Medicamentos bioterapéuticos: uso de toxinas botulínicas en la era de biosimilares

Introducción: Las toxinas botulínicas son medicamentos bioterapéuticos con grandes aplicaciones en el campo de la neurología, como la cefalea y los movimientos anormales. Debido a la importancia médica y al incremento de las indicaciones terapéuticas de la toxina botulínica, este artículo pretende hacer claridad acerca de la terminología básica con respecto a la naturaleza de este medicamento, a las diferencias estructurales con medicamentos convencionales y aspectos importantes en relación con su potencia biológica e inmunogenicidad, para así comprender las potenciales diferencias entre las toxinas disponibles y conceptuar en torno a la no intercambiabilidad o sustitución de una toxina por otra. Materiales y métodos: Revisión no sistemática, según lo recomendado en la Escala para la Verificación de los Artículos Revisiones Narrativas (Sanra). Conclusiones: Los medicamentos biológicos no son intercambiables entre sí, aunque demuestren bioequivalencia. No se pueden evaluar como medicamentos genéricos intercambiables porque son biológicos; no existen estudios comparativos cabeza a cabeza; son diferentes, debido al proceso individual de manufactura.

Introduction: Botulinum toxins are biotherapeutic drugs with great applications in the field of neurology such as headache and abnormal movements. Due to the medical importance and the increase in therapeutic indications of botulinum toxin, this article aims to clarify the basic terminology regarding the nature of this drug, the structural differences with conventional drugs and important aspects in relation to its biological potency and immunogenicity in order to understand the potential differences between the available toxins and conceptualize regarding the non-interchangeability or substitution of one toxin for another. Materials and methods: Non-systematic review as recommended in the Scale for the Verification of Narrative Review Articles (SANRA). Conclusions: Biological drugs are not interchangeable with each other, even if they demonstrate bioequi-valence. They cannot be evaluated as interchangeable generic drugs because they are biologics. There are no head-to-head comparative studies. They are different due to the individual manufacturing process.

Validation of a new strategy for the identification of SARS-CoV-2 variants by sequencing the spike gene by Sanger.

INTRODUCTION: The emergence of multiple variants of SARS-CoV-2 during the COVID-19 pandemic is of great world concern. Until now, their analysis has mainly focused on next-generation sequencing. However, this technique is expensive and requires sophisticated equipment, long processing times, and highly qualified technical personnel with experience in bioinformatics. To contribute to the analysis of variants of interest and variants of concern, increase the diagnostic capacity, and process samples to carry out genomic surveillance, we propose a quick and easy methodology to apply, based on Sanger sequencing of 3 gene fragments that code for protein spike. METHODS: Fifteen positive samples for SARS-CoV-2 with a cycle threshold below 25 were sequenced by Sanger and next-generation sequencing methodologies. The data obtained were analyzed on the Nextstrain and PANGO Lineages platforms. RESULTS: Both methodologies allowed the identification of the variants of interest reported by the WHO. Two samples were identified as Alpha, 3 Gamma, one Delta, 3 Mu, one Omicron, and 5 strains were close to the initial Wuhan-Hu-1 virus isolate. According to in silico analysis, key mutations can also be detected to identify and classify other variants not evaluated in the study. CONCLUSION: The different SARS-CoV-2 lineages of interest and concern are classified quickly, agilely, and reliably with the Sanger sequencing methodology.

Validación de una nueva estrategia para la identificación de variantes de SARS-CoV-2 mediante secuenciación del gen espiga por Sanger / Validation of a new strategy for the identification of SARS-CoV-2 variants by sequencing the spike gene by Sanger

Introducción: La aparición de múltiples variantes del SARS-CoV-2 durante la pandemia de COVID-19 es motivo de gran preocupación mundial. Hasta el momento, su análisis se ha centrado principalmente en la secuenciación de nueva generación. Sin embargo, esta técnica es costosa y requiere equipos sofisticados, largos tiempos de procesamiento y personal técnico altamente cualificado con experiencia en bioinformática. Para contribuir al análisis de variantes de interés y de preocupación, aumentar la capacidad diagnóstica y procesar muestras para realizar vigilancia genómica, proponemos una metodología rápida y fácil de aplicar, basada en la secuenciación Sanger de 3 fragmentos del gen que codifica para la proteína espiga. Métodos: Se secuenciaron 15 muestras positivas para SARS-CoV-2 con un valor de umbral de ciclo inferior a 25 por metodologías Sanger y secuenciación de nueva generación. Los datos obtenidos fueron analizados en las plataformas Nextstrain y PANGO Lineages. Resultados: Ambas metodologías permitieron identificar las variantes de interés reportadas por la OMS. Se identificaron 2 muestras como alfa, 3 gamma, una delta, tres mu, una ómicron y 5 cepas cercanas al aislado inicial del virus Wuhan-Hu-1. Según el análisis in silico, también se pueden detectar mutaciones clave para identificar y clasificar otras variantes no evaluadas en el estudio. Conclusión: Los diferentes linajes de interés y preocupación de SARS-CoV-2 se clasifican de forma rápida, ágil y fiable con la metodología de secuenciación de Sanger.(AU)

Introduction: The emergence of multiple variants of SARS-CoV-2 during the COVID-19 pandemic is of great world concern. Until now, their analysis has mainly focused on next-generation sequencing. However, this technique is expensive and requires sophisticated equipment, long processing times, and highly qualified technical personnel with experience in bioinformatics. To contribute to the analysis of variants of interest and variants of concern, increase the diagnostic capacity, and process samples to carry out genomic surveillance, we propose a quick and easy methodology to apply, based on Sanger sequencing of 3 gene fragments that code for protein spike. Methods: Fifteen positive samples for SARS-CoV-2 with a cycle threshold below 25 were sequenced by Sanger and next-generation sequencing methodologies. The data obtained were analyzed on the Nextstrain and PANGO Lineages platforms. Results: Both methodologies allowed the identification of the variants of interest reported by the WHO. Two samples were identified as Alpha, 3 Gamma, one Delta, 3 Mu, one Omicron, and 5 strains were close to the initial Wuhan-Hu-1 virus isolate. According to in silico analysis, key mutations can also be detected to identify and classify other variants not evaluated in the study. Conclusion: The different SARS-CoV-2 lineages of interest and concern are classified quickly, agilely, and reliably with the Sanger sequencing methodology.(AU)

Pharmacokinetic/Pharmacodynamic Index Linked to In Vivo Efficacy of the Ampicillin-Ceftriaxone Combination against Enterococcus faecalis.

Combination therapy with ampicillin plus ceftriaxone (AMP+CRO) is the first-line therapy for treating severe infections due to Enterococcus faecalis. However, the pharmacokinetic/pharmacodynamic (PK/PD) index linked to the in vivo efficacy of the combination is not yet defined, hindering dose optimization in the clinic. Because classical PK/PD indices are not directly applicable to antimicrobial combinations, two novel indices were tested in the optimized murine model of infection by E. faecalis to delineate the potentiation of AMP by CRO: the time above the CRO threshold (T>threshold) and the time above the AMP instantaneous MIC (T>MICi). The potential clinical relevance was evaluated by simulating human doses of AMP and CRO. Hill's equation fitted well the exposure-response data in terms of T>threshold, with a CRO threshold of 1 mg/L. The required exposures were 46%, 49%, and 52% for stasis and 1- and 2-log10 killing, respectively. Human ceftriaxone doses of 2 g every 12 h (q12h) would reach the target in >90% of strains with thresholds ≤64 mg/L. The AMP T>MICi index also fitted well, and the required exposures were 37%, 41%, and 46% for stasis and 1- and 2-log10 killing, respectively. In humans, the addition of CRO would allow use of lower AMP doses to reach the same T>MICi and to treat strains with higher MICs. This is the first report of the PK/PD indices and required magnitudes linked to AMP+CRO against E. faecalis; these results can be used as the basis to guide the design of clinical trials to improve combined therapy against enterococci.

[Validation of a new strategy for the identification of SARS-CoV-2 variants by sequencing the spike gene by Sanger]. / Validación de una nueva estrategia para la identificación de variantes de SARS-CoV-2 mediante secuenciación del gen espiga por Sanger.

Introduction: The emergence of multiple variants of SARS-CoV-2 during the COVID-19 pandemic is of great world concern. Until now, their analysis has mainly focused on next-generation sequencing. However, this technique is expensive and requires sophisticated equipment, long processing times, and highly qualified technical personnel with experience in bioinformatics. To contribute to the analysis of variants of interest and variants of concern, increase the diagnostic capacity, and process samples to carry out genomic surveillance, we propose a quick and easy methodology to apply, based on Sanger sequencing of 3 gene fragments that code for protein spike. Methods: Fifteen positive samples for SARS-CoV-2 with a cycle threshold below 25 were sequenced by Sanger and next-generation sequencing methodologies. The data obtained were analyzed on the Nextstrain and PANGO Lineages platforms. Results: Both methodologies allowed the identification of the variants of interest reported by the WHO. Two samples were identified as Alpha, 3 Gamma, one Delta, 3 Mu, one Omicron, and 5 strains were close to the initial Wuhan-Hu-1 virus isolate. According to in silico analysis, key mutations can also be detected to identify and classify other variants not evaluated in the study. Conclusion: The different SARS-CoV-2 lineages of interest and concern are classified quickly, agilely, and reliably with the Sanger sequencing methodology.

Validación de una técnica de PCR dúplex usando el gen E y RNasa P para el diagnóstico de SARS-CoV-2 / Validation of a duplex PCR technique using the gen E and RNase P for the diagnosis of SARS-CoV-2

Introducción: El estándar de diagnóstico para SARS-CoV-2 es la reacción en cadena de la polimerasa (PCR). La Organización Mundial de la Salud recomendó el protocolo de Charité-Berlín para el diagnóstico de COVID-19; esta metodología implica tres PCR, limitando la capacidad de procesamiento y retrasando los resultados. Con el fin de reducir estas limitaciones, se validó una PCR dúplex para la detección del gen E y RNasa P. Métodos: Se comparó el límite de detección, sensibilidad y especificidad de la técnica de PCR dúplex (gen E más RNasa P), comparada contra el estándar monoplex (gen E), en muestras de ARN de un aislado de SARS-CoV-2 y de 88 especímenes clínicos, con resultados previamente conocidos. Se determinó la repetibilidad y reproducibilidad de los valores de ciclos umbrales (cycle threshold [Ct]), en dos laboratorios independientes de la Facultad de Medicina de la Universidad de Antioquia, usando reactivos y equipos diferentes. Resultados: No hay diferencias significativas (p = 0,84) en los resultados de Ct entre ambas estrategias. Al utilizar como referencia el gen E amplificado en monoplex, el análisis de concordancia demostró fuerte similitud entre las dos estrategias, con un coeficiente kappa de Cohen de 0,89, una sensibilidad del 90%, y una especificidad del 87%. Conclusión: La PCR dúplex no afecta la sensibilidad y especificidad informadas por el protocolo Charité, Berlín, siendo una herramienta útil para el cribado de SARS-CoV-2 en muestras clínicas.(AU)

Introduction: Reverse transcriptase - polymerase chain reaction (RT-PCR) is the standard technique for SARS-CoV-2 diagnosis. The World Health Organization recommends the Charité-Berlin protocol for COVID-19 diagnosis, which requires triple PCR, limiting the process capability of laboratories and delaying the results. In order to reduce these limitations, a duplex PCR is validated for the detection of the E and RNase P genes. Methods: We compared the limit of detection, sensitivity and specificity of the duplex PCR technique (E gene and RNase P) against the monoplex standard (E gene) in RNA samples from a SARS-CoV-2 isolate and 88 clinical specimens with previously known results. The repeatability and reproducibility of the threshold cycle values (Ct) were determined in two independent laboratories of the Faculty of Medicine of the Universidad de Antioquia, using different reagents and real time instruments. Results: There were no significant differences in the Ct results between both techniques (p = 0.84). Using the monoplex PCR of E gene as a reference, the interrater reliability analysis showed similarity between the two techniques, with a kappa coefficient of 0.89, the sensitivity and the specificity of duplex PCR were 90% and 87%, respectively. Conclusions: Duplex PCR does not affect the sensitivity and specificity reported by the Charité, Berlin protocol, being a useful tool for SARS-CoV-2 screening in clinical samples.(AU)

Validation of a duplex PCR technique using the gen E and RNase P for the diagnosis of SARS-CoV-2.

INTRODUCTION: Reverse transcriptase - polymerase chain reaction (RT-PCR) is the standard technique for SARS-CoV-2 diagnosis. The World Health Organization recommends the Charité-Berlin protocol for COVID-19 diagnosis, which requires triple PCR, limiting the process capability of laboratories and delaying the results. In order to reduce these limitations, a duplex PCR is validated for the detection of the E and ribonuclease P genes. METHODS: We compared the limit of detection, sensitivity and specificity of the duplex PCR technique (E gene and Rnasa P) against the monoplex standard (E gene) in RNA samples from a SARS-CoV-2 isolate and 88 clinical specimens with previously known results. The repeatability and reproducibility of the threshold cycle values ​​(Ct) were determined in two independent laboratories of the Faculty of Medicine of the Universidad de Antioquia, using different reagents and real time instruments. RESULTS: There were no significant differences in the Ct results between both techniques (P = .84). Using the monoplex PCR of E gene as a reference, the interrater reliability analysis showed similarity between the two techniques, with a kappa coefficient of 0.89, the sensitivity and the specificity of duplex PCR were 90% and 87%, respectively. CONCLUSIONS: Duplex PCR does not affect the sensitivity and specificity reported by the Charité, Berlin protocol, being a useful tool for SARS-CoV-2 screening in clinical samples.

Validation of a duplex PCR technique using the gen E and RNase P for the diagnosis of SARS-CoV-2. / Validación de una técnica de PCR dúplex usando el gen E y RNasa P para el diagnóstico de SARS-CoV-2.

INTRODUCTION: Reverse transcriptase - polymerase chain reaction (RT-PCR) is the standard technique for SARS-CoV-2 diagnosis. The World Health Organization recommends the Charité-Berlin protocol for COVID-19 diagnosis, which requires triple PCR, limiting the process capability of laboratories and delaying the results. In order to reduce these limitations, a duplex PCR is validated for the detection of the E and RNase P genes. METHODS: We compared the limit of detection, sensitivity and specificity of the duplex PCR technique (E gene and RNase P) against the monoplex standard (E gene) in RNA samples from a SARS-CoV-2 isolate and 88 clinical specimens with previously known results. The repeatability and reproducibility of the threshold cycle values (Ct) were determined in two independent laboratories of the Faculty of Medicine of the Universidad de Antioquia, using different reagents and real time instruments. RESULTS: There were no significant differences in the Ct results between both techniques (p = 0.84). Using the monoplex PCR of E gene as a reference, the interrater reliability analysis showed similarity between the two techniques, with a kappa coefficient of 0.89, the sensitivity and the specificity of duplex PCR were 90% and 87%, respectively. CONCLUSIONS: Duplex PCR does not affect the sensitivity and specificity reported by the Charité, Berlin protocol, being a useful tool for SARS-CoV-2 screening in clinical samples.

Population Pharmacokinetic Models of Antituberculosis Drugs in Patients: A Systematic Critical Review.

BACKGROUND: Tuberculosis (TB) remains one of the most important infectious diseases. Population pharmacokinetic (pop-PK) models are widely used to individualize dosing regimens of several antibiotics, but their application in anti-TB drug studies is scant. The aim of this study was to provide an insight regarding the status of pop-PK for these drugs and to compare results obtained through both parametric and nonparametric approaches to design precise dosage regimens. METHODS: First, a systematic approach was implemented, searching in PubMed and Google Scholar. Articles that did not include human patients, that lacked an explicit structural model, that analyzed drugs inactive against M. tuberculosis, or were without full-text access, were excluded. Second, the PK parameters were summarized and categorized as parametric versus nonparametric results. Third, a Monte Carlo simulation was performed in Pmetrics using the results of both groups, and an error term was built to describe the imprecision of each PK modeling approach. RESULTS: Thirty-three articles reporting at least 1 pop-PK model of 19 anti-TB drug were found; 46 different models including PK parameter estimates and their relevant covariates were also reported. Only 9 models were based on nonparametric approaches. Rifampin was the drug most studied, but only using parametric approaches. The simulations showed that nonparametric approaches improve the error term compared with parametric approaches. CONCLUSIONS: More and better models, ideally using nonparametric approaches linked with clear pharmacodynamic goals, are required to optimize anti-TB drug dosing, as recommended in the WHO End TB strategy.

A new pharmacodynamic approach to study antibiotic combinations against enterococci in vivo: Application to ampicillin plus ceftriaxone.

The combination of ampicillin (AMP) and ceftriaxone (CRO) is considered synergistic against Enterococcus faecalis based on in vitro tests and the rabbit endocarditis model, however, in vitro assays are limited by the use of fixed antibiotic concentrations and the rabbit model by poor bacterial growth, high variability, and the use of point dose-effect estimations, that may lead to inaccurate assessment of antibiotic combinations and hinder optimal translation. Here, we tested AMP+CRO against two strains of E. faecalis and one of E. faecium in an optimized mouse thigh infection model that yields high bacterial growth and allows to define the complete dose-response relationship. By fitting Hill's sigmoid model and estimating the parameters maximal effect (Emax) and effective dose 50 (ED50), the following interactions were defined: synergism (Emax increase ≥2 log10 CFU/g), antagonism (Emax reduction ≥1 log10 CFU/g) and potentiation (ED50 reduction ≥50% without changes in Emax). AMP monotherapy was effective against the three strains, yielding valid dose-response curves in terms of dose and the index fT>MIC. CRO monotherapy showed no effect. The combination AMP+CRO against E. faecalis led to potentiation (59-81% ED50 reduction) and not synergism (no changes in Emax). Against E. faecium, the combination was indifferent. The optimized mouse infection model allowed to obtain the complete dose-response curve of AMP+CRO and to define its interaction based on pharmacodynamic parameter changes. Integrating these results with the pharmacokinetics will allow to derive the PK/PD index bound to the activity of the combination, essential for proper translation to the clinic.

Use of low-molecular-weight heparin in severe paraquat poisoning: a case report.

BACKGROUND: Acute paraquat ingestion remains a leading cause of mortality in developing countries. There is currently no evidence that treatment with high-dose immunosuppressants and antioxidants improves survival in patients with paraquat poisoning, and better options are urgently needed. Here, we describe the unexpected survival and recovery of a patient with a potentially fatal paraquat poisoning. CASE PRESENTATION: After ingesting 28 mL of paraquat (20% ion w/v), confirmed by a deep blue color in the urine dithionite test (UDT), a 17-year-old Hispanic Colombian boy was treated according to the hospital protocol with cyclophosphamide, methylprednisolone, N-acetylcysteine, vitamin E and propranolol. Gastrointestinal endoscopy showed extensive ulceration and necrosis. As a novelty, enoxaparin at a single dose of 60 mg was added to his treatment. Despite the evidence of severe mucosal burns in the gastrointestinal tract and high paraquat concentrations found in the UDT, the clinical condition began to improve after 1 day of treatment, with full recovery and discharge from hospital after 21 days. CONCLUSIONS: Although the amount of paraquat ingested by the patient was large and the UDT indicated severe poisoning with a somber prognosis, unexpected survival of the patient was observed, and the addition of enoxaparin was the only change from the standard treatment.

Un registro de hipertrofia del trago del murciélago frugívoro de gran tamaño Artibeus lituratus (Chiroptera: Phyllostomidae) / A record of hypertrophy of the tragus of great fruit-eating bat Artibeus lituratus (Chiroptera: Phyllostomidae)

Resumen En este trabajo, reportamos y describimos evidencia de una anomalía en el trago de un individuo de Artibeus lituratus, capturado en los Andes Centrales de Colombia. En junio de 2019, durante un trabajo de campo en el Departamento de Caldas, municipio de Aranzazu, quedó atrapado un individuo de A. lituratus con inusual forma de trago. Este individuo tenía un trago de forma cilíndrica y asimetría. El individuo fue recogido y depositado en el Museo de Historia Natural de la Universidad de Caldas (MHN-UCa). Se realizó una revisión de la literatura para encontrar casos similares utilizando motores de búsqueda, pero no se encontraron informes previos de la anomalía. Además, revisamos el trago de los especímenes en el MHNUCa y ninguno de ellos presentaba malformaciones similares. Concluimos que esta anomalía no se había registrado previamente en Chiroptera.

Abstract In this work, we report and describe evidence of an anomaly in the tragus of an individual of Artibeus lituratus, captured in the Central Andes of Colombia. During field work in the Department of Caldas, municipality of Aranzazu, one individual of A. lituratus with unusual tragus form was trapped. This individual had a tragus with cylindrical shape and asymmetry. The individual was collected and deposited at the Museum of Natural History of the University of Caldas (MHN-UCa). A literature review was conducted to find similar cases using searching engines, but no previous reports of the anomaly were find. Furthermore, we reviewed the tragus of vouchers at the MHN-UCa and none of these had similar malformations. We concluded that this anomaly has not previously registered in Chiroptera.

Social and economic variables related with Paraquat self-poisoning: an ecological study.

BACKGROUND: Paraquat self-poisonings constitute a significant contributor to the global burden of suicide. Our aim was to evaluate the relationship between social and economic variables with the incidence of self-poisoning with Paraquat in the northeast of Colombia. METHODS: Records of 154 cases of self-poisoning with Paraquat and several socio-economic variables of six regions of northeast of Colombia were analyzed. RESULTS: Most of the cases were mestizos, farmworkers, between 20 and 29 years, with intentional exposure using the oral route. Multivariate analyses revealed significant associations among the incidence of self-poisoning with PQ with the ecological factors such as poverty greater than 30% (IRR 15.9 IC95% 5.56-44.72), land Gini index < 0.7 (IRR 7.11 IC95% 3.58-14.12), private health insurance < 40% (IRR 3.39 IC95% 1.30-8.82) and planted area > 10% (IRR 2.47 IC95% 1.60-3.80). CONCLUSION: There is a relationship between ecological factors and, as such, this study opens the way to further developments in the field.

A counterfeit multivitamin product inducing severe bleeding disorders in humans.

Context: During a period of 6 months, 36 people reported to health authorities in the Department of Antioquia, Colombia, presenting episodes of bleeding in varying magnitude and locations in the body and alterations in coagulation tests, after having taken a falsified dietary supplement. The identification of the first four cases were to the cell-phone line at the Drug and Poison Research Information Center (CIEMTO). The successive presentation of cases with similar manifestations, taking the same product, served to suspect a possible common link.Case details: All of the patients needed hospitalization, the administration of blood products and / or vitamin K to reverse the clinical manifestations, and to stop the oral consumption of the falsified supplement. For each patient there was a full recovery of coagulation and improvement of haemorrhagic manifestations after the first week of management. The Food and Drug administration of Colombia (INVIMA), withdrew the product from the market, alerted the medical community and the general public and conducted an investigation that finally showed warfarin as a the main contaminant in the dietary supplement.Conclusion: This cases series emphasize the importance of the Poison Control Center to detect promptly potential new exposure of hazards to hundreds of products to the population, some of them fraudulent.

Toxicity induced by multiple high doses of vitamin B12 during pernicious anemia treatment: a case report.

Context: The clinical consequences of excess vitamin B12 induced by multiple oral doses of cyanocobalamin are not well-known.Case details: A young woman was treated with multiple daily doses of 1 mg of cyanocobalamin for severe pernicious anemia. After a total dose of 12 mg, she developed acne, palpitations, anxiety, akathisia, facial ruddiness, headache, and insomnia. She improved two weeks after stopping the drug. There were no sequelae nor complications.Discussion: Although these symptoms of cobalamin toxicity were unexpected and unusual, the case reminds us that the administration of any drug is not entirely safe.

Optical Coherence Tomography (OCT) for the evaluation of internal adaptation of class V resin restorations on Dentin.

Internal adaptation of adhesive restorations affects their longevity. In a clinical setting, the dentists use visual and tactile examination to evaluate marginal adaptation, while radiographs provide somewhat reliable information about adaptation or secondary caries present. For class V restorations located on the vestibular (buccal) surfaces, none of the tools available can provide any information about the internal adaptation or the presence of secondary caries. OCT has been proven to be a useful tool for non-destructive assessment of internal adaptation of adhesive restorations. This paper is evaluating the use of a new high-resolution handheld OCT prototype with a pen-shaped intraoral tip and an imaging depth of 8mm to examine the internal adaptation and the presence of demineralization under resin restorations on the vestibular dentin surface. The Axsun OCT system helped evaluate the internal adaptation of composite restorations, differentiate between healthy and demineralised dentin, adhesive, and restoration layers. OCT provided a unique visualization and characterization of internal structures as well as non-contact assessment of marginal adaptation.

[Effectiveness of the antibiotic combinations for enterococcal infections treatment: a critical review]. / Eficacia de las combinaciones antimicrobianas para el tratamiento de infecciones enterocócicas: una revisión crítica.

During the last decades, enterococci have emerged as important etiological agents in bacteremia, osteomyelitis, endocarditis and soft tissue infections. Antimicrobial combinations have been the most used therapeutic strategies for these infections, aiming for a bactericidal synergistic effect. However, besides in vitro and in vivo models, the clinical usefulness of such combinations is controversial, especially in non-endocardic systemic infections. For example, although beta-lactam and aminoglycoside combinations or double beta-lactam treatment have achieved high cure rates in endocarditis, the optimal treatment has not yet been clarified or if these combinations are useful in other infections. The aim of this review was to analyze and summarize the results from several experimental models of antienterococcal combined therapy and from clinical trials available in PubMed/Medline, to better assess the evidence that supports the use of these combinations. In conclusion, the available information is scarce, and more and better in vivo models and clinical studies are required to confirm the potential synergistic activity of antienterococcal combinations.

Artralgia inducida por levofloxacina: Reporte de un caso / Levofloxacin induced arthralgia: a case report

Mujer quien inició tratamiento de rescate de segunda línea para Helicobacter pylori con levofloxacina un gramo cada 12 horas, amoxicilina 500 mg cada 8 horas y lansoprazol 40 mg cada 24 horas. Al quinto día de tratamiento manifestó mialgias generalizadas seguido por artralgias y limitación del movimiento en rodillas y codos. Al séptimo día, sin mejora, la paciente suspende la medicación y presenta resolución completa de los síntomas una semana después. No hubo secuelas, ni complicaciones, ni re-exposición al medicamento. El caso fue clasificado como probable, con un puntaje de siete en la escala de Naranjo. Este caso nos recuerda que la administración de fluoroquinolonas puede asociarse con artralgias y artropatía reversible aguda, y debería ser la primera sospecha diagnóstica en pacientes sin comorbilidad.

Woman who initiated second-line rescue therapy for Helicobacter pylori with levofloxacin one gram every 12 hours, amoxicillin 500 mg every 8 hours and lansoprazole 40 mg every 24 hours. On the fifth day of treatment, she manifested generalized myalgia followed by bilateral knee and elbow arthralgia with limitation of movements. On the seventh day, without improvement, the patient discontinues the medication and achieve complete resolution of the symptoms one week later. There were no sequelae, no complications, no re-exposure to the drug. The case was classified as probable attaining a score of seven under the Naranjo's scale. This case reminds us that administration of fluoroquinolones may be associated with arthralgia and acute reversible arthropathy and should be the first diagnostic suspicion in patients without comorbidity.

Nonparametric Population Pharmacokinetic Modeling of Isoniazid in Colombian Patients With Tuberculosis.

BACKGROUND: Isoniazid (INH) is a first-line antituberculosis (TB) agent with a pharmacokinetic profile characterized by high interindividual variation; however, population pharmacokinetic studies in patients with TB are scarce. The aim was to develop a population model for INH in Colombian patients with TB suitable for predicting drug exposure and assessing the probability of target attainment of pharmacodynamic goals. METHODS: Ten hospitalized adult patients with TB undergoing INH treatment were recruited. After an 8-hour fasting, subjects took 300 mg of INH, and 10 samples were taken from 0 to 12 hours. INH was quantified by high-performance liquid chromatography-UV, and data were analyzed with the Pmetrics R package software. A Monte Carlo simulation with the model parameters was run to determine the probability of target attainment for optimal efficacy. RESULTS: The best model included 2 compartments, first-order absorption (Ka), delayed absorption (Tlag), and linear clearance (CL). Median Tlag was 0.25 hours, 5.54 hour for Ka, (Equation is included in full-text article.)for CL, (Equation is included in full-text article.)for the volume of the central compartment (Vc), 1.04 L/h for intercompartmental clearance (Q), and 788 L for the volume of the peripheral compartment (Vp). CL and Vc were allometrically scaled on basis of the normalized body weight. CONCLUSIONS: The Monte Carlo simulation indicated that 300 mg of INH per day is appropriate for Mycobacterium tuberculosis strains with minimal inhibitory concentration (MIC) up to 0.03 mg/L (target: area under the concentration-time curve/MIC >597); however, to cover strains with MIC up to 0.125 mg/L (80% of clinical isolates), a dose of 900 mg per day would be required.

Eficacia de las combinaciones antimicrobianas para el tratamiento de infecciones enterocócicas: una revisión crítica / Effectiveness of the antibiotic combinations for enterococcal infections treatment: a critical review

Resumen Durante las últimas décadas, especies del género Enterococcus han emergido como importantes agentes etiológicos de bacteriemia, osteomielitis, endocarditis e infecciones de tejidos blandos. La combinación de antibacterianos ha sido la estrategia terapéutica más utilizada para dichas infecciones, buscando un potencial efecto sinérgico bactericida. Sin embargo, aparte de los modelos in vitro e in vivo, la utilidad clínica del tratamiento combinado genera controversia, especialmente en infecciones sistémicas no endocárdicas. Aunque las combinaciones entre β-lactámicos y aminoglucósidos o el tratamiento dual con β-lactámicos, han mejorado las tasas de curación de la endocarditis, aún no se ha esclarecido cuál es su tratamiento óptimo o si estas combinaciones también son útiles en otro tipo de infecciones graves sistémicas. El propósito de esta revisión es analizar y resumir los resultados obtenidos de diferentes modelos experimentales de combinaciones anti-enterocócicas y de los estudios clínicos disponibles en PubMed/Medline, a fin de evaluar mejor la evidencia que soporta la utilización de estas combinaciones. En conclusión, la información disponible es escasa, e indica la necesidad de mejores modelos in vivo y estudios clínicos que permitan comprobar la potencial actividad sinérgica de las combinaciones anti-enterocóciccas.

During the last decades, enterococci have emerged as important etiological agents in bacteremia, osteomyelitis, endocarditis and soft tissue infections. Antimicrobial combinations have been the most used therapeutic strategies for these infections, aiming for a bactericidal synergistic effect. However, besides in vitro and in vivo models, the clinical usefulness of such combinations is controversial, especially in non-endocardic systemic infections. For example, although beta-lactam and aminoglycoside combinations or double beta-lactam treatment have achieved high cure rates in endocarditis, the optimal treatment has not yet been clarified or if these combinations are useful in other infections. The aim of this review was to analyze and summarize the results from several experimental models of antienterococcal combined therapy and from clinical trials available in PubMed/Medline, to better assess the evidence that supports the use of these combinations. In conclusion, the available information is scarce, and more and better in vivo models and clinical studies are required to confirm the potential synergistic activity of antienterococcal combinations.