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.

Heads, MRSA. Tails, possibly MRSA.

Cepheid just issued a recall notice on the Xpert MRSA/SA BC test, the rapid, real-time assay that is designed to quickly identify MRSA vs. MSSA in positive blood cultures. Seems MRSA can evolve (!), and there are now some isolates that are not detected, resulting in false-negative results (that's what us clin micro types call a "very major error"). Here is the text of the notification:

Dear Valued Customer:

Based on the recall announced July 1, 2010, Cepheid is initiating a recall of all lots of Xpert MRSA/SA BC (blood culture) product. The recall is a corrective action, which does not require return of product to the manufacturer. Customers may continue to use the product; however, when a MRSA negative/SA positive result is obtained, the results should be interpreted as MRSA indeterminate/Staphylococcus aureus positive, antimicrobial susceptibility testing pending. Further testing should be performed using an FDA-cleared, phenotypic antimicrobial susceptibility testing method on isolated colonies recovered from the blood culture bottle. MRSA positive/SA positive results can still be reported as such. The new instructions will be incorporated in the product labeling. The Xpert MRSA/SA BC product produces false-negative MRSA results, which could potentially contribute to incorrect treatment of an MRSA infection.

The following statement will be added to the Interpretation of Results section of the package insert for "MRSA Negative/SA Positive" results:

The results should be interpreted as "MRSA indeterminate/SA Positive, antimicrobial susceptibility testing pending". Further testing should be performed using a FDA-cleared, phenotypic antimicrobial susceptibility testing method on isolated colonies recovered from the blood culture bottle.

Although the product appears to continue to meet performance claims as outlined in the current product labeling, an ongoing failure investigation has identified the emergence of novel MRSA strain types as one of the causes of false-negative MRSA results. The failure investigation has not fully determined the remaining causes of the false-negative MRSA results. To date, one adverse event has been reported to the FDA through the MDR process.