Pharmacokinetics of Intravenous Polymyxin B in Critically Ill Patients

Zavascki, Alexandre Prehn; Goldani, Luciano Zubaran; Cao, Guoying; Superti, Silvana; Lutz, Larissa; Barth, Afonso Luís; Ramos, Fabiano; Boniatti, Márcio Manozzo; Nation, Roger L.; Li, Jian

doi:10.1086/592577

Cited by 216 publications

(205 citation statements)

References 29 publications

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“…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.…”

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confidence: 84%

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Critical Need for Clarity in Polymyxin B Dosing

Onufrak

Rao

Forrest

et al. 2017

Antimicrob Agents Chemother

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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.

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confidence: 84%

“…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).…”

mentioning

confidence: 98%

Critical Need for Clarity in Polymyxin B Dosing

Onufrak

Rao

Forrest

et al. 2017

Antimicrob Agents Chemother

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“…Note that the IC 50 values of polymyxin B in Stx-binding assays with human neutrophils fit within the range of plasma concentrations measured in pharmacokinetic experiments in treated patients after i.v. administration of the antibiotic (50).…”

Section: Discussionmentioning

confidence: 99%

The Antibiotic Polymyxin B Impairs the Interactions between Shiga Toxins and Human Neutrophils

Carnicelli

Arfilli

Ricci

et al. 2016

The Journal of Immunology

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Hemolytic uremic syndrome (HUS) is the life-threatenig sequela of intestinal infections by Shiga toxin (Stx)–producing Escherichia coli (STEC) in children. Human neutrophils specifically bind Stx through TLR4, the receptor of LPS. The binding could be considered protective (Stx sequestration) or harmful (toxin delivery to target organs). The amount of Stx on neutrophils is in equilibrium with the amount of Stx present in the gut, and it is also related to renal and neurologic symptoms. The TLR4-mediated interaction of LPS with innate immune cells is hampered by the well-known antibiotic polymyxin B. In this study, we show that the same antibiotic impairs the binding of Stx to neutrophils, also blocking their functional effects (release of CXCL8, formation of neutrophil/platelet aggregates) involved in HUS pathogenesis. Controls for contaminating LPS in Stx-induced neutrophil responses inhibited by polymyxin B were performed. Stx interact with human neutrophils through their A chain, since these leukocytes do not express globotriaosylceramide, the specific receptor for Stx B chains. Consistently, polymyxin B blocked the enzymatic activity of Stx1, Stx2, Stx1 A chain, and the analogous plant protein gelonin, whereas the antibiotic did not show any protective effect on Stx-induced cytotoxicity in globotriaosylceramide-expressing Raji cells. Antibiotic administration is not recommended in human STEC infections during the prodromal intestinal phase, and the toxicity of polymyxin B could further discourage its therapeutic use. However, nontoxic, nonbactericidal polymyxin derivatives have been developed and might be used in animal models of STEC infection to study their efficacy in preventing the onset of HUS during the systemic blood phase of Stx.

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“…So CMS dosing should be adjusted in renal impaired patients according to estimated glomerular filtration rate or creatinine clearance (31,39), and polymyxin B used to be so (43). However, recent data suggest that polymyxin B does not require adjustment for renal dysfunction (78,85,86). Polymyxin B is eliminated mainly by nonrenal pathways, and the total body clearance appears to be relatively insensitive to renal function (86).…”

Section: Dosing Strategiesmentioning

confidence: 99%

Intravenous polymyxins: Revival with puzzle

Fei

et al. 2017

BST

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Pharmacokinetics of Intravenous Polymyxin B in Critically Ill Patients

Cited by 216 publications

References 29 publications

Critical Need for Clarity in Polymyxin B Dosing

Critical Need for Clarity in Polymyxin B Dosing

The Antibiotic Polymyxin B Impairs the Interactions between Shiga Toxins and Human Neutrophils

Intravenous polymyxins: Revival with puzzle

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