Critical Need for Clarity in Polymyxin B Dosing

Abstract

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). A sensitivity analysis using lower CL CR threshold values of Ͻ60 and Ͻ40 ml/min yielded similar results.This study adds to mounting evidence that polymyxin B undergoes negligible renal excretion; thus, dose adjustment based solely on a patient's renal function may not be prudent (2, 3). Unfortunately, such observations conflict with current polymyxin B labeling, which instructs physicians to decrease doses in the setting of "renal impairment" (4). Administering less than the suggested 1.5 to 2.5 mg/kg of actual body weight daily may, in fact, be detrimental, increasing the risk of death as a consequence of insufficient drug exposure (5). However, the potential for nephrotoxicity and interpatient variability must also be considered when selecting polymyxin B dosing regimens (6). This raises two important questions: (i) what steps are necessary to provide clarity in polymyxin B dosing that will simultaneously achieve adequate pharmacodynamic (PD) response and minimize toxicodynamic (TD) events?; and (ii) how can we best apply information gained from the present (1) and previous (2, 3) studies to optimize polymyxin B dosing regimens?The first question may be answered by considering the overall paucity of polymyxin B clinical pharmacokinetic (PK) studies; with the inclusion of Thamlikitkul et al. 's cohort, the literature is composed of 65 patients' data (1-3, 7-10). While such reports conclude that polymyxin B doses should not be modified because of differences in renal function (1-3, 7-9), larger, prospective studies are necessary to confirm their findings. Such efforts are under way; a multicenter clinical study will enroll 250 critically ill patients treated with intravenous polymyxin B, assessing the drug's PK, PD, and TD characteristics, expanding the evidence base nearly 4-fold (NCT02682355). The solution to the second question lies in the ability to harness the predictive power of combining population PK models with adaptive feedback control to derive patient-specific PK information (11, 12). Leveraging population PK parameter estimates, their degree of interpatient variability, and measured drug concentrations, a Bayesian estimator indiCitation Onufrak NJ, Rao GG, Forrest A, Pogue JM, Scheetz MH, Nation RL, Li J, Kaye KS. 2017. Critical need for clarity in polymyxin B dosing. Antimicrob Agents Chemother 61:e00208-17.

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)

“…Also, different conventions are used to describe dosing of the polymyxins, particularly colistin; product information is outdated; and uncertainties remain regarding susceptibility testing . Thus a lack of clarity remains about how optimally to utilize and dose colistin and polymyxin B . Unfortunately, polymyxins are highly nephrotoxic agents, and acute kidney injury (AKI) occurs frequently with conventional doses .…”

“…3,4 Thus a lack of clarity remains about how optimally to utilize and dose colistin and polymyxin B. 5,6 Unfortunately, polymyxins are highly nephrotoxic agents, and acute kidney injury (AKI) occurs frequently with conventional doses. 7,8 Given the narrow therapeutic windows (low therapeutic indices) of polymyxins, this guideline provides clinicians with a practical framework for use in treating infections caused by MDR and XDR gram-negative pathogens.…”

Use of polymyxin B in patients with renal impairment: A retrospective examination of 5 cases

“…1 was 70 kg. The patient received polymyxin B according to 1.25-1.5 mg/kg every 12 h ( 9-14 ) and, therefore, 87.5-105 mg every 12 h should be given. However, the patient had renal impairment and polymyxin B can induce nephrotoxicity ( 20 , 21 ).…”

“…As a result, usage and dosage (including calculation and administration of the loading dose) are mainly based on international clinical literature, for example, 1.25-1.5 mg/kg every 12 h (2.5-3 mg/kg daily) by intravenous (i.v.) drip ( 9-14 ). Polymyxin B is mainly eliminated by non-renal pathways, and continuous renal replacement therapy (CRRT) has limited effects in the clearance of polymyxin B ( 14-16 ).…”

Review of the international consensus guidelines for the optimal use of the polymyxins

“…Кроме того, для описания дозирования полимиксинов, в частности колистина, используются различные подходы, информация о продукте устарела, и остаются вопросы в отношении методик определения чувствительности к антимикробным препаратам [3,4]. Таким образом, нет достаточной ясности в вопросе оптимального использования и дозирования колистина и полимиксина В [5,6]. К сожалению, полимиксины являются препаратами с высокой нефротоксичностью, и часто при использовании обычных доз развивается острое повреждение почек (ОПП) [7,8].…”