FDA has completed its review of the rationale document titled, “Aminoglycoside Breakpoints for Enterobacterales and Pseudomonas aeruginosa” submitted by the Clinical and Laboratory Standards Institute (CLSI) to the public docket FDA-2017-N-5925-0037 in January 2025.¹ 

Gentamicin, tobramycin, and amikacin are aminoglycoside antibacterial drugs approved for the treatment of serious infections including those caused by P. aeruginosa and several Enterobacterales species.  In March 2023, the Clinical and Laboratory Standards Institute (CLSI) published revised breakpoints for gentamicin, tobramycin, and amikacin against Enterobacterales and P. aeruginosa in their M100-Ed 33 supplement.

For Enterobacterales CLSI lowered the gentamicin, tobramycin, and amikacin breakpoints (Table 1). For P. aeruginosa, CLSI removed the gentamicin breakpoints, lowered the tobramycin breakpoints, and left the amikacin breakpoints numerically unchanged but limited their applicability to urinary isolates only (Table 2). 

Table 1. Historical^a and Current^b CLSI Gentamicin, Tobramycin, and Amikacin Breakpoints against Enterobacterales

_{S = Susceptible; I = Intermediate; R = Resistant; MIC = minimum inhibitory concentration
^, designation for agents that have the potential to concentrate in the urine
^a These breakpoints have been recognized by FDA.  
^b First published in CLSI M100-Ed33, March 2023.}  

Table 2. Historical^a and Current^b CLSI Gentamicin, Tobramycin, and Amikacin Breakpoints against Pseudomonas aeruginosa  

_{S = Susceptible; I = Intermediate; R = Resistant; MIC = minimum inhibitory concentration
^, designation for agents that have the potential to concentrate in the urine
^a These breakpoints have been recognized by FDA.  
^b First published in CLSI M100-Ed33, March 2023.
^c (U) for reporting on urinary isolates only} 

The dosing regimens that were used to establish the CLSI breakpoints include 7 mg/kg intravenously (IV) every 24 hours for gentamicin and tobramycin, and 15 mg/kg IV every 24 hours for amikacin.

To minimize dissection of the wild-type bacterial population and preserve reproducibility of susceptibility testing, CLSI used the net bacterial stasis endpoint in the probability of target attainment (PTA) analyses because 1-log colony-forming unit (CFU) reduction was not attainable for MICs representing the high end of the wild-type population, i.e., the epidemiological cutoff MIC.  Moreover, for P. aeruginosa and gentamicin and amikacin, even the net stasis endpoint was not attainable for a large segment of the wild population. Consequently, CLSI eliminated the gentamicin breakpoints against P. aeruginosa. Amikacin breakpoints for P. aeruginosa were retained but limited to urinary isolates only on the basis that amikacin concentrates in the urine and that clinical efficacy data demonstrate that favorable outcomes are most reliable for infections originating in the urinary tract.

FDA acknowledges the limitations of the data but agrees that the revised breakpoints would be more predictive of clinical outcomes as compared to the currently recognized FDA breakpoints, and therefore, recognizes the CLSI gentamicin, tobramycin, and amikacin breakpoints for Enterobacterales and P. aeruginosa as displayed above.  

---

¹ Comment from Clinical and Laboratory Standards Institute (CLSI)