Differences in Antimicrobial Drug Exposures
Study Objective: To calculate and compare 24-hour area under the unbound drug concentration-time curves (AUC_0-24) of antimicrobials with dosing recommendations from six commonly used dosing references.
Intervention: Unbound plasma concentration-time profiles of 13 antimicrobial agents (4 penicillins, 3 cephalosporins, 2 carbapenems, aztreonam, 3 fluoroquinolones) were simulated at steady state using a one-compartment open model for a 70-kg adult based on pharmacokinetic parameters obtained from peer-reviewed literature. Simulations were performed at five levels of creatinine clearance (Cl_cr).
Measurements and Main Results: Differences in AUC_0-24 for each antimicrobial agent were noted among the six references at each level of Cl_cr as well as within references across the range of Cl_cr. In addition, up to 16-fold and 3-fold ranges in AUC_0-24 values were observed for




-lactams and fluoroquinolones, respectively, in one reference based on dosing recommendations at a single level of Cl _cr (due to more than one dose and/or dosing interval).
Conclusion: Clinicians should be aware of differences among common references when selecting dosages of antimicrobial agents, especially for patients with moderate-to-severe renal impairment.


Drugs that are eliminated primarily by glomerular filtration have prolonged serum half-lives as a result of decreased clearance in patients with renal impairment. Depending on the extent of renal impairment, drug regimens may be altered by adjusting the dose and/or dosing interval to avoid accumulation and potential toxicity while maintaining clinically effective drug concentrations. Fortunately, references are available to help clinicians determine appropriate dosages of antimicrobials in patients with altered renal function. One would assume that recommendations among these references would be similar in terms of recommended doses and dosing intervals. Furthermore, one might assume that recommendations for patients with renal impairment would result in similar daily drug exposure, as reflected by the 24-hour area under the unbound drug concentration-time profile (AUC_0-24), compared with those with normal renal function. However, references that routinely recommend higher than necessary dosages in patients with impaired renal function may increase the chance of toxicity without adding clinical benefit. It may be possible to alter such regimens, such as administering smaller dosages, resulting in cost savings in terms of drug costs as well as avoiding costs associated with drug-related toxicity. We assessed variability among six standard references for patients with normal and various degrees of renal impairment that often are encountered in clinical practice by comparing the resulting drug exposure using recommended regimens from these sources.