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FDA Rationale for Recognition Decision: Ceftaroline fosamil

FDA has reevaluated the rationale document titled, “Ceftaroline Breakpoints for Staphylococcus aureus,” submitted by the Clinical and Laboratory Standards Institute (CLSI) to FDA public docket # FDA-2017-N-5925-020 in November 2019. The initial review was completed by FDA in April 2020. At that time FDA did not recognize the ceftaroline breakpoints against S. aureus set by CLSI.1

The CLSI ceftaroline breakpoints for S. aureus 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 defined an SDD STIC category.

Ceftaroline, the active metabolite of the prodrug ceftaroline fosamil, is a cephalosporin with activity against methicillin-resistant S. aureus (MRSA). Ceftaroline is approved for the treatment of acute bacterial skin and skin structure infections and community-acquired bacterial pneumonia. The approved dosage in adults with creatinine clearance > 50 mL/min is 600 mg administered every 12 hours over a 5- to 60-minute intravenous (IV) infusion.

The current FDA and CLSI breakpoints for ceftaroline against S. aureus are presented below (the ceftaroline breakpoints for other bacteria are not included).

Current FDA and CLSI Ceftaroline Breakpoints for S. aureus including MRSA

 

Minimum Inhibitory Concentrations
(mcg/mL)

Disk Diffusion
(zone diameter in mm)

Sa

 SDDb

I

R

S

SDD

I

R

FDA

≤ 1

-

2

≥ 4

≥ 24

-

21 - 23

≤ 20

CLSI

≤ 1

2 – 4

-

≥ 8

≥ 25

20 - 24

-

≤ 19

Abbreviations: I, Intermediate; R, resistant; S, susceptible; SDD, susceptible-dose dependent; MRSA, methicillin-resistant S. aureus
a. The S breakpoint is based on a dosage regimen of 600 mg every 12 hours.
b. The SDD breakpoint is based on a dosage regimen of 600 mg every 8 hours over 2 hours.

FDA reviewed available safety data on ceftaroline 600 mg every 8-hour dosing and has not identified a safety concern. While clinical data on the efficacy of ceftaroline against S. aureus isolates with MIC in the SDD range are limited given the rarity of such isolates, pharmacodynamic/pharmacokinetic analyses based on ceftaroline dosing of 600 mg every 8 hours as a 2-hour infusion yield >90% probability of target attainment at MICs up to 4 µg/mL. FDA concludes that the data are aligned with the SDD definition and recognizes the M100 standard for ceftaroline breakpoints against S. aureus including MRSA.


1 FDA Rationale for Recognition Decision: Ceftaroline fosamil. https://www.fda.gov/drugs/development-resources/fda-rationale-recognition-decision-ceftaroline-fosamil

 
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