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FDA Rationale for Recognition Decision: Meropenem

Currently, there are no FDA-recognized susceptibility test interpretive criteria (breakpoints) for meropenem for Acinetobacter spp. The Clinical and Laboratory Standards Institute (CLSI) submitted a comment to the open public docket, requesting recognition of meropenem breakpoints for Acinetobacter spp. (see: https://www.regulations.gov/document?D=FDA-2017-N-5925-0018). FDA has completed their review of the CLSI comment to the docket and provides additional information below regarding recognition of these breakpoints.

FDA has determined, based on the available clinical, microbiology and pharmacokinetic information, that a meropenem dosing regimen of 1 gram every 8 hours infused over 60 minutes supports the following interpretive criteria for meropenem against Acinetobacter spp.:

  • ≤2 mcg/mL (susceptible)
  • 4 mcg/mL (intermediate)
  • ≥8 mcg/mL (resistant)

Two recent publications with clinical outcome data suggest the following breakpoints for meropenem against Acinetobacter species in patients with bacteremia: ≤4 mcg/mL (susceptible) and ≥8 mcg/mL (resistant) 1,2. Despite their limitations [e.g., retrospective cohort studies from a single country spanning a period from 2005 to 2015 during which time the resistance profile of Acinetobacter spp. may have changed, data were not limited to treatment with meropenem (i.e., approximately half of the patients received imipenem instead of meropenem), some patients were included in both studies, high MIC could be a marker for other factors that can impact the outcome such as comorbidities and potentially exposure to healthcare facilities, etc.], both studies provide some data which may help correlate the carbapenem breakpoints with clinical outcomes in patients with Acinetobacter spp. bacteremia.

The pharmacokinetic/pharmacodynamic data from the literature support the following breakpoints against Acinetobacter spp. using a meropenem dose of 1 gram every 8 hours by 30-min infusion: ≤1 mcg/mL (susceptible), 2 mcg/mL (intermediate), and ≥4 mcg/mL (resistant) and higher breakpoints by using a higher dose and/or longer infusion time of meropenem. The maximum labeled adult dose of meropenem for approved indications is 1 gram every 8 hours infused over 15 to 30 minutes. For bacterial meningitis (pediatric patients 3 months of age and older only), 2 grams every 8 hours infused over 15 to 30 minutes is recommended. From a safety standpoint, the 60-minute infusion is unlikely to be associated with a safety profile that is different from that of the labeled infusion time of 30 minutes and so it was considered acceptable to use the 60-minute infusion time to support the interpretive criteria.

The disk diffusion criteria of ≥18 mm (susceptible), 15-17 mm (intermediate), and ≤14 mm (resistant) are also recognized.

1 Yang YS, Wang YC, Kuo SC, et al. Multicenter Study of the Relationship between Carbapenem MIC Values and Clinical Outcome of Patients with Acinetobacter Bacteremia. Antimicrob Agents Chemother. 2017;61(9)
2 Lee YT, Chiang MC, Kuo SC, et al. Carbapenem Breakpoints for Acinetobacter baumannii Group: Supporting Clinical Outcome Data from Patients with Bacteremia. PLoS One. 2016;11(9)