Optimal Use of Polymyxin Antibiotics Clinical Practice Guidelines (2019)

American College of Clinical Pharmacy (ACCP)

This is a quick summary of the guidelines without analysis or commentary. For more information, go directly to the guidelines by clicking the link in the reference.

February 28, 2019

International consensus guidelines for the optimal use of the polymyxins were released on February 2, 2019, by the American College of Clinical Pharmacy (ACCP).[1]

These guidelines are the first-ever consensus recommendations issued for colistin and polymyxin B therapy. The guidelines are intended to guide optimal clinical use. They have been endorsed by the 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 standard broth microdilution ISO‐74 20776 is recommended as the reference method for minimum inhibitory concentration (MIC) testing of colistin. Cation‐adjusted Mueller Hinton broth should be used, with sulfate salts of colistin in plain polystyrene trays without additives. Sulphate salts of polymyxins must be used. The CLSI/EUCAST Joint Working Group clinical breakpoints for colistin are recommended.

For colistin, the guidelines recommend an area under the plasma concentration‐time curve across 24 hours at steady state (AUCss,24 hr) of approximately 50 mg·hour/L, equating to a target average steady‐state plasma concentration (Css,avg) of approximately 2 mg/L for total drug. This should be regarded as a maximum tolerable exposure.

The guidelines recommend that targets for polymyxin B be similar to those listed for colistin, although data for AUCss,24 hr targets for polymyxin B are lacking.

The exposures described above for polymyxin B and colistin should be regarded as maximum tolerable exposures. These recommended exposures should result in bacterial killing at the current MIC breakpoints based on a mouse model, but these exposures for both drugs were found to be substantially less effective in mouse lung infection when administered systemically.

Polymyxin Pharmacokinetics

Clinicians should have access to parenteral products of both colistin methanesulfonate (CMS) and polymyxin B so they can choose between the two based on the clinical scenario.

Polymyxin B is preferred for routine systemic use in the treatment of invasive infections, since polymyxin B has a superior pharmacokinetic profile and is less likely to cause nephrotoxicity.

Colistin is the preferred polymyxin in the treatment of lower urinary tract infection (LUTI).

Colistin Intravenous Dosing

Prescription orders and hospital guidelines should specify doses of CMS in either milligrams of colistin base activity (CBA) or number of international units (IU), based on the specific country’s labeling conventions. One million IU is equivalent to approximately 33 mg CBA.

Intravenous therapy should be initiated with a CMS loading dose of approximately 9 million IU infused over 0.5-1 hours. The first maintenance dose should be administered 12-24 hours later.

Patients with normal renal function should receive a daily dose of approximately 9-10.9 million IU divided in half and infused over 0.5-1 hour at 12‐hour intervals. Renal function should be monitored and daily dose adjusted accordingly.

CMS dose adjustments should be made in patients with renal insufficiency.

Polymyxin B Intravenous Dosing

For polymyxin B, a loading dose of 2.0-2.5 mg/kg based on total body weight (TBW) (equivalent to 20,000-25,000 IU/kg) over 1 hour is recommended.

For 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 should be infused over 1 hour.

In patients with renal impairment, daily maintenance doses of polymyxin B should not be adjusted.

In patients receiving renal replacement therapy, neither the loading dose nor maintenance dose should be adjusted.

Therapeutic drug monitoring (TDM) and adaptive feedback control (AFC) should be used whenever possible for both colistin and polymyxin B.

Concomitant nephrotoxic agents should be avoided, if possible, in patients receiving colistin or polymyxin B.

If TDM is not being used, doses greater than those listed in this guideline for colistin or polymyxin B should be avoided.

If both agents are available, polymyxin B is preferred to limit the rate of polymyxin‐associated acute kidney injury (AKI).

Routine use of antioxidants is not recommended if only to reduce polymyxin‐associated nephrotoxicity.

If AKI develops in a patient receiving colistin, decrease the daily dose to the appropriate renally adjusted dose for a plasma colistin Css,avg of 2 mg/L.

Doses should not be decreased except based on renal dosing recommendations for colistin, particularly if AKI develops when polymyxin B or colistin is being given for a life‐threatening infection or a deep‐seated infection or when the infecting pathogen has a MIC above 1 mg/L. If targeting a lower plasma concentration may be adequate based on the infecting pathogen’s MIC and/or nature of the infection, consider decreasing the dose to target a different Css,avg of colistin.

Therapy cessation may be considered if AKI develops if the infection diagnosis is unclear or if an alternate less-nephrotoxic drug is available.

Polymyxin Combinations

Invasive carbapenem‐resistant Enterobacteriaceae (CRE) infections should be treated with polymyxin B or colistin in combination with any other agents to which the pathogen shows a susceptible MIC. If the infecting CRE strain shows a susceptible MIC to a second active agent that is unavailable, polymyxin B or colistin should be used in combination with a second and/or third nonsusceptible agent. A nonsusceptible agent with the lowest MIC relative to the respective susceptibility breakpoint is preferred.

Invasive carbapenem‐resistant Acinetobacter baumannii (CRAB) infections should be treated with polymyxin B or colistin in combination with any other agents to which the pathogen shows a susceptible MIC.

Invasive carbapenem‐resistant Pseudomonas aeruginosa (CRPA) infections should be treated with polymyxin B or colistin in combination with any other agents to which the pathogen shows a susceptible MIC. If the infecting CRPA strain shows a susceptible MIC to a second active agent that is unavailable, polymyxin B or colistin should be used in combination with a second and/or third nonsusceptible agent. A nonsusceptible agent with the lowest MIC relative to the respective susceptibility breakpoint is preferred.

Intrathecal and Intraventricular Administration of Polymyxins

Ventriculitis or meningitis caused by multidrug-resistant (MDR) or XDR gram‐negative pathogens should be treated with intraventricular (IVT) or intrathecal (ITH) administration of polymyxins at a dosage of 125,000 IU CMS or 5 mg (50,000 IU) polymyxin B per day with concomitant intravenous polymyxin.

CMS is the preferred polymyxin for intraventricular or intrathecal administration.

For more Clinical Practice Guidelines, please go to Guidelines.

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