David's New Book

Sunday, September 18, 2011

Hope from ICAAC 2011

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Hello out there in blog-land.  I am writing from the 51st ICAAC here in Chicago.  David Livermore gave an opening address where he reviewed antibiotic resistance in Gram-negative bacteria – focusing on common Enterobacteriaceae like E. coli, a frequent cause of urinary tract and other infections. David pointed out the rapid emergence not only of resistance to our latest cephalosporin antibiotics, but also to our last line antibiotics for these bacteria, the carbapenems. He ended his talk by noting the regulatory hurdles (FDA) that are stifling development of new antibiotics and by also stating that the pipeline of new antibiotics to address the resistance problem is woefully inadequate.  The only compound David recognized as possibly addressing the emerging resistance was the boron-containing GSK-052 that has a strong Gram-negative profile and which is in phase II development. While I agree with David’s view of the threat of resistance emerging in Gram-negative pathogens on a global basis, I take slight issue with him on the promise of the late stage antibiotic pipeline to address this threat. 

I will be giving a talk myself tomorrow afternoon focusing on new Beta-lactam-beta-lactamase inhibitor combinations in the late stage pipeline for Gram-negative infections. I will cover CXA-201, a combination of the anti-pseudomonal cephalosporin, CXA-101, with the older beta-lactamase inhibitor, tazobactam. This antibiotic is very active against resistant strains of Pseudomonas aeruginosa that can cause very serious infections in our hospitals – especially pneumonia .  These infections are associated with a high mortality.  There are more and more of these infections caused by strains resistant to all or almost all currently available antibiotics.  CXA-201, being developed by Cubist, is active against many of these strains.  Phase II trials in urinary tract infection and in intra-abdominal infections have already been completed with promising results.  Phase III trials in urinary tract infection have been initiated.

A new class of beta-lactamase inhibitor, called the bicyclo-diaza-octanes, was discovered at Aventis.  These compounds were spun off into Novexel in 2005 (the lead drug was called NXL-104). In combination with ceftazidime, the drug (now called avibactam) inhibits most organisms resistant to our last line carbapenem antibiotics including Pseudomonas.  The only exception is those emerging but still rare bacteria carrying a metalo-beta-lactamase that is resistant to the new class of inhibitors.  Novexel developed the inhibitor in combination with ceftazidime through phase II trials in intraabdominal infection and in urinary tract infection.  These trials demonstrated that the combination works in the clinic and is able to cure infections caused by ceftazidime-resistant Gram negatives.  Avibactam is now being developed by Astra-Zeneca. Phase III trials are hopefully imminent.

Avibactam + ceftaroline is being developed by Forest/Cerexa.  Ceftaroline is a cephalosporin that is active against MRSA – a rarity.  When combined with avibactam, the drug can inhibit an extremely broad spectrum of Gram negative and Gram-positive pathogens – but is not very active against Pseudomonas. This combination just entered phase II development in urinary tract infection.

Merck is developing its own version of avibactam combined with their carbapenem, imipenem.  It is called MK-7655. Imipenem-MK7655 is active against many imipenem-resistant Gram-negatives and is still in phase I development.

Finally, even though the beta-lactamase inhibitor avibactam inhibits most beta-lactamases causing resistance to cephalosporins and carbapenems, it does not inhibit the metallo-beta-lactamases as I noted above. But, certain beta-lactam drugs, like the monobactams, themselves are not hydrolyzed by the metallo-beta-lactamases.  Therefore, a combination of a monobactam with avibactam should be active against these types of superbug (like NDM-1).  I have mentioned this in a blog after the last ICAAC. In fact, David Livermore’s lab has shown that this prediction is accurate. Currently, no such combination is under development – but what a great idea.

It is true that these antibiotics do not cover all the resistant pathogens that are emerging today.  Note that I have not mentioned Acinetobacter.  But there are new products for them too – like TP-434, a novel tetracycline from Tetraphase that is now in phase II clinical trials and which is also the subject of a presentation tomorrow afternoon.

So my message is one of hope for patients and physicians confronted by these highly resistant pathogens.  There are antibiotics in the late stage pipeline that will address many but not all of our current medical needs in this regard.  If a company would/could develop a monobactam-avibactam combination, we could treat most infections caused by even the most resistant of the superbugs. I am hoping that this will come to pass . . .

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