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.
- [Show abstract] [Hide abstract]
ABSTRACT: Streptomycin is an aminoglycoside antibiotic with an antituberculosis activity commonly used in clinical practice due to its good antimicrobial characteristics. A well-known undesirable side effect of this drug is ototoxicity, which may be caused by overproduction of reactive oxygen species and loss of melanocytes in the inner ear. The aim of this study was to examine the effect of streptomycin on melanogenesis and antioxidant defense system in cultured normal human melanocytes (HEMa-LP). Streptomycin induced concentration-dependent loss in melanocytes viability. The value of EC50 was determined to be ~5.0 mM. It has been shown that streptomycin causes inhibition of tyrosinase activity and reduces melanin content in human melanocytes in a concentration-dependent manner. Significant changes in the activity of cellular antioxidant enzymes: superoxide dismutase, catalase, and glutathione peroxidase were also stated. The results obtained in vitro may explain a potential role of melanocytes and melanin in the causative mechanisms of aminoglycosides ototoxic effects in vivo.Molecular and Cellular Biochemistry 07/2013; · 2.33 Impact Factor
- 05/2013: pages 33-56; , ISBN: 978-953-51-1145-0
- [Show abstract] [Hide abstract]
ABSTRACT: Background Outbreaks of nosocomial infection due to carbapenem-resistant Enterobacteriaceae (CRE), mostly Klebsiella spp., have become a worldwide phenomenon. Aim To investigate the risk factors for the acquisition of clonal multidrug-resistant Klebsiella oxytoca (MDRKO) producing the metallo-β-lactamase IMP-8 and hyperproducing chromosomal OXY-2 β-lactamase during a well-characterized outbreak, and to describe the clinical features of infections due to MDRKO. Methods A four-wave outbreak due to MDRKO occurred in the intensive care unit of a Spanish hospital between 2009 and 2011. The risk factors for acquisition of MDRKO during waves 1 and 2 (in which colonized patients served as the main reservoir for the epidemic strain) were analysed using a case–control study by Cox regression and logistic regression analysis. Clinical data and treatments of patients infected with MDRKO were also analysed. Findings For the study of risk factors, 26 cases and 45 controls were studied. None of the variables studied in the Cox regression analysis showed an association with MDRKO acquisition; time at risk was the only associated variable by logistic regression analysis. Colonization pressure was not associated with earlier acquisition. Overall, 14 patients were infected with MDRKO; ventilator-associated pneumonia (seven patients) was the most frequent type of infection. Monotherapy tended to be associated with higher mortality than combination therapy [60% (3/5) vs 16.6% (1/6); P = 0.07]. Conclusions Time at risk was the most significant risk determinant for the acquisition of carbapenem-resistant Enterobacteriaceae (CRE) in this epidemiological context and should be included in any study of risk factors for the acquisition of multidrug-resistant bacteria. Combination therapy may be superior to monotherapy for the treatment of CRE infections.Journal of Hospital Infection. 01/2014;