medical tourism (two patients had gone to India for cosmetic surgery) -- was bringing the high rates of antibiotic resistance in India back to a UK medical system that is already challenged by serious infection-control problems.
And now it's here. The special challenge of NDM-1 (which as today's finding suggests is on a mobile genetic element that has carried the resistance mechanism between species) is not only that it adds to an accumulating rogues' gallery of resistance factors that are rapidly making gram-negative bacteria ferociously drug-resistant, but also that there are so few drugs under development for gram-negatives that truly untreatable infections are not far off. The UK clearly is already struggling with attempting to use drugs that are old and toxic, untested against these organisms (and therefore with no agreed-upon dosing), or wrong for the organ systems affected:
Treatment presents major challenges. Most isolates with NDM-1 enzyme are resistant to all standard intravenous antibiotics for treatment of severe infections. Polymyxin is usually active in vitro ... but of uncertain clinical efficacy, especially in pneumonia, owing to poor lung penetration. Tigecycline is often active in vitro, but has low serum levels, is unsuitable for urinary infections and, more generally, is of unproven efficacy in severe infections.
The CDC's alert today asks any clinicians who come up against carbapenem-resistant gram-negatives to ask about contact with India or Pakistan as part of history-taking, and to forward isolates through state public health labs to the the CDC.
Update + fodder: I flipped over to my RSS reader and also discovered this paper posted overnight by Clinical Infectious Diseases, about extended-spectrum beta-lactamases in a particular strain of E. coli ("an important new public health threat"), and this one in Emerging Infectious Diseases, about carbapenem resistance moving between Klebsiella and E. coli.
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Add one more to the list. I'm really getting the feeling that between fossil fuel depletion, climate change, various undesirable social changes, drug-resistant pathogens, etc. that my generation (Boomers) had it about as good as any generation gets -- my great-grandchildren will be looking at infectious disease mortality rates not that much different from my grandparents.
There is hope -- http://en.wikipedia.org/wiki/Beta-lactamase_inhibitor ... these will competitively inhibit and irreversibly bind to the beta lactamase, allowing the antibiotics to work as usual. I haven't looked at any studies of its use with actual patients, though.