The Pharmacodynamics of Aminoglycosides

Abstract

Recently, a more complete understanding of the pharmacodynamics of aminoglycosides has been recognized, indicating that this class of antibiotics exhibits both concentration-dependent bactericidal activity and a postantibiotic effect. This pharmacodynamic information, along with better knowledge of the mechanisms responsible for aminoglycoside toxicity, established the foundation for once-daily aminoglycoside dosing regimens. This new approach to aminoglycoside dosing appears to be safe, efficacious, and cost-effective, resulting in its increasing popularity in clinical practice.Although aminoglycoside antibiotics have been used sucat the binding site for a finite period of time [5]. The presence cessfully for ú50 years [1], recent data suggest that the convenof the antibiotic prohibits normal biochemical reactions and, tional dosing approach has not optimized bacterial killing. therefore, the organism dies. The concentration needed to ocThese recent observations, together with a more complete uncupy the critical number of sites necessary for this to occur is derstanding of pharmacodynamics, have led to the application not known. However, an easily measured and probably proporof new aminoglycoside dosing regimens [2, 3]. In this report tional concentration, such as the MIC or the MBC, is used in we discuss the pharmacodynamics of aminoglycosides and the its place. new dosing strategies for this class of antibiotics.It is also important to realize that the concentration of drug The in vitro antimicrobial spectrum of activity of the aminoin the area of binding sites is controlled by drug concentration glycosides includes a broad range of aerobic gram-negative in the media in which bacteria reside, usually interstitial-like bacilli, many staphylococci, and certain mycobacteria [4].fluid. Antibiotics in such fluids have generally been found to Aminoglycosides exert their bactericidal effects by irreversibly rapidly become in equilibrium with the blood; therefore, antibibinding to the 30S ribosomal subunit of susceptible bacteria, otic blood (serum, plasma) concentrations are an important which results in the inhibition of protein synthesis [4]. An parameter in bactericidal activity. Bactericidal activity is thereenergy-and oxygen-dependent transport mechanism is required fore a function of antibiotic concentration in the serum and the for aminoglycosides to penetrate the outer bacterial membrane duration of time that antibiotic exists in the body. of susceptible bacteria [4]. It is for this reason that this classIn pharmacodynamic terms, one can say that bactericidal of antibiotics demonstrates poor activity against anaerobes and activity is a function of the time that serum concentrations has decreased ability to penetrate the bacteria within abscesses remain above some critical value, i.e., the MIC. Pharmacokinetthat may have limited oxygen.ically, the product of concentration and time is termed the area In general, the aminoglycosides are clinically used in the under the serum-time curve (AUC), and therefore it i...

Efficacy of zincoderm G cream against wound infection by Pseudomonas aeruginosa in Sprague-Dawley rats

“…Previous studies have repeatedly demonstrated a concentration-dependent killing effect of aminoglycosides against Gram-negative bacteria. [7][8][9][10] The uptake of an aminoglycoside antibiotic such as gentamicin into P. aeruginosa has been recognized as a multifactorial process involving an initial ionic interaction with the exterior of the cell, followed by two energy-dependent phases requiring an energized cytoplasmic membrane. [11][12][13] One of the studies suggests that zinc has significantly increased in the MICs of imipenem for P. aeruginosa, and, to a lesser extent, for other Gram-negative bacilli in Muller-Hinton agar.…”

Application of Antibiotic Pharmacodynamics and Dosing Principles in Patients With Sepsis

“…46 As a class, aminoglycosides have concentrationdependent bactericidal activity via irreversible binding to the 30S ribosomal subunit of susceptible bacteria, inhibiting bacterial protein synthesis. 47 In vitro and clinical outcome studies 48,49 have shown that Cmax:MIC ratios of 8:1 to 10:1 maximize the bacterial killing and clinical success of aminoglycosides. In addition to their primary antibacterial effect, aminoglycosides have a postantibiotic effect: bacterial killing continues even after the concentration at the infection site (eg, blood, tissue) decreases to less than the bacterial MIC.…”

“…The postantibiotic effect is due to the intracellular, irreversible activity of aminoglycosides at bacterial ribosomes and ranges from 0.5 to 8 hours, depending on the C max achieved. 47,50 Aminoglycosides are hydrophilic (V d 0.2-0.3 L/kg) and doses should be based on ideal body weight or, in obese patients, on adjusted body weight. 51,52 Aminoglycosides are almost exclusively renally cleared, leading to increased urinary concentrations, a potential advantage in treating urinary tract infections.…”

Comparative Study of Erythrocyte Sedimentation Rate after Aminoglycoside and Aminocyclitol Treatment in Goats (Capra hircus)

“…In order to minimize the adverse effects of the drugs now they are commonly used once daily in contrast with the previous treatment 2-3 times per day. Given the effectiveness of these drugs is concentration-dependent and count on rapid achievement of high serum concentrations, the first dose can be injected intravenously, and the next ones -intramuscularly (Lacy et al, 1998). Well known are the nephrotoxic changes caused by these antibiotics in high doses (Hottendorf and Gordon 1980;Schentag et al, 1981) and in this respect there are comparative trials (Brion et al, 1984;Hottendorf and Gordon, 1980;Rankin et al, 1980;Schentag et al, 1981).…”