David's New Book

Monday, July 29, 2013

FDA Reboot of Antibiotic Development

Today you can see our commentary (Shlaes, Sahm, Opiela and Spellberg) (you need a subscription – sorry), published in Antimicrobial Agents and Chemotherapy, entitled, The FDA Reboot of Antibiotic Development. In our commentary, we explore the disaster of the last decade of FDA regulation of antibiotic development, the recent record of FDA antibiotic approvals and the state of antibiotic resistance in the US. In short, the FDA now realizes that their oversight of antibiotic development over the last 10-15 years has, in part, led to a dangerously thin pipeline of new antibiotics.  And they are (thank goodness) rebooting as Janet Woodcock had promised over a year ago.

As part of our analysis of the situation in the US, we looked at key bacterial pathogens in a representative sample of US hospitals both within and outside of intensive care units for the years 2009-2012. We focused on resistance to third generation cephalosporins (exemplified by ceftazidime-resistance) and on resistance to carbapenems (exemplified by imipenem). We realize that there are drawbacks to these choices, but our data was the most robust for these antibiotics. What we found was astounding and is shown in the Table below (from the article) (click on the table to enlarge).

The Centers for Disease Control (using methods different from ours) conducted a study published in 2008. In the CDC data, taken from ICU isolates, the resistance among E. coli to third generation cephalosporins was 5% while in our analysis it stands at 8-11%. K. pneumoniae resistance to third generation cephalosporins was 15% in the CDC study.  In our updated analysis it ranges from 20-27%.  Resistance to carbapenems among these isolates is now between 7 and 11%. For A. baumannii the resistance is even more drastic.  In the CDC report 11% were carbapenem resistant while our data show that number to be over 50%.

These data indicate that for Acinetobacter baumannii infections, the carbapenems are already obsolete.   This holds true for both intensive care and non-intensive care patients and for urinary and non-urinary infections. The same can be said for our third-generation cephalosporins (here indicated by ceftazidime) in the treatment of K. pneumoniae infections.  For these organisms, the carbapenems are also rapidly losing efficacy. Even among E. coli isolates, our third generation cephalosporins are no longer completely reliable although the carbapenems remain a solid backup.

Clearly, if this does not yet constitute a public health crisis, we are rapidly moving towards one. We will continue to face more and more infections for which are treatment options are worse and worse, even with the late stage pipeline of new antibiotics we now have in place. The FDA is responding to this desparate need.  They have issued new guidance (as covered in a previous blog) on the development of antibiotics targeting patients with highly resistant infections. They still need to revamp more traditional approaches to antibiotic development before their reboot can be considered to be near completion. The next steps on the FDA reboot cannot come too soon.

In our commentary, we also point out that regulatory reform will still probably not be enough.  We will still need value-based pricing (see last blog) in order to make the final leap to enticing large pharmaceutical companies back into antibiotic R&D. We hope that both complete regulatory reform and value based pricing come to pass since the alternative is too terrible to contemplate.