Impact of high-flux haemodialysis on the probability of target attainment for oral amoxicillin/clavulanic acid combination therapy

Int J Antimicrob Agents. 2017 Jul;50(1):110-113. doi: 10.1016/j.ijantimicag.2017.02.021. Epub 2017 May 11.

Abstract

Clearance of small molecules such as amoxicillin and clavulanic acid is expected to increase during high-flux haemodialysis, which may result in lower concentrations and thus reduced efficacy. To date, clearance of amoxicillin/clavulanic acid (AMC) during high-flux haemodialysis remains largely unexplored. Using published pharmacokinetic parameters, a two-compartment model with first-order input was simulated to investigate the impact of high-flux haemodialysis on the probability of target attainment (PTA) of orally administered AMC combination therapy. The following pharmacokinetic/pharmacodynamic targets were used to calculate the PTA. For amoxicillin, the time that the free concentration remains above the minimum inhibitory concentration (MIC) of ≥50% of the dosing period (≥50%ƒT>MIC) was used. For clavulanic acid, the time that the free concentration was >0.1 mg/L of ≥45% of the dosing period (≥45%ƒT>0.1 mg/L) was used. Dialysis clearance reported in low-flux haemodialysis for both compounds was doubled to represent the likely clearance during high-flux haemodialysis. Monte Carlo simulations were performed to produce concentration-time profiles over 10 days in 1000 virtual patients. Seven different regimens commonly seen in clinical practice were explored. When AMC was dosed twice daily, the PTA was mostly ≥90% for both compounds regardless of when haemodialysis commenced. When administered once daily, the PTA was 20-30% for clavulanic acid and ≥90% for amoxicillin. The simulations suggest that once-daily orally administered AMC in patients receiving high-flux haemodialysis may result in insufficient concentrations of clavulanic acid to effectively treat infections, especially on days when haemodialysis occurs.

Keywords: Amoxicillin/clavulanic acid; Antibiotics; Haemodialysis; Monte Carlo simulation.

MeSH terms

  • Amoxicillin-Potassium Clavulanate Combination / administration & dosage*
  • Amoxicillin-Potassium Clavulanate Combination / pharmacokinetics*
  • Anti-Bacterial Agents / administration & dosage*
  • Anti-Bacterial Agents / pharmacokinetics*
  • Drug Therapy, Combination / methods
  • Humans
  • Microbial Sensitivity Tests
  • Monte Carlo Method
  • Plasma / chemistry
  • Renal Dialysis / methods*
  • Time Factors
  • beta-Lactamase Inhibitors / administration & dosage*
  • beta-Lactamase Inhibitors / pharmacokinetics*

Substances

  • Anti-Bacterial Agents
  • beta-Lactamase Inhibitors
  • Amoxicillin-Potassium Clavulanate Combination