Antimicrobial Susceptibility Breakpoints for Gentamicin and Cefepime
Current CLSI Breakpoints for Enterobacterales
For Enterobacterales, the CLSI 2023 breakpoints for gentamicin are ≤2 mg/L (susceptible), 4 mg/L (intermediate), and ≥8 mg/L (resistant), representing a significant reduction from the previous ≤4/≥16 mg/L criteria. 1
Gentamicin Breakpoints
- Susceptible: ≤2 mg/L
- Intermediate: 4 mg/L
- Resistant: ≥8 mg/L 1
The CLSI lowered these breakpoints in 2023 from the previous criteria of ≤4 mg/L (susceptible) and ≥16 mg/L (resistant) to align with pharmacokinetic/pharmacodynamic parameters used for other antimicrobials. 1
Cefepime Breakpoints for Enterobacterales
- Susceptible: ≤4 mg/L (zone diameter ≥15 mm)
- Intermediate: 8 mg/L (zone diameter 13-14 mm)
- Resistant: ≥16 mg/L (zone diameter ≤12 mm) 2
These newer cefepime breakpoints may fail to identify many ESBL-producing Enterobacteriaceae, as some ESBL-producing isolates remain susceptible to cefepime under the current criteria. 3, 4
Current CLSI Breakpoints for Pseudomonas aeruginosa
Gentamicin Breakpoints
- Susceptible: ≤4 mg/L (zone diameter ≥15 mm)
- Intermediate: 8 mg/L (zone diameter 13-14 mm)
- Resistant: ≥16 mg/L (zone diameter ≤12 mm) 2
Note that Pseudomonas aeruginosa retained the older breakpoint criteria for gentamicin (≤4/≥16 mg/L), unlike Enterobacterales which had more stringent criteria applied. 2
Cefepime Breakpoints for Pseudomonas aeruginosa
- Susceptible: ≤4 mg/L (zone diameter ≥15 mm)
- Intermediate: 8 mg/L (zone diameter 13-14 mm)
- Resistant: ≥16 mg/L (zone diameter ≤12 mm) 2
For Pseudomonas aeruginosa infections, achieving cefepime exposures of >60% fT>MIC (percentage of time the free drug concentration remains above the MIC) is critical to minimize microbiological failure, which typically requires doses of at least 2 g every 8 hours in patients with normal renal function. 5
Clinical Impact of Breakpoint Changes
Effect on Enterobacterales Susceptibility Reporting
The 2023 CLSI breakpoint changes for gentamicin drastically reduced susceptibility rates for multidrug-resistant Enterobacterales from 94.0% to 71.0%, for ESBL-producing isolates from 96.9% to 79.7%, and for carbapenem-resistant Enterobacterales from 75.2% to 59.0%. 1
For cefepime, the resistance rate in Escherichia coli increased from 2.1% to 8.2% and in Enterobacter cloacae from 1.3% to 6.9% when comparing older CLSI criteria to EUCAST 2011 guidelines. 6
Effect on Pseudomonas aeruginosa Susceptibility Reporting
- Cefepime resistance rates in P. aeruginosa increased from 12.2% to 19.8% when comparing CLSI 2009-2011 with EUCAST 2011 guidelines. 6
Important Clinical Caveats
ESBL-Producing Organisms
ESBL-producing bacteria demonstrate resistance to all cephalosporins, including cefepime, despite some isolates appearing susceptible by current breakpoints. 7
Carbapenems remain the treatment of choice for serious ESBL infections, as ESBL enzymes hydrolyze all cephalosporins including cefepime. 7
Routine ESBL confirmatory testing is no longer required before reporting results under newer interpretive criteria, but remains valuable for epidemiological surveillance and infection control. 7
Aminoglycoside Limitations
For Salmonella and Shigella species, aminoglycosides including gentamicin may appear active in vitro but are not effective clinically, and results should not be reported as susceptible. 2
For staphylococci that test susceptible to gentamicin, aminoglycosides are used only in combination with other active agents, not as monotherapy. 2
Co-resistance to aminoglycosides is frequently observed in ESBL-producing organisms. 7