Tocilizumab reduces the risk of ICU admission and mortality in patients with SARS-CoV-2 infection.

OBJECTIVE: In some patients the immune response triggered by SARS-CoV-2 is unbalanced, presenting an acute respiratory distress syndrome which in many cases requires intensive care unit (ICU) admission. The limitation of ICU beds has been one of the major burdens in the management around the world; therefore, clinical strategies to avoid ICU admission are needed. We aimed to describe the influence of tocilizumab on the need of transfer to ICU or death in non-critically ill patients. METHODS: A retrospective study of 171 patients with SARS-CoV-2 infection that did not qualify as requiring transfer to ICU during the first 24h after admission to a conventional ward, were included. The criteria to receive tocilizumab was radiological impairment, oxygen demand or an increasing of inflammatory parameters, however, the ultimate decision was left to the attending physician judgement. The primary outcome was the need of ICU admission or death whichever came first. RESULTS: A total of 77 patients received tocilizumab and 94 did not. The tocilizumab group had less ICU admissions (10.3% vs. 27.6%, P=0.005) and need of invasive ventilation (0 vs 13.8%, P=0.001). In the multivariable analysis, tocilizumab remained as a protective variable (OR: 0.03, CI 95%: 0.007-0.1, P=0.0001) of ICU admission or death. CONCLUSIONS: Tocilizumab in early stages of the inflammatory flare could reduce an important number of ICU admissions and mechanical ventilation. The mortality rate of 10.3% among patients receiving tocilizumab appears to be lower than other reports. This is a non-randomized study and the results should be interpreted with caution.

Efficacy of Telavancin in Comparison to Linezolid in a Porcine Model of Severe Methicillin-Resistant Staphylococcus aureus Pneumonia.

Current guidelines recommend vancomycin and linezolid as first-line agents against methicillin-resistant Staphylococcus aureus (MRSA) nosocomial pneumonia. Telavancin is a potential new therapeutic alternative, specifically in monomicrobial MRSA pneumonia. This study compared the efficacies of telavancin versus linezolid in a porcine model of severe MRSA pneumonia. In 18 mechanically ventilated pigs (32.11 ± 1.18 kg), 75 ml of 106 CFU/ml of MRSA was administered into each pulmonary lobe. After the onset of pneumonia, pigs were randomized into three groups: a control group, a group receiving 22.5 mg/kg of body weight every 24 h (q24h) of telavancin, and a group receiving 10 mg/kg q12h of linezolid intravenously. Tracheal aspirate and bronchoalveolar lavage (BAL) fluids were cultured every 24 h. After 48 h of treatment, tissue samples were collected from the ventral and dorsal sections of each lobe. Microbiological and histopathological analyses were performed. Lung tissue concentrations differed among the groups (P = 0.019), with the lowest MRSA lung burden in the telavancin group (P < 0.05 versus the control). MRSA was detected in 46.7%, 40.0%, and 21.7% of the lung tissue samples from the control, linezolid, and telavancin groups, respectively (P < 0.001). MRSA concentrations differed among the groups in tracheal aspirate fluid (P = 0.011) but not in BAL fluid. Furthermore, there was no increased risk of kidney injury during telavancin use. Thus, telavancin has higher bactericidal efficacy than linezolid during the first 48 h of treatment in a porcine model of severe MRSA pneumonia. However, studies are needed to confirm the benefits of telavancin in treating MRSA nosocomial pneumonia.

Population pharmacokinetics of daptomycin in critically ill patients.

Daptomycin has shown activity against a wide range of Gram-positive bacteria; however, the approved dosages usually seem insufficient for critically ill patients. The aim of this study was to develop a population pharmacokinetic model for daptomycin in critically ill patients and to estimate the success of the therapy by applying pharmacokinetic/pharmacodynamic (PK/PD) criteria. Sixteen intensive care unit patients were included, four of whom underwent continuous renal replacement therapies (CRRT). Blood and, when necessary, effluent samples were drawn after daptomycin administration at previously defined time points. A population approach using NONMEM 7.3 was performed to analyse data. Monte Carlo simulations were executed to evaluate the suitability of different dosage regimens. The probabilities of achieving the PK/PD target value associated with treatment success (ratio of the area under the plasma concentration-time curve over 24 h divided by the minimum inhibitory concentration (AUC24/MIC ≥ 666)) and to reach daptomycin concentrations linked to toxicity (minimum concentration at steady-state (Cminss) ≥ 24.3 mg/L) were calculated. The pharmacokinetics of daptomycin was best described by a one-compartment model. Elimination was conditioned by the creatinine clearance (Clcr) and also by the extra-corporeal clearance when patients were subjected to continuous renal replacement therapy (CRRT). The PK/PD analysis confirmed that 280- and 420-mg/d dosages would not be enough to achieve high probabilities of target attainment for MIC values ≥ 1 mg/L in patients with Clcr ≥ 60 mL/min or in subjects with lower Clcrs but receiving CRRT. In these patients, higher dosages (560-840 mg/d) should be needed. When treating infections due to MIC values ≥ 4 mg/L, even the highest dose would be insufficient.

What to expect and when: benznidazole toxicity in chronic Chagas' disease treatment.

Background: Benznidazole is one of the two most effective antiparasitic drugs for Chagas' disease treatment. However, knowledge about its toxicity profile is mostly based on post-marketing observational studies. Objectives: Our study combines data from two prospective clinical trials designed to assess the safety of the drug newly produced by ELEA Laboratories (Abarax®). Methods: Eligible participants were selected using a consecutive sampling strategy in the CINEBENZ and BIOMARCHA studies between 2013 and 2016 (EUDRACT 2011-002900-34 and 2012-002645-38, respectively, and clinicaltrials.gov NCT01755403 and NCT01755377, respectively). Enrolled subjects received treatment with 5 mg/kg/day benznidazole orally in two divided doses for 8 weeks and were followed up fortnightly. Results: We observed 305 adverse reactions in 85 of 99 participants (85.9%). Each patient had a median of three adverse reactions, 89.5% were mild and the median duration was 12 days. Most adverse reactions appeared in the first month of treatment except arthritis and peripheral neuropathy. Twenty-six patients did not complete treatment: 2 were withdrawn, 1 for ectopic pregnancy and 1 for epilepsy relapse due to cysticercosis; 2 were lost to follow-up; and 22 were owing to adverse reactions, two of them severe. We observed some unexpected adverse reactions that have not been described previously, such as psychiatric symptoms, erectile dysfunction, menstrual cycle alterations and lung infiltration. Conclusions: There is a very high frequency of adverse reactions to benznidazole. Most adverse reactions are mild, but the treatment burden is significant and unexpected reactions are not rare. Severe reactions are uncommon, but they can be life-threatening. Further studies are necessary to optimize treatment.

Fosfomycin plus ß-Lactams as Synergistic Bactericidal Combinations for Experimental Endocarditis Due to Methicillin-Resistant and Glycopeptide-Intermediate Staphylococcus aureus.

The urgent need of effective therapies for methicillin-resistant Staphylococcus aureus (MRSA) infective endocarditis (IE) is a cause of concern. We aimed to ascertain the in vitro and in vivo activity of the older antibiotic fosfomycin combined with different beta-lactams against MRSA and glycopeptide-intermediate-resistant S. aureus (GISA) strains. Time-kill tests with 10 isolates showed that fosfomycin plus imipenem (FOF+IPM) was the most active evaluated combination. In an aortic valve IE model with two strains (MRSA-277H and GISA-ATCC 700788), the following intravenous regimens were compared: fosfomycin (2 g every 8 h [q8h]) plus imipenem (1 g q6h) or ceftriaxone (2 g q12h) (FOF+CRO) and vancomycin at a standard dose (VAN-SD) (1 g q12h) and a high dose (VAN-HD) (1 g q6h). Whereas a significant reduction of MRSA-227H load in the vegetations (veg) was observed with FOF+IPM compared with VAN-SD (0 [interquartile range [IQR], 0 to 1] versus 2 [IQR, 0 to 5.1] log CFU/g veg; P = 0.01), no statistical differences were found with VAN-HD. In addition, FOF+IPM sterilized more vegetations than VAN-SD (11/15 [73%] versus 5/16 [31%]; P = 0.02). The GISA-ATCC 700788 load in the vegetations was significantly lower after FOF+IPM or FOF+CRO treatment than with VAN-SD (2 [IQR, 0 to 2] and 0 [IQR, 0 to 2] versus 6.5 [IQR, 2 to 6.9] log CFU/g veg; P < 0.01). The number of sterilized vegetations after treatment with FOF+CRO was higher than after treatment with VAN-SD or VAN-HD (8/15 [53%] versus 4/20 [20%] or 4/20 [20%]; P = 0.03). To assess the effect of FOF+IPM on penicillin binding protein (PBP) synthesis, molecular studies were performed, with results showing that FOF+IPM treatment significantly decreased PBP1, PBP2 (but not PBP2a), and PBP3 synthesis. These results allow clinicians to consider the use of FOF+IPM or FOF+CRO to treat MRSA or GISA IE.

Population pharmacokinetics of benznidazole in adult patients with Chagas disease.

The aim of the present study was to build a population pharmacokinetic (popPK) model to characterize benznidazole (BNZ) pharmacokinetics in adults with chronic Chagas disease. This study was a prospective, open-label, single-center clinical trial approved by the local ethics committee. Patients received BNZ at 2.5 mg/kg of body weight/12 h (Abarax, Elea Laboratory, Argentina) for 60 days. Plasma BNZ samples were taken several times during the study and analyzed by high-performance liquid chromatography with UV-visible detection (HPLC-UV). The popPK analysis was done with NONMEMv.7.3. Demographic and biological data were tested as covariates. Intraindividual, interoccasion, and residual variabilities were modeled. Internal and external validations were completed to assess the robustness of the model. Later on, simulations were performed to generate BNZ concentration-time course profiles for different dosage regimens. A total of 358 plasma BNZ concentrations from 39 patients were included in the analysis. A one-compartment PK model characterized by clearance (CL/F) and the apparent volume of distribution (V/F), with first-order absorption (Ka) and elimination, adequately described the data (CL/F, 1.73 liters/h; V/F, 89.6 liters; and Ka, 1.15 h(-1)). No covariates were found to be significant for CL/F and V/F. Internal and external validations of the final model showed adequate results. Data from simulations revealed that a dose of 2.5 mg/kg/12 h might lead to overexposure in most patients. A lower dose (2.5 mg/kg/24 h) was able to achieve trough BNZ plasma concentrations within the accepted therapeutic range of 3 to 6 mg/liter. In summary, we developed a population PK model for BNZ in adults with chronic Chagas disease. Dosing simulations showed that a BNZ dose of 2.5 mg/kg/24 h will adequately keep BNZ trough plasma concentrations within the recommended target range for the majority of patients. (This study has been registered at EudraCT under number 2011-002900-34 and at ClinicalTrials.gov under number NCT01755403.).

Changes in the treatment of Enterococcus faecalis infective endocarditis in Spain in the last 15 years: from ampicillin plus gentamicin to ampicillin plus ceftriaxone.

The aim of this study was to assess changes in antibiotic resistance, epidemiology and outcome among patients with Enterococcus faecalis infective endocarditis (EFIE) and to compare the efficacy and safety of the combination of ampicillin and gentamicin (A+G) with that of ampicillin plus ceftriaxone (A+C). The study was a retrospective analysis of a prospective cohort of EFIE patients treated in our centre from 1997 to 2011. Thirty patients were initially treated with A+G (ampicillin 2 g/4 h and gentamicin 3 mg/kg/day) and 39 with A+C (ampicillin 2 g/4 h and ceftriaxone 2 g/12 h) for 4-6 weeks. Increased rates of high-level aminoglycoside resistance (HLAR; gentamicin MIC ≥512 mg/L, streptomycin MIC ≥1024 mg/L or both) were observed in recent years (24% in 1997-2006 and 49% in 2007-2011; p 0.03). The use of A+C increased over time: 1997-2001, 4/18 (22%); 2002-2006, 5/16 (31%); 2007-2011, 30/35 (86%) (p <0.001). Renal failure developed in 65% of the A+G group and in 34% of the A+C group (p 0.014). Thirteen patients (43%) in the A+G group had to discontinue treatment, whereas only one patient (3%) treated with A+C had to discontinue treatment (p <0.001). Only development of heart failure and previous chronic renal failure were independently associated with 1-year mortality, while the individual antibiotic regimen (A+C vs. A+G) did not affect outcome (OR, 0.7; 95% CI, 0.2-2.2; p 0.549). Our study shows that the prevalence of HLAR EFIE has increased significantly in recent years and that alternative treatment with A+C is safer than A+G, with similar clinical outcomes, although the sample size is too small to draw firm conclusions. Randomized controlled studies are needed to confirm these results.

Tratamiento de la intoxicación digitálica. Bases para el uso de los anticuerpos antidigital / Digitalis poisoning: the basis for treatment with antidigoxin antibodies

La intoxicación digitálica, sobre todo asociada a un tratamiento crónico con este fármaco, es un motivo recurrente de consulta a los servicios de urgencias españoles. La intoxicación aguda es excepcional y podría presentarse tanto en una tentativa de suicidio como por la ingesta de plantas presentes en nuestro medio y que contienen glucósidos digitálicos. La insuficiencia renal, al modificar la cinética de la digoxina, es un importante factor precipitante de reacciones adversas y graves a este medicamento. Las manifestaciones clínicas son inespecíficas, y predominan las digestivas (náuseas, vómitos, diarreas, dolor abdominal) y circulatorios (inestabilidad, mareos, síncope, lipotimia). Las bradiarritmias (fibrilación auricular lenta, bloqueos de conducción) son frecuentes y pueden acabar en asistolia. Las taquiarritmias podrían conducir a la fibrilación ventricular. En las intoxicaciones agudas, la hiperpotasemia es un factor de riesgo de parada cardiaca. La concentración plasmática de digoxina permite evaluar la gravedad de una intoxicación, siempre y cuando se haya alcanzado el equilibrio de distribución entre las concentraciones plasmáticas y tisulares. El tratamiento de la intoxicación aguda precisa la administración de carbón activado en las primeras horas tras la ingesta. En las intoxicaciones agudas o por tratamiento crónico, es necesaria la monitorización electrocardiográfica continua y normalizar, en caso necesario, las concentraciones de potasio y magnesio. Las bradiarritmias se tratan con atropina como fármaco de primera elección y las arritmias ventriculares con fenitoína o lidocaína. Las situaciones de riesgo vital requieren eluso de anticuerpos antidigital, y se recomienda la disponibilidad de este antídoto en loshospitales considerados de referencia o alta tecnología, el cual deberá dosificarse en función de la carga corporal total de digoxina (AU)

Digitalis poisoning, particularly in persons under long-term digoxin therapy, is a reason for repeated visits to Spanish emergency departments. Acute poisoning is rare but may occur as a result of attempted suicide or the intake of plants that contain cardiac glycosides. Kidney failure modifies digoxin pharmacokinetics and is an important trigger for severe adverse reactions to the drug. Clinical manifestations are nonspecific but usually include gastrointestinal events (nausea, vomiting, diarrhea, and abdominal pain) along with circulatory effects (hemodynamic instability, dizziness or lightheadedness, and syncope). Bradycardia (slow atrial fibrillation, conduction blocks) is common and may cause systole. Tachyarrhythmias may lead to ventricular fibrillation. In acute digitalis poisoning, hyperkalemia is a risk factor for cardiac arrest. The digoxin plasma concentration can indicate the severity of the poisoning, provided the tissue-to plasma ratio is at steady state. To treat acute poisoning, administer activated charcoal within the first few hours after digitalis intake. In such cases, or in poisoning during long-term digoxin therapy, continuous electrocardiographic monitoring is essential and potassium and magnesium concentrations should be brought within the normal range. The first-line treatment for bradycardia is atropine. Ventricular arrhythmias are treated with phenytoin or lidocaine. In life threatening situations, antidigox in antibodies must be used. They should be available in all referral or high-level tertiary care facilities and are administered according to the total digoxin body load (AU)

Emulsión lipídica intravenosa: un nuevo antídoto para uso en reanimación / Intravenous lipid emulsion: a new antidote for use in resuscitation

Los objetivos de esta revisión han sido, por un lado examinar aspectos farmacológicos y cinéticos de la emulsión lipídica para el uso intravenoso y, por otro lado, revisar la literatura médica disponible sobre sus indicaciones en el campo de la terapéutica toxicológica. Aunque el nivel de evidencia científica es bajo, la emulsión lipídica de uso intravenoso parece tener hoy en día un papel indiscutible, no sólo en la reanimación de la cardiotoxicidad de los anestésicos locales, sino también la de otros tipos de efectos tóxicos sobre el aparato cardiovascular (AU)

This review examines the pharmacologic and pharmacokinetic aspects of the intravenous infusion of lipid emulsion and surveys the literature on the indications for using this treatment in cases of intoxication. Although the level of evidence is low, intravenous lipid emulsion seems now to occupy an undisputed position as an antidote, not only in cardiotoxicity induced by local anesthetics but also in resuscitation after other toxic insults affecting the cardiovascular system (AU)

Pharmacokinetic monitoring of antiepileptic drugs.

Monitoring plasma levels of antiepileptic drugs for the treatment and prophylaxis of epilepsy is one of the strategies enabling clinical results to improve by reducing adverse affects and increasing effectiveness. The objective of this article is to review the basic aspects in the monitoring of antiepileptic drugs using a consensus document prepared and endorsed by the pharmacokinetics and pharmacogenetics working group (PK.gen) of the Sociedad Española de Farmacia Hospitalaria (Spanish Society of Hospital Pharmacists).

Daptomycin is effective for treatment of experimental endocarditis due to methicillin-resistant and glycopeptide-intermediate Staphylococcus epidermidis.

This study evaluated the daptomycin activity against two methicillin-resistant Staphylococcus epidermidis (MRSE) clinical isolates with different vancomycin susceptibilities: MRSE-375, with a vancomycin MIC of 2 microg/ml, and NRS6, a glycopeptide-intermediate S. epidermidis (GISE) strain with a vancomycin MIC of 8 microg/ml. The in vivo activity of daptomycin at two different doses (standard dose [SD-daptomycin], 6 mg/kg of body weight/day intravenously [i.v.]; high dose [HD-daptomycin], 10 mg/kg/day i.v.) was evaluated in a rabbit model of infective endocarditis and compared with that of a standard dose of vancomycin (SD-vancomycin; 1 g i.v. every 12 h) for 2 days. For the MRSE-375 strain, high-dose vancomycin (HD-vancomycin; 1 g i.v. every 6 h) was also studied. For MRSE-375, SD- and HD-daptomycin therapy sterilized significantly more vegetations than SD-vancomycin therapy (9/15 [60%] and 11/15 [73%] vegetations, respectively, versus 3/16 [19%] vegetations; P = 0.02 and P = 0.002, respectively). HD-daptomycin sterilized more vegetations than HD-vancomycin (11/15 [73%] versus 5/15 [33%] vegetations; P = 0.03) and was more effective than SD- and HD-vancomycin in reducing the density of bacteria in valve vegetations (0 log(10) CFU/g vegetation [interquartile range {IQR}, 0 to 1 log(10) CFU/g vegetation] versus 2 log(10) CFU/g vegetation [IQR, 2 to 2 log(10) CFU/g vegetation] and 2 log(10) CFU/g vegetation [IQR, 0 to 2.8 log(10) CFU/g vegetation]; P = 0.002 and P = 0.01, respectively). For the NRS6 strain, SD- and HD-daptomycin were significantly more effective than vancomycin in reducing the density of bacteria in valve vegetations (3.7 log(10) CFU/g vegetation [IQR, 2 to 6 log(10) CFU/g vegetation] versus 7.1 log(10) CFU/g vegetation [IQR, 5.2 to 8.5 log(10) CFU/g vegetation]; P = 0.02). In all treatment arms, isolates recovered from vegetations remained susceptible to daptomycin and vancomycin and had the same MICs. In conclusion, daptomycin at doses of 6 mg/kg/day or 10 mg/kg/day is more effective than vancomycin for the treatment of experimental endocarditis due to MRSE and GISE.

An experimental model of pneumonia induced by methicillin-resistant Staphylococcus aureus in ventilated piglets.

The objectives of the study were to validate a model of methicillin-resistant Staphylococcus aureus (MRSA) pneumonia in ventilated piglets and to study the time-course of biological markers and histopathological changes. 12 piglets were intubated and inoculated with 15 mL of a suspension of 10(6) colony forming units of MRSA in every lobe through the bronchoscope channel. The piglets were ventilated for 12 h (n = 6) and 24 h (n = 6). Clinical parameters were assessed every 6 h and pro-inflammatory cytokines were measured in serum and in bronchoalveolar lavage (BAL) at baseline and sacrifice. Histopathology of each lobe and cultures from blood, lungs and BAL were performed. Animals developed histopathological evidence of pneumonia at necropsy. At 12 h, pneumonia was present in all animals and was severe pneumonia at 24 h. Microbiological studies confirmed the presence of MRSA. A significant increase in interleukin (IL)-6, IL-8 and tumour necrosis factor-α values was seen in BAL at 24 h and IL-6 at 12 h. In serum, only IL-6 levels had increased significantly at 24 h. In ventilated piglets, bronchoscopic inoculation of MRSA induces pneumonia at 12 h and severe pneumonia at 24 h. This severity was associated with a corresponding increase in systemic and local inflammatory response.

[Measuring linezolid in biological fluids using high-efficiency liquid chromatography]. / Determinación de linezolid en fluidos biológicos mediante cromatografía líquida de alta eficacia.

OBJECTIVE: Evaluation of an analytic method for determining linezolid concentrations in biological fluids including plasma, vitreous humour and cerebrospinal fluid using high-efficiency liquid chromatography and subsequent ultraviolet detection. METHOD: The method was validated by studying the following parameters: accuracy, precision, sensitivity, linearity and recovery. The drug was extracted from the biological matrix by means of a protein precipitation with perchloric acid. Chromatographic separation was performed by eluting linezolid with a mobile phase consisting of 80% K2HPO4 buffer solution (15 mM; pH=5) and 20% acetonitrile, and a stationary phase, NOVAPAK C18 150x3.9 mm with precolumn. The wavelength reading was 254 nm and the working flow rate was 1 ml/min. RESULTS: We obtained values with accuracies between 94.4 and 106.1%, and precisions between 0.88-6% and 3.7-5.6% for intra-and inter-day variability, respectively. Recovery obtained after analysing the plasma samples was at 93%. The method showed itself to be linear for the concentration levels under study. DISCUSSION: The method's behaviour can be described as linear, precise and accurate. Furthermore, the method is fast, sensitive, and inexpensive. It is useful for determining linezolid concentrations in multiple biological matrices. It can also be used as a basis for further clinical pharmacokinetic studies.

Determinación de linezolid en fluidos biológicos mediante cromatografía líquida de alta eficacia / No disponible

Objetivo Validación de un método analítico para la determinación de concentraciones de linezolid (LNZ) en fluidos biológicos: plasma, humor vítreo y líquido cefalorraquídeo mediante cromatografía líquida de alta eficacia y posterior detección ultravioleta. Método El método se validó mediante el estudio de los siguientes parámetros: exactitud, precisión, sensibilidad, linealidad y recuperación. El fármaco se extrajo de la matriz biológica mediante una precipitación proteica con ácido perclórico. La separación cromatográfica se realizó mediante la elución de LNZ con una fase móvil compuesta por el 80% de un tampón de fosfato dipotásico-monohidrogenado (K2HPO4) (15mM; pH=5) con el 20% de acetonitrilo y una fase estacionaria NOVAPAK® C18 150×3,9mm con precolumna. La longitud de onda de lectura fue de 254nm y el flujo de trabajo fue de 1ml/min. Resultados Se obtuvieron valores de exactitud entre el 94,4–106,1% y de precisión entre el 0,88–6% y el 3,7–5,6% para la variabilidad intradía e interdía, respectivamente. La recuperación obtenida tras el análisis de las muestras de plasma fue del 93%. El método mostró ser lineal para los intervalos de concentraciones estudiados. Discusión El método se comporta de forma lineal, precisa y exacta. Además, es rápido, sensible y de bajo coste económico. Es un método útil para la determinación de concentraciones de LNZ en múltiples matrices biológicas. Es posible su utilización como base para posteriores estudios de farmacocinética clínica (AU)

Objective Evaluation of an analytic method for determining linezolid concentrations in biological fluids including plasma, vitreous humour and cerebrospinal fluid using high-efficiency liquid chromatography and subsequent ultraviolet detection. Method The method was validated by studying the following parameters: accuracy, precision, sensitivity, linearity and recovery. The drug was extracted from the biological matrix by means of a protein precipitation with perchloric acid. Chromatographic separation was performed by eluting linezolid with a mobile phase consisting of 80% K2HPO4 buffer solution (15mM; pH=5) and 20% acetonitrile, and a stationary phase, NOVAPAK C18 150×3.9mm with precolumn. The wavelength reading was 254nm and the working flow rate was 1ml/min. Results We obtained values with accuracies between 94.4 and 106.1%, and precisions between 0.88–6% and 3.7–5.6% for intra-and inter-day variability, respectively. Recovery obtained after analysing the plasma samples was at 93%. The method showed itself to be linear for the concentration levels under study (AU)

Addition of gentamicin or rifampin does not enhance the effectiveness of daptomycin in treatment of experimental endocarditis due to methicillin-resistant Staphylococcus aureus.

This study evaluated the activity of daptomycin combined with either gentamicin or rifampin against three methicillin-resistant Staphylococcus aureus (MRSA) clinical isolates in vitro and one isolate in vivo against a representative strain (MRSA-572). Time-kill experiments showed that daptomycin was bactericidal against these strains at concentrations over the MIC. Daptomycin at sub-MIC concentrations plus gentamicin at 1x and 2x the MIC yielded synergy, while the addition of rifampin at 2 to 4 microg/ml resulted in indifference (two strains) or antagonism (one strain). The in vivo activity of daptomycin (6 mg/kg of body weight once a day) was evaluated +/- gentamicin (1 mg/kg intravenously [i.v.] every 8 h [q8h]) or rifampin (300 mg i.v. q8h) in a rabbit model of infective endocarditis by simulating human pharmacokinetics. Daptomycin plus gentamicin (median, 0 [interquartile range, 0 to 2] log10 CFU/g vegetation) was as effective as daptomycin alone (0 [0 to 2] log10 CFU/g vegetation) in reducing the density of bacteria in valve vegetations (P = 0.83), and both were more effective than daptomycin plus rifampin (3 [2 to 3.5] log10 CFU/g vegetation; P < 0.05) for the strain studied. In addition, daptomycin sterilized a ratio of vegetations that was similar to that of daptomycin plus gentamicin (10/15 [67%] versus 9/15 [60%]; P = 0.7), and both regimens did so more than daptomycin plus rifampin (3/15 [20%]; P = 0.01 and P = 0.02, respectively). No statistical difference was noted between daptomycin plus gentamicin and daptomycin alone for MRSA treatment. In the combination arm, all isolates from vegetations remained susceptible to daptomycin, gentamicin, and rifampin. Sixty-one percent of the isolates (8/13) acquired resistance to rifampin during monotherapy. In the daptomycin arm, resistance was detected in only one case, in which the daptomycin MIC rose to 2 microg/ml among the recovered bacteria. In conclusion, the addition of gentamicin or rifampin does not enhance the effectiveness of daptomycin in the treatment of experimental endocarditis due to MRSA.

Penetration of levofloxacin into the anterior chamber (aqueous humour) of the human eye after intravenous administration.

In the study presented here, levofloxacin concentrations in serum samples and the aqueous humour (AH) of 16 patients undergoing cataract extraction were measured in order to determine the penetration characteristics of levofloxacin into the AH of the non-inflamed human eye. Cataract removal was performed at various times (from 90 to 270 min) after the end of a 30-min intravenous infusion of 500 mg of levofloxacin. Serum samples were obtained 1 h after the end of levofloxacin administration (Cmax); AH and a second serum sample were taken simultaneously during the operation, and the concentrations of levofloxacin in AH (C(AH)) and serum (C(S)) were determined using a rapid high-performance liquid chromatography assay. The mean Cmax was 6.07 microg/ml (range 3.75-9.53 microg/ml, SD 1.83). The mean C(AH) at the first hour following levofloxacin administration was 1.37 microg/ml (range 1.17-1.6 microg/ml, SD 0.22) and the mean ratio (R=C(AH)/C(S)) was 0.26 (range 0.24-0.3, SD 0.02). The mean C(AH) at 125-270 min following levofloxacin administration was 1.39 microg/ml (range 0.82-1.98 microg/ml, SD 0.33) and the mean R was 0.3 (range 0.15-0.53, SD 0.11). Of 16 patients, 15 had a C(AH) of >1 microg/ml 1 h after levofloxacin administration. In conclusion, 1 h after administration of 500 mg of levofloxacin, the levels obtained were higher than the MIC at which 90% of methicillin-susceptible Staphylococcus aureus and certain gram-negative bacteria strains are inhibited.

Alpha-1-antitrypsin deficiency: optimal therapeutic regimen based on population pharmacokinetics.

BACKGROUND: Exogenous doses of 60 mg/kg alpha(1)-antitrypsin (AAT) every 7 days are recommended in patients with severe AAT deficiency. However, long term administration of weekly doses is not well accepted by patients. Using pharmacokinetic simulations, we evaluated whether steady state minimum concentrations of total AAT can be maintained above the threshold of 0.5 g/l with longer intervals between doses. METHODS: Several sets of exogenous AAT versus time simulations were studied using a non-linear mixed effect approach with dosage regimens every 7, 14, 21, and 28 days. For each regimen the mean exogenous AAT trough concentrations and 5/95th percentiles were determined. The results obtained were applied to estimate the individual optimal dose at 7, 14, and 21 days in six patients using Bayesian analysis. RESULTS: The simulations showed that a dose of 50 mg/kg AAT every 7 days was sufficient to obtain nadir concentrations. Doses of 120 and 100 mg/kg every 14 days were also adequate, but 180 mg/kg given every 21 days required total AAT monitoring to avoid underdosage. Longer intervals were inappropriate. Dosage individualisation confirmed that AAT infusions given every 14 days maintained the nadir level of 0.5 g/l without a significant dose increase compared with current practice. When the time span between doses was fixed at 21 days, a mean relative AAT dose enhancement of 91% and 13%, respectively, was required to achieve sustained total AAT concentrations above the target level for 100% and 85% of the interval between doses. CONCLUSIONS: It is feasible to extend the interval between doses of AAT to 14 or 21 days to achieve adequate trough total AAT concentrations. This study might be used as a starting point for clinical evaluation of the regimens described.