Image via WikipediaYou know there is trouble brewing when the latest superbug hits the New England Journal of Medicine. That’s just what happened this week with the publication of a perspective on the latest superbug – or super resistance gene – NDM-1 – by Bob Moellering. NDM-1 stands for New Delhi Metallo-Beta-lactamase. It is actually a gene encoding an enzyme (beta-lactamase) that chews up our most advanced antibiotics. Having a metal ion in its active site and not a serine, it is resistant to our usual Beta-lactamase inhibitors including the latest addition to our pipeline for the treatment of serious Gram-negative infections, NXL-104. Luckily, NDM-1 does not attack one of our antibiotics, aztreonam. Most of the pathogens that carry NDM-1 also carry other B-lactamases that do hydrolyze aztreonam. They also carry a host of other resistance genes. This may be related to the fact that this gene and the plasmid that carries it evolved in India and is widespread on the Indian subcontinent. In India, there is widespread use of antibiotics without prescription and frequently in low dosage or for only a few days resulting in inadequate therapy perfect for selecting resistant bacteria.
Dr. Moellering cites the Centers for Disease Control as stating that NDM-1 bearing bacteria should respond to the usual infection control measures. While that may be true, our experience with other new Beta-lactamases, with MRSA and with all the other superbugs has been that once they start to spread, with the exception of a few especially diligent centers, the cat is out of the bag. NDM-1 has already found its way to the UK and even over here to the US. It is probably just a matter of time before it becomes even more widespread.
Once again, we will need new antibiotics to fight this infection.
NXL-104 is an inhibitor of Beta-lactamase with serine at their active sites – so not NDM-1. But it does hit some of the most difficult of these enzymes like those that hydrolyze our most valuable antibiotics like imipenem. NXL-104 was originally discovered at Aventis (now Sanofi-Aventis) but was spun off into Novexel at the end of 2004. Novexel took the compound through Phase II trials in combination with ceftazidime, another antibiotic plagued with resistance – but which is susceptible to hydrolysis by NDM-1. Forest is developing NXL-104 in combination with their recently approved antibiotic, ceftaroline.
Last year at the ICAAC meeting, David Livermore pleaded with industry to combine NXL-104 with aztreonam. With aztreonam being resistant to NDM-1 and with 104 inhibiting the enzymes that might otherwise hydrolyze aztreonam – NXL-104-aztreonam could clearly be a winner for this particular superbug. Is there enough of a medical need? Will there be enough of a medical need in the next five years (when NXL-104 might be launched)? I don’t know. But I am sure that these are exactly the questions Astra-Zeneca and Forest are asking themselves.
Astra-Zeneca and Forest acquired Novexel in a complicated deal at the end of 2009 – almost exactly one year ago. In their annual report from 2009, Astra-Zeneca stated that ceftazidime-104 should enter phase III trials at the end of 2010. So far (to my knowledge), that has not happened. So I wonder what happened to NXL-104 and whether the powers that be are seriously considering David Livermore’s suggestion . . . .
Of course, I should also have mentioned Merck's beta-lactamase inhibitor, MK7655. It is very similar in structure and activity to Novexel/AZ/Forest's NXL-104 and could also be paired with aztreonam. As of the last ICAAC meeting, it looked like Merck originally planned to pair it with their imipenem.
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