Guest posting : Dr Jonathan Ash, Advanced training registrar, John Hunter Hospital.

Ventriculitis is a rare but potentially disastrous complication of external ventricular drain placement, and with increasing rates of multi-drug resistant organisms, effective parenteral antibiotic choices are limited.

Colistin has an established role in the treatment of infections caused by MDR Gram negatives, particularly Acinetobacter baumannii and Pseudomonas aeruginosa. However, penetration into the CSF with systemic administration is poor- only approximately 5% of the concentration of the systemic circulation reached. In contrast to beta-lactam agents, CSF penetration does not increase significantly in the presence of inflamed meninges. As a result, direct inoculation of the CSF is required to allow sufficient concentrations of colistin for antimicrobial effect.

Limited pharmacokinetic data has demonstrated that administration of >62,500 IU/daily of colistimethate sodium (CMS) via the intraventricular route (IVT) results in CSF concentrations continuously >2 mcg/mL, exceeding the MIC for MDR gram-negative organisms including P. aeruginosa, A. baumannii and K. pneumoniae. There is significant inter-patient variability in CSF colistin levels, which could result from several factors including:

• Hydrolysis of CMS to (the active agent) colistin (not complete)
• The volume of CSF
• Volume of CSF drained externally and spontaneous clearance of CSF drug
• Non-uniform distribution within the CSF

Importantly, it has been shown that with total daily doses of up to 125,000 IU (approx. 4 mg colistin base or 10 mg CMS) in those draining <70 mL CSF/day, accumulation does not occur.

These pharmacokinetic variations result in a recommended 125,000 IU/daily dosing in IDSA guidelines. An important  recent review of intraventricular colistin identified 169 patients that received IVT colistin in the literature (either alone [15 cases] or in combination with IV colistin or other systemic antibiotics). Pooled results demonstrated highest cure rates with daily dosing of at least 125,000 IU for a period of at least 21 days. Although interestingly, the 15 cases treated with IVT colistin monotherapy were all reported to have had a ‘cure,’ it is generally recommended to use combination IVT/IV therapy. Also, rather arbitrarily, it is recommended to clamp the EVD for between 20-60 minutes post dosing, while it may also be prudent to aspirate a few mL of CSF prior to administration to limit the potential for raised intracranial pressure.

Adverse events attributed to IVT colistin were uncommon (4%) which included seizures, chemical meningitis and one case of cauda equina syndrome. All complications resolved with discontinuation of therapy.

Whilst not recommended as first line therapy, observational evidence suggests that intraventricular colistin could be an alternative therapy in ventriculitis by MDR gram negative organisms not responding to systemic therapy alone, where a reasonable regimen would be 125,000 IU via an EVD combined with systemic therapy for a period of 21 days.

DOSING NOTE: All dosing is for CMS, there are 2 different companies that market CMS which use different units of measurement just to confuse everyone.  The first is Colomycin (Dumex-Alpharma A/S, Copenhagen, Denmark) which is measured in IU (what most articles in literature seem to use) where 80mg = 1,000,000 IU. The second (which is used in HNELHD) is Coly-Mycin (Parkedale Pharmaceuticals, NY, USA) which is measured as colistin base where 150mg colistin base is approx 4,500,000 IU.

References

1. Imberti R, Cusato M, Accetta G, Marinò V, Procaccio F, Del Gaudio A, Iotti GA, Regazzi M. Cerebrospinal fluid pharmacokinetics of colistin after intraventricular administration of colistin methanesulfonate. Antimicrob. Agents Chemother. 2012; 56(8):4416–4421.
2. Bargiacchi O, De Rosa FG. Intrathecal or intraventricular colistin: a review. Infez Med. 2016;24(1):3-11.

3. Nation-R et al. Dosing Guidance for Intravenous Colistin in Critically Ill Patients. Clin Infect Dis (2017) 64 (5): 565-571. Excellent recent summary.

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