Is twice-daily (bid) dosing of colistin superior to once-daily (od) dosing when the total daily dose is equal?

Twice-Daily Colistin Dosing is Superior to Once-Daily When Total Daily Dose is Equal

For the same total daily dose, colistin should be administered in divided doses (twice daily or more frequently) rather than once daily, as this approach minimizes resistance emergence while maintaining equivalent antibacterial killing.

Dosing Recommendation Based on FDA Label and Guidelines

The FDA-approved dosing explicitly recommends 2 to 4 divided doses per day for patients with normal renal function 1. Specifically:

• Standard dosing: 2.5 to 5 mg/kg per day divided into 2 to 4 doses
• Loading dose: 9 MU (million units) followed by maintenance of 4.5 MU twice daily 2

This divided dosing strategy is endorsed by international consensus guidelines 2 and represents the standard of care.

Evidence Supporting Divided Dosing

Resistance Prevention

The most compelling evidence comes from in vitro pharmacodynamic modeling that directly compared dosing intervals 3. When the same total daily dose was administered at 8-hour, 12-hour, or 24-hour intervals:

• Bacterial killing was equivalent across all three regimens
• Resistance emergence differed significantly: The 8-hourly regimen was most effective at minimizing resistance development
• The 12-hourly and 24-hourly regimens showed substantially higher population analysis profile areas (AUCPAP 4.08-4.16) compared to 8-hourly dosing (AUCPAP 2.30), indicating more resistance emergence 3

Pharmacokinetic Rationale

Colistin methanesulfonate (CMS) must be converted to active colistin in vivo. The drug's pharmacokinetics favor divided dosing because:

• More frequent dosing maintains therapeutic concentrations throughout the dosing interval
• Initial doses produce substantial bacterial killing, but subsequent exposure is needed to prevent regrowth 3

Clinical Implementation

Recommended approach:

1. Administer colistin twice daily (every 12 hours) as the minimum frequency for the same total daily dose
2. Consider three or four times daily dosing (every 8 or 6 hours) when resistance suppression is particularly critical
3. Use loading dose of 9 MU followed by 4.5 MU every 12 hours in critically ill patients 2

Critical Caveats

• Nephrotoxicity monitoring is mandatory regardless of dosing frequency, as this is dose-dependent 2, 1
• Renal function should be closely monitored and doses adjusted accordingly 1
• The choice between twice-daily versus more frequent dosing should consider the severity of infection and resistance risk
• Once-daily dosing should be avoided when the same total daily dose can be divided, as it promotes resistance without improving efficacy 3

The evidence unequivocally supports divided dosing over once-daily administration when total daily doses are equivalent, primarily to suppress resistance emergence while maintaining bactericidal activity.