Gentamicin once-daily in enterococcal endocarditis

Bassetti, Matteo; Righi, Elda; Crapis, Massimo; Cojutti, Pier Giorgio; Venturini, Sergio; Viale, Pierluigi; Pea, Federico

doi:10.1016/j.ijcard.2013.07.225

Cited by 12 publications

(4 citation statements)

References 9 publications

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“…Among aminoglycoside class, gentamicin is one of the most frequently prescribed antibiotics since it was proved most potent in the treatment of several types of bacterial infections, involved in bone infections (Fleiter et al., 2014 ), endocarditis (Bassetti et al., 2013 ), and life-threatening sepsis especially in newborns or immunocompromised persons (Thomson et al., 2003 ). It is therefore on the World Health Organization’s list of essential medicines.…”

Section: Introductionmentioning

confidence: 99%

SS-31 peptide enables mitochondrial targeting drug delivery: a promising therapeutic alteration to prevent hair cell damage from aminoglycosides

et al. 2017

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Aminoglycoside-induced hearing loss stems from damage or loss of mechanosensory hair cells in the inner ear. Intrinsic mitochondrial cell death pathway plays a key role in that cellular dysfunction for which no proven effective therapies against oto-toxicities exist. Therefore, the aim of the present study was to develop a new mitochondrial targeting drug delivery system (DDS) that provided improved protection from gentamicin. Particularly, SS-31 peptide-conjugated geranylgeranylacetone (GGA) loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles were constructed successfully via emulsion-solvent evaporation method. The zebrafish lateral line sensory system was used as an in vivo evaluating platform to investigate the protective efficiency against gentamicin. SS-31 modification significantly reduced the activity of mechanoelectrical transduction (MET) channel and gentamicin uptake in zebrafish lateral line hair cells. As expected, SS-31 conjugated nanoparticles showed mitochondrial specific accumulation in hair cells when compared with unconjugated formulations. Furthermore, intracellular SS-31 modified PLGA NPs slightly enhanced mitochondrial membrane potential (MMP, ΔΨ) and then returned to a steady-state, indicating their effect on the respiratory chain complexes in mitochondria. GGA loaded SS-31 conjugated nanoparticles demonstrated the most favorable hair cells survivals against gentamicin when compared with unconjugated groups whereas blank formulations failed to exhibit potency, indicating that the efficiency was attributed to drug delivery of GGA. These results suggest that our constructed mitochondria-targeting PLGA based DDS have potential application in protecting hair cells from ototoxic agents.

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Section: Introductionmentioning

confidence: 99%

SS-31 peptide enables mitochondrial targeting drug delivery: a promising therapeutic alteration to prevent hair cell damage from aminoglycosides

et al. 2017

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“…Guidelines recommend the use of gentamicin combined with beta-lactams as antimicrobial treatment, mainly for Gram-positive pathogens [9,10]. Beta-lactams are thought to increase access of gentamicin to the bacterial cell membrane of Gram-positive micro-organisms, causing a synergistic effect [11]. …”

Section: Introductionmentioning

confidence: 99%

“…Its clinical efficacy is predicted by the pharmacodynamic factor C max :MIC, which is the ratio of the gentamicin peak level in serum (C max ) and the minimum inhibitory concentration (MIC) of the micro-organism [12]. For systemic infections, gentamicin needs to be administered intravenously, displaying a short half-life of 2–3 hours [11–13]. This hydrophilic molecule has a volume of distribution (Vd) similar to the extracellular fluid, and a clearance proportional to the glomerular filtration rate (90% renal clearance) [12,14].…”

Section: Introductionmentioning

confidence: 99%

“…Trough levels determine both ototoxicity (hearing loss, tinnitus) and nephrotoxicity (usually reversible), with decreasing renal clearance causing drug accumulation [12,19]. Toxicity also depends on patient characteristics (age, hydration status, blood pressure) and simultaneous medication with similar toxic potential [11,12,20], and toxicity earlier in the course of treatment is observed with higher peak levels (opposing previous reports [11,13]). Peak levels indeed correlate indirectly with nephrotoxicity, via the area under the serum concentration-time curve (AUC) [21,22].…”

Section: Introductionmentioning

confidence: 99%

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Pharmacokinetic modeling of gentamicin in treatment of infective endocarditis: Model development and validation of existing models

et al. 2017

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Gentamicin shows large variations in half-life and volume of distribution (Vd) within and between individuals. Thus, monitoring and accurately predicting serum levels are required to optimize effectiveness and minimize toxicity. Currently, two population pharmacokinetic models are applied for predicting gentamicin doses in adults. For endocarditis patients the optimal model is unknown. We aimed at: 1) creating an optimal model for endocarditis patients; and 2) assessing whether the endocarditis and existing models can accurately predict serum levels. We performed a retrospective observational two-cohort study: one cohort to parameterize the endocarditis model by iterative two-stage Bayesian analysis, and a second cohort to validate and compare all three models. The Akaike Information Criterion and the weighted sum of squares of the residuals divided by the degrees of freedom were used to select the endocarditis model. Median Prediction Error (MDPE) and Median Absolute Prediction Error (MDAPE) were used to test all models with the validation dataset. We built the endocarditis model based on data from the modeling cohort (65 patients) with a fixed 0.277 L/h/70kg metabolic clearance, 0.698 (±0.358) renal clearance as fraction of creatinine clearance, and Vd 0.312 (±0.076) L/kg corrected lean body mass. External validation with data from 14 validation cohort patients showed a similar predictive power of the endocarditis model (MDPE -1.77%, MDAPE 4.68%) as compared to the intensive-care (MDPE -1.33%, MDAPE 4.37%) and standard (MDPE -0.90%, MDAPE 4.82%) models. All models acceptably predicted pharmacokinetic parameters for gentamicin in endocarditis patients. However, these patients appear to have an increased Vd, similar to intensive care patients. Vd mainly determines the height of peak serum levels, which in turn correlate with bactericidal activity. In order to maintain simplicity, we advise to use the existing intensive-care model in clinical practice to avoid potential underdosing of gentamicin in endocarditis patients.

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