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Clin Pharmacokinet 2002; 41 (10): 791-792 0312-5963/02/0010-0791/$25.00/0 © Adis International Limited. All rights reserved.
Aminoglycoside Dosage Regimens After Therapeutic Drug Monitoring In a recent paper, Tod et al.[1] reported on the available methods of dose-individualisation for ‘once daily’ aminoglycoside therapy. The area under the curve (AUC) method proposed by Begg et al.[2] was discussed but, unfortunately, was misunderstood. Tod et al. stated that this method was ‘based on the implicit assumption that antibacterial effect and toxicity are related only to AUC, and that the shape of the concentration-time profile is not important’. We were surprised that the method was interpreted in this way, because for aminoglycosides the shape of the concentration-time profile is critically important. The method should perhaps have been called the ‘high peak, very low trough, AUC method’ to avoid ambiguity. The AUC method was developed to take into account the newer findings about aminoglycosides, i.e. concentration-dependent killing, postantibiotic effect and adaptive resistance. The major ideals of this method were to achieve: (i) the highest peak possible to maximise concentrationdependent killing and the post-antibiotic effect, and; (ii) a low or ‘drug free’ period within the administration interval to assist with the reversal of adaptive resistance and to decrease drug accumulation (and therefore toxicity). The concept of targeting an ‘AUC’ was to maintain control over the total drug exposure, while enabling high peak concentrations. The AUC chosen was that equivalent to the 24-hour AUC in patients with normal renal function receiving a conventional regimen aiming for a peak of 8 mg/L and a trough of 1.5 mg/L, i.e. approximately 100 mg • h/L. In order for ‘once daily administration’, perhaps better termed ‘extended interval administration’, to be distinguished from conventional regimens, a ‘threshold’ for the peak concentration of >10 mg/L was defined, i.e. greater than the 6 to 10 mg/L often
recommended for multiple daily administration. This optimises the pharmacokinetic-pharmacodynamic profile of gentamicin, i.e. the ratio of peak concentration to minimum inhibitory concentration (Cmax/MIC). We also have some reservations about the conclusions by Tod et al.[1] that the Hartford nomogram is the preferred method because of its simplicity and strong rationale with regard to current knowledge of aminoglycoside pharmacodynamics. First, there is no evidence that once daily administration requires less monitoring than conventional regimens. With conventional regimens, dose-individualisation methods were superior to nomograms at achieving desired peak and trough concentrations.[3] Why should we regress to nomograms with once daily administration? The AUC method is a more scientific approach to individualised once daily administration that also enables rational dose adjustment thereafter. Furthermore, there is increasing evidence that it is easy to overdose patients when the Hartford nomogram is used,[4,5] which may be accompanied by increased ototoxicity.[6,7] In summary, the ‘AUC method’ is actually a ‘high peak, very low trough, AUC method’ that is easy to use and continues the ideals of concentration monitoring that have been established for the aminoglycosides. It is easy to perform by simple one-compartment calculations or Bayesian methods.[8,9] It is widely used in Australia and New Zealand.
Carl M.J. Kirkpatrick Department of Clinical Pharmacology Christchurch Hospital Christchurch New Zealand Evan J. Begg Department of Clinical Pharmacology Christchurch Hospital Christchurch New Zealand
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Murray L. Barclay Department of Clinical Pharmacology Christchurch Hospital Christchurch New Zealand
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Stephen B. Duffull School of Pharmacy University of Queensland Brisbane Australia
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7. 8.
References 1. Tod MM, Padoin C, Petitjean O. Individualising aminoglycoside dosage regimens after therapeutic drug monitoring: simple or complex pharmacokinetic methods? Clin Pharmacokinet 2001; 40 (11): 803-14 2. Begg EJ, Barclay ML, Duffull SB. A suggested approach to
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once-daily aminoglycoside dosing. Br J Clin Pharmacol 1995; 39: 605-9 Begg EJ, Barclay ML. Aminoglycosides -50 years on. Br J Clin Pharmacol 1995; 39: 597-603 Finnell DL, Davis GA, Cropp CD, et al. Validation of the Hartford nomogram in trauma surgery patients. Ann Pharmacother 1998; 32 (4): 417-21 Kirkpatrick CMJ, Duffull SB, Begg EJ. Once-daily aminoglycoside therapy: potential ototoxicity. Antimicrob Agents Chemother 1997; 41 (4): 879-80 Singer C, Smith C, Kreiff D. Once-daily aminoglycoside therapy: potential ototoxicity. Antimicrob Agents Chemother 1996; 40 (9): 2209-11 El Bakri F, Pallett A, Smith AG, et al. Ototoxicity induced by once-daily gentamicin. Lancet 1998; 351: 1407-8 Duffull SB, Kirkpatrick CMJ, Begg EJ. Comparison of two Bayesian approaches to dose-individualisation for once-daily aminoglycoside regimens. Br J Clin Pharmacol 1997; 43: 125-35 Kirkpatrick CMJ, Duffull SB, Begg EJ. Pharmacokinetics of gentamicin in 957 patients with varying renal function dosed once daily. Br J Clin Pharmacol 1999; 47: 637-43
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