title: Suboptimal antimicrobial drug exposure in patients with renal impairment.
abstract: BACKGROUND
  Recommendations on drug dose adjustment in patients with renal impairment may vary between the references. It is often unknown which approach the dosing schemes were based on and what drug exposure is likely to be achieved.
  
  
  OBJECTIVE
  To develop a simple method to evaluate recommended dosing schemes for patients with renal impairment, to apply this method to selected antibacterial drugs in order to evaluate expected drug concentrations using dosing schemes recommended for patients with severe infections, and to evaluate the expected consequences.
  
  
  METHODS
  This was a theoretical study, which was based on data from published clinical trials.
  
  
  METHODS
  Clinically established dosing schemes for 46 antibacterial drugs, as recommended for patients with renal impairment in the Summary of Product Characteristics, were analysed using a newly developed graphical method. Consistency of the dosing schemes with two general dose adjustment rules, the proportional rule and the eliminated fraction rule, was determined and drug exposure was predicted.
  
  
  METHODS
  Predicted drug exposure. Consistency of recommended dosing schemes with the general dose adjustment rules.
  
  
  RESULTS
  Only 30% of the recommended dosing schemes were associated with similar average concentrations as expected in patients with normal renal function (44 % were associated with higher and 26% with lower concentrations). The highest median exposure was found in beta-lactams (170%, range 58-443%, for creatinine clearance of <15 ml/min, and 155%, range 54-232%, for creatinine clearance of 15 to <30 ml/min), where the medians were significantly different from 100% (P < 0.02). Consistency with a dosing rule was found in 59% of the dosing schemes (proportional rule 46%, eliminated fraction rule 50%, both rules 4%).
  
  
  CONCLUSIONS
  Relative low exposure was found for several drugs, including ceftazidime, cefotaxime, imipenem, erythromycin, ciprofloxacin, levofloxacin, and teicoplanin, where dosing schemes should be reconsidered or used only in clinical situations where a lower than maximum exposure appears adequate. General application of the proportional rule for calculating drug dose adjustments would lead to lower than clinically established dose practice for 44% of drugs.
authors.affiliation: Department of Clinical Pharmacology and Pharmacoepidemiology, University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany. david.czock@med.uni-heidelberg.de.
authors.forename: David
authors.initials: D
authors.lastname: Czock
authors.affiliation: Department of Nuclear Medicine, University Hospital Ulm, Ulm, Germany.
authors.forename: Martino
authors.initials: M
authors.lastname: Spitaletta
authors.affiliation: Division of Nephrology, Department of Internal Medicine I, University Hospital Ulm, Ulm, Germany.
authors.forename: Frieder
authors.initials: F
authors.lastname: Keller
mesh_terms: D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D001424:Bacterial Infections / Q000150:complications* / Q000188:drug therapy*; D054796:Drug Dosage Calculations; D006801:Humans; D008954:Models, Biological; D051437:Renal Insufficiency / Q000150:complications* / Q000382:microbiology
chemical_list: D000900:Anti-Bacterial Agents
keywords: Antibiotics; Dose adjustment; PKnephro database; Pharmacokinetics; Renal impairment