Aminoglycosides exhibit concentration-dependent bactericidal activity. A clinical pharmacologist explains that once-daily dosing ('extended interval dosing') achieves better efficacy and reduced nephrotoxicity compared to traditional thrice-daily dosing. What are the two pharmacodynamic/pharmacokinetic principles underlying this rationale?

• A Once-daily dosing reduces the duration of drug exposure (time above MIC) and minimizes cumulative renal tubular drug accumulation by allowing drug-free 'washout' intervals
• B Once-daily dosing reduces protein binding saturation and increases the volume of distribution, improving tissue penetration
• C High peak-to-MIC ratio achieves concentration-dependent killing and the 'post-antibiotic effect' (PAE) maintains bactericidal effect during the trough; drug-free washout intervals prevent saturation of renal proximal tubule transport, reducing nephrotoxicity ✓
• D Single large doses trigger adaptive resistance mechanisms that paradoxically protect against gram-positive coverage while maintaining gram-negative efficacy

Explanation

Aminoglycosides exhibit concentration-dependent killing — the higher the peak concentration relative to MIC, the greater the rate and extent of bacterial killing. Once-daily dosing achieves a much higher Cmax (peak:MIC ratio typically >10), maximizing concentration-dependent bactericidal effect. Additionally, aminoglycosides produce a prolonged post-antibiotic effect (PAE) of 2-8 hours after drug concentrations fall below MIC, maintaining antibacterial effect during the low-concentration trough period. For nephrotoxicity: aminoglycosides are taken up by saturable transporters (megalin/cubilin) in renal proximal tubular cells. With once-daily dosing, the trough period allows tubular cell saturation to reverse and drug to exit cells ('washout'), reducing cumulative intracellular aminoglycoside accumulation and nephrotoxicity.

Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.