David's New Book

Saturday, January 9, 2010

And then there was none.

I was contacted recently by a journalist about antibiotics in development for Gram negative infections. The subject of carbapenem resistance in Klebsiella and other Enterobacteriaeceae like E. coli, came up and started me thinking about my next blog.
What am I talking about? These bacteria can cause everything from minor infections of the urinary tract and surgical wounds to serious, life-threatening pneumonia. Most of the time, they occur in hospitalized patients, but they also cause serious infections in those in chronic care facilities and even within our communities. In years past, we had a wide choice of antibiotics active against these bacteria. The sulfa drugs and tetracycline worked. Ampicillin or the combination of amoxicillin (similar to ampicillin) plus an inhibitor of the enzyme that destroys ampicillin, B-lactamase, worked (Augmentin). Most of the cephalosporins (similar to ampicillin but with activity against a wider array of bacteria) were also effective. Hospitals had the luxury of deciding which of the many effective drugs they would put on their formularies. In many parts of the world, including the US, those days are long gone.
In many hospitals and chronic care facilities today, resistance has gotten to the point where only one (essentially) class of antibiotics is left for physicians and patients, the carbapenems. For these physicians and patients, our antibiotic of last resort has become our drug of first choice. Given the “you use it you lose it” rule of antibiotics, you can guess what is happening now. These Gram negative pathogens, especially Klebsiella have acquired a gene for a new enzyme (B-lactamase) that can destroy the carbapenems. Its called KPC for Klebsiella pneumoniae carbapenemase. The first one of these was isolated from a patient in North Carolina in 1996. The new enzyme destroys the penicillins like ampicillin, even our most modern cephalosporins, and our last line drugs, the carbapenems. KPC is not inhbited by currently marketed B-lactamase inhibitors – so those combinations like Augmentin and others are not effective. In addition to KPC, these bacteria are frequently resistant to multiple other antibiotics, even the quinolones like ciprofloxacin or levofloxacin. To treat infections by these pan-resistant strains, physicians are going back to a really old antibiotic, colisitin. Colistin was discovered in 1947. Given the time when it was approved for use, we don’t really know how well it works nor do we know how toxic it really is. My own personal experience treating patients with colistin was not encouraging on either front.
KPC Klebsiella are now spread throughout the world. We don’t have good survey data for many geographic locales. (I can’t understand why this is so). In New York City, about 30% of hospital Klebseilla carry KPC. The strains are also widespread in urban hospitals of Pennsylvania and New Jersey. Israel, Greece and China also have significant epidemics of infection with these strains.
Do we have antibiotics effective against KPC bearing bacteria coming through the pipeline? We have a new B-lactamase inhibitor from Novexel, lovingly called NXL-104, which is highly active against the KPC enzymes. NXL-104 is being developed in combination with cephalosporins (ceftazidime and ceftaroline) by Novexel, soon to be Astra-Zeneca and Forest. NXL-104 containing combinations are extremely effective against the KPC bearing bacteria. To my knowledge, there is nothing else in the later stages of development for these bacterial pathogens.
There is hope, but one new B-lactamase inhibitor is not much of a global strategy when our last line antibiotic has already become our drug of first choice.