Pharmacokinetics/Pharmacodynamics and tolerability of cefiderocol in the clinical setting.

Cefiderocol is a new cephalosporin with a catechol in its chemical structure faciliting its access to the interior of bacteria through iron channels. In addition, it is broadly stable to beta-lactamases. The pharmacokinetic profile is a beta-lactam one: no oral absorption, and with a wide distribution within the vascular space and the interstitial fluid of well vascularized tissues, reaching therapeutic concentrations in the alveolar lavage fluid and within the macrophage. The binding of cefiderocol to human plasma proteins, primarily albumin, is moderate (range 40-60%). The terminal elimination half-life in healthy adult subjects was 2 to 3 hours. Cefiderocol is mainly renally eliminated, so dose adjustments are recommended in subjects with moderate / severe renal impairment, in case of dialysis, and probably in patients with external clearance. Like other beta-lactams, the PK / PD parameter that has been shown to best correlate with efficacy is the efficacy time of unbound plasma concentrations (%fT>MIC), which must be close to 100% to achieve a bactericidal effect. This is possible with 2 g in a 3-hour infusion every 8 hours. In controlled trials appears to be well tolerated, similar to comparators: meropenem or imipenem-cilastatin. Cefiderocol has no apparent clinically significant effect on ECG parameters nor on plasma iron values.

Optimization of antimicrobial treatment in sepsis.

Sepsis represents a serious risk to the life of any patient, which is why it is crucial to start an effective treatment in all its extremes as soon as possible, that is, the chosen antibiotics must have activity against the pathogen that produces the condition and, in addition, they must be dosed considering the patient's situation in all its extremes. It should be considered that it will be necessary to adjust the dose when there is edema (drugs with reduced volume of distribution), hypoproteinemia (drugs bound to proteins in a high proportion), obesity, and also when they require the use of external techniques such as ECMO or any of the different types of hemodialysis and hemofiltration.

The pharmacodynamic bases of the prescription of antimicrobials.

In the past, the dose of an antibiotic was chosen, always from among those that were well tolerated, by considering those with the ability to exceed the MIC of bacteria in plasma. This approach, which has still not widely changed, is contrast-ed with the pharmacokinetic and pharmacodynamic (PK/PD) relationships, which indicate that the efficacy of antibiotics is directly related to parameters that relate the sequence of con-centrations over time with a parameter of the MIC effect in vitro. Until now, three types of PK/PD relationships have been established for antibiotics: the inhibitory coefficient (Cmax/MIC), the efficacy time (T>CMI) and the relationship between the exposure of the drug and the MIC (AUC/MIC).

Ceftobiprole: pharmacokinetics and PK/PD profile.

Ceftobiprole shows many similar pharmacokinetic properties to other cephalosporins, except for not being orally bioactive, and that it is administered by IV infusion as the prodrug ceftobiprole medocaril, which is subsequently hydrolyzed in the blood into the active molecule. Distribution focus in extracellular fluid and active antibiotic concentration has been proven in different corporal tissues using dosing regimen of 500 mg intravenous infusion over 2 h every 8 h. Ceftobiprole is eliminated exclusively into the urine, thus the reason why dose adjustment is required for patients with moderate or severe renal impairment, or increased creatinine clearance. However, there is no need for dose adjustments related with other comorbidities and patients' conditions such as age, body weight. Although considering distribution features, molecular weight and dose fraction, increase dosing regimen might be necessary in patients using renal replacement therapy. The half-life of ceftobiprole is more than 3 h, allowing to easily reach optimal PK/PD parameters with the infusion time of 2 h, using the usual dosing regimen.

Pharmacokinetics of anidulafungin in critically ill patients with Candida peritonitis.

OBJECTIVE: To describe the pharmacokinetic (PK) profile of anidulafungin and to evaluate its concentration in the peritoneal fluid (PF) of patients suspected of suffering from peritoneal infection undergoing abdominal surgery, in order to ensure that therapeutic levels are achieved within the peritoneal cavity. METHODS: A descriptive, open, prospective, observational, multicentre and non-interventional study was performed. Anidulafungin was used at conventional doses. Blood and PF samples were obtained on day 2 of treatment or on any of the following days. RESULTS: A total of 31 patients in a serious clinical condition, as demonstrated by high mean clinical severity scale scores (APACHE II and SOFA scores), were included in the study. The mean area under the curve (AUC) in PF was 30% (31±19%) of that determined in the plasma and the maximum concentration (Cmax) reached in PF (mg/l) was close to 1 (0.9±0.5). No adverse effects were observed in any of the 31 patients. CONCLUSIONS: Anidulafungin at conventional doses reaches PF concentrations that exceed the minimum inhibitory concentration of the usual Candida spp, which explains the proven efficacy of this echinocandin in the treatment of Candida peritonitis in critically ill patients.

Absence of microglial CX3CR1 impairs the synaptic integration of adult-born hippocampal granule neurons.

Microglia are immune cells that play a crucial role in maintaining brain homeostasis. Among the mechanisms of communication between microglia and neurons, the CX3CL1/CX3CR1 axis exerts a central modulatory role. Animals lacking CX3CR1 microglial receptor (CX3CR1-/- mice) exhibit marked alterations not only in microglia but also in neurons located in various regions of the brain. Here we show that microglial depletion of CX3CR1 leads to the deficient synaptic integration of adult-born granule neurons in the dentate gyrus (DG), both at the afferent and efferent level. Regarding the alterations in the former level, these cells show a reduced number of dendritic spines, which also exhibit morphological changes, namely enlargement and shortening. With respect to changes at the efferent level, these cells show a reduced area of axonal terminals. Both at the afferent and efferent level, synapses show ultrastructural enlargement, but they are depleted of synaptic vesicles, which suggests impaired functionality. We also show that selective increased microglial activation and extracellular matrix deposition in the zones in which the afferent synaptic contacts of these cells occur, namely in the molecular and the granule layer of the DG. In order to evaluate the impact of these structural alterations from a functional point of view, we performed a battery of behavioral tests related to hippocampal-dependent emotional behavior. We observed that female CX3CR1-/- mice exhibit a hyperactive, anxiolytic-like and depressive-like phenotype. These data shed light on novel aspects of the regulation of adult hippocampal neurogenesis by microglia that could be highly relevant for research into mood disorders.

Soluble Tau has devastating effects on the structural plasticity of hippocampal granule neurons.

Tau is a neuronal microtubule-associated protein with countless physiological functions. Although the detrimental effects of insoluble aggregated Tau have been widely studied, recent evidence supports the notion that soluble Tau (composed mostly of monomers and dimers) is also toxic for neurons. Here we evaluated the long-term impact of a single stereotaxic injection of human soluble Tau on hippocampal granule neurons in mice. At the ultrastructural level, soluble Tau reduced the number of afferent synapses and caused a dramatic depletion of synaptic vesicles both in afferent and efferent synapses. Furthermore, the use of an RFP-expressing retrovirus revealed that soluble Tau altered the morphology of newborn granule neurons and reduced their afferent (dendritic spines) and efferent (mossy fiber terminals) connectivity. Finally, soluble Tau caused specific impairment of behavioral pattern separation capacity. Our results thus demonstrate for the first time that soluble Tau causes long-term detrimental effects on the morphology and connectivity of newborn granule neurons and that these effects correlate with impaired behavioral pattern separation skills. These data might be relevant for the field of neurodegenerative disorders, since they contribute to reinforcing the pathological roles played by distinct Tau species in vivo.

[Aflibercept. An approach to pharmacology]. / Aflibercept. Una aproximación a la farmacología.

Aflibercept is a fusion protein whose chemical structure combines the constant fraction of any IgG with a variable fraction constructed with fundamental parts of VEGF receptors. Consequently, it is able to bind to various VEGF as well as to placental growth factor (PIGF), which has been related to a possible synergistic effect in efficacy. The affinity of this drug is higher than that of ranibizumab and bevacizumab. Moreover, it has an intraocular antiinflammatory effect. Intravitreal administration leads to the presence of traces of the drug in plasma but the concentrations are so reduced that the presence of systemic adverse effects, including arterial hypertension, is practically nil. Because of its prolonged intraocular elimination half-life and high affinity, the drug can be administered in convenient regimens, since, after an initial monthly injection for the first three doses, the interval between injections is increased to one every two months and, after the first 12 months, the dosing will depend on the visual and anatomical results.

Ranibizumab frente a bevacizumab. Consideraciones farmacológicas / Ranibizumab versus bevacizumab. Pharmacological considerations

Bevacizumab es capaz de atravesar las barreras oculares en la administración intravítrea y generar concentraciones plasmáticas que producen un efecto inhibidor del factor de crecimiento endotelial vascular (VEGF) en el plasma, con lo que no pueden descartarse efectos sistémicos. El hecho de que se trate de una inmunoglobulina G (IgG) completa explica este fenómeno a través de la participación de receptores FcRn, cuya fijación, al igual quela de cualquier otra IgG, implica su internalización, el traslado a la membrana celular, y la externalización al espacio extracelular y a la sangre. Este proceso ocurre en cualquier tejido que disponga de células que expresen este tipo de receptor, entre los que se encuentra el ojo. Además, la ausencia de una formulación específica para la administración intravítrea supone la manipulación de la formulación i.v., que conlleva la generación de agregados de tamaño elevado, riesgo potencial de problemas con la esterilidad de la solución y de reducción del efecto farmacológico. Ranibizumab no es una IgG completa, sino sólo una fracción variable de ésta dotada de actividad anti-VEGF. La ausencia en su estructura de fracción constante implica la imposibilidad de fijación al receptor FcRn y, con ello, la ausencia de proceso de transporte hasta las angre. Por consiguiente, su biodisponibilidad sistémica tras la administración intravítrea es nula, lo que evita efectos en otros territorios del cuerpo humano distintos al ojo. Además, la formulación está preparada de forma específica para la administración intraocular, lo que evita problemas derivados de la manipulación. La experiencia acumulada con estos fármacos permite trasladar las diferencias existentes en la farmacología a la práctica cotidiana, en referencia a la eficacia y tolerabilidad de estos fármacos(AU)

Bevacizumab is able to cross ocular barriers when administered through the intravitreal route and to generate plasma concentrations with an inhibitory effect on plasma vascular endothelial growth factor (VEGF). Consequently, systemic effects cannot be ruled out. The fact that bevacizumab is a full-length IgG explains this phenomenon through the participation of FcRn receptors, whose binding-like that of all IgGs-implies their internalization, transfer to the cell membrane, and externalization to the intracellular space and blood. This process occurs in all tissues with cells expressing this type of receptor, such as the eye. Moreover, because of the absence of a specific formulation for intravitreal administration, an intravenous formulation must be manipulated, generating large-sized aggregates, leading to potential problems of the solution’s sterility and reducing the pharmacological effect. Ranibizumab is not a full-length IgG but is rather a variable IgG fraction with anti-VEG Factivity. Because of the absence of a constant fraction in its structure, this drug cannot bind to the FcRn receptor and, as a result, cannot be transported to the blood. Consequently, its systemic bioavailability after intravitreal administration is nil, thus avoiding effects in parts of the body other than the eye. Moreover, the formulation is specifically prepared for intraocular administration, avoiding problems due to manipulation. The experience gained with these drugs allows the differences in their efficacy and tolerability to be transferred to daily practice(AU)

[Ranibizumab versus bevacizumab. Pharmacological considerations]. / Ranibizumab frente a bevacizumab. Consideraciones farmacológicas.

Bevacizumab is able to cross ocular barriers when administered through the intravitreal route and to generate plasma concentrations with an inhibitory effect on plasma vascular endothelial growth factor (VEGF). Consequently, systemic effects cannot be ruled out. The fact that bevacizumab is a full-length IgG explains this phenomenon through the participation of FcRn receptors, whose binding-like that of all IgGs-implies their internalization, transfer to the cell membrane, and externalization to the intracellular space and blood. This process occurs in all tissues with cells expressing this type of receptor, such as the eye. Moreover, because of the absence of a specific formulation for intravitreal administration, an intravenous formulation must be manipulated, generating large-sized aggregates, leading to potential problems of the solution's sterility and reducing the pharmacological effect. Ranibizumab is not a full-length IgG but is rather a variable IgG fraction with anti-VEGF activity. Because of the absence of a constant fraction in its structure, this drug cannot bind to the FcRn receptor and, as a result, cannot be transported to the blood. Consequently, its systemic bioavailability after intravitreal administration is nil, thus avoiding effects in parts of the body other than the eye. Moreover, the formulation is specifically prepared for intraocular administration, avoiding problems due to manipulation. The experience gained with these drugs allows the differences in their efficacy and tolerability to be transferred to daily practice.

Bilastine for the relief of allergy symptoms.

Bilastine is a potent inhibitor of the histamine H1 receptor. It was recently approved in 28 countries of the European Union for the symptomatic treatment of allergic rhinoconjunctivitis and urticaria in adults and children older than 12 years. Data from preclinical studies confirmed its selectivity for the histamine H1 receptor over other receptors, and demonstrated antihistaminic and antiallergic properties in vivo. Studies in healthy volunteers and patients have shown that bilastine does not affect driving ability, cardiac conduction or alertness. Bilastine has demonstrated a good safety profile, without serious adverse effects or antimuscarinic effects in clinical trials. There were no significant changes in laboratory tests, electrocardiograms or vital signs. In clinical studies, oral treatment with bilastine 20 mg once daily improved allergic rhinitis with greater efficacy than placebo and comparable to cetirizine and desloratadine. Bilastine 20 mg was more effective than placebo and equivalent to levocetirizine in chronic urticaria, relieving symptoms, improving quality of life and controlling sleep disorders.

Oral versus intravenous therapy in the treatment of systemic mycosis.

The great majority of systemic fungal infections require long-term therapy that often extends 6-12 months, particularly in immunosuppressed patients. It can be difficult to comply with this requirement when the drug to be used is only available for intravenous administration, because problems related to maintaining a permeable venous pathway for long periods arise. The availability of an intravenously (IV) and orally (PO) administered drug can solve this problem by making sequential therapy possible. Voriconazole is a new antifungal agent that, apart from satisfying this requirement because it has a high oral bioavailability, presents a broad spectrum of antifungal activity that makes its use possible, a priori, in the initial and/or sequential IV/PO treatment of any systemic mycotic infection. Based on current costs there is potential for savings compared with liposomal amphotericin B.

Farmacología de antimicrobianos utilizados en el tratamiento de las infecciones graves por bacterias grampositivas / Pharmacology of antimicrobials used in the treatment of serious Gram-positive bacteria infections

Los antimicrobianos con actividad frente a patógenos grampositivos (glucopéptidos, estreptograminas y oxazolidinonas) presentan diferencias farmacocinéticas que es importante conocer. Linezolid y teicoplanina pueden ser administrados por vía extravascular, al presentar una absorción adecuada. Este hecho permite su uso en terapia secuencial en pacientes que precisan tratamiento prolongado. La difusión de todos ellos al espacio extracelular es adecuada, incluso en el caso de teicoplanina debido al equilibrio existente entre la fracción de fármaco fijada y la no fijada a proteínas y su elevada semivida de eliminación. La eliminación de los glucopéptidos es casi exclusivamente renal, por lo que se precisa ajustar su posología en pacientes con deterioro renal. Quinupristina-dalfopristina y linezolid son eliminados en su mayor parte por metabolismo. El sistema CYP450 se encuentra implicado en la eliminación de las estreptograminas (AU)

[Pharmacology of antimicrobials used in the treatment of serious Gram-positive bacteria infections]. / Farmacología de antimicrobianos utilizados en el tratamiento de las infecciones graves por bacterias grampositivas.

Antimicrobials with specific activity against Gram-positive cocci (glycopeptides, oxazolidinones and streptogramins) have pharmacokinetic differences that are important to know. Linezolid and teicoplanin can be administered extravascularly due to their good bioavailability, allowing their use as sequential therapy in patients requiring prolonged treatment. All of these antimicrobials have an adequate distribution in extracellular tissues, even teicoplanin, due to the balance between the fraction that is bound and unbound to plasma proteins and its long terminal half-life. As the elimination of glycopeptides is almost exclusively renal, it is necessary to perform a posology adjustment in patients with renal failure. Quinupristin/dalfopristin and linezolid are metabolized by the liver, but CYP450 is only involved in streptogramin elimination.