John Bartlett's Game Changers in Infectious Disease: 2011

John G. Bartlett, MD


October 26, 2011

In This Article

Vancomycin Guidelines

This paper violates my rule that guidelines should never be selected as the most important publications, owing to the lack of originality, but the article by Rybak and colleagues[35] is included because:

  • Vancomycin is the most frequently prescribed antibiotic in US hospitals[36];

  • The guidelines recommend a significant change in the way we use the drug[35]; and

  • The entire guideline is 3 pages in length.[35]

According to antibacterial claims data for 22 university hospitals from 2000-2006, vancomycin is the most frequently used antibiotic,[36] becoming number 1 in 2004. More recent data are not available, although those who practice contemporary medicine will not be surprised at this ranking.

The new guidelines represent concerns about serum drug levels achieved with the previously standard dose of 1 g of vancomycin, administered intravenously, twice daily.[35] Controversies about this agent touch on some very fundamental issues, which is surprising considering that we have had this drug for more than 50 years. New concerns include: definition of resistance, questions of potency, probable need for higher trough levels, and rebirth of concerns about nephrotoxicity.

In 2006, the recommendation was made to reduce the breakpoint that defines MRSA susceptibility from 4 mg/L to 2 mg/L, based on a 60% clinical failure rate for infections involving strains with a minimum inhibitory concentration (MIC) value of 4 mg/L. More recently, concern has been expressed about increasing resistance at 2 mg/L and the need to establish an area under the serum drug concentration/time curve to MIC (AUC/MIC) ratio of 400, based on the pharmacokinetic-pharmacodynamic requirements of the drug.[37]

Why Is This a Game Changer?

Simply stated, vancomycin requires a high trough level. Thus, the new recommendations for serious infectionsinvolving S aureus include dosing to reach trough concentrations of 15-20 µg/mL, which, based on tests of more than 400 for strains with MIC ≤ 1 mg/L, should achieve the target AUC/MIC. However, this will not be achieved if the MIC is 2 mg/L, leading to the paradoxical suggestion that strains with a MIC of 2 mg/L (which account for 20%-30% of MRSA in many hospitals[38]) are sensitive by lab definition. Strains with this sensitivity should not be treated with vancomycin.[37,39]

The toxicity of vancomycin has always been controversial. In 1960, the initial form of vancomycin was brown in color and often referred to as "Mississippi mud."[40] Vancomycin was subsequently purified by the manufacturer and not believed to be nephrotoxic in animals or man. A statement in the new guidelines warns that "vancomycin nephrotoxicity should be considered if the serum creatinine concentration increases by 0.5 mg/dL or more than 50% above baseline."[35] Of note, in the same issue of Clinical Infectious Diseases is a sophisticated analysis of the vancomycin concentration-time profile, indicating that the target serum level of 15-20 mg/L resulted in nephrotoxicity in 20% of patients![41]

Another potentially important report[42] suggested that the available generic products of vancomycin often failed to show in vivo activity in a mouse model of a MRSA thigh infection. The implication is that generic forms of the drug may vary in potency and toxicity possibly as a result of variations in purity. Most pharmacies purchase vancomycin on the basis of price and not purity.

What Does This Mean to the Practitioner?

One of our oldest and most revered antibiotics is under the microscope with respect to adequacy for its main target -- MRSA. The recent developments include an entirely new dose recommendation and the paradoxical message that an MIC of 2 mg/L will mean that the lab will report sensitivity but we should use an alternative drug. The need for an alternative agent for serious infections involving MRSA with an MIC of 2 mg/L was shown clinically in a study of ventilator-associated pneumonia where mortality was directly correlated with the MRSA MIC.[43]

Furthermore, although the assumption is that generic forms of vancomycin are therapeutically equivalent, pharmacy decisions driven by cost may result in a suboptimal product. The poor clinical outcomes associated with MRSA infections involving strains with relatively high vancomycin MICs may simply reflect increased virulence,[44] but concerns for potency of generic vancomycin are under review. Vancomycin has been used for 60 years, it is the most frequently ordered antibiotic in US hospitals, and we still do not seem to know much about it.