Concentration Dependent Antibiotic Killing

Concentration-dependent killing means that the rate and extent of bacterial killing increase as drug concentration rises over the MIC. The best-known examples are the aminoglycosides, fluoroquinolones, daptomycin, metronidazole, polymyxins and, to a degree, azithromycin. The pharmacodynamic index is the peak (Cmax) to MIC ratio for aminoglycosides and the AUC24/MIC ratio for fluoroquinolones, daptomycin and polymyxins.

Mechanism. Higher concentrations produce faster, more complete killing, often with a prolonged post-antibiotic effect, which allows long drug-free intervals without regrowth. A peak concentration of 8 to 10 times the MIC with aminoglycosides gives better outcomes and lower resistance emergence. High peaks also close the mutant selection window, the range between the MIC and the mutant prevention concentration in which resistant mutants are selected.

Adaptive resistance. Aminoglycoside uptake falls after the first exposure and recovers over several hours; once-daily dosing exploits this to restore uptake and reduce toxicity.

• Aminoglycosides: target peak over 8 to 10 times the MIC; the PAE lasts several hours.
• Fluoroquinolones: AUC24/MIC over 125 for Gram-negatives (including Pseudomonas) and 30 to 40 for pneumococci; underdosing selects resistance.
• Daptomycin: higher doses (8 to 12 mg/kg) in bacteraemia, enterococcal and bone infection to improve killing and prevent resistance.
• Metronidazole: rapidly bactericidal; the exposure target is met with once-daily or twice-daily dosing in some settings, though three-times-daily dosing is usual.
• Polymyxins: AUC24/MIC with loading doses to reach early target.

Strategies.

• Give the full daily dose of aminoglycosides once daily (gentamicin 5 to 7 mg/kg, amikacin 15 to 20 mg/kg), adjusting the interval by a level at 6 to 14 hours.
• Use high-dose fluoroquinolone regimens (ciprofloxacin 750 mg every 12 hours, levofloxacin 750 mg daily) for Pseudomonas and serious Gram-negative infection when the drug is appropriate.
• Use weight-based daptomycin dosing with the dose increased for bacteraemia and enterococcal infection.
• Use loading doses for colistin and polymyxin B.
• Avoid under-dosing and avoid dividing concentration-dependent drugs into small frequent doses.

Exceptions. Once-daily aminoglycoside dosing is not used in pregnancy, dialysis, severe burns, cystic fibrosis with altered kinetics, endocarditis synergy dosing, or neonates without adaptation.

Risks. Toxicity of aminoglycosides depends on trough accumulation and duration, not peak, so the drug-free interval reduces nephrotoxicity and ototoxicity. Fluoroquinolone toxicity (tendon, CNS, QT) is dose- and exposure-related. Daptomycin myopathy is linked to trough levels and renal impairment.

Monitoring. Aminoglycoside levels (pre-dose under 1 mg/L), creatinine every 2 to 3 days, audiometry in prolonged courses; creatine kinase weekly with daptomycin; ECG and tendon symptoms with fluoroquinolones; renal function with polymyxins.

Special groups. Renal impairment: lengthen the interval rather than reducing the dose to keep the peak; use levels. Obesity: use adjusted weight for aminoglycosides. Critical illness: larger volume of distribution lowers peaks, so a full loading dose is needed. Region: gentamicin is the most available agent in East Africa, so correct once-daily dosing, creatinine monitoring and avoidance of prolonged courses are the practical safeguards.