Pharmacokinetics of polymyxin B in patients on continuous venovenous haemodialysis

Sandri, Ana Maria; Landersdorfer, Cornelia B.; Jacob, Jovan; Boniatti, Márcio Manozzo; Dalarosa, Micheline Gisele; Falci, Diego Rodrigues; Behle, Tainá F.; Saitovitch, David; Wang, Jiping; Forrest, Alan; Nation, Roger L.; Zavascki, Alexandre Prehn; Li, Jian

doi:10.1093/jac/dks437

Cited by 66 publications

(62 citation statements)

References 12 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.…”

supporting

confidence: 84%

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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supporting

confidence: 84%

Critical Need for Clarity in Polymyxin B Dosing

Onufrak

Rao

Forrest

et al. 2017

Antimicrob Agents Chemother

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“…8 Polymyxin B does not suffer from these limitations as it is administered as the active antibiotic. The pharmacokinetic (PK) and pharmacodynamic (PD) knowledge necessary to optimize dosing for polymyxin B is limited, 9,10 and suboptimal dosing at currently recommended doses may have contributed to increased resistance in Gram-negative pathogens. 10,11 Dose escalation of daily doses of polymyxin B is impractical as nephrotoxicity is a major dose-limiting adverse effect that occurs in up to 60% of patients even with currently recommended dosage regimens as administered.…”

Section: Introductionmentioning

confidence: 99%

Polymyxin B in combination with doripenem against heteroresistant Acinetobacter baumannii : pharmacodynamics of new dosing strategies

Rao

Bulitta

et al. 2016

J. Antimicrob. Chemother.

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Objectives: Polymyxin B is being increasingly utilized as a last resort against resistant Gram-negative bacteria. We examined the pharmacodynamics of novel dosing strategies for polymyxin B combinations to maximize efficacy and minimize the emergence of resistance and drug exposure against Acinetobacter baumannii. Methods:The pharmacodynamics of polymyxin B together with doripenem were evaluated in time -kill experiments over 48 h against 10 8 cfu/mL of two polymyxin-heteroresistant A. baumannii isolates (ATCC 19606 and N16870). Pharmacokinetic/pharmacodynamic relationships were mathematically modelled using S-ADAPT. A hollow-fibre infection model (HFIM) was also used to simulate clinically relevant polymyxin B dosing strategies (traditional, augmented 'front-loaded' and 'burst' regimens), together with doripenem, against an initial inoculum of 10 9 cfu/mL of ATCC 19606.Results: In static time -kill studies, polymyxin B concentrations .4 mg/L in combination with doripenem 25 mg/L resulted in rapid bactericidal activity against both strains with undetectable bacterial counts by 24 h. The mathematical model described the rapid, concentration-dependent killing as subpopulation and mechanistic synergy. In the HFIM, the traditional polymyxin B combination regimen was synergistic, with a .7.5 log 10 reduction by 48 h. The polymyxin B 'front-loaded' combination resulted in more rapid and extensive initial killing (.8 log 10 ) within 24 h, which was sustained over 10 days. With only 25% of the cumulative drug exposure, the polymyxin B 'burst' combination demonstrated antibacterial activity similar to traditional and 'front-loaded' combination strategies. The polymyxin B 'front-loaded' and 'burst' combination regimens suppressed the emergence of resistance.Conclusions: Early aggressive dosing regimens for polymyxin combinations demonstrate promise for treatment of heteroresistant A. baumannii infections.

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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%

“…A report of 8 continuous ambulatory peritoneal dialysis (CAPD) patients suggested that CMS doses should not be increased during CAPD because clearance by CAPD was low for both CMS and formed colistin (90). Little is known about the effect of dialysis on the clearance of polymyxin B, and a case report of 2 patients indicated that the recommended polymyxin B doses should not be reduced for patients on continuous venovenous hemodialysis (CVVHD) (85).…”

Section: Dosing Strategiesmentioning

confidence: 99%