It is a rare study I read that makes me want to literally stop everything else I am doing and write a blog post about it. It is a dreary, gray Sunday morning and I was just catching up on some backlogged journal reading when I picked up the August 2010 issue of Antimicrobial Agents and Chemotherapy. I came across a paper out of the University of Antioquia in Medellin, Columbia by Omar Vesga and colleagues entitled “Generic Vancomycin Products Fail in vivo despite Being Pharmaceutical Equivalents of the Innovator” (PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/20547818) . Regular readers of this blog and the Handbook, and those who have attended my lectures, know that I have not been particularly kind to vancomycin given significant failure rates reported in numerous studies. This study might explain why there are so many failures.
Vancomycin was first developed by Eli Lilly after it was discovered as a fermentation product of Amycolatopsis orientalis found in a sample of dirt sent to Lilly from Borneo in 1955. Early formulations had significant impurities which, along with lending the product a brown color, hence leading to its’ early moniker “Mississippi Mud”, also was felt to lead to significant adverse events. Lilly eventually found ways to highly purify the product to the relatively safe drug we know today. Apparently, those extra steps were kept secret until they were finally sold as recently as 2005. I clearly remember a Lilly sales rep calling on me 20 some years ago when the drug first went generic. He pulled out a vial of the newly generic vancomycin and it was sandy brown in color. He then pulled out a vial of the brand named Vancocin and it was, indeed, Lilly white…pun intended. His point was simply, “Doc, which would you rather have going into your patients’ vein?” Of course, hospital formularies being the way they were/are we really did not have a choice as to which we wanted to use.
Back to the Vesga study: The investigators studied 3 generic versions of vancomycin vs. the “innovator” product to determine concentrations and clinical efficacy via numerous techniques both in vitro and in an in vivo mouse model. In my opinion this was an elegantly designed, complex study which used multiple techniques including time-kill curves (TKC), broth microdilution and a neutropenic mouse thigh infection model, along with others, while using different strains of S. aureus. Their findings were fascinating! To directly quote the Abstract:
“Vancomycin generics were virtually undistinguishable from the innovator based on concentrations and potency, protein binding, in vitro antibacterial effect determined by minimal inhibitory or bactericidal concentration and TKC, and serum pharmacokinetics. Despite such similarities, all generic products failed in vivo to kill S. aureus while the innovator displayed the expected bactericidal efficacy…” (Emphasis added)
The authors conclude that the current standard of “pharmaceutical equivalence predicting therapeutic equivalence” is not true, at least for vancomycin. They make it clear that they are not claiming that the tested generics were in any way poor quality. They certainly met all of the current regulations governing the necessary equivalence to make it to the market. But this study raises a number of questions: Is this finding of pharmacologic equivalence not equaling clinical efficacy unique to vancomycin or could it be a factor in other generic antibiotics? Could the universal use of generic vancomycin in hospital pharmacies account for the increasing clinical failures being seen not only in clinical trials but everyday practice?