Intraventricular or intrathecal colistin for the treatment of central nervous system infections caused by multidrug-resistant Gram-negative bacteria

Abstract

Central nervous system infections caused by Gram-negative bacteria susceptible only to colistin are rare but life-threatening and increasing in prevalence. Given the current antibiotic development pipeline it is likely that the paucity of therapeutic options will continue for the next years. Colistin is an amphipathic bactericidal antibiotic which is administered systemically as colistin methanesulfonate (also known as colistimethate sodium). Colistin methanesulfonate is the inactive prodrug, and in cerebrospinal fluid undergoes spontaneous hydrolysis to colistin (the active form with antimicrobial activity). In this review, we describe and evaluate the clinical and experimental data supporting the use of intraventricular (IVT) or intrathecal (IT) colistin against multidrug-resistant Gram-negative infections of the central nervous system, describe the permeability of the blood-brain barrier to colistin, the pharmacokinetics of colistin after IVT administration of colistin methanesulfonate, its anti-endotoxin activity, discuss the opportunity to administer colistin intraventricularly or intrathecally and the dose regimen, and provide recommendations based on the available evidence.

Keywords::

• blood–brain barrier
• cerebrospinal fluid
• colistin
• intraventricular
• meningitis
• ventriculitis

Acknowledgement

We thank R Stenner for her linguistic revision of this manuscript.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• CNS infections caused by Gram-negative bacteria susceptible only to colistin are rare but life-threatening and increasing.

• Colistin methanesulfonate and colistin cross the blood–cerebrospinal fluid (CSF) and blood–brain barriers poorly even if the meninges are inflamed. Therefore, the intraventricular (IVT) and intrathecal (IT) routes of administration are the only reasonable routes to attain appropriate concentrations of colistin in the CSF.

• Colistin methanesulfonate, which is the inactive prodrug, in CSF undergoes spontaneous but non-linear hydrolysis to colistin (the active form with antimicrobial activity).

• Published experimental, pharmacokinetic and clinical data indicate that the use of IVT or IT colistin is effective and safe. Neurotoxicity, mainly aseptic meningitis, is frequent, but generally resolves without sequelae.

• CNS infections caused by Gram-negative bacteria are frequently associated with the presence of a ventricular catheter. Since these infections are very severe, it is advisable to replace the catheter.

• The daily dose of IVT or IT colistin methanesulfonate in adult patients suggested by Infectious Diseases Society of America is 10 mg (about 120,000 IU); randomized controlled studies are not available for definite conclusions.

Notes