Dagoberto Soto

Monitorización terapéutica de antibióticos: Nuevas metodologías: biosensores

The pharmacokinetics of antibiotics, especially in severely ill patients, may be profoundly altered due to multiple pathophysiological changes. Recent studies have shown that empiric dosing recommendations for ICU patients are inadequate to effectively treat a broad range of susceptible organisms and need to be reconsidered. Therapeutic drug monitoring (TDM) is an important mean for optimizing drug utilization and doses for the purpose of improving the clinical effectiveness. However, it is very challenging to quantify plasma antibiotic concentrations in clinical situations as a routine practice, because of the high costs and complexities associated with advanced instrumental techniques. Currently there are not routine and low cost methods to determine the presence and concentration of β-lactam antibiotics in plasma patients in a clinical setup. Indeed, such analytical methods are based on chromatographic techniques mainly used in research. Here we describe and comment different techniques, focusing on our preliminary experience using biosensors.

Method Based on the β-Lactamase PenPC Fluorescent Labeled for β-Lactam Antibiotic Quantification in Human Plasma.

Recently, Wong et al. have successfully developed a fluorescent biosensor based on the PenPC β-lactamase which changes its intrinsic fluorescence in presence of β-lactam antibiotics (BLAs). Here, we studied systematically this correlation among the fluorescence change of the biosensor and the concentration of different BLAs aimed at developing a novel method for estimating the concentration of a wide range of BLAs. This method showed high precision and specificity and very low interference from clinically relevant samples. We were able to monitor the pharmacokinetics of meropenem in healthy volunteers as well as in an ill animal model too, indicating that the implemented method could be suitable for clinical practice.

Determinantes precoces en el desarrollo de injuria renal aguda durante la sepsis abdominal experimental

Background: Sepsis-induced acute kidney injury (AKI) is an early and frequent organ dysfunction, associated with increased mortality. Aim: To evaluate the impact of macro hemodynamic and microcirculatory changes on renal function and histology during an experimental model of intra-abdominal sepsis. Material and Methods: In 18 anaesthetized pigs, catheters were installed to measure hemodynamic parameters in the carotid, right renal and pulmonary arteries. After baseline assessment and stabilization, animals were randomly divided to receive and intra-abdominal infusion of autologous feces or saline. Animals were observed for 18 hours thereafter. Results: In all septic animals, serum lactate levels increased, but only eight developed AKI (66%). These animals had higher creatinine and interleukin-6 levels, lower inulin and para-aminohippurate clearance (decreased glomerular filtration and renal plasma flow), and a negative lactate uptake. Septic animals with AKI had lower values of mean end arterial pressure, renal blood flow and kidney perfusion pressure, with an associated increase in kidney oxygen extraction. No tubular necrosis was observed in kidney histology. Conclusions: The reduction in renal blood flow and renal perfusion pressure were the main mechanisms associated with AKI, but were not associated with necrosis. Probably other mechanisms, such as microcirculatory vasoconstriction and inflammation also contributes to AKI development.

0101. Early and severe impairment of lactate clearance in endotoxic shock is not related to liver hypoperfusion: preliminary report

Although the prognostic value of persistent hyperlactatemia in septic shock is unequivocal, its physiological determinants are controversial. In particular, the role of impaired hepatic clearance has been considered as relevant only in severe shock with liver ischemia or advanced cirrhosis. However, very few studies have addressed this subject.

Evaluation of Meropenem Pharmacokinetics in an Experimental Acute Respiratory Distress Syndrome (ARDS) Model during Extracorporeal Membrane Oxygenation (ECMO) by Using a PenP β-Lactamase Biosensor.

Introduction: The use of antibiotics is mandatory in patients during extracorporeal membrane oxygenation (ECMO) support. Clinical studies have shown high variability in the antibiotic concentrations, as well as sequestration of them by the ECMO circuit, suggesting that the doses and/or interval administration used during ECMO may not be adequate. Thus, a fast response sensor to estimate antibiotic concentrations in this setting would contribute to improve dose adjustments. The biosensor PenP has been shown to have a dynamic range, sensitivity and specificity useful for pharmacokinetic (PK) tests in healthy subjects. However, the use of this biosensor in the context of a complex critical condition, such as ECMO during acute respiratory distress syndrome (ARDS), has not been tested. Objectives: To describe, by using PenP Biosensor, the pharmacokinetic of meropenem in a 24-h animal ARDS/ECMO model. Methods: The PK of meropenem was evaluated in a swine model before and during ECMO. Results: The PK parameters such as maximum concentration (Cmax), elimination rate constant (Ke), and cleareance (Cl), were not significantly altered during ECMO support. Conclusions: (a) ECMO does not affect the PK of meropenem, at least during the first 24 h; and (b) PenP has the potential to become an effective tool for making medical decisions associated with the dose model of antibiotics in a critical patient context.

Dexmedetomidine ameliorates gut lactate production and impairment of exogenous lactate clearance in an endotoxic sheep model

The mechanisms of persistent hyperlactemia during endotoxic shock are probably multifactorial. Both hypoperfusion-related anaerobic production and adrenergic-driven aerobic generation have been implicated. More recently an early and severe impairment in exogenous lactate clearance has also been described [1]. Theoretically, an excessive adrenergic response could influence all these mechanisms and thus aggravate the problem.

Effect of a Lung Rest Strategy During Ecmo in a Porcine Acute Lung Injury Model

ECMO is used to treat patients who develop refractory hypoxemia and to provide a more protective ventilation. Several guidelines recommend “lung rest” strategies based on variable ventilatory parameters. However, there is limited evidence to support this strategy.

0671. Extended extracorporeal lung support in a porcine acute lung injury model. Feasibility and preliminary data

During the last years there has been a renewed interest in using extracorporeal membrane oxygenation (ECMO) to treat severe ARDS. ECMO may correct hypoxemia but may also aid in protecting the lungs [1]. However, there is scarce data about the optimal way to ventilate the lungs during ECMO. Experimental models of acute lung injury with ECMO are usually too short.