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Updated: Feb 25, 2026
Intraventricular Drug Delivery and Sampling for Pharmacokinetics and Pharmacodynamics Study
Published on: March 31, 2022
Polymyxins for CNS infections: Pharmacology and neurotoxicity
Tony Velkov1, Chongshan Dai2, Giuseppe D Ciccotosto3
1Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
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'.
Insights
Polymyxins like colistin are crucial for treating central nervous system (CNS) infections from multi-drug resistant bacteria. Understanding polymyxin neurotoxicity is key for safer, effective CNS infection treatments.
Area of Science:
- Infectious Diseases
- Neuroscience
- Pharmacology
Background:
- Central nervous system (CNS) infections caused by multi-drug resistant (MDR) Gram-negative bacteria pose a significant global health challenge.
- The limited antibiotic pipeline necessitates the use of polymyxins (polymyxin B, colistin) as last-resort treatments for MDR Gram-negative infections, including those affecting the CNS.
- MDR Acinetobacter baumannii, Pseudomonas aeruginosa, and Klebsiella pneumoniae are particularly challenging pathogens in CNS infections.
Purpose of the Study:
- To review the current understanding of polymyxin disposition and neurotoxicity mechanisms in the context of CNS infections.
- To explore the potential of neuroprotective agents in mitigating polymyxin-related neurotoxicity.
- To highlight the need for improved pharmacokinetic/pharmacodynamic data to guide safer and more effective intrathecal/intraventricular polymyxin therapy.
Main Methods:
- Literature review of existing studies on polymyxin pharmacokinetics, pharmacodynamics, and neurotoxicity.
- Analysis of mechanisms underlying polymyxin disposition and neurotoxic effects.
- Examination of research on combined therapies involving polymyxins and neuroprotective agents.
Main Results:
- Polymyxins demonstrate efficacy against MDR Gram-negative CNS infections but their use is limited by potential neurotoxicity.
- Current dosing recommendations for intrathecal/intraventricular polymyxins are largely empirical due to insufficient understanding of their CNS behavior.
- Research into polymyxin neurotoxicity mechanisms and neuroprotection strategies is in its early stages.
Conclusions:
- Further research into polymyxin pharmacokinetics/pharmacodynamics and neurotoxicity is essential for optimizing CNS infection treatment.
- Developing strategies to mitigate neurotoxicity will enable safer and more effective use of polymyxins against life-threatening MDR Gram-negative bacterial CNS infections.
- Progress in understanding polymyxin neurotoxicity is critical for advancing therapeutic options for challenging CNS infections.
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