Pharmacokinetic monitoring during aminoglycosides: optimal therapy method of individual amikacin dosing]

One of the most successful approaches to adjustment of dosage regimens on the basis of single determinations of drug contents in blood specimens provides the blood sampling at the "ideal" moment (t*), i. e. at the time equal to the inverse value of the elimination rate constant. The above version of the one-point method is applicable to drugs obeying the one-compartment model. In practice, however, it is never known a priori whether the individual pharmacokinetic profile (PKP) is monoexponential or not. An attempt was made to apply the one-point method to individual amikacin (Am) intravenous bolus dosing in 27 patients with PKPs described not only by mono- but also by biexponential equations. The individual doses (Dc) estimated on the basis of Am concentrations recorded at the "ideal", point (2.75 hours after the administration) by the equation Dc = Dp.Cp(t*)/Ci(t*) were compared to the doses (DCl) found on the basis of greater than or equal to 4 determinations of the Am concentration (within 0.5 to 6 hours after the administration), i. e. by the equation DCl = Dp.Cli/Clp, where: Dp is the population value of an Am dose (7.5 mg/kg); Cp (t*) is the population value of an Am concentration at t* (6.7 mg/l), Clp is that of the total clearance [81.2 ml/(h.kg)] and Ci (t*) and Cli are the individual values of an Am concentration and clearance, respectively. The correlation coefficient of the DCl vs. Dc estimates was equal to 0.87. In 17 patients with monoexponential PKPs it was higher (r = 0.99).(ABSTRACT TRUNCATED AT 250 WORDS)     

Glyco-optimization of aminoglycosides: new aminoglycosides as novel anti-infective agents

Glyco-optimization (OPopS) of aminoglycosides has been performed by replacing the existing sugar moiety with a variety of sugar derivatives. Glycosylation of the 6-position of nebramine provided a library of novel 4,6-linked aminoglycosides (AMGs). Among them, compounds 8b,g,i,l, and 8u with 2"-amino, 2",3"-diamino, 2",4"-diamino, 3",4"-diamino, 3"-amino groups, respectively, showed significant antimicrobial activity against Gram-(+) and -(-) bacteria. Several were particularly potent against Pseudomonus aeruginosa with MICs in the 1-2 microg/mL range.     

Mechanism of bactericidal action of aminoglycosides

[This corrects the article on p. 341 in vol. 51.].     

Enhanced RNA binding of dimerized aminoglycosides.

Aminoglycoside antibiotics have recently emerged as an intriguing family of RNA binding molecules and they became leading structures for the design of novel RNA ligands. The demystification of the aminoglycoside-RNA recognition phenomenon is required for the development of superior binders. To explore the existence of multiple binding sites in a large RNA molecule, we have synthesized covalently linked symmetrical and nonsymmetrical dimeric aminoglycosides. These unnatural derivatives were compared to their natural "monomeric" counterparts in their ability to inhibit the Tetrahymena ribozyme. The dimeric aminoglycosides inhibit ribozyme function 20 to 1.2 x 10(3) fold more effectively than their natural parent compounds. The inhibition curves of dimeric aminoglycosides have characteristic shapes suggesting the presence of at least two high affinity-binding sites within the ribozyme's three-dimensional fold. The interaction of a dimeric aminoglycoside with two complementary sites of the RNA molecule is proposed. This binding motif may have implications on the development of new drugs targeting pivotal RNA molecules of bacterial and viral pathogens.     

Biosynthetic pathways of aminoglycosides and their engineering

1. Download : Download high-res image (231KB)
2. Download : Download full-size image

     

Current methodologies for the analysis of aminoglycosides

The aminoglycosides are a large and diverse class of antibiotics that characteristically contain two or more aminosugars linked by glycosidic bonds to an aminocyclitol component. Structures are presented for over 30 of the most important members of this family of compounds. The use of aminoglycosides in clinical and veterinary medicine and in agriculture is described. Qualitative methods for aminoglycoside analysis include X-ray crystallography, nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry (MS). The major part of this article comprises a comprehensive review of quantitative methods for the determination of aminoglycosides. These are microbiological assay, radiochemical assay, radioimmunoassay, enzyme immunoassay, fluoroimmunoassay and other immunoassays, spectrophotometric and other non-separative methods, gas chromatography (GC), thin-layer chromatography (TLC), high-performance liquid chromatography (HPLC), and capillary electrophoresis (CE). Simple spectrophotometric methods may be adequate for the assay of bulk pharmaceuticals and their formulations. Microbiological assays make useful semi-quantitative screening tests for the analysis of veterinary drug residues in food, but rapid enzyme immunoassays are more suitable for accurate measurements of aminoglycosides in complex matrices. Automated immunoassays are the most appropriate methods for serum aminoglycoside determinations during therapeutic drug monitoring. HPLC techniques provide the specificity and sensitivity required for pharmacokinetic and other research studies, while HPLC–MS is employed for the confirmation of veterinary drug residues. The potential for further development of chromatographic and CE methods for the analysis of biological samples is outlined.     

Action of aminoglycosides on platelet aggregation in vitro

The authors tested the influence of gentamicin, spectinomycin dihydrostreptomycin on the ADP and epinephrine in vitro induced platelet aggregation. Our aim was to demonstrate if platelet aggregation in vitro had some influences by antibiotics. A reduction in platelet aggregability, strictly dependent from the used antibiotic dose was observed. We have studied platelet function thanks to Born's method, adding to PRP gradual therapeutics doses of antibiotics. The results showed a reduction of platelet function which was dose-depended, and, particularly, gentamicin seemed to be the most effective among aminoglycosides. An interference between these drugs and the ADP and epinephrine binding to specific platelet receptor sites is proposed.     

Effect of aminoglycosides on surface hydrophobicity of Acinetobacter baumannii

Effects of amikacin, gentamicin, netilmicin and tobramycin at subinhibitory concentrations (sub-MICs) (11/4, 1/8, 1/16 or 1/32 of their MICs) on the cell surface hydrophobicity of two Acinetobacter baumannii strains (7194 and 16265) were evaluated. Hydrophobicity was determined by two different methods - by adherence of bacteria to hydrocarbon (xylene) and by aggregation of bacteria in ammonium sulphate solutions at various concentrations. The adherence of A. baumannii strains to xylene decreased, mainly, after treatment with netilmicin at 1/4, 1/8 or 1/16 of the MIC (to 6.4%, 17.0% or 24.5% of the control value) (strain 7194) and after treatment with amikacin and gentamicin at 1/4 of their MICs (to 58.4% or 54.4%) (strain 16265). A decrease in surface hydrophobicity of exposed strains under these conditions was shown in salting-out test, too. Tobramycin reduced hydrophobic properties of A. baumannii strains at all tested sub-MICs to only a small extent.