International Consensus Guidelines for the Optimal Use of the Polymyxins have been released. These guidelines provide the first ever consensus recommendations for colistin and polymyxin B therapy that is intended to guide optimal clinical use. They have been endorsed by American College of Clinical Pharmacy (ACCP), Infectious Diseases Society of America (IDSA), International Society of Anti‐Infective Pharmacology (ISAP), Society for Critical Care Medicine (SCCM), and Society of Infectious Diseases Pharmacists (SIDP). The international expert panel has made therapeutic recommendations regarding the pharmacokinetic and pharmacodynamic properties of the drugs and pharmacokinetic targets, polymyxin agent selection, dosing, dosage adjustment and monitoring of colistin and polymyxin B, use of polymyxin‐based combination therapy, intrathecal therapy, inhalation therapy, toxicity, and prevention of renal failure.
Susceptibility and Pharmacokinetics/Pharmacodynamics
1: 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. We recommend that the CLSI/EUCAST Joint Working Group clinical breakpoints be used for colistin
2: We recommend that for colistin, an area under the plasma concentration‐time curve across 24 hours at steady state (AUCss,24 hr) of ~50 mg·hour/L is required that equates to a target average steady‐state plasma concentration (Css,avg) of ~2 mg/L for a total drug. Concentrations higher than this were shown to increase both the incidence and severity of AKI.
3: We recommend similar targets for polymyxin B as those listed for colistin. However, we note that data are lacking for AUCss,24 hr targets for polymyxin B. Emerging evidence suggest a different toxicodynamic (TD) profile for polymyxin B than colistin. Some evidence indicates that an AUCss,24 hr target of 50–100 mg · hour/L, corresponding to a Css,avg of 2–4 mg/L, may be acceptable from a toxicity standpoint.
4: We recommend that the exposures just described for polymyxin B and colistin should be considered the maximally 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.
5: We recommend that clinicians have access to parenteral products of both CMS and polymyxin B, so they can choose between the two in particular circumstances.
6: 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.
7: We recommend colistin as the preferred polymyxin for the treatment of lower urinary tract infections given a renal clearance of the prodrug CMS that then converts to the active moiety colistin in the urinary tract.
Colistin Intravenous Dosing
8: 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 labelling 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.
9: We recommend initiating IV therapy with a CMS loading dose of 300 mg CBA (~9 million IU) infused over 0.5–1 hour and to administer the first maintenance dose 12–24 hours later.
10: We recommend that for a patient with normal renal function, administer a daily dose of 300–360 mg 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 using the recommendations in Table 2.
11: We recommend that CMS dose adjustments be made in patients with renal insufficiency.
12: We recommend that to target a plasma colistin Css,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.
13: We recommend that to target a plasma colistin Css,avg of 2 mg/L in patients prescribed sustained low‐efficiency dialysis (SLED) that 10% of the CMS does be added to the baseline daily dose per 1 hour of SLED.
14: We recommend that for patients prescribed continuous renal replacement therapy (CRRT), for a plasma colistin Css,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).
Polymyxin B Intravenous Dosing
15: 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.
16: 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.
17: We recommend that daily maintenance doses of polymyxin B should not be adjusted if the patient has renal impairment.
18: We recommend that neither the loading dose nor maintenance dose is adjusted in patients receiving renal replacement therapy.
19: We recommend that TDM and adaptive feedback control (AFC) be used wherever possible for both colistin and polymyxin B.
20: We recommend, wherever possible, that concomitant nephrotoxic agents should be avoided in patients receiving colistin or polymyxin B.
21: We recommend that doses greater than those listed in this guideline for colistin or polymyxin B be avoided in the absence of TDM.
22: In countries where both agents are available, we recommend preferential use of polymyxin B to limit the rate of polymyxin‐associated AKI.
23: Until further data become available, we do not recommend the routine use of antioxidants for the primary purpose of reducing polymyxin‐associated nephrotoxicity.
24: We recommend that if a patient develops AKI while on colistin, the daily dose should be decreased to the appropriate renally adjusted dose for a plasma colistin Css,avg of 2 mg/L.
25: We recommend that doses should not be decreased, outside of the renal dosing recommendations for colistin, particularly in patients who develop AKI when colistin or polymyxin B is being administered for a life‐threatening infection, a deep‐seated infection, or when the infecting pathogen has a MIC higher than 1 mg/L (Strong recommendation, low‐quality evidence). If the MIC of the infecting pathogen and/or the nature of the infection suggest that targeting a lower plasma concentration may be adequate, consideration should be given to decreasing the dose to target a different Css,avg of colistin.
26: 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.
27: 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.
28: 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.
29: 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.
30: 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 a monotherapy.
31: 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.
32: If a second active agent to which the infecting CRPA displays a susceptible MIC is unavailable, we recommend polymyxin B and 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.
33: We recommend that patients requiring IV polymyxin therapy for suspected or documented XDR gram‐negative HAP or VAP should receive adjunctive polymyxin aerosol therapy.
34: We recommend that for polymyxin aerosol therapy, either colistin or polymyxin B is appropriate.
Intrathecal and Intraventricular Administration of Polymyxins
35: 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.
36: Due to limited experience with polymyxin B, CMS is the preferred polymyxin for intraventricular or intrathecal administration.
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