Polymyxin Acute Kidney Injury: Dosing and Other Strategies to Reduce Toxicity

Nation, Roger L.; Rigatto, Maria Helena; Falci, Diego Rodrigues; Zavascki, Alexandre Prehn

doi:10.3390/antibiotics8010024

Cited by 105 publications

(103 citation statements)

References 116 publications

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“…However, the low stability of polymyxins in the bloodstream requires the administration of high doses of the drug to reach the therapeutic threshold. This practice has led to the emergence of negative side-effects, such as neuro-, hepato- and nephrotoxicity [ 7 , 8 ]. Currently, the nephrotoxicity is the major factor limiting the wide applications of polymyxins in clinical practice [ 9 , 10 ].…”

Section: Introductionmentioning

confidence: 99%

Polypeptide Self-Assembled Nanoparticles as Delivery Systems for Polymyxins B and E

et al. 2020

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Polymyxins are peptide antibiotics that are highly efficient against many multidrug resistant pathogens. However, the poor stability of polymyxins in the bloodstream requires the administration of high drug doses that, in turn, can lead to polymyxin toxicity. Consequently, different delivery systems have been considered for polymyxins to overcome these obstacles. In this work, we report the development of polymyxin delivery systems based on nanoparticles obtained from the self-assembly of amphiphilic random poly(l-glutamic acid-co-d-phenylalanine). These P(Glu-co-dPhe) nanoparticles were characterized in terms of their size, surface charge, stability, cytotoxicity, and uptake by macrophages. The encapsulation efficiency and drug loading into P(Glu-co-dPhe) nanoparticles were determined for both polymyxin B and E. The release kinetics of polymyxins B and E from nanoformulations was studied and compared in buffer solution and human blood plasma. The release mechanisms were analyzed using a number of mathematical models. The minimal inhibitory concentrations of the nanoformulations were established and compared with those determined for the free antibiotics.

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Section: Introductionmentioning

confidence: 99%

Polypeptide Self-Assembled Nanoparticles as Delivery Systems for Polymyxins B and E

et al. 2020

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“…The exact rates of nephrotoxicity vary in the literature depending upon which polymyxin is used (colistimethate or polymyxin B) and the definition of acute kidney injury (AKI), but rates are generally between 31% and 50%. 14 CT, in addition to maintaining activity against many of these MDR isolates, is better tolerated than the polymyxins. In the ASPECT-cUTI and ASPECT-cIAI trials no patients were reported to have developed AKI; the most common ADR in the cUTI trial was headache (5.8%; 31/533) and nausea in the cIAI trial (7.9%; 38/482).…”

Section: Discussionmentioning

confidence: 99%

Ceftolozane–tazobactam for the treatment of osteomyelitis caused by multidrug-resistant pathogens: a case series

Tan

Moenster

2019

Therapeutic Advances in Drug Safety

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Ceftolozane–tazobactam (CT) is a recently approved novel cephalosporin and β-lactamase inhibitor combination agent with in vitro activity against various Gram-positive and Gram-negative pathogens, including several multidrug-resistant (MDR) Gram-negative organisms. CT is currently approved by the US Food and Drug Administration for the treatment of complicated intrabdominal infection and complicated urinary tract infection at a dose of 1.5 g intravenously every 8 h. This agent is an attractive option for MDR osteomyelitis (OM) treatment, but clinical data is limited to case reports and series. Here we report a series of five patients with MDR OM who were treated with CT. Pathogens involved in these infections were MDR Acinetobacter baumannii (two isolates) and MDR Pseudomonas aeruginosa (four isolates). Two patients were disease free 6 months after therapy was discontinued, one required an additional curative surgical procedure, and two (both on high-dose therapy) developed adverse reactions likely related to CT that necessitated early antibiotic discontinuation.

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“…Contemporary dosing of intravenous PB recommends it be administered in 2 divided doses based on a weight-based total daily dose (26, 44). It has been suggested that PB-induced kidney injury could be minimized by optimizing dosing intervals, similar to that observed with aminoglycosides (7, 45).…”

Section: Discussionmentioning

confidence: 99%

Evaluation of Dose Fractionated Polymyxin B on Acute Kidney Injury: A Translational In Vivo Model

Liu

Pais

Avedissian

et al. 2019

Preprint

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2 0 injury, biomarker, KIM1 2 1 2 2 Acknowledgements: None 2 3 Polymyxin B dose fractionation Abstract 2 4The polymyxins are last-line defense for highly resistant infections. Nephrotoxicity, however, is a dose-limiting 2 5factor. Yet, approaches to mitigate nephrotoxicity are poorly defined. This study aimed to investigate the impact of 2 6 dose fractionated (once, twice and thrice daily) polymyxin B (PB) on acute kidney injury (AKI) in a pre-clinical 2 7model. Secondarily, we aimed to describe the pharmacokinetic (PK) profile of PB. Sprague-Dawley rats were 2 8 assigned to experimental groups with different dosing intervals but constant total daily exposure (12 mg/kg/day into 2 9 single, twice daily, and thrice daily doses) and controls received normal saline subcutaneously over 3 days. Blood 3 0 and urine samples were collected, and kidneys were harvested at necropsy. A three-compartment model best 3 1 described the data and Bayesian observed vs. predicted concentration demonstrated bias, imprecision, and R 2 of 3 2 0.129 mg/L, 0.729 mg 2 /L 2 and 0.652, respectively. PB exposure (i.e. AUC 24h ) were similar across treatment groups 3 3 over time (p=0.87). As a representative, urinary KIM-1 were elevated on days 1 and 2 for experimental groups 3 4 compared to controls, and thrice daily group experienced the most KIM-1 increase [mean increase (95% CI) day 1 3 5 from day -1, 4.44 (0.89, 8.00) ng/mL; p=0.018] as compared to control [mean increase (95% CI) day 1 from day -1, 3 6 0.03 (-0.42, 0.49) ng/mL; p=0.99]. Correspondingly, significant histopathological damage was observed with the 3 7same group (p=0.013) (controls as a referent). Our findings suggested that fractionating the PB dose thrice daily 3 8 resulted in the most injury in a rat model.

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Polymyxin Acute Kidney Injury: Dosing and Other Strategies to Reduce Toxicity

Cited by 105 publications

References 116 publications

Polypeptide Self-Assembled Nanoparticles as Delivery Systems for Polymyxins B and E

Polypeptide Self-Assembled Nanoparticles as Delivery Systems for Polymyxins B and E

Ceftolozane–tazobactam for the treatment of osteomyelitis caused by multidrug-resistant pathogens: a case series

Evaluation of Dose Fractionated Polymyxin B on Acute Kidney Injury: A Translational In Vivo Model

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