Pharmacological considerations for the proper clinical use of aminoglycosides.
ABSTRACT Aminoglycosides constitute one of the oldest classes of antimicrobials. Despite their toxicity, mainly nephrotoxicity and ototoxicity, aminoglycosides are valuable in current clinical practice, since they retain good activity against multidrug-resistant Gram-negative pathogens, such as Pseudomonas aeruginosa and Acinetobacter spp. Time-kill studies have shown a concentration-dependent and partially concentration-dependent bacterial killing against Gram-negative and Gram-positive bacteria, respectively. Pharmacodynamic data gathered over recent decades show that the administration of aminoglycosides by an extended-interval dosing scheme takes advantage of the maximum potential of these agents, with the goal of achieving an area under the concentration-time curve (AUC) of 100 mg · h/L over 24 hours and a peak plasma drug concentration (C(max)) to minimum inhibitory concentration (MIC) ratio of 8-10. Several clinical conditions that are common in seriously ill patients result in expansion of the extracellular space and can lead to a lower than desirable C(max) with the usual loading dose. Extended-interval dosing schemes allow adequate time to decrease bacterial adaptive resistance, a phenomenon characterized by slow concentration-independent killing. Adaptive resistance is minimized by the complete clearance of the drug before the subsequent dose, thus favouring the extended-interval dosing schemes. The efficacy of these schemes is also safeguarded by the observed post-antibiotic sub-MIC effect and post-antibiotic leukocyte enhancement, which inhibit bacterial regrowth when the serum aminoglycoside levels fall below the MIC of the pathogen. In everyday clinical practice, aminoglycosides are usually used empirically to treat severe sepsis and septic shock while awaiting the results of antimicrobial susceptibility testing. The European Committee on Antimicrobial Susceptibility Testing acknowledges the regimen-dependent nature of clinical breakpoints for aminoglycosides, i.e. of MIC values that classify bacterial isolates into sensitive or resistant, and bases its recommendations on extended-interval dosing. To a large extent, the lack of correlation between in vitro antimicrobial susceptibility testing and clinical outcome is derived from the fact that the available clinical breakpoints for aminoglycosides are set based on mean pharmacokinetic parameters obtained in healthy volunteers and not sick patients. The nephrotoxicity associated with once- versus multiple-daily administration of aminoglycosides has been assessed in numerous prospective randomized trials and by several meta-analyses. The once-daily dosing schedule provides a longer time of administration until the threshold for nephrotoxicity is met. Regarding ototoxicity, no dosing regimen appears to be less ototoxic than another. Inactivation of aminoglycosides inside the bacterial pathogens occurs by diverse modifying enzymes and by operation of multidrug efflux systems, making both of these potential targets for inhibition. In summary, despite their use for several decades, the ideal method of administration and the preferred dosing schemes of aminoglycosides for most of their therapeutic indications need further refinement. Individualized pharmacodynamic monitoring has the potential of minimizing the toxicity and the clinical failures of these agents in critically ill patients.
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ABSTRACT: Therapeutic drug monitoring of patients receiving once daily aminoglycoside therapy can be performed using pharmacokinetic (PK) formulas or Bayesian calculations. While these methods produced comparable results, their performance has never been checked against full PK profiles. We performed a PK study in order to compare both methods and to determine the best time-points to estimate AUC0-24 and peak concentrations (C max). We obtained full PK profiles in 14 patients receiving a once daily aminoglycoside therapy. PK parameters were calculated with PKSolver using non-compartmental methods. The calculated PK parameters were then compared with parameters estimated using an algorithm based on two serum concentrations (two-point method) or the software TCIWorks (Bayesian method). For tobramycin and gentamicin, AUC0-24 and C max could be reliably estimated using a first serum concentration obtained at 1 h and a second one between 8 and 10 h after start of the infusion. The two-point and the Bayesian method produced similar results. For amikacin, AUC0-24 could reliably be estimated by both methods. C max was underestimated by 10-20 % by the two-point method and by up to 30 % with a large variation by the Bayesian method. The ideal time-points for therapeutic drug monitoring of once daily administered aminoglycosides are 1 h after start of a 30-min infusion for the first time-point and 8-10 h after start of the infusion for the second time-point. Duration of the infusion and accurate registration of the time-points of blood drawing are essential for obtaining precise predictions.European Journal of Clinical Pharmacology 04/2014; · 2.70 Impact Factor
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ABSTRACT: The aim of this study was to develop a semi-mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model to evaluate the in vitro synergy between vertilmicin and ceftazidime against Pseudomonas aeruginosa. The in vitro antimicrobial activity of vertilmicin alone was initially assessed by static and dynamic time-kill experiments against three bacterial strains, including MSSA, MRSA and P. aeruginosa. The combined killing effect with ceftazidime was then evaluated in a static time-kill study against P. aeruginosa. Vertilmicin displayed a concentration-dependent killing effect against the three bacterial strains, and its short half-life may possibly have a dramatic impact on antimicrobial activities. A two-compartment pharmacodynamic model consisting of drug-susceptible and -resistant compartments was developed to characterise the relationship between drug exposure and bacterial response for the time-kill curves from both monotherapy and combination therapy. Loewe additivity was incorporated into the pharmacodynamic model to describe the drug-drug interactive effect in the combination therapy. For monotherapy, the estimated EC50 of the dynamic time-kill study against each strain was close to its MIC but was higher than that of the static time-kill study. The EC50 of combination therapy was estimated at 2.67mg/L compared with 4.54mg/L in monotherapy, indicating an enhanced bactericidal capacity. The drug-drug interactive effect was not significantly synergistic but highly varied at each specific combination. Potential synergistic combinations could be screened using PK/PD modelling and simulation. These results demonstrated that PK/PD modelling provides an innovative approach to assist dose selection of combination vertilmicin and ceftazidime for future clinical study design. Copyright © 2014 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.International Journal of Antimicrobial Agents 11/2014; · 4.26 Impact Factor
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ABSTRACT: Despite their inherent toxicity and the acquired bacterial resistance that continuously threaten their long-term clinical use, aminoglycosides (AGs) still remain valuable components of the antibiotic armamentarium. Recent literature shows that the AGs' role has been further expanded as multi-tasking players in different areas of study. This review aims at presenting some of the new trends observed in the use of AGs in the past decade, along with the current understanding of their mechanisms of action in various bacterial and eukaryotic cellular processes.Medicinal Chemistry Communication 07/2014; 5(8). · 2.63 Impact Factor