FDA has reevaluated data supporting amoxicillin/clavulanate breakpoints against Haemophilus influenzae. The review included a publication describing the Clinical and Laboratory Standards Institute (CLSI) rationale for revision of the amoxicillin/clavulanate breakpoints for H. influenzae.1
Amoxicillin/clavulanate is approved in several oral formulations. Approved indications where H. influenzae infections are relevant include lower respiratory tract infections, acute bacterial otitis media, and sinusitis. CLSI revised the amoxicillin/clavulanate breakpoints for H. influenzae in 2022. The table below presents the current CLSI and FDA breakpoints.
Current CLSI and FDA Amoxicillin and Clavulanate Breakpoints for H. influenzae
Minimum Inhibitory Concentration (mcg/mL) |
Disk Diffusion (zone diameter in mm |
|||||
|---|---|---|---|---|---|---|
S |
I |
R |
S |
I |
R |
|
CLSI a |
≤ 2/1 |
4/2 |
≥ 8/4 |
- |
- |
- |
FDA b |
≤ 4/2 |
- |
≥ 8/4 |
≥ 20 |
- |
≤ 19 |
a.First published in the 32nd edition of CLSI supplement M100; 2022. Breakpoints are based on a dosing regimen of amoxicillin/clavulanate of 875/125 mg PO every 12 hours or 500/125 mg PO every 8 hours. Additional disk correlate data are pending before disk diffusion breakpoints with these dosing regimens can be established.
b.FDA breakpoints correspond to the CLSI breakpoints prior to the 2022 revision.
Minimum inhibitory concentration (MIC) distribution data included the MIC mode, range, and estimated epidemiological cutoff value (ECV) of 0.5/0.25 mcg/mL, 0.06/0.03–16/8 mcg/mL, and 2/1 mcg/mL, respectively. Clinical data for H. influenzae infections were limited, and included studies in community-acquired pneumonia and sinusitis with no resistant isolates and no outcomes reported by ampicillin/clavulanate MIC.
The FDA review team was not able to identify a specific pharmacokinetic-pharmacodynamic (PK-PD) target for amoxicillin/clavulanate against H. influenzae. This was consistent with the findings from the publication by Narayanan et al.2 The PK data suggest MIC ≥ 4/2 mcg/mL are not reliably achievable with amoxicillin/clavulanate dosing regimens of 875/125 mg PO every 12 hours or 500/125 mg PO every 8 hours, supporting lowering the susceptible breakpoint. Overall, CLSI concluded that lowering the MIC susceptible breakpoint from ≤ 4/2 mcg/mL to ≤ 2/1 mcg/mL was compatible with the totality of data including the wild-type MIC distribution/ECV, PK/PD target attainment, and available clinical data. Adding an intermediate MIC category of 4/2 mcg/mL provides a buffer zone for expected technical variability of antimicrobial susceptibility testing.
In conclusion, FDA agrees with the CLSI rationale and recognizes the amoxicillin/clavulanate MIC susceptible, intermediate, and resistant breakpoints against H. influenzae of ≤ 2/1 mcg/mL, 4/2 mcg/mL, and ≥ 8/4 mcg/mL, respectively. Additional disk correlate data are needed to establish disk diffusion breakpoints.
