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. (, )

R5: We recommend that clinicians have access to parenteral products of both colistin methanesulfonate (CMS) and polymyxin B, so they can choose between the two in particular circumstances. (, )

R6: We recommend polymyxin B as the preferred agent for routine systemic use in invasive infections. The rationale for this recommendation is that polymyxin B has superior PK characteristics in humans as well as a decreased potential to cause nephrotoxicity. (, )

R7: We recommend colistin as the preferred polymyxin for the treatment of lower urinary tract infections given renal clearance of the prodrug CMS that then converts to the active moiety colistin in the urinary tract. (, )

R8: We recommend that hospital guidelines and prescription orders specify doses of CMS in either number of international units (IU) or milligrams of colistin base activity (CBA), corresponding to the labeling convention used in the specific country. Because of the international scope of these guidelines, doses in the following sections are expressed in the approximate equivalents of both of these conventions. The conversion factor is 1 million IU is equivalent to ~33 mg CBA. (, )

R9: We recommend initiating IV therapy with a CMS loading dose of 300 mg CBA (~9 million IU) infused over 0.5–1 hours and to administer the first maintenance dose 12–24 hours later. (, )

R10: We recommend that for a patient with normal renal function, administer a daily dose of 300–360 mg colistin base activity (CBA) (~9–10.9 million IU), divided into two and infused over 0.5–1 hour at 12-hour intervals. Monitor renal function and adjust the daily dose accordingly. (, )

R11: We recommend that CMS dose adjustments be made in patients with renal insufficiency. (, )

R12: We recommend that to target a plasma colistin C_ss,avg of 2 mg/L in a patient on intermittent hemodialysis (IHD), the following dosing schedule be utilized: On a nondialysis day, administer a CMS dose of 130 mg CBA/day (~3.95 million IU/day). On a dialysis day, administer a supplemental dose of CMS 40 mg CBA (~1.2 million IU) or 50 mg CBA (~1.6 million IU) for a 3- or 4-hour IHD session, respectively. If possible, the supplement to the baseline (nondialysis) daily dose should be administered with the next regular dose, after the dialysis session has ended. Conduct IHD sessions as late as possible within a CMS dosage interval to minimize the amount of CMS and formed colistin lost to the extracorporeal system. (, )

R13: We recommend that to target a plasma colistin C_ss,avg of 2 mg/L in patients prescribed sustained low-efficiency dialysis (SLED) that 10% of the CMS dose be added to the baseline daily dose per 1 hour of SLED. (, )

R14: We recommend that for patients prescribed continuous renal replacement therapy (CRRT), for a plasma colistin C_ss,avg of 2 mg/L, to administer CBA 440 mg/day (~13.3 million IU/day). This equates to 220 mg CBA every 12 hours (~6.65 million IU every 12 hours). (, )

R15: We recommend a loading dose of 2.0–2.5 mg/kg for polymyxin B, based on total body weight (TBW) (equivalent to 20,000–25,000 IU/kg) over 1 hour. (, )

R16: We recommend that for patients with severe infections, a polymyxin B dose of 1.25–1.5 mg/kg (equivalent to 12,500–15,000 IU/kg TBW) every 12 hours is infused over 1 hour. (, )

R17: We recommend that daily maintenance doses of polymyxin B should not be adjusted if the patient has renal impairment. (, )

R26: We recommend that cessation of therapy may be considered in patients who develop AKI if infection diagnosis is uncertain or when an alternative less nephrotoxic drug is available. (, )

R27: We recommend that for invasive infections due to CRE, polymyxin B or colistin be used in combination with one or more additional agents to which the pathogen displays a susceptible MIC. (Very Low, Strong)

R28: If a second active agent to which the infecting CRE displays a susceptible MIC is unavailable, we recommend that polymyxin B or colistin be used in combination with a second and/or third nonsusceptible agent (e.g., a carbapenem). Preference should be given to a nonsusceptible agent with the lowest MIC relative to the respective susceptibility breakpoint. (, )

R29: We recommend that for invasive infections due to CRAB, polymyxin B or colistin should be used in combination with one or more additional agents to which the pathogen displays a susceptible MIC. (, )

R30: If a second active agent to which the infecting CRAB displays a susceptible MIC is unavailable, we recommend that polymyxin B or colistin should be used alone as monotherapy. (Moderate, Weak)

R31: We recommend that for invasive infections due to CRPA, polymyxin B or colistin should be used in combination with one or more additional agents to which the pathogen displays a susceptible MIC. (, )

R33: We recommend that patients requiring IV polymyxin therapy for suspected or documented XDR gram-negative HAP or VAP should receive adjunctive polymyxin aerosol therapy. (Low, Weak)

R34: We recommend that for polymyxin aerosol therapy, either colistin or polymyxin B is appropriate. (Very Low, Weak)

R35: Intraventricular (IVT) or intrathecal (ITH) administration of polymyxins at a dosage of 125,000 IU CMS (~4.1 mg CBA) or 5 mg (50,000 IU) polymyxin B per day with concomitant IV polymyxin is recommended for ventriculitis or meningitis caused by MDR and XDR gram-negative pathogens. (, )

R36: Due to limited experience with polymyxin B, CMS is the preferred polymyxin for intraventricular or intrathecal administration. (, )