Vancomycin: even worse than you thought?
This month’s issue of Antimicrobial Agents and Chemotherapy has a disturbing report comparing three generic versions of vancomycin with the brand name version (referred to as “the innovator” in pharma parlance). All three vancomycin generics had similar in vitro activity to the innovator (i.e. same antibacterial effect by MIC testing and time-kill curves), and had similar pharmacokinetics and protein binding. However, none of the generics could kill S. aureus in vivo (in a neutropenic mouse thigh infection model), while the innovator exhibited the expected bactericidal activity. In the authors’ words, “pharmaceutical equivalence does not imply therapeutic equivalence for vancomycin”. But the WHO and other agencies consider therapeutic equivalence to be “self-evident” for compounds that exhibit pharmaceutical equivalence.
How can two versions of vancomycin exhibit similar in vitro activity but different in vivo activity? It turns out that the manufacturing process for vancomycin is tricky, and results in the formation of fermentation impurities known as “crystalline degradation products” (CDPs). CDPs bind to the vancomycin target (D-Ala-D-Ala) just like the active drug, but with much less efficacy, exhibiting an “agonistic-antagonistic” pharmacodynamic pattern. Eli Lilly developed a purification method that effectively reduced the concentration of CDPs, but generic preparations have been shown to have 2-3 times the CDP concentration. Interestingly, one of the generic manufacturers was quickly able to produce effective vancomycin immediately after Eli Lilly sold them their brand name rights and manufacturing secrets in 2005.
How can two versions of vancomycin exhibit similar in vitro activity but different in vivo activity? It turns out that the manufacturing process for vancomycin is tricky, and results in the formation of fermentation impurities known as “crystalline degradation products” (CDPs). CDPs bind to the vancomycin target (D-Ala-D-Ala) just like the active drug, but with much less efficacy, exhibiting an “agonistic-antagonistic” pharmacodynamic pattern. Eli Lilly developed a purification method that effectively reduced the concentration of CDPs, but generic preparations have been shown to have 2-3 times the CDP concentration. Interestingly, one of the generic manufacturers was quickly able to produce effective vancomycin immediately after Eli Lilly sold them their brand name rights and manufacturing secrets in 2005.
Excellent post Dan and very scary. I wonder how much of the morbidity/mortality of MRSA could be explained by these results? Since vancomycin is the primary therapy for MRSA, any outcomes associated with MRSA would be tighly linked to the efficacy of vancomycin. If have mecA+ S. aureus may be harmful because it forces clinicians to give you an ineffective antibiotic, then this might change how we see MRSA. Of course we would need to know the proportion of vancomycin used in the US and elsewhere that was generic.
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