Polymyxins for CNS infections

Pharmacology and neurotoxicity

Tony Velkov, Chongshan Dai, Giuseppe D. Ciccotosto, Roberto Cappai, Daniel Hoyer, Jian Li

Research output: Contribution to journalReview ArticleResearchpeer-review

10 Citations (Scopus)

Abstract

Central nervous system (CNS) infections caused by multi-drug resistant (MDR) Gram-negative bacteria present a major health and economic burden worldwide. Due to the nearly empty antibiotic discovery pipeline, polymyxins (i.e. polymyxin B and colistin) are used as the last-line therapy against Gram-negative 'superbugs' when all other treatment modalities have failed. The treatment of CNS infections due to multi-drug resistant Gram-negative bacteria is problematic and associated with high mortality rates. Colistin shows significant efficacy for the treatment of CNS infections caused by MDR Gram-negative bacteria that are resistant to all other antibiotics. In particular, MDR Acinetobacter baumannii, Pseudomonas aeruginosa and Klebsiella pneumoniae which are resistant to expanded-spectrum and fourth-generation cephalosporins, carbapenems and aminoglycosides, represent a major therapeutic challenge, although they can be treated with colistin or polymyxin B. However, current dosing recommendations of intrathecal/intraventricular polymyxins are largely empirical, as we have little understanding of the pharmacokinetics/pharmacodynamics and, importantly, we are only starting to understand the mechanisms of potential neurotoxicity. This review covers the current knowledge-base on the mechanisms of disposition and potential neurotoxicity of polymyxins as well as the combined use of neuroprotective agents to alleviate polymyxins-related neurotoxicity. Progress in this field will provide the urgently needed pharmacological information for safer and more efficacious intrathecal/intraventricular polymyxin therapy against life-threatening CNS infections caused by Gram-negative 'superbugs'.

Original languageEnglish
Pages (from-to)85-90
Number of pages6
JournalPharmacology and Therapeutics
Volume181
DOIs
Publication statusPublished - Jan 2018

Keywords

  • CNS infections
  • Colistin
  • Multi-drug resistance
  • Neurotoxicity
  • Polymyxins

Cite this

Velkov, Tony ; Dai, Chongshan ; Ciccotosto, Giuseppe D. ; Cappai, Roberto ; Hoyer, Daniel ; Li, Jian. / Polymyxins for CNS infections : Pharmacology and neurotoxicity. In: Pharmacology and Therapeutics. 2018 ; Vol. 181. pp. 85-90.
@article{a99a9a654e574e198e65cd1fb9e4ac29,
title = "Polymyxins for CNS infections: Pharmacology and neurotoxicity",
abstract = "Central nervous system (CNS) infections caused by multi-drug resistant (MDR) Gram-negative bacteria present a major health and economic burden worldwide. Due to the nearly empty antibiotic discovery pipeline, polymyxins (i.e. polymyxin B and colistin) are used as the last-line therapy against Gram-negative 'superbugs' when all other treatment modalities have failed. The treatment of CNS infections due to multi-drug resistant Gram-negative bacteria is problematic and associated with high mortality rates. Colistin shows significant efficacy for the treatment of CNS infections caused by MDR Gram-negative bacteria that are resistant to all other antibiotics. In particular, MDR Acinetobacter baumannii, Pseudomonas aeruginosa and Klebsiella pneumoniae which are resistant to expanded-spectrum and fourth-generation cephalosporins, carbapenems and aminoglycosides, represent a major therapeutic challenge, although they can be treated with colistin or polymyxin B. However, current dosing recommendations of intrathecal/intraventricular polymyxins are largely empirical, as we have little understanding of the pharmacokinetics/pharmacodynamics and, importantly, we are only starting to understand the mechanisms of potential neurotoxicity. This review covers the current knowledge-base on the mechanisms of disposition and potential neurotoxicity of polymyxins as well as the combined use of neuroprotective agents to alleviate polymyxins-related neurotoxicity. Progress in this field will provide the urgently needed pharmacological information for safer and more efficacious intrathecal/intraventricular polymyxin therapy against life-threatening CNS infections caused by Gram-negative 'superbugs'.",
keywords = "CNS infections, Colistin, Multi-drug resistance, Neurotoxicity, Polymyxins",
author = "Tony Velkov and Chongshan Dai and Ciccotosto, {Giuseppe D.} and Roberto Cappai and Daniel Hoyer and Jian Li",
year = "2018",
month = "1",
doi = "10.1016/j.pharmthera.2017.07.012",
language = "English",
volume = "181",
pages = "85--90",
journal = "Pharmacology and Therapeutics",
issn = "0163-7258",
publisher = "Elsevier",

}

Polymyxins for CNS infections : Pharmacology and neurotoxicity. / Velkov, Tony; Dai, Chongshan; Ciccotosto, Giuseppe D.; Cappai, Roberto; Hoyer, Daniel; Li, Jian.

In: Pharmacology and Therapeutics, Vol. 181, 01.2018, p. 85-90.

Research output: Contribution to journalReview ArticleResearchpeer-review

TY - JOUR

T1 - Polymyxins for CNS infections

T2 - Pharmacology and neurotoxicity

AU - Velkov, Tony

AU - Dai, Chongshan

AU - Ciccotosto, Giuseppe D.

AU - Cappai, Roberto

AU - Hoyer, Daniel

AU - Li, Jian

PY - 2018/1

Y1 - 2018/1

N2 - Central nervous system (CNS) infections caused by multi-drug resistant (MDR) Gram-negative bacteria present a major health and economic burden worldwide. Due to the nearly empty antibiotic discovery pipeline, polymyxins (i.e. polymyxin B and colistin) are used as the last-line therapy against Gram-negative 'superbugs' when all other treatment modalities have failed. The treatment of CNS infections due to multi-drug resistant Gram-negative bacteria is problematic and associated with high mortality rates. Colistin shows significant efficacy for the treatment of CNS infections caused by MDR Gram-negative bacteria that are resistant to all other antibiotics. In particular, MDR Acinetobacter baumannii, Pseudomonas aeruginosa and Klebsiella pneumoniae which are resistant to expanded-spectrum and fourth-generation cephalosporins, carbapenems and aminoglycosides, represent a major therapeutic challenge, although they can be treated with colistin or polymyxin B. However, current dosing recommendations of intrathecal/intraventricular polymyxins are largely empirical, as we have little understanding of the pharmacokinetics/pharmacodynamics and, importantly, we are only starting to understand the mechanisms of potential neurotoxicity. This review covers the current knowledge-base on the mechanisms of disposition and potential neurotoxicity of polymyxins as well as the combined use of neuroprotective agents to alleviate polymyxins-related neurotoxicity. Progress in this field will provide the urgently needed pharmacological information for safer and more efficacious intrathecal/intraventricular polymyxin therapy against life-threatening CNS infections caused by Gram-negative 'superbugs'.

AB - Central nervous system (CNS) infections caused by multi-drug resistant (MDR) Gram-negative bacteria present a major health and economic burden worldwide. Due to the nearly empty antibiotic discovery pipeline, polymyxins (i.e. polymyxin B and colistin) are used as the last-line therapy against Gram-negative 'superbugs' when all other treatment modalities have failed. The treatment of CNS infections due to multi-drug resistant Gram-negative bacteria is problematic and associated with high mortality rates. Colistin shows significant efficacy for the treatment of CNS infections caused by MDR Gram-negative bacteria that are resistant to all other antibiotics. In particular, MDR Acinetobacter baumannii, Pseudomonas aeruginosa and Klebsiella pneumoniae which are resistant to expanded-spectrum and fourth-generation cephalosporins, carbapenems and aminoglycosides, represent a major therapeutic challenge, although they can be treated with colistin or polymyxin B. However, current dosing recommendations of intrathecal/intraventricular polymyxins are largely empirical, as we have little understanding of the pharmacokinetics/pharmacodynamics and, importantly, we are only starting to understand the mechanisms of potential neurotoxicity. This review covers the current knowledge-base on the mechanisms of disposition and potential neurotoxicity of polymyxins as well as the combined use of neuroprotective agents to alleviate polymyxins-related neurotoxicity. Progress in this field will provide the urgently needed pharmacological information for safer and more efficacious intrathecal/intraventricular polymyxin therapy against life-threatening CNS infections caused by Gram-negative 'superbugs'.

KW - CNS infections

KW - Colistin

KW - Multi-drug resistance

KW - Neurotoxicity

KW - Polymyxins

UR - http://www.scopus.com/inward/record.url?scp=85026291945&partnerID=8YFLogxK

U2 - 10.1016/j.pharmthera.2017.07.012

DO - 10.1016/j.pharmthera.2017.07.012

M3 - Review Article

VL - 181

SP - 85

EP - 90

JO - Pharmacology and Therapeutics

JF - Pharmacology and Therapeutics

SN - 0163-7258

ER -