FDA Rationale for Recognition Decision: Daptomycin (original) (raw)

As of August 24, 2020, the FDA-revised breakpoints (BPs), also referred to as susceptibility test interpretive criteria (STIC) for daptomycin for Enterococcus faecalis (including vancomycin-susceptible and vancomycin-resistant isolates) based on a dosing regimen of 4 mg/kg administered intravenously every 24 hours (q24h) are as follows:

• ≤2 mcg/mL (susceptible, “S”)
• 4 mcg/mL (intermediate, “I”)
• ≥8 mcg/mL (resistant, “R”)

In March 2019, the Clinical and Laboratory Standards Institute (CLSI) revised the BPs for daptomycin for enterococci based on two different dosing regimens (6 mg/kg q24h for Enterococcus spp. other than E. faecium; and 8-12 mg/kg q24h for E. faecium) published in the M100-S29 document. In this document, CLSI noted the following revisions in M100-S29:

• Revised the daptomycin BPs by having separate BPs for E. faecium and Enterococcus spp. (other than E. faecium).
• For E. faecium, the Susceptible-Dose-Dependent (SDD) and resistant BPs are ≤4 mcg/mL and ≥8 mcg/mL, respectively, based on a daptomycin dose of 8 to 12 mg/kg q24h. No susceptible or intermediate BPs are proposed for E. faecium.
• For Enterococcus spp. (other than E. faecium), the susceptible, intermediate and resistant BPs are ≤2 mcg/mL, 4 mcg/mL, and ≥8 mcg/mL, respectively, based on a dosing regimen of 6 mg/kg q24h.

FDA has completed its review of the CLSI-revised BPs and provides additional information below regarding these BPs. FDA reviewed the available clinical, microbiology and pharmacokinetic information and determined that the daptomycin BPs should be revised only for E. faecalis (including vancomycin-susceptible and vancomycin-resistant isolates). This is based on the following:

• FDA agrees with the revision of BPs for Enterococcus faecalis, but does not agree that they be based on a daptomycin dosing regimen of 6 mg/kg q24h. This dosing regimen has been approved for the treatment of S. aureus bacteremia only. Microbiological data, pharmacokinetic/pharmacodynamic data, and limited clinical outcome data support the revised BPs of ≤2 mcg/mL (susceptible), 4 mcg/mL (intermediate), and ≥8 mcg/mL (resistant) for E. faecalis only, based on the FDA-approved daptomycin dosing regimen of 4 mg/kg q24h for complicated skin and skin structure infections (cSSSI).
• The CLSI-revised SDD BP of ≤4 mcg/mL and resistant BP of ≥8 mcg/mL for E. faecium based on a dosing regimen of 8 to 12 mg/kg q24h are not recognized because this dosing regimen is not approved by FDA.