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

Abstract

High prevalence of clinical MRSA strains with elevated vancomycin MIC (2 microg/mL) requires aggressive empirical vancomycin dosing to achieve a trough greater than 15 microg/mL. Combination or alternative therapy should be considered for invasive infections caused by these strains.

Elevated vancomycin trough is not associated with nephrotoxicity among inpatient veterans

“…The data on nephrotoxicity at these higher troughs are limited. Previous studies that address the relationship between higher vancomycin troughs and nephrotoxicity suffer from small sample size 29,33 ; do not address reversibility of nephrotoxicity 9,26,[29][30][31]33 ; may not account for the temporal relationship between the development of nephrotoxicity and high trough levels, 9,28-31 or examine patient populations at relatively high 27 or low 30 risk for renal injury apart from receipt of vancomycin. A recent expert consensus statement identified these factors as limiting the strength of evidence for a direct causal relationship between elevated vancomycin troughs and nephrotoxicity.…”

“…We initially decided to use maximum vancomycin trough !15 mg/L as the vancomycin exposure variable of interest to include in multivariable models, as we felt that (1) trough !15 mg/L is clinically relevant given current guidelines that recommend aiming for trough !15 mg/L for treatment of most invasive staphylococcal disease, 31 and (2) prior studies identified a single trough !15 mg/L as a possible risk factor for nephrotoxicity. 9,27,29,31 However, we also generated other multivariable models that included either maximum vancomycin trough !20 mg/L, mean vancomycin trough !15 mg/L, or mean vancomycin trough !20 mg/L, and models in which maximum and mean vancomycin troughs were treated as continuous variables. All variables were initially included in multivariable models; nonsignificant variables were removed from the models in a backwards stepwise fashion until likelihood ratio testing determined that removal of any variable was associated with likelihood ratio test P value <0.20 in comparing the full to reduced model.…”

“…7 Low vancomycin trough levels have been implicated in the emergence of hVISA, and several studies have demonstrated a higher rate of vancomycin treatment failure, longer duration of fever, and prolonged hospitalization with hVISA and strains with elevated MIC compared to vancomycin-susceptible MRSA. [8][9][10][11][12] Until recently, vancomycin was frequently dosed to target trough levels <10 mg/L. The above concerns, combined with pharmacodynamic data suggesting that maintaining a ratio of vancomycin area under the curve to minimum inhibitory concentration (AUC/ MIC) !400 may be associated with improved clinical outcome, 13 have prompted an expert consensus to recommend targeting higher vancomycin trough levels (typically 15-20 mg/L) for invasive MRSA infections and general avoidance of trough levels <10 mg/L.…”

“…In that study, patients who developed nephrotoxicity were more likely to receive other nephrotoxic agents, and troughs collected before or after nephrotoxicity onset were not distinguished. 9 This is an important distinction, as vancomycin is frequently continued with dose adjustment even after nephrotoxicity occurs, with the nephrotoxicity resulting in subsequent higher troughs. Jeffres et al demonstrated that maximum vancomycin trough !15 mg/L was associated with nephrotoxicity in patients with healthcare-associated MRSA pneumonia; this study was retrospective and focused on a particularly ill patient population.…”

Impact of administration of vancomycin or linezolid to critically ill patients with impaired renal function

“…In addition to tolerability and renal toxicity problems, a high treatment failure rate in severe infections has been reported for VAN, probably related to its poor tissue penetration in the lung, bone tissue, central nervous system (CNS), and inflammatory fluids (16)(17)(18)(19)(20). This requires use of higher doses, with the resultant increase in adverse events, one of the most significant of which is renal function impairment (21)(22)(23)(24)(25)(26). Despite these limitations, this glycopeptide continues to be widely used at Spanish ICUs.…”