Evaluation of Daptomycin Exposure and Efficacy and Safety Endpoints To Support Risk-versus-Benefit Considerations

Abstract

bThe choice of an antimicrobial agent must balance optimization of efficacy endpoints with the minimization of safety events. The risk versus benefit of daptomycin for patients with Staphylococcus aureus bacteremia with or without infective endocarditis receiving daptomycin at 6, 8, and 10 mg/kg of body weight/day was assessed. The relationships between the area under the concentration-time curve over 24 h (AUC)/MIC ratio and both clinical response and time to decreased susceptibility were evaluated using data from patients with such infections who received daptomycin at 6 mg/kg/day. Using these relationships, plus the previously identified relationship between the minimum concentration and an elevation in the creatine phosphokinase (CPK) concentration (CPK elevation) (S. M. Bhavnani, C. M. Rubino, P. G. Ambrose, and G. L. Drusano, Clin Infect Dis 50:1568 -1574, 2010) and Monte Carlo simulation, the probability of each outcome by MIC for daptomycin at 6, 8, and 10 mg/kg/day was calculated. The function for exposure-response relationships for clinical response (P ‫؍‬ 0.06) and time to decreased susceptibility (P ‫؍‬ 0.01) resembled U and inverted U shapes, respectively. Multivariable analyses demonstrated AUC/MIC ratio, creatinine clearance, albumin concentration, and disease category to be predictors of clinical response. The results of simulations failed to demonstrate large improvements in the probabilities of clinical success among cohorts of simulated patients defined by the abovedescribed predictive factors or the probability of decreased susceptibility at 30 days when the daptomycin dose was increased from 6 to 10 mg/kg/day. The probability of CPK elevation increased from 0.073 to 0.156 over this dose range. These data can be used to inform risk-versus-benefit decisions for daptomycin dose selection in patients with S. aureus bacteremia with or without infective endocarditis. The risk of CPK elevation, which is reversible, should be weighed in the context of the mortality and severe morbidity associated with these types of serious staphylococcal infections.A s with all drugs, the choice of antimicrobial agent must balance efficacy with safety. Safety considerations may have an impact upon the choice of dosing regimen and the duration of therapy. This is the case with aminoglycoside antimicrobial agents, for which clinicians must explicitly balance the need for efficacy against the risk of nephrotoxicity (1). On the other hand, some drug toxicities are of less concern relative to the risk of clinical failure in patients with serious and life-threatening infections. Thus, there is more flexibility with the use of higher doses and longer treatment durations. For daptomycin-treated patients with Staphylococcus aureus infective endocarditis, the need for efficacy may supersede the concern regarding an elevation in the creatine phosphokinase (CPK) concentration (referred to here as CPK elevation), a sensitive biochemical signal of potential muscle toxicity which has been observed during daptomycin therapy but wh...

Daptomycin for Complicated Skin Infections: A Randomized Trial

“…In adults, daptomycin has the potential to cause CPK elevations, in particular at the higher doses used to treat bacteremia. 25 In our study, increased CPK was not more frequent in daptomycin-than in SOC-treated children, suggesting there is no need TESAE, treatment-emergent serious AE. a TEAE that occurred from the time of the fi rst dose of the study drug through the last study evaluation or preexisting AEs that were aggravated in severity or frequency during the dosing period.…”

Relationship between Fosfomycin Exposure and Amplification of Escherichia coli Subpopulations with Reduced Susceptibility in a Hollow-Fiber Infection Model

“…Indeed, this phenomenon has also been observed using data from daptomycin-treated patients with Staphylococcus aureus bacteremia with or without infective endocarditis. At 30 days after the start of therapy, the relationship between the probability of decreased susceptibility and AUC/MIC ratio resembled an inverted-U shape (19). The strength of the in vitro hollow-fiber infection model is that drug exposures beyond those that can be attained clinically can be examined.…”

Association of Higher Daptomycin Dose (7 mg/kg or Greater) with Improved Survival in Patients with Methicillin‐Resistant Staphylococcus aureus Bacteremia

“…38 Using these data, Monte Carlo simulations suggested improved clinical success (clinical cure or partial improvement in clinical signs and symptoms not requiring further treatment) with increased daptomycin exposure among certain patient populations stratified by outcome probability of response. 38 In our study, we observed survival benefits with increased daptomycin exposure, which builds on the results of the simulation study 38 because our CART analysis identified clinical benefit with higher doses than the label daptomycin dose regimens among patients with worse survival probabilities. Two studies have suggested that a fixed daptomycin dose may be an alternative to a milligram/kilogram dose.…”

“…Before the present study, the most relevant work in determining the impact of higher daptomycin dose on clinical outcomes in patients with MRSA BSI was from simulation modeling performed using data from a randomized noninferiority study comparing daptomycin with the standard of care for right‐sided infective endocarditis . In the multivariable analysis of the simulation study, 24‐hour area under the concentration‐time curve to minimum inhibitory concentration (MIC) ratio, Cl cr clearance, albumin level, and disease category (left‐sided endocarditis, right‐sided endocarditis or complicated bacteremia, or uncomplicated bacteremia) were found to be predictors of clinical response . Using these data, Monte Carlo simulations suggested improved clinical success (clinical cure or partial improvement in clinical signs and symptoms not requiring further treatment) with increased daptomycin exposure among certain patient populations stratified by outcome probability of response .…”