Impact of Dose De-Escalation and Escalation on Daptomycin's Pharmacodynamics against Clinical Methicillin-Resistant Staphylococcus aureus Isolates in anIn VitroModel

Abstract

ABSTRACTDe-escalation and escalation therapeutic strategies are commonly employed by clinicians on the basis of susceptibility results and patient response. Since noin vitroorin vivodata are currently available to support one strategy over the other for daptomycin, we attempted to evaluate the effects of dose escalation and de-escalation on daptomycin activity against methicillin-resistantStaphylococcus aureus(MRSA) isolates using anin vitropharmacokinetic/pharmacodynamic (PK/PD) model with simulated endocardial vegetations. Three clinical MRSA isolates, including one heterogeneous vancomycin-intermediateS. aureus(hVISA) isolate and one vancomycin-intermediateS. aureus(VISA) isolate, were exposed to daptomycin at 10 or 6 mg/kg of body weight/day for 8 days using a starting inoculum of ∼109CFU/g of vegetations, with dose escalation and de-escalation initiated on the fourth day. Daptomycin MIC values ranged from 0.5 to 1 μg/ml. In the PK/PD model, high-dose daptomycin (10 mg/kg/day) and de-escalation simulation (10 to 6 mg/kg/day) appeared to be the most efficient regimens against the three tested isolates, exhibiting the fastest bactericidal activity (4 to 8 h) compared to that of the standard regimen of 6 mg/kg/day and the escalation therapy of 6 to 10 mg/kg/day. The differences in the numbers of CFU/g observed between dose escalation and de-escalation were significant for the hVISA strain, with the de-escalation simulation exhibiting a better killing effect than the escalation simulation (P< 0.024). Although our results need to be carefully considered, the use of high-dose daptomycin up front demonstrated the most efficient activity against the tested isolates. Different therapeutic scenarios including isolates with higher MICs and prolonged drug exposures are warranted to better understand the outcomes of escalation and de-escalation strategies.