As antibiotic resistance increases over the years, originally established susceptibility breakpoints (S-I-R) are becoming less relevant. This ‘creep’ towards higher MICs over time is a unique but well-known feature of antimicrobials ultimately making these drugs obsolete.
In the past, FDA and CLSI did not bother to update breakpoints in a consistent fashion. Physicians just dealt with this situation by reviewing resistance trends from antibiogram data as compiled by their local microbiology labs on a yearly basis.
Ever since FDA was given the mandate to update breakpoints for antibiotics, a massive and by definition a never-ending effort, we began to appreciate just how difficult this assignment was.
Unfortunately, critical pieces in this data update puzzle only became available with significant lag time. It took years to down-adjust the vancomycin breakpoints. How about other drug classes? There are new breakpoints for carbapenems and cephalosporins.
Carbapenem Revised Breakpoints
Cephalosporin Revised Breakpoints – Enterobacteriaceae
Modified from J Hindler http://www.swacm.org/annualmeeting/2010/Antimicrobial_Susceptibility.pdf
Despite such fairly recent changes, PK/PD experts tell us that the tigecycline breakpoints were too high all along, and cefepime breakpoints have come under renewed discussion.
The transcript of the recent FDA Ad Board (Oct 17, 2013) on this topic makes for interesting reading. It is clearly important to select breakpoints based on PK/PD considerations (animal and clinical data, Monte Carlo simulation, protein binding, infection site, disease severity), and consider ADME and safety / tolerability issues.
All this makes good sense and helps select an ‘appropriate’ dose, but can we actually increase drug doses as would be required by PK/PD calculations and MICs which can vary by a factor of > 100 between the many susceptible and the few resistant?
The proposal to push the antibiotic dose to the highest levels for which an antibiotic has been tested makes good sense but only allows for modest increases by a factor of 2-4 in the best of cases. Ciprofloxacin IV underwent a steady dose escalation in its history, starting with 200 mg BID which was eventually ramped up to 400 mg q8h, a 3x higher daily drug exposure. Even chromosomally mediated resistance can easily overcome such relatively small dose escalation.
Obviously, there are major safety concerns when pushing up to higher doses. With around 30% of patients experiencing GI problems with standard doses of tigecycline, doses higher than 50 mg q12h seem problematic. Studies have shown dose-related QT prolongation with quinolones, like moxifloxacin, hence further dose increases are a non-starter.
In the end, we will have much new regulatory action on breakpoints all of which will undoubtedly be set much lower than currently posted in the package inserts.
This effort will predictably increase the awareness that we have few drugs for problem organisms, which is a good thing.
It will also drive overuse of those fewer antibiotics on the “S” list and drive these towards earlier obsolescence. This cannot be a good thing.
Great blog. Congratulations for making the time.