High-Dose Vancomycin therapy for Methicillin-Resistant Staphylococcus aureus Infections

Background:  There has been a rise in treatment failure when using vancomycin to treat Methicillin-resistant Staphylococcus aureus (MRSA), which has prompted the Clinical and Laboratory Standards Institute (CLSI) to lower the breakpoint for vancomycin susceptibility from 4 μg/mL to 2 μg/mL.  In return, dosing guidelines have also changed to now recommend a vancomycin trough level 15-20 μg/mL for those MRSA strains with a minimum inhibitory concentration (MIC) ≥ 2 μg/mL. 

Objective:  The purposes of this study were to determine the distribution of vancomycin MICs among various infectious MRSA strains and to evaluate the risk of nephrotoxicity and efficacy associated with the use of vancomycin doses needed to target a trough of 15-20 μg/mL. 

Methods:  This was a retrospective cohort study conducted at a 525-bed community hospital.  Inclusion criteria included age ≥ 18 years, nosocomial infection (48 hours or more after hospital admission or acquired in a skilled nursing facility), and vancomycin therapy for at least 72 hours.  No exclusion criteria were stated.  Ninety-five patients were included in the study.  Primary outcomes were clinical response, infection-related mortality and nephrotoxicity.  The efficacy measure was determined using subgroups of high or low vancomycin MIC (≥ 2 or < 2 μg/mL, respectively).  The nephrotoxicity measure was determined using subgroups of high or low trough levels (≥ 15 or < 15 μg/mL, respectively).  Secondary outcomes were time to achieve clinical stability and length of hospital stay. 

Results:  Ninety-five patients were included in the study.  Of the 95 patients enrolled, 54% (51 patients) had high vancomycin MICs and were more associated with bloodstream infections than those with low vancomycin MICs (35% vs 14%; p = 0.02; OR 3.5; 95% CIC 1.2 – 9.7).  Low vancomycin MICs were observed more often in those with wound infections than high vancomycin MICs (27% vs 15%; p = 0.21).  Only 86 patients were included in the efficacy measure.  Although target trough was attained initially, at the final assessment those with high MICs were less responsive to vancomycin therapy than those with low MICs (62% vs 85%; p = 0.02).  Also, those with either a bloodstream infection or pneumonia were less likely to respond to vancomycin therapy than wound or urine infections (66% vs 91%; p = 0.03).  Eleven out of 63 patients (12%) who attained a high vancomycin trough developed nephrotoxicity compared with 0 patients in the low trough group (p = 0.01).   Of these 11 patients, 10 had received concurrent therapy with other nephrotoxic drugs and 4 had preexisting renal dysfunction.  Concurrent therapy with other nephrotoxic drugs was the major predictor of nephrotoxicity development (p = 0.003).  The authors concluded that for those infections with a high MIC, either aggressive empirical vancomycin therapy (trough ≥ 15 μg/mL), combination therapy, or another agent should be used. 

Strengths:  Bias was not a concern of this study, since the authors were associated with either a university or a hospital.  The authors were aware of and listed many of the flaws of the study.

Weaknesses:  there were several weaknesses in the study.  One is the study design.  This was a retrospective cohort study, which is not a very strong study design due to the lack of control of the different variables.  Another was the occurrence of non-statistically significant results that could be due to Type II error, especially since power was not stated in the study.  The strains of MRSA evaluated were not assessed for the presence of vancomycin-resistant strains, and this could have skewed the results. 

Conclusion:  No direct conclusion can be made from this study, due to the study’s limitations.  However, the question does emerge about the empiric treatment of bacteremia or pneumonia due to MRSA.  A more appropriately designed study should investigate this question to determine the full effect of aggressive vancomycin therapy in these infections. 

Kimberly Bowsher, Pharm.D. Candidate, 2007

Hidayat LK, Hsu DI, Quist R, et al. High-Dose Vancomycin therapy for Methicillin-Resistant Staphylococcus aureus Infections. Arch Intern Med. 2006;166:2138-2144.