Dosing and Pharmacokinetics of Polymyxin B in Patients with Renal Insufficiency

Abstract

Polymyxin B remains the last-line treatment option for multidrug-resistant Gram-negative bacterial infections. Current U.S. Food and Drug Administration-approved prescribing information recommends that polymyxin B dosing should be adjusted according to the patient's renal function, despite studies that have shown poor correlation between creatinine and polymyxin B clearance. The objective of the present study was to determine whether steady-state polymyxin B exposures in patients with normal renal function were different from those in patients with renal insufficiency. Nineteen adult patients who received intravenous polymyxin B (1.5 to 2.5 mg/kg [actual body weight] daily) were included. To measure polymyxin B concentrations, serial blood samples were obtained from each patient after receiving polymyxin B for at least 48 h. The primary outcome was polymyxin B exposure at steady state, as reflected by the area under the concentration-time curve (AUC) over 24 h. Five patients had normal renal function (estimated creatinine clearance [CL CR ] Ն 80 ml/min) at baseline, whereas 14 had renal insufficiency (CL CR Ͻ 80 ml/min). The mean AUC of polymyxin B Ϯ the standard deviation in the normal renal function cohort was 63.5 Ϯ 16.6 mg·h/liter compared to 56.0 Ϯ 17.5 mg·h/liter in the renal insufficiency cohort (P ϭ 0.42). Adjusting the AUC for the daily dose (in mg/kg of actual body weight) did not result in a significant difference (28.6 Ϯ 7.0 mg·h/liter versus 29.7 Ϯ 11.2 mg·h/liter, P ϭ 0.80). Polymyxin B exposures in patients with normal and impaired renal function after receiving standard dosing of polymyxin B were comparable. Polymyxin B dosing adjustment in patients with renal insufficiency should be reexamined.KEYWORDS polymyxins, dosing adjustment, drug exposure P arenteral polymyxins (polymyxin B and polymyxin E [colistin]) have become one of the most important antibiotics for therapy of extensively drug-resistant Gramnegative bacterial infections over the past decade, including infections caused by carbapenem-resistant nonfermenters and carbapenem-resistant Enterobacteriaceae. The similarities and differences between polymyxin B and colistin have been reviewed elsewhere (1). Polymyxin B has been increasingly used due to the active drug form used, more straight-forward dosing, more favorable pharmacokinetics, and potentially lower incidence of nephrotoxicity than colistin (2, 3). Current U.S. Food and Drug Administration-approved prescribing information recommends polymyxin B dosing adjustment in patients with renal insufficiency (package inserts from Bedford Laboratories,

Critical Need for Clarity in Polymyxin B Dosing

“…Consistent with previous reports (2,3,(7)(8)(9), the paper by Thamlikitkul et al (1). provides further evidence of the dissonance between contemporary PK studies of polymyxin B and the product label.…”

“…W e read with interest the report by Thamlikitkul et al describing polymyxin B exposures in 19 adult patients with and without renal insufficiency (1). No significant difference was observed in the dose-normalized 24-h area under the concentration-time curve (AUC 24 ) at steady state between those with normal renal function, defined as an estimated creatinine clearance (CL CR ) of Ն80 ml/min (n ϭ 5; mean CL CR , 90.0 Ϯ 12.5 ml/min; mean AUC 24 , 28.6 Ϯ 7.0 mg · h/liter) and those with renal insufficiency (n ϭ 14; mean CL CR , 40.8 Ϯ 21.8 ml/min; mean AUC 24 , 29.7 Ϯ 11.2 mg · h/liter; P ϭ 0.80).…”

International Consensus Guidelines for the Optimal Use of the Polymyxins: Endorsed by the American College of Clinical Pharmacy (ACCP), European Society of Clinical Microbiology and Infectious Diseases (ESCMID), Infectious Diseases Society of America (IDSA), International Society for Anti‐infective Pharmacology (ISAP), Society of Critical Care Medicine (SCCM), and Society of Infectious Diseases Pharmacists (SIDP)

“…No specific recommendation is available in the package insert concerning the duration of infusion. However, in recent PK analyses reflecting real‐world use of polymyxin B, doses were safely administered over 1–4 hours in most patients . Because there might be a potential benefit on renal toxicity of higher peak‐to‐trough differences, infusions over 1 hour might be preferred over longer infusions if well tolerated by patients.…”

“…Polymyxin B is not significantly eliminated by the kidneys, and clinical PK studies demonstrate that polymyxin B clearance does not depend on Cl cr . Therefore, no PK rationale exists for adjusting doses according to renal function.…”

“…6,32 The pharmacokinetics of polymyxin B are not similarly affected by renal function, and therefore it is possible to attain a plasma polymyxin B C ss,avg of 2 mg/L reliably with approved daily doses, even in patients with Cl cr greater than 80 mL/minute (see Section XI). [44][45][46][47] The risk of AKI appears to be less with polymyxin B, [48][49][50][51][52][53][54] although some of the comparative studies are confounded by issues with different experimental designs. 8,42,43 Therapeutic drug monitoring (TDM) is inherently more difficult for colistin because of the need to ensure that samples are collected in such a way as to minimize ongoing in vitro conversion of CMS to colistin.…”