What to do with a vancomycin MIC?

In response to a spate of papers suggesting that elevated vancomycin MICs within the susceptible range are associated with poor clinical outcome, many clinicians now reflexively change to alternative therapy (daptomycin or linezolid) for treatment of any MRSA isolate with a vancomycin MIC of 2 mcg/mL. The most recent such paper can be found here.

As a result of this evolving standard of practice, one particular section of the new IDSA MRSA treatment guideline is generating discussion on our clinical microbiology listserv:

How should results of vancomycin susceptibility testing be used to guide therapy?

For isolates with a vancomycin minimum inhibitory concentration (MIC) ≤2 μg/mL (eg, susceptible according to Clinical and Laboratory Standards Institute [CLSI] breakpoints), the patient's clinical response should determine the continued use of vancomycin, independent of the MIC (A-III).

--If the patient has had a clinical and microbiologic response to vancomycin, then it may be continued with close follow-up

--If the patient has not had a clinical or microbiologic response to vancomycin despite adequate debridement and removal of other foci of infection, an alternative to vancomycin is recommended regardless of MIC.

For isolates with a vancomycin MIC >2 μg/mL (eg, vancomycin-intermediate S. aureus [VISA] or vancomycin-resistant S. aureus [VRSA]), an alternative to vancomycin should be used (A-III).

The bottom line? S is S, I is I, R is R. Treat the patient, not the MIC. If the patient is responding, good. If not, then you ought to be seeking alternatives, regardless of the exact MIC.

I agree with this approach for several reasons, not the least of which is that exact vancomycin MICs are method and laboratory dependent. In addition, +/- 1 dilution step in MIC is within the usual variability of our clinical laboratory MIC testing (MIC quality control ranges usually encompass 3 or 4 dilution steps). Even if every clinical microbiology laboratory did population analysis profiling of each MRSA strain, other treatment and host factors would likely have overriding impact on the clinical outcome.

Despite the fact that vancomycin is a bad (and mysterious) drug, we still lack alternatives that have been convincingly shown to be better for most MRSA infections….

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.