Vancomycin AUC:MIC versus T>MIC

There is a significant amount of controversy regarding the most appropriate therapeutic goal for vancomycin therapy. The difference of opinion stems from the pharmacodynamic activity of vancomycin.

Definitions

  • MIC (minimum inhibitory concentration) – The minimum concentration of antibiotic to inhibit the growth of an organism.
  • AUC (area under the curve) – The total exposure of an antibiotic to an organism

Types of Pharmacodynamic Killing

  • T>MIC – Once the concentration of an antibiotic is above the MIC (typically 3-5 times greater than the MIC), there is not an increased rate of killing with increasing concentrations of antibiotic.  Prototypical antibiotics: B-lactams, clindamycin, linezolid, macrolides
  • The T>MIC pharmacodynamic killing graph shows that as antibiotic concentration continues to increase, there is a maximum rate of bacterial killing (a ceiling effect)
  • Peak:MIC – As the concentration of an antibiotic increases, its rate of killing increases.  Prototypical antibiotic: aminoglycosides
  • The Peak:MIC (or concentration-dependent) pharmacodynamic killing graph shows that the rate of bacterial killing increases linearly as antibiotic concentration increases
  • AUC:MIC – A combination of both T>MIC and Peak:MIC. The rate of bacterial killing is both related to the amount of time above the MIC and the total exposure of antibiotic to the organism.  Prototypical antibiotic: fluoroquinolones
  • The AUC:MIC pharmacodynamic killing graph shows that the rate of bacterial killing increases with higher concentrations, but the rate begins to level off as antibiotic concentrations increase.  Unlike T>MIC, there is no ceiling effect where the rate of bacterial killing becomes unchanged as antibiotic concentration increases.

Vancomycin as T>MIC

Traditionally, vancomycin has been thought to have pharmacodynamic characteristics similar to B-lactam antibiotics given its similar mechanism of action. Proponents of this theory will target a serum trough concentration of 15-20 mcg/mL, although historically target trough levels were as low as 5-10 mcg/mL.

Vancomycin as AUC:MIC

More recently, AUC:MIC has emerged as a proposed alternative to the T>MIC theory. The primary basis of AUC:MIC theory stems from a neutropenic mouse model,1 where AUC:MIC better correlated to bacterial killing compared to T>MIC. Proponents of this theory will target an AUC:MIC ratio of 400 mcg*hr/mL (based on Moise-Broder et al2) Because numerous vancomycin levels are not drawn (in order to calculate a true AUC), this goal generally correlates to a serum peak of 40 mcg/mL and a trough of 15 mcg/mL (assuming an MIC of 1 mcg/mL).

Clinical Evidence

In vivo human clinical evidence is scare and poorly described in the literature.

  • An article by Moise-Broder et al2 described 108 patients with S. aureus pneumonia. The authors concluded that AUC:MIC > 400 mcg*hr/mL was better correlated to clinical outcomes (defined as resolution of symptoms) than T>MIC.
  • An article by Jeffres et al3 described 102 patients with MRSA pneumonia (as defined by a BAL culture). The authors concluded that neither trough concentrations nor AUC:MIC values correlated to in-hospital mortality.

Further Reading

For more information, the following articles provide an excellent review of current literature:

  • DeRyke CA, Alexander DP. Optimizing vancomycin dosing trough pharmacodynamic assessment targeting area under the concentration-time curve/minimum inhibitory concentration. Hosp Pharm. 2009;44:751–65.
  • Rybak M, Lomaestro B, Rotschafer JC, et al. Therapeutic monitoring of vancomycin in adult patients: a consensus review of the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, and the Society of Infectious Diseases Pharmacists. Am J Health Syst Pharm. 2009 Jan 1;66(1):82-98. PMID 19106348.

References

  1. Craig WA. Basic pharmacodynamics of antibacterials with clinical applications to the use of beta-lactams, glycopeptides, and linezolid. Infect Dis Clin North Am. 2003 Sep;17(3):479-501. PMID 14711073.
  2. Moise-Broder PA, Forrest A, Birmingham MC, et al. Pharmacodynamics of vancomycin and other antimicrobials in patients with Staphylococcus aureus lower respiratory tract infections. Clin Pharmacokinet. 2004;43(13):925-42. PMID 15509186.
  3. Jeffres MN, Isakow W, Doherty JA, et al. Predictors of mortality for methicillin-resistant Staphylococcus aureus health-care-associated pneumonia: specific evaluation of vancomycin pharmacokinetic indices. Chest. 2006 Oct;130(4):947-55. PMID 17035423.

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