What is the role of colistin in treating bacterial meningitis, particularly in cases with multidrug-resistant organisms and impaired renal function?

Colistin in Bacterial Meningitis

Colistin should be reserved for multidrug-resistant gram-negative bacterial meningitis when no other options exist, and must be administered via combined intravenous plus intrathecal/intraventricular routes to achieve therapeutic CNS concentrations. 1

Role in Multidrug-Resistant Meningitis

Colistin is not a first-line agent for bacterial meningitis but serves as a salvage therapy for carbapenem-resistant gram-negative organisms, particularly Acinetobacter baumannii and Pseudomonas aeruginosa, when these pathogens are susceptible only to polymyxins. 1

Critical Limitation: Poor CNS Penetration

• Intravenous colistin alone achieves inadequate CSF concentrations even with inflamed meninges, with CSF levels reaching only approximately 25% of serum concentrations—insufficient for reliable bacterial eradication. 1, 2
• Monotherapy via IV route has demonstrated poor CNS penetration and should not be relied upon as sole therapy. 1

Recommended Administration Strategy

Combined IV + Intrathecal/Intraventricular Approach

For multidrug-resistant gram-negative meningitis/ventriculitis, administer colistin via both systemic and direct CNS routes simultaneously:

• Intravenous dosing: Loading dose of 9 million IU (300 mg colistin base activity), followed by maintenance dose of 4.5 million IU every 12 hours in patients with normal renal function. 1
• Intrathecal/intraventricular dosing: 125,000 IU once daily via Ommaya reservoir or external ventricular drain. 1
• A loading dose of 500,000 IU intrathecally has been advocated by some experts for more rapid therapeutic effect. 1

This combined approach achieved 89% clinical and bacteriological success in 83 patients with A. baumannii CNS infections. 1

Alternative: Aminoglycosides for Susceptible Organisms

If the organism demonstrates susceptibility to aminoglycosides, intrathecal/intraventricular aminoglycosides (10-50 mg amikacin or 5-20 mg tobramycin daily) constitute a valid alternative to colistin with potentially better safety profiles. 1

Dosing Considerations in Renal Impairment

Critical Principle: Always Give Full Loading Dose

Never reduce the loading dose of 9 million IU regardless of renal function—this is essential to rapidly achieve therapeutic levels and prevent treatment failure. 3, 4, 5

Maintenance Dose Adjustments

Adjust only maintenance doses based on creatinine clearance: 5

• CrCl ≥80 mL/min: 4.5 million IU every 12 hours
• CrCl 50-79 mL/min: 2.5-3.8 mg/kg divided into 2 doses daily
• CrCl 30-49 mL/min: 2.5 mg/kg once daily
• CrCl 10-29 mL/min: 1.5 mg/kg every 36 hours

Intrathecal/Intraventricular Dosing Remains Unchanged

The intrathecal/intraventricular dose of 125,000 IU daily does not require adjustment for renal impairment, as this route bypasses systemic clearance. 1

Nephrotoxicity Management

High Risk Profile

Colistin carries definitive nephrotoxicity with an incidence of approximately 36-39% in critically ill patients, representing a 2.4-fold increased risk compared to β-lactam regimens. 3, 6

Mandatory Monitoring

• Monitor renal function 2-3 times weekly during therapy. 1, 3, 4
• Acute kidney injury during colistin treatment is a major predictor of clinical failure and mortality. 1, 3

Risk Mitigation Strategies

• Avoid concomitant nephrotoxins (especially aminoglycosides systemically) unless absolutely necessary. 4, 6
• Correct shock states, hypoalbuminemia, and other nephrotoxic exposures. 3, 6
• Consider sulbactam as alternative for A. baumannii with MIC ≤4 mg/L, which demonstrates better safety profile. 1, 3

Critical Pitfall to Avoid

Do not underdose colistin in an attempt to reduce nephrotoxicity—subtherapeutic levels lead to treatment failure and increased mortality while still carrying nephrotoxic risk. 3, 4

Duration of Therapy

• Continue antimicrobial therapy for 3 weeks for gram-negative meningitis/ventriculitis. 1
• Monitor CSF sterilization with serial cultures to guide duration. 1
• Three negative CSF cultures on separate days are required before discontinuing intrathecal/intraventricular therapy. 1

Combination Therapy Considerations

Colistin should be combined with one or more additional agents to which the pathogen displays in vitro susceptibility whenever possible. 1

• If no susceptible second agent is available, combine colistin with a second or third agent (e.g., carbapenem) with the lowest MIC, even if technically "resistant." 1
• Evidence for combination superiority over monotherapy remains controversial for systemic infections, but the principle of avoiding monotherapy for serious CNS infections is prudent. 1

Preferred Alternatives When Available

• Meropenem remains the drug of choice for nosocomial gram-negative meningitis when organisms are susceptible. 1
• For carbapenem-resistant organisms with low sulbactam MIC (≤4 mg/L), high-dose sulbactam (9-12 g/day) may be preferable given superior safety profile. 1
• Fluoroquinolones (ciprofloxacin, moxifloxacin) should be considered for multidrug-resistant gram-negative meningitis when patients cannot receive or have failed standard therapy. 1

Safety in Hepatic Impairment

Colistin is safe to use in patients with transaminitis and liver disease as it is renally cleared and requires no dose adjustment for hepatic impairment. 7

• Dose adjustment is based solely on creatinine clearance, not liver enzymes. 7
• Do not withhold colistin based on elevated transaminases alone. 7