FDA Rationale for Recognition Decision: Daptomycin

FDA has reevaluated the rationale document titled, “Daptomycin Breakpoints for Enterococci,” submitted by the Clinical and Laboratory Standards Institute (CLSI) to FDA public docket # FDA-2017-N-5925-020 in September 2019. The initial review was completed by FDA in August 2020. At that time FDA recognized the daptomycin breakpoints for Enterococcus faecalis but did not recognize breakpoints for E. faecium¹.

The CLSI daptomycin breakpoints for E. faecium include a susceptible-dose dependent (SDD) breakpoint. At the time of the initial review, an SDD susceptibility test interpretive criteria (STIC) category was not adopted by FDA. Subsequently, FDA has defined an SDD STIC category.

Daptomycin is an antibacterial drug approved in 2003 for the treatment of complicated skin and skin structure infections (cSSSI) including those caused by Enterococcus faecalis (vancomycin-susceptible isolates only). In 2006 the indication for the treatment of Staphylococcus aureus bloodstream infections including right-sided infective endocarditis was added. The adult dosing regimen for cSSSI is 4 mg/kg every 24 hours and for S. aureus bloodstream infections is 6 mg/kg every 24 hours. Due to limited treatment options, daptomycin has been used off-label for the treatment of E. faecium bacteremia. FDA recognizes that daptomycin is one of a few treatment options for serious E. faecium infections, and that susceptibility test interpretive criteria are important in informing the selection of antimicrobial drugs.

The current and historical FDA and CLSI breakpoints for enterococci are presented in Table 1. No disk diffusion breakpoints for daptomycin against enterococci have been established because susceptibility testing of daptomycin requires the presence of fixed concentrations of divalent calcium ions that cannot be controlled in Mueller-Hinton agar and disk diffusion testing is not possible at present.²

Table 1. Current and Historical CLSI and FDA Daptomycin Breakpoints for Enterococci

		Minimum Inhibitory Concentrations (mcg/mL)
		S	SDD^a	I	R
Current CLSI breakpoints, (published in M100, 29 ed. in March 2019)	E. faecium only	-	≤4	-	≥8
	Enterococcus spp. other than E. faecium	≤2	-	4	≥8
Current FDA breakpoints (published in Sep 2020)	E. faecalis (including vancomycin-resistant isolates)	≤2	-	4	≥8

S= susceptible; SDD=susceptible-dose dependent; I=intermediate; R=resistant
^a. The SDD breakpoint is based on the dose of 8–12 mg/kg IV every 24 hours.

FDA has reviewed microbiological, pharmacokinetic/pharmacodynamic (PK/PD) data, and clinical data concerning daptomycin and E. faecium. Microbiological data indicate that a susceptible breakpoint should not be set lower than 4 mcg/mL to avoid splitting the wild-type population of E. faecium. Available PK-PD data supporting the breakpoints are limited. At MIC of 4 mcg/mL the probability of target attainment (PTA) that would support a susceptible breakpoint was achieved only in the murine target using the dosage of 10-12 mg/kg/day. However, the model has notable limitations. Clinical PK-PD data indicates that even the highest simulated dosage of 12 mg/kg/day resulted in PTA around 83%. However, clinical PK-PD data are also limited as estimated daptomycin exposures in clinical studies relied not on measured daptomycin plasma concentrations but on PK modeling. Despite limitations related to retrospective or non-randomized design of clinical studies, the data suggest a dose-dependent clinical response indicating that daptomycin doses of > 6 mg/kg are needed to optimize clinical outcomes, including decrease in mortality, in E. faecium infections. Given variable reproducibility of E. faecium MICs in the 1–4 mcg/mL range, the fact that the MIC of 4 mcg/mL represents the epidemiological cutoff for daptomycin and E. faecium, and a relative rarity of clinical isolates with MICs of ≥ 8 mcg/mL, analyses of clinical outcomes by MIC are less informative. FDA reviewed available safety data for daptomycin doses > 6 mg/kg and has not identified a safety concern. FDA concludes that the data are aligned with the SDD definition and recognizes the M100 standard for daptomycin and E. faecium.

In the interest of harmonization, FDA extends the previous recognition for daptomycin and E. faecalis (including vancomycin-resistant isolates) to Enterococcus spp. other than E. faecium.

¹ https://www.fda.gov/drugs/development-resources/fda-rationale-recognition-decision-daptomycin
² Turnidge J. et al. Daptomycin in the treatment of enterococcal bloodstream infections and endocarditis: a EUCAST position paper. Clin Microbiol Infect, 2020. 26(8): p. 1039-1043.