Optimal Use of the Polymyxins

R1: The joint European Committee on Antimicrobial Susceptibility Testing (EUCAST) and Clinical and Laboratory Standards Institute (CLSI) polymyxin breakpoint working group recommended that standard broth microdilution ISO-74 20776 be used as the reference method for the MIC testing of colistin and be performed with cation-adjusted Mueller Hinton broth, with sulfate salts of colistin in plain polystyrene trays without additives such as polysorbate-80. Sulphate salts of polymyxins must be used (the methanesulfonate derivative of colistin must not be used - it is an inactive pro-drug that breaks down slowly in solution). Agar dilution, disk diffusion, and gradient diffusion are not currently recommended by CLSI-EUCAST as these methods yield unacceptably high error rates compared to broth microdilution. We recommend that the CLSI/EUCAST Joint Working Group clinical breakpoints be used for colistin. (, )

R2: We recommend that for colistin, an area under the plasma concentration-time curve across 24 hours at steady state (AUC_ss,_{24 hr}) of ~50 mg·hour/L is required that equates to a target average steady-state plasma concentration (C_ss,avg) of ~2 mg/L for total drug. Although this target might be suboptimal for lower respiratory tract infections, it is noted that this should be considered as a maximum tolerable exposure. Concentrations higher than this were shown to increase both the incidence and severity of AKI. (, )

R3: We recommend similar targets for polymyxin B as those listed for colistin. However, we note that data are lacking for AUC_ss,_{24 hr} targets for polymyxin B. Emerging evidence suggest a different toxicodynamic (TD) profile for polymyxin B than colistin. Some evidence indicates that an AUC_{ss,24 hr} target of 50–100 mg · hour/L, corresponding to a C_ss,avg of 2–4 mg/L, may be acceptable from a toxicity standpoint. (, )

R4: We recommend that the exposures just described for polymyxin B and colistin should be considered the maximal tolerable exposures. Although these recommended exposures should achieve bacterial killing at the current MIC breakpoints based on the mouse thigh infection model, both colistin and polymyxin B when administered systemically (i.e., not directly into the lungs) were shown in the mouse lung infection model to be substantially less effective. (, )