In my last post I talked about the under-appreciated emergence of “nightmare bacteria” (those are the Centers for Disease Control and Prevention’s words, not mine) that are widely distributed in hospitals and nursing homes around the world and do not respond to a last-ditch small family of antibiotics called carbapenems. That seemed dire enough, but new research suggests the problem, bad as it looks, has been understated.
There’s an ahead-of-print article in Antimicrobial Agents and Chemotherapy whose authors include David Shlaes, a physician-researcher and former pharmaceutical executive, now consultant, and Brad Spellberg, an infectious disease physician on the UCLA medical faculty and author among other books of Rising Plague, about antibiotic resistance. In a commentary examining the Food and Drug Administration’s promised “reboot” of antibiotic development rules, they analyze privately gathered data on resistance in the United States and conclude the incidence of highly resistant bacteria is greater than the CDC has estimated.
I’ll let them tell it (I’ve reparagraphed for clarity). For non-medical readers, the organisms being discussed here are Klebsiella and Acinetobacter, common causes of ICU infections that have become resistant first to a class of drugs called the third-generation cephalosporins, and after that, to the carbapenems. After the carbapenems, there are literally one to two drugs left, neither of them very effective (and one of them quite toxic).
In the report from CDC in 2008, taken from ICU isolates, the resistance among E. coli to third generation cephalosporins was 5% while in our analysis (using different methods) 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… 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.
…None of the …antibiotics (currently in the development pipeline) by themselves can address all these resistance problems. We will therefore continue to confront serious infections caused by pathogens for which are treatment options are either limited or non-existent.
The researchers made this dire analysis as part of an argument pressing the FDA to revise its rules of clinical-trial design in hopes of coaxing pharmaceutical manufacturers back into the antibiotic market. Their analysis is pretty granular, but these paragraphs sum it up:
…the FDA process of determining how antibacterial trials should be conducted has badly lost its way. As a result, 1) many companies do not invest in the trials; 2) those that do(,) enroll patients where it is possible to withhold therapy while the patients are enrolled in trials, with resulting ethical concerns; 3) the results become less meaningful and relevant to patients in the US because US patients are not enrolled. Pharmaceutical companies have voted with their feet. Twenty years ago, more than twenty large companies had active discovery and development programs for antibacterial agents; in 2013, only four have active discovery programs. Our approval rate for new antibiotics has fallen to dismally low levels.
The “reboot” of antibiotic programs at the FDA — promised a year ago, according to the paper — has not yet happened. It’s clear, from the details of this analysis, that there are going to be controversial aspects to any reframing of trial design. It’s hard to imagine that any new effort can be stood up quickly. About all we can say for sure is that the further emergence of resistance won’t wait for us to catch up.
Cite: Shlaes DM et al. The FDA Reboot of Antibiotic Development. AAC Accepts, published online ahead of print on 29 July 2013. Antimicrob. Agents Chemother. doi:10.1128/AAC.01277-13
Update: Almost exactly as I published this, Mike the Mad Biologist was posting about a possible new treatment for carbapenem-resistant bacteria. Take a look.