Wednesday, September 15, 2010

Superbug - NDM-1

While at the ICAAC meeting (ending today), I learned a great deal about the emerging threat of the NDM-1 (New Delhi Metallo) beta-lactamase and its rapid spread throughout the world. Beta-lactamases are enzymes found in resistant bacteria that hydrolyze penicillin, cephalosporin and carbapenem antibiotics.  While they do not hydrolyze the monobactam antibiotics of which oly aztreonam is sold on the market, most organisms that have NDM-1 also have other enzymes that hydrolyze aztreonam.  So this means that our most powerful and least toxic antibiotics are off the table to treat these infections.  In fact, most strains are only susceptible to two or three antibiotics.  Tigecycline, a drug I helped develop, remains active against most strains.  Colistin is active in vitro, but since we don’t exactly know how to use it or how toxic it is, physicians are hesitant to use it unless absolutely necessary.  Many strains are also susceptible to an antibiotic called fosfomycin that is mainly used for urinary tract infections.

One good approach to NDM-1 bearing pathogens is to combine aztreonam with an inhibitor of the aztreonam hydrolyzing beta-lactamase enzymes.  There are currently two such inhibitors in clinical development – NXL-104 from Novexel and now at Astra-Xeneca and Forest, and MK-7655, a very similar molecule from Merck. These inhibitors are currently being developed in combination with ceftazidime (Astra Zeneca), ceftaroline (Forest) and imipenem-cilastatin (Merck).  None are pairing them with aztreonam.  When the clinical development of these inhibitors was first contemplated, metallo-beta-lactamases were not the threat that they are today.  The options for the companies are to add yet another combination for treatment of metallo-beta-lactamase bearing pathogens using the inhibitor plus aztreonam or to replace their current partner with aztreonam or do nothing and hope the NDM-1 problem will fizzle.  At ICAAC, David Livermore made an impassioned plea for the development of the combination with aztreonam.

Governments could, in fact, provide additional funding for the companies to develop such a combination and could commit to purchasing some minimum volume of drug. I would hate to bring the government in to such considerations because they move even slower than big pharma.  But this is something that governments should now be contemplating – especially the one in the UK where the numbers of NDM-1 infected patients are rising rapidly.