Vancomycin 24-Hour Area under the Curve/Minimum Bactericidal Concentration Ratio as a Novel Predictor of Mortality in Methicillin-Resistant Staphylococcus aureus Bacteremia

Abstract

T he incidence of methicillin-resistant Staphylococcus aureus (MRSA) infections in health care and community settings has increased in recent years (1). Vancomycin (VAN) has been a mainstay in the armamentarium against MRSA for nearly half a century, but changes in susceptibility patterns have presented new treatment challenges (2). The gradual reduction in susceptibility of MRSA isolates to VAN occurring over the last 2 decades has been associated with increased treatment failure and mortality (3, 4). While the relationship between VAN MIC and clinical outcomes in MRSA bacteremia (MRSA-B) is well established, the importance of VAN minimum bactericidal concentration (MBC) is less clear (5).Multiple studies have highlighted the importance of bactericidal therapy in treating S. aureus bacteremia (SAB). Previous research has demonstrated that in vitro 24-h bactericidal activity by VAN is associated with a decrease in the duration of MRSA-B clinically compared to in vitro bacteriostatic activity (6). Additionally, decreased in vitro VAN killing activity over 72 h also has been associated with an increase in 30-day mortality in patients with MRSA-B treated with VAN (7). Sakoulas et al. reported an association between elevated VAN MIC and treatment failure but also noted that reduced bactericidal activity had a similar effect (8).Lastly, multiple studies have demonstrated improved clinical outcomes with ␤-lactam therapy compared to those with VAN for methicillin-susceptible SAB, which may be partially attributed to the superior killing activity of ␤-lactams compared to that of VAN (9,10). Thus, there is evidence to suggest that VAN bactericidal activity plays an influential role in clinical outcomes of SAB, including MRSA-B.Consensus recommendations support a VAN area under the curve (AUC)/MIC ratio of Ն400 as a pharmacodynamic predictor of therapeutic effectiveness for MRSA infections (11). An AUC/ MIC ratio of Ն421 also has been associated with clinical success in MRSA-B (12). Due to the trend toward improved outcomes with increased bactericidal activity of VAN, we hypothesized that VAN exposure as a function of MBC rather than MIC may be a more important predictor of VAN effectiveness in the treatment of MRSA-B. Therefore, the objectives of this study were to (i) evaluate the association between pharmacodynamic parameters (VAN AUC 24 /MIC ratio determined by broth microdilution [MIC BMD ], VAN AUC 24 /MIC ratio determined by Etest [MIC Etest ], and VAN AUC 24 /MBC ratio) and 30-day mortality and (ii) quantify the VAN AUC 24 /MBC threshold associated with an increased probability of mortality in a cohort of hospitalized patients with MRSA-B.

Revising Pediatric Vancomycin Dosing Accounting for Nephrotoxicity in a Pharmacokinetic-Pharmacodynamic Model

“…Neither vancomycin trough concentrations nor AUC correlated with treatment failure in this pediatric patient population with a variety of bloodstream infections (Table 4 and Fig. S3), although several studies in adults with methicillin-resistant Staphylococcus aureus bloodstream infections concluded that the PKPD endpoint of an AUC/MIC value of Ն400 mg•h/liter was clinically relevant (16)(17)(18). A plausible explanation for this discrepancy is the large number of coagulase-negative Staphylococcus infections ( Table 3).…”

“…Coagulase-negative Staphylococcus infections are likely the result of line infections (25) or contamination and cause limited morbidity. For the remaining 22 Gram-positive bloodstream infections, there was insufficient statistical power to refute AUC target attainment of Ն400 mg•h/liter (16)(17)(18). The fact that only 22 of 785 patients had confirmed Gram-positive isolates on blood culture highlights the lack of infections at the study center, possibly due to good infection control procedures, and shows how difficult running prospective pediatric antimicrobial clinical trials is when so few patients have identifiable infections.…”

“…Current pediatric initial vancomycin dosing regimens, 15 mg/kg of body weight every 8 h (q8h) for children 0 to 1 month, 10 to 15 mg/kg q6h for children 1 month to 11 years, and 15 to 20 mg/kg q8h to q12h for children 12 years and above (1), were revisited using the developed population pharmacokinetic model and 2,000 stochastic simulations. As the efficacy analysis in this study did not yield target levels in the pediatric patient population, a vancomycin AUC target attainment of Ն400 was adopted from an adult (16)(17)(18). Most patients achieved target attainment when the current standard dosing regimens were stratified by bodyweight, although a clear positive correlation with increased plasma creatinine was apparent; hence, patients in the lower creatinine band displayed a lower vancomycin AUC (Fig.…”

“…The vancomycin AUC/MIC value was found to be more predictive of efficacy than time above MIC with methicillin-resistant Staphylococcus aureus sepsis or with methicillinresistant Staphylococcus aureus infection of the lower respiratory tract (16,17). Adult patients with a target AUC/MIC value of Ն400 mg•h/liter appeared to have a lower risk of treatment failure (16)(17)(18), and as free antibiotic concentrations drive the antibacterial effects, AUC free /MIC of Ն200 mg•h/liter has consequently been reported as the target efficacy threshold (14).…”

The Impact of Pediatric-Specific Vancomycin Dosing Guidelines: A Quality Improvement Initiative

“…13 There is poor correlation between vancomycin trough levels and clinical outcomes in the therapy of S. aureus infections. 14 The AUC/MIC pharmacodynamic index is best predictive of vancomycin efficacy, [15][16][17] and trough e8…”