Transição de via de linezolida endovenosa para via oral: uma análise de custo-minimização / Switching from intravenous to oral linezolid therapy: a cost-minimization analysis

Objetivo: Comparar custos da terapia endovenosa exclusiva com linezolida com os custos da terapia iniciada por via endovenosa com transição para via oral após 72 horas, como estratégia de intervenção em programas de gestão de antimicrobianos. Métodos: Avaliação econômica de custo-minimização comparando custos diretos da terapia endovenosa exclusiva com linezolida com a terapia endovenosa seguida de transição para via oral em cenário simulado, sob a perspectiva do Sistema Único de Saúde (SUS), com árvore de decisão como modelo para tomada de decisão. Resultados: A alternativa englobando a transição de via mostrou-se a mais econômica em todos os cenários analisados. Para 28 dias de tratamento com linezolida, houve redução de 22% nos custos, considerando o paciente internado. Ao considerar alta após o sexto dia de tratamento, a redução de custos variou de 26%, com financiamento pelo SUS do restante do tratamento, a 84%, com financiamento do tratamento pós-alta pelo paciente. Conclusão: Conclui-se que a transição de via de linezolida é uma importante estratégia nos programas de gerenciamento de antimicrobianos, capaz de gerar economia significativa para a instituição. As avaliações econômicas de custo-minimização, nesse contexto, são uma importante ferramenta para demonstrar o aspecto econômico com potencial para sensibilizar gestores e tomadores de decisão.

Objective: To compare the direct costs of linezolid intravenous therapy with the costs of intravenous therapy switching to oral therapy after 72 hours as an intervention strategy in antimicrobial stewardship programs. Methods: Economic evaluation cost-minimization comparing direct costs of exclusive linezolid intravenous therapy with intravenous therapy for 72 hours and after switching to oral therapy in a simulated scenario, from the perspective of the National Health Service, with a decision tree as a decision modeling. Results: The alternative encompassing the therapy transition proved to be the most economical in all analyzed scenarios. For 28 days of treatment with linezolid, there was a 22% reduction in costs, considering the hospitalized patient. When considering discharge after the sixth day of treatment, the cost reduction ranged from 26%, with funding from the National Health Service for the rest of the treatment, to 84%, with funding for the post-discharge treatment by the patient. Conclusion: It was concluded that the linezolid therapy transition is an important strategy in antimicrobial management programs, capable of generating significant savings for the institution. In this context, economic cost-minimization assessments are an important tool to demonstrate the economic aspect with the potential to raise awareness among managers and decision-makers.

Risk of acute kidney injury and cost-effectiveness analysis comparing vancomycin and linezolid for the treatment of pediatric patients infected with Gram-positive bacteria / Risco de lesão renal aguda e custo-efetividade comparando vancomicina e linezolida para o tratamento de pacientes pediátricos infectados por bactérias Gram-positivas

Objective: This study aimed to compare the occurrence of acute kidney injury (AKI) in pediatric patients who used vancomycin (VAN) or linezolid (LNZ) to treat Gram-positive coccus (GPC) infections and to assess which treatment (VAN or LNZ) is the most cost-effective considering a pediatric hospital perspective. Methods: A retrospective cohort was performed to evaluate the occurrence of nephrotoxicity in pediatric patients without previous AKI, with GPC infections that used LNZ, or VAN monitored by serum VAN levels. Initially, descriptive analysis and Fisher and chisquare test were performed for this comparison. Then, a cost-effectiveness analysis was conducted through a decision tree model. The outcomes of interest were the rate of AKI related to the drug and the rate of admission to the intensive care unit (ICU) and cure. Results: In patients without previous acute kidney injury (AKI), 20% developed nephrotoxicity associated with VAN versus 9.6% in the LNZ group (p = 0.241). As there was no difference in nephrotoxicity between VAN andlinezolid (LNZ), vancomycin (VAN) monitored by serum VAN levels can optimize and rationalize the treatment. The nephrotoxicity risk criterion should not guide the prescription for LNZ. Furthermore, the average global cost of treatment with VAN was approximately R$ 43,000, while for LNZ, it was R$ 71,000. Conclusion: VAN was considered dominant (lower cost and greater effectiveness) over LNZ for treating patients with GPC infection.

Objetivo: Este estudo objetivou comparar a ocorrência de lesão renal aguda (LRA) em pacientes pediátricos que usaram vancomicina (VAN) ou linezolida (LNZ) para tratar infecções por cocos Gram-positivos (CGP) e avaliar qual tratamento (VAN ou LNZ) é o mais custo-efetivo considerando a perspectiva de um hospital pediátrico. Métodos: Foi realizada uma coorte retrospectiva para avaliar a ocorrência de nefrotoxicidade em pacientes pediátricos sem LRA prévia, com infecções por CGP que utilizaram LNZ ou VAN, combinada com vancocinemia. Para essa comparação, inicialmente foram realizados análise descritiva e testes de Fisher e qui-quadrado. Em seguida, foi realizada uma análise de custo-efetividade por meio de um modelo de árvore de decisão. Os desfechos de interesse foram a taxa de LRA relacionada ao medicamento e a taxa de internação em unidade de terapia intensiva e cura. Resultados: Nos pacientes sem LRA prévia, 20% deles desenvolveram nefrotoxicidade associada à VAN versus 9,6% no grupo LNZ (p = 0,241). Como não houve diferença na nefrotoxicidade entre VAN e LNZ, a VAN combinada com a vancocinemia pode otimizar e racionalizar o tratamento, e a prescrição de LNZ não deve ser guiada pelo critério de risco de nefrotoxicidade. Além disso, o custo médio global do tratamento com VAN foi de aproximadamente R$ 43.000, enquanto para LNZ foi de R$ 71.000. Conclusão: Assim, a VAN foi considerada dominante (menor custo e maior eficácia) sobre a LNZ para o tratamento de pacientes com infecção por CGP.

Síndrome serotoninérgico como reacción adversa infrecuente ante la sinergia entre Linezolid y Fentanilo: presentación de caso / Serotonin syndrome as an infrequent adverse reaction to synergy between Linezolid and Fentanyl: case presentation

Resumen El síndrome serotoninérgico es una condición potencialmente mortal causada por medicamentos que afectan el metabolismo de la serotonina o que actúan como agonistas directos del receptor de esta o una combinación de ambos. El síndrome da lugar a una variedad de manifestaciones mentales, autonómicas y neuromusculares, que pueden variar desde leves hasta potencialmente mortales. Se reporta el caso clínico de un paciente el cual desarrolló este síndrome por la coadministración y sinergismo de linezolid y fentanilo, con una gran variedad de características clínicas, desde las más sutiles, como cifras tensionales altas de difícil manejo mientras se encontraba bajo el efecto de sedoanalgesia, hasta las manifestaciones más floridas del síndrome posterior a la suspensión de esta. La asociación de estos medicamentos representa una etiología poco informada que puede favorecer la aparición del síndrome, mientras que el uso de benzodiazepinas puede enmascarar el cuadro dificultando su diagnóstico. MÉD.UIS.2020;33(3): 59-66

Abstract Serotonin syndrome is a life-threatening condition caused by medications that affect serotonin metabolism or that act as direct agonists for serotonin receptor or a combination of both. The syndrome gives rise to a variety of mental, autonomic, and neuromuscular manifestations, which can range from mild to life-threatening. We report a clinical case of a patient who developed this syndrome due to the co-administration and synergism of linezolid and fentanyl, with a wide variety of clinical characteristics, from the most subtle, such as high blood pressure levels difficult to manage while under the effect of sedoanalgesia, to the most florid manifestations of the syndrome after 48 hours of its suspension. The association of these drugs represents a poorly reported etiology that may favor the appearance of the syndrome, while the use of benzodiazepines may mask the condition, making its diagnosis difficult. MÉD.UIS.2020;33(3): 59-66

A retrospective cohort study to screen linezolid-induced thrombocytopenia in adult patients hospitalized in the Midwestern Region of Brazil

ABSTRACT Background: Thrombocytopenia (TP) is the major event associated with linezolid (LZD) therapy. We investigated the incidence and risk factors for thrombocytopenia in hospitalized adults who received LZD (1200 mg/day) between 2015 and 2017. HIV-positive, death during follow-up and those with a baseline platelet count ≤100 × 103/mm3 were excluded. Method: TP was defined as a decrease in platelet count of ≥20% from the baseline level at the initiation of linezolid therapy and a final count of <100 × 103/mm3. The odds ratios (OR) for thrombocytopenia were obtained using multivariate stepwise logistic regression analysis. Main results: A total of 66 patients were included (mean age [SD] 62 [18], male gender [%], 37 [56]). LZD-associated TP was identified in 12 patients (18.2%). For TP, the adjusted OR [95% CI] of the platelet count ≤200 × 103/mm3, serum creatinine and renal impairment at baseline were 5.66 [1.15-27.9], 4.57 [1.26-16.5] and 9.41 [1.09-80.54], respectively. Male gender and dosage per weight per day (DPWD) >20 mg/kg/day were not risk factors. Conclusion: The results showed that the incidence of linezolid-induced thrombocytopenia was lower in patients with normal renal function and higher in those with platelet counts ≤200 × 103/mm3 or serum creatinine >1.5 mg/dL at the start of the treatment.

Microorganismos más frecuentes en infecciones cutáneas en el Hospital Provincial General Ambato / Most frequent microorganisms in skin infections at the General Provincial Hospital "Ambato"

Las infecciones cutáneas producidas por microorganismos afectan directamente a la piel, partes blandas y tejidos, donde proliferan y ocasionan graves alteraciones. Estas infecciones constituyen un problema de salud pública, ya que muchos microorganismos muestran resistencia a antimicrobianos comunes y no comunes, lo cual incide directamente en la aplicación del tratamiento adecuado al paciente. El objetivo de este estudio fue identificar los microorganismos más frecuentes en infecciones cutáneas, su sensibilidad y resistencia a los antibióticos en los pacientes con infección que acudieron al Hospital Provincial General "Ambato" en el período mayo 2017 ­ junio 2018. La metodología empleada en esta investigación se basa en un estudio descriptivo, de corte transversal y enfoque cuali-cuantitativo, empleando la técnica documental y el reporte de resultados como instrumento. La información se tabuló y analizó mediante el paquete operativo Microsoft 2010. Se encontró que en el 29% de las muestras procesadas se aisló Staphylococcus aureus como el más frecuente en este tipo de infecciones, con mayor sensibilidad a Clindamicina, Doxacilina y Linezolid (100%) y resistencia a Penicilinas y Oxacilina (47,82%). Es importante destacar que el 47,83 % de las cepas de S. aureus aisladas expresaron fenotípicamente el gen mecA. La entidad clínica más frecuente asociada a este tipo de infección fue el ectima con un 55%. En conclusión, se comprobó la resistencia de cepas a diversos antibióticos presentando las más relevantes como meticilino resistentes, vancomicina resistentes y Klebsiella pneumoniae carbapenemasas

The skin infections caused by microorganisms directly alter the skin, soft tissues and tissues cause serious damage and the proliferation of them, which is a problem for health centers and hospitals, since these microorganisms are often resistant to antibacterial which are not very common is a problem for the treatment of the patient. The objective of this study was to identify the most frequent microorganisms in cutaneous infections, their sensitivity and resistance to antibiotics in the patients with infection who when to the General Provincial Hospital "Ambato", in the period May 2017 - June 2018 the methodology used in this investigation is based on a descriptive cutting study cross-section and qualitative-quantitative approach, using the documentary technique and the report of results as an instrument. The information was tabulated and analyzed using the Microsoft 2010 operating package. It was found that 29% of the samples processed were isolated Staphylococcus aureus as the most frequent in this type of infections, with greater sensitivity to Clindamycin, Doxacillin and Linezolid (100%) and resistance to Penicillins and Oxacillin (47,82%). It is important to note that 47,82% of strains of S. aureus were expressly phenotypically expressed in the mecA gene. The most frequent clinical entity associated with this type of infection was efficacy with 55%. In conclusion, the resistance of strains in several antibiotics was proved, presenting the most relevant ones as methicillin resistant, vancomycin resistant and Klebsiella pneumoniae carbapenemasas.

Informe diário de evidências COVID-19: busca realizada em 17 de julho de 2020 / COVID-19 daily evidence report: search conducted on July 17, 2020

O Informe Diário de Evidências é uma produção do Ministério da Saúde que tem como objetivo acompanhar diariamente as publicações científicas sobre tratamento farmacológico e vacinas para a COVID-19. Dessa forma, são realizadas buscas estruturadas em bases de dados biomédicas, referentes ao dia anterior desse informe. Não são incluídos estudos pré-clínicos (in vitro, in vivo, in silico). A frequência dos estudos é demonstrada de acordo com a sua classificação metodológica (revisões sistemáticas, ensaios clínicos randomizados, coortes, entre outros). Para cada estudo é apresentado um resumo com avaliação da qualidade metodológica. Essa avaliação tem por finalidade identificar o grau de certeza/confiança ou o risco de viés de cada estudo. Para tal, são utilizadas ferramentas já validadas e consagradas na literatura científica, na área de saúde baseada em evidências. Cabe ressaltar que o documento tem caráter informativo e não representa uma recomendação oficial do Ministério da Saúde sobre a temática. Foram encontrados 14 artigos e 13 protocolos.

Molecular detection of chloramphenicol-florfenicol resistance (cfr) genes among linezolid resistant MRSA isolates in Sokoto State, Nigeria / Detecção molecular de genes de resistência ao cloranfenicol-florfenicol (cfr) entre isolados de MRSA resistentes a linezolida no estado de Sokoto, Nigéria

Objective: we investigated previous literatures for documentation of the trend in Sokoto, Nigeria and found none. We deemed it fit to determine the frequency of linezolid resistance mediated by cfr gene among MRSA isolates from Sokoto State-owned hospitals. Methods: Bacterial species identification was carried out with Microgen™ Staph-ID System kit (Microgen, Surrey, UK). Disc agar diffusion method (Modified Kirby-Bauer's) following Clinical and Laboratory Standards Institute (CLSI 2018) guidelines was used in antimicrobial susceptibility testing. The results were interpreted and managed using WHONET 5.6 software (WHO, Switzerland). Oxacillin resistant screening agar base (ORSAB) culture was used to determine phenotypic methicillin resistance. Polymerase chain reaction (PCR) was carried out to determine the presence of cfr-gene. Results: A total of 81 S. aureus isolates were phenotypically identified. Of this number, 46.91% (38/81) were MRSA; Healthcare workers (39.5%), Outpatient (28.9%), In patient (21%), Security men and Cleaners (5.3% each). Importantly linezolid resistance rate among the MRSA isolates was 44.7%. Analysis of antimicrobial susceptibility profile also showed a multiple antibiotics resistance burden of MDR (5.9%), possible XDR (47.1%), XDR (41.1%) and PDR (5.9%) amongst LR-MRSA. About 52.9% (9/17) of LR-MRSA harbored the cfr gene. Conclusions: This is the first report to document cfr gene in LR-MRSA strains in Sokoto. The cfr gene was found among the studied LR-MRSA strains and if cfr-mediated linezolid resistance is not properly checked, its phenotypic expression may result in an outbreak of multiple antibiotic resistant strains.

Objetivo: avaliar a incidência de resistência linezolida cfr-mediada entre os isolados de MRSA dos hospitais do Estado de Sokoto. Métodos: A identificação das espécies bacterianas foi realizada com Microgen™ Staph-ID System kit (Microgen, Surrey, UK). Método de difusão em ágar de disco (Kirby-Bauer modificado) seguindo as diretrizes do Clinical and Laboratory Standards Institute (CLSI 2018). O resultado foi interpretado e gerido com WHONET 5.6 (OMS, Suíça) software. A cultura ORSAB (Oxacillin resistant screening agar) foi utilizada para determinar a resistência fenotípica à meticilina. A PCR foi realizada para determinar a presença de cfr-gene. Resultados: um total de 81 isolados de S. aureus foi identificada fenotipicamente. Desse número, 46,91% (38/81) eram de MRSA; Profissionais de saúde (39,5%), Ambulatoriais (28,9%), Em paciente (21%), Homens de segurança e Limpadores (5,3% cada). A taxa de resistência linezolida entre os isolados de MRSA foi de 44,7%. A análise do perfil de sensibilidade antimicrobiana também mostrou uma carga de resistência a antibióticos múltiplos de MDR (5,9%), possível XDR (47,1%), XDR (41,1%) e PDR (5,9%) entre LR-MRSA. Um total de, 52,9% (9/17) da LR-MRSA abrigava o gene cfr. Conclusões: Este é o primeiro relatório a documentar o cfr-gen nas estirpes LR-MRSA em Sokoto. O gene cfr está presente entre as cepas estudadas de LR-MRSA, e se a resistência cfr-mediated linezolida não for adequadamente verificada, sua expressão fenotípica pode resultar em um surto de múltiplas cepas resistentes a antibióticos.

Shortened tuberculosis treatment regimens: what is new? / Esquemas mais curtos de tratamento da tuberculose: o que há de novo?

ABSTRACT Given the global burden of tuberculosis, shortened treatment regimens with existing or repurposed drugs are needed to contribute to tuberculosis control. The long duration of treatment of drug-susceptible tuberculosis (DS-TB) is associated with nonadherence and loss to follow up, and the treatment success rate of multidrug-resistant tuberculosis (MDR-TB) is low (approximately 50%) with longer regimens. In this review article, we report recent advances and ongoing clinical trials aimed at shortening regimens for DS-TB and MDR-TB. We discuss the role of high-dose rifampin, as well as that of clofazimine and linezolid in regimens for DS-TB. There are at least 5 ongoing clinical trials and 17 observational studies and clinical trials evaluating shorter regimens for DS-TB and MDR-TB, respectively. We also report the results of observational studies and clinical trials evaluating a standardized nine-month moxifloxacin-based regimen for MDR-TB. Further studies, especially randomized clinical trials, are needed to evaluate regimens including newer drugs, drugs proven to be or highly likely to be efficacious, and all-oral drugs in an effort to eliminate the need for injectable drugs.

RESUMO Em virtude da carga global da tuberculose, esquemas mais curtos de tratamento com medicamentos já existentes ou reaproveitados são necessários para contribuir para o controle da doença. A longa duração do tratamento da tuberculose sensível (TBS) está relacionada com não adesão e perda de seguimento, e a taxa de sucesso do tratamento da tuberculose multirresistente (TBMR) é baixa (de aproximadamente 50%) com esquemas mais longos. Neste artigo de revisão, relatamos avanços recentes e ensaios clínicos em andamento cujo objetivo é encurtar os esquemas de tratamento de TBS e TBMR. Discutimos o papel da rifampicina em altas doses, assim como o da clofazimina e linezolida em esquemas de tratamento de TBS. Relatamos também os resultados de estudos observacionais e ensaios clínicos de avaliação de um esquema padronizado de nove meses à base de moxifloxacina para o tratamento de TBMR. Mais estudos, especialmente ensaios clínicos randomizados, são necessários para avaliar esquemas que incluam medicamentos mais novos, medicamentos comprovadamente ou provavelmente eficazes e medicamentos exclusivamente orais na tentativa de dispensar o uso de medicamentos injetáveis.

Blefarite: epidemiologia, etiologia, apresentações clínicas, tratamento e evolução de nossos pacientes / Blepharitis: epidemiology, etiology, clinical presentations, treatment and evolution of our patients

Resumo Objetivo: A blefarite é uma das condições mais comumente encontradas na prática oftalmológica e se constitui em uma causa frequente de irritação e desconforto ocular. Por ser uma doença de difícil tratamento, os autores buscaram compreender melhor a epidemiologia, etiologia, apresentações clínicas, tratamento e evolução de seus pacientes, visando maior sucesso terapêutico. Métodos: Foram avaliados retrospectivamente e transversalmente o prontuário de 124 pacientes do Centro de Oftalmologia Tadeu Cvintal, os quais apresentavam blefarite e foram submetidos à classificação de gravidade e coleta de secreções palpebrais para cultura bacteriana e antibiograma. Resultados: A media da idade dos pacientes foi de 67,4 anos, o sexo feminino foi responsável por 70 (56,4%) casos e o masculino por 54 (43,5%). Quanto à gravidade da doença, constatou-se 71 casos de blefarite leve (56,8%), 52 (41,6%) com intensidade moderada e 2 (1,6%) casos graves. Avaliando o seguimento do tratamento da doença, foi observado que 103 (82,4%) pacientes não retornaram para avaliar o resultado do tratamento e apenas 22 (17,6%) retornaram. Em relação às culturas realizadas, 82 (66,1%) não apresentaram crescimento microbiano. Dentre as 42 (33,8%) amostras positivas, os Staphylococcus coagulase negativo foram os mais prevalentes, sobretudo os Staphylococcus epidermidis, responsável por 35 (83,3%) delas. Quanto à sensibilidade aos antibióticos, os agentes de nossa amostra demonstraram maior resistência à Penicilina, Eritromicina e Ciprofloxacino e 100% de sensibilidade à Linezolida, Vancomicina e Daptomicina. Conclusão: Conhecendo melhor as características epidemiológicas da blefarite e a sensibilidade antimicrobiana das bactérias envolvidas, é possível oferecer tratamentos mais eficazes.

Abstract Objective: Blepharitis is one of the most commonly encountered conditions in ophthalmic practice and is a frequent cause of eye irritation and discomfort. Being a difficult to treat disease, the authors sought to better understand the epidemiology, etiology, clinical presentations, treatment and evolution of their patients, aiming at greater therapeutic success. Methods: The medical records of 124 patients of Centro de Oftalmologia Tadeu Cvintal who had blepharitis were retrospectively and cross-sectionally evaluated and underwent severity classification and collection of eyelid secretions for bacterial culture and antibiogram. Results: The mean age of the patients was 67.4 years, females accounted for 70 (56.4%) cases and males for 54 (43.5%). Regarding the severity of the disease, there were 71 cases of mild blepharitis (56.8%), 52 (41.6%) with moderate intensity and 2 (1.6%) severe cases. Evaluating the follow-up of treatment of the disease, it was observed that 103 (82.4%) patients did not return to evaluate the treatment outcome and only 22 (17.6%) returned. In respect of the cultures performed, 82 (66.1%) did not show microbial growth. Among the 42 (33.8%) positive samples, coagulase-negative staphylococci were the most prevalent, especially Staphylococcus epidermidis, responsible for 35 (83.3%) of them. As for antibiotic sensitivity, the agents in our sample showed greater resistance to Penicillin, Erythromycin and Ciprofloxacin and 100% sensitivity to Linezolid, Vancomycin and Daptomycin. Conclusion: By better understanding the epidemiological characteristics of blepharitis and the antimicrobial sensitivity of the bacteria involved, it is possible to offer more effective treatments.

Stability-indicating capillary zone electrophoresis assay for the analysis of linezolid in tablets

A simple and fast alternative methodology using capillary zone electrophoresis (CZE) to analyze linezolid and its cationic photodegradation products in tablets has been developed. The separation was carried out on fused silica capillary and conducted using 100 mM formic acid (pH 3.0) and by applying 30 KV voltage. Detection was performed at UV 254 nm. The optimized method was validated in terms of linearity, limits of detection and quantification, precision (repeatability), stability studies (selectivity) and accuracy. Good linearity (8-20 mg L-1) was obtained and the limit of detection was 0.95 mg L-1. The greatest advantages of the CZE method were the rapid set-up of instrumentation and capillary equilibration, short analysis time (12 min), low running cost and low waste generation. The method showed good stability in determining linezolid submitted to degradation by light and to a climatic chamber and can be used as an alternative for evaluation in stability studies of linezolid in tablets, as well as for the analysis of the drug in raw materials and finished products.

Mielosupresión inducida por linezolid: un caso pediátrico / Myelosupression induced by linezolid: a pediatric case

El linezolid es un antibiótico de la familia de las oxazolidinonas, que actúa inhibiendo la síntesis proteica. Se emplea en infecciones graves por cocos Gram-positivos multirresistentes. Sus principales efectos secundarios son los gastrointestinales y, con menor frecuencia, la neuropatía periférica, la acidosis láctica y la mielosupresión. Se presenta el caso clínico de un niño de 12 años con diagnóstico de osteoartritis séptica de cadera derecha con osteomielitis femoral en tratamiento con linezolid, que presentó un cuadro de intolerancia digestiva, asociado a astenia y pérdida de peso. Presentaba, además, anemia normocítica, junto con leucopenia y trombopenia leves, con datos sugestivos de alteración de la hematopoyesis en el frotis sanguíneo, sugerente de toxicidad por fármacos. El cuadro se resolvió con la interrupción de la administración del fármaco. La mielosupresión reversible asociada a linezolid se relaciona con tratamientos prolongados (> 28 días), por lo que son necesarios los controles hematológicos periódicos durante ellos.

Linezolid is an antibiotic of oxazolidinones family that inhibits proteical synthesis. It is used in several Gram-positive multirresistent infections. Its more frequent side effects are gastrointestinal, followed by peripheral neuropathy and myelosuppression. We report the case of a 12-year-old boy diagnosed with septic osteoarthritis of the hip and femoral osteomyelitis, following treatment with linezolid, who complained about digestive intolerance and weight loss. He showed severe normocytic anemia and mild leukopenia and thrombocytopenia with data of hematopoiesis disorder in the blood smear that suggested drug toxicity. These findings reverted when the treatment was discontinued. Reversible myelosuppression associated with linezolid is related to long treatments (more than 28 days). So it is necessary to check the blood count during long treatments.

Efectos adversos relacionados con la linezolida en la práctica clínica pediátrica / Linezolid-related adverse effects in clinical practice in children

Introducción. La linezolida puede causar efectos adversos, como trombocitopenia, que, según lo observado, se relacionan con la administración de linezolida durante más de 2 semanas. Se ha realizado una cantidad limitada de estudios sobre la seguridad y el momento de aparición de los efectos adversos relacionados con la linezolida en los niños. El objetivo de este estudio fue evaluar la incidencia de los efectos adversos asociados con la linezolida, especialmente en relación con el momento de su aparición. Población y métodos. Se incluyeron a todos los niños (< 18 años de edad) que recibieron tratamiento con linezolida durante > 3 días. Se evaluaron los efectos adversos atribuidos a la linezolida y el momento de aparición de los efectos secundarios. Resultados. En total, se incluyeron 179 niños. La mediana de edad de los pacientes fue 4 años (entre 6 días y 17 años). Durante el tratamiento con linezolida, 36 (20,1%) pacientes tuvieron efectos adversos. El efecto adverso más frecuente fue la trombocitopenia, detectada en 26 (14,5%) pacientes. Los demás efectos adversos fueron: elevación de las enzimas hepáticas en 4 pacientes, leucopenia y anemia en 2 pacientes, disfunción renal en 1 y reacciones cutáneas graves en 3 pacientes. Los efectos adversos se detectaron dentro de una mediana de 7,5 días de tratamiento (intervalo: de 4 a 18 días). Entre los 36 pacientes, 26 (72,2%) presentaron un efecto adverso en los primeros 10 días de tratamiento. Conclusiones. Se detectaron efectos adversos transitorios en el 20,1% de los pacientes durante el tratamiento con linezolida. Estos efectos adversos podrían detectarse antes de los 10 días de tratamiento. La linezolida debe recetarse de manera segura a los niños siempre que se vigilen los efectos adversos, en especial el recuento de trombocitos y el nivel de enzimas hepáticas.

Introduction: Linezolid may cause adverse effects such as thrombocytopenia, which were found to be dependent on receiving linezolid for longer than 2 weeks. There are limited studies concerning the safety and timing of linezolid-related adverse effects in children. Objective of this study was to evaluate the incidence of adverse effects associated with linezolid, with especially focusing on the time of occurrence. Population and Methods: All children (<18 years of age) who received >3 days of linezolid therapy were included in this study. Adverse effects attributed to linezolid and time of occurrence of side effects was evaluated. Results: A total of 179 children were enrolled to the study. The patients' median age was 4 years (6 days to 17 years). During linezolid treatment, 36 (20.1%) patients experienced adverse effects. The most common adverse effect was thrombocytopenia that was detected in 26 patients (14.5%). Other adverse effects were as following; elevated liver enzymes in 4 patients, leucopenia and anemia in 2 patients, renal function impairment in one patient, and serious skin reactions in 3 patients. Adverse effects were detected within median 7.5 days of therapy (ranging from 4 to 18 days). Among 36 patients, 26 (72.2%) patients had adverse effect on the first 10 days of therapy. Conclusions: Transient adverse effects were detected in 20.1% of the patients during linezolid therapy. These adverse effects may be detected earlier than ten days of treatment. Linezolid should be prescribed safely in children with monitoring adverse effects especially platelet count and level of liver enzymes.

In vitro susceptibility of methicillin-resistant Staphylococcus aureus isolates from skin and soft tissue infections to vancomycin, daptomycin, linezolid and tedizolid

Abstract Introduction Treatment of multidrug-resistant Gram-positive infections caused by Staphylococcus aureus remains as a clinical challenge due to emergence of new resistance mechanisms. Tedizolid is a next-generation oxazolidinone, recently approved for skin and soft tissues infections. We conducted a study to determine in vitro susceptibility to vancomycin, daptomycin, linezolid and tedizolid in MRSA clinical isolates from adult patients with skin and soft tissue infections. Material and methods Methicillin-resistant S. aureus isolates were collected in three tertiary-care hospitals of Medellin, Colombia, from February 2008 to June 2010 as part of a previous study. Clinical characteristics were assessed by medical records and MIC values were determined by Epsilometer test. Genotypic analysis included spa typing, MLST, and SCCmec typing. Results A total of 150 MRSA isolates were evaluated and tedizolid MIC values obtained showed higher in vitro activity than other antimicrobials, with MIC values ranging from 0.13 µg/mL to 0.75 µg/mL and lower values of MIC50 and MIC90 (0.38 µg/mL and 0.5 µg/mL). In contrast, vancomycin and linezolid had higher MIC values, which ranged from 0.5 µg/mL to 2.0 µg/mL and from 0.38 µg/mL to 4.0 µg/mL, respectively. Tedizolid MICs were 2- to 5-fold lower than those of linezolid. Clinical characteristics showed high previous antimicrobial use and hospitalization history. The majority of the strains belong to the CC8 harboring the SCCmec IVc and were associated with the spa t1610 (29.33%, n = 44). Conclusion In vitro effectiveness of tedizolid was superior for isolates from skin and soft tissue infections in comparison with the other antibiotics evaluated. The above added to its less toxicity, good bioavailability, daily dose and unnecessity of dosage adjustment, make tedizolid in a promising alternative for the treatment of infections caused by MRSA.

Avances en el tratamiento de la tuberculosis multirresistente / Advances in the treatment of multi-drug resistant tuberculosis

Resumen El tratamiento de las tuberculosis multidrogorresistentes (TBC-MDR) se basa en esquemas de fármacos con diseños muy variables, en pacientes con patrones de resistencia heterogéneos y seguimientos no estandarizados, lo que hace dificil plantear recomendaciones con fuerte nivel de evidencia. Además, sólo una minoría de estos enfermos recibe tratamiento a nivel mundial y con los actuales esquemas menos del 50% de los que logran ser tratados curan. Afortunadamente, durante los últimos años han aparecido nuevos medicamentos, (bedaquilina, delamanid y pretomanid), que están demostrando ser de real utilidad para estos pacientes en ensayos con mejor diseño y seguimiento, donde se puede establecer con mayor precisión la eficacia, toxicidad y grado de recaídas. Además, algunos fármacos ya conocidos, (fluoroquinolonas, linezolid, clofazimina) están siendo introducidos dentro de los nuevos esquemas de tratamiento.

Abstract Therapy of multi-drug resistant tuberculosis (MDR TB) is based on trials with drugs with highly variable patterns of resistance and non-standardized follow-ups that make it difficult to provide recommendations with strong levels of evidence. Also, the vast majority of MDR-TB patients fail to receive therapy and those who receive it, only achieve around 50% of good results. Fortunately new drugs have emerged (bedaquiline, delamanid, pretomanid) that are being useful for these patients with better designed trials and monitoring, in which the efficacy, toxicity and degree of relapses can be evaluated more accurately. Some drugs already known (fluorquinolones, linezolid and clofazimine) are also being introduced in new schemes of therapy.

Osteítis infecciosa del pubis. A propósito de un caso / Infectious osteitis pubis. A propos of a case

Se presenta un caso de osteitis del pubis por Staphylococcus aureus, en un varón de 30 años y tratado exitosamente con linezolid y levofloxacina.

We describe a case o infectious osteitis pubis in one male patient of 30 years. The patient had favorable clinical course after treament with linezolid and levofloxacin.

Molecular epidemiology of coagulase-negative bloodstream isolates: detection of Staphylococcus epidermidis ST2, ST7 and linezolid-resistant ST23

Abstract The mechanisms contributing to persistence of coagulase-negative staphylococci are diverse; to better understanding of their dynamics, the characterization of nosocomial isolates is needed. Our aim was to characterize phenotypic and molecular characteristics of Staphylococcus epidermidis and Staphylococcus haemolyticus human blood isolates from two tertiary care hospitals in Mexico, the Hospital Universitario in Monterrey and the Hospital Civil in Guadalajara. Antimicrobial susceptibility was determined. Biofilm formation was assessed by crystal violet staining. Detection of the ica operon and Staphylococcal Cassette Chromosome mec typing were performed by PCR. Clonal relatedness was determined by Pulsed-fiel gel electrophoresis and Multi locus sequence typing. Methicillin-resistance was 85.5% and 93.2% for S. epidermidis and S. haemolyticus, respectively. Both species showed resistance >70% to norfloxacin, clindamycin, levofloxacin, trimethoprim/sulfamethoxazole, and erythromycin. Three S. epidermidis and two S. haemolyticus isolates were linezolid-resistant (one isolate of each species was cfr+). Most isolates of both species were strong biofilm producers (92.8% of S. epidermidis and 72.9% of S. haemolyticus). The ica operon was amplified in 36 (43.4%) S. epidermidis isolates. SCCmec type IV was found in 47.2% of the S. epidermidis isolates and SCCmec type V in 14.5% of S. haemolyticus isolates. No clonal relatedness was found in either species. Resistance to clindamycin, levofloxacin, erythromycin, oxacillin, and cefoxitin was associated with biofilm production for both species (p < 0.05). A G2576T mutation in 23S rRNA gene was detected in an S. haemolyticus linezolid-resistant isolate. All linezolid-resistant S. epidermidis isolates belonged to ST23; isolate with SCCmec type IV belonged to ST7, and isolate with SCCmec type III belonged to ST2. This is the first report of ST7 in Mexico. There was a high genetic diversity in both species, though both species shared characteristics that may contibute to virulence.

Efficacy, safety, tolerability and population pharmacokinetics of tedizolid, a novel antibiotic, in Latino patients with acute bacterial skin and skin structure infections

Abstract Acute bacterial skin and skin structure infections are caused mainly by Gram-positive bacteria which are often treated with intravenous vancomycin, daptomycin, or linezolid, with potential step down to oral linezolid for outpatients. Tedizolid phosphate 200 mg once daily treatment for six days demonstrated non-inferior efficacy, with a favourable safety profile, compared with linezolid 600 mg twice daily treatment for 10 days in the Phase 3 ESTABLISH-1 and -2 trials. The objective of the current post-hoc analysis of the integrated dataset of ESTABLISH-1 and -2 was to evaluate the efficacy and safety of tedizolid (N = 182) vs linezolid (N = 171) in patients of Latino origin enrolled into these trials. The baseline demographic characteristics of Latino patients were similar between the two treatment groups. Tedizolid demonstrated comparable efficacy to linezolid at 48–72 h in the intent-to-treat population (tedizolid: 80.2% vs linezolid: 81.9%). Sustained clinical success rates were comparable between tedizolid- and linezolid-treated Latino patients at end-of-therapy (tedizolid: 86.8% vs linezolid: 88.9%). Tedizolid phosphate treatment was well tolerated by Latino patients in the safety population with lower abnormal platelet counts at end-of-therapy (tedizolid: 3.4% vs linezolid: 11.3%, p = 0.0120) and lower incidence of gastrointestinal adverse events (tedizolid: 16.5% vs linezolid: 23.5%). Population pharmacokinetic analysis suggested that estimated tedizolid exposure measures in Latino patients vs non-Latino patients were similar. These findings demonstrate that tedizolid phosphate 200 mg, once daily treatment for six days was efficacious and well tolerated by patients of Latino origin, without warranting dose adjustment.

Seguridad y eficacia de linezolid en el tratamiento de tuberculosis extremadamente resistente / Safety and efficacy of linezolid in the treatment of extremely resistant tuberculosis

INTRODUCCIÓN: Antecedentes: El presente informe expone la evaluación del medicamento linezolid, respecto a su uso en pacientes con tuberculosis extremadamente resistente (TB- XDR). Aspectos Generales: La tuberculosis continúa siendo un problema de salud pública mundial importante. A pesar que la incidencia de TB está disminuyendo globalmente aproximadamente 2% cada año y la mortalidad relacionada con la TB disminuyo un 45% entre los años 1995 y 2012, el número de casos de TB en el mundo es aún ingente, con 8.6 millones de personas con la enfermedad y 1.3 muertes en el 2012. Además, los casos de tuberculosis multidrogo resistente (TB-MDR) y tuberculosis extremadamente resistente (TB-XDR) presentan nuevos y enormes retos para el manejo y control de esta enfermedad. Tecnologia Sanitaria de Interés: Linezolid: El Linezolid pertenece a la clase de antibióticos denominada oxazolidinonas. Este medicamento se une a la subunidad ribosomal 50S inhibiendo la formación del complejo de iniciación y previniendo la traducción y síntesis de proteínas. Este mecanismo de acción tiene la ventaja de limitar la reacción cruzada con otros inhibidores de la síntesis de proteínas, haciéndolo atractivo para las infecciones resistentes. METODOLOGÍA: Estrategia de Búsqueda: La búsqueda de la literatura respecto a la eficacia y seguridad de linezolid para el \r\ntratamiento de pacientes con TB-XDR incluyo la búsqueda de guías de práctica clínica, evaluaciones de tecnologías sanitarias, revisiones sistemáticas y estudios primarios. La búsqueda de GPC se realizó en las páginas de internet de la Organización Mundial de la Salud, de los Centros para el Control y Prevención de las Enfermedades (CDC), la National Institute for Health and Care Excellence (NICE), la Scottish Intercollegiate Guidelines Network (SIGN) y el repositorio creado por la agencia para la investigación \r\nen salud y calidad (Agency for Healthcare Research and Quality (AHRQ)). Se utilizaron las bases creadas por NICE, SIGN y Cochrane para la búsqueda de evaluaciones de tecnología sanitaria. La búsqueda de las revisiones sistemáticas y los estudios primarios fueron realizados en las bases de datos de OVID MEDLINE y TRIPDATABASE. RESULTADOS: Se realizó la búsqueda bibliográfica y de evidencia científica para el sustento del uso del linezolid en los esquemas de tratamiento antituberculoso para pacientes adultos y niños \r\ncon TB-XDR. Guías Clínicas: la búsqueda identificó tres guías desarrolladas por la OMS para el manejo de la tuberculosis multidrogo resistente: la guía de la OMS para el manejo programático de la tuberculosis resistente 2008, la guía de la OMS para el manejo programático de la tuberculosis resistente 2011, y la guía de la OMS para los programas nacionales de tuberculosis para el manejo de la tuberculosis en los niños 2014. Evaluaciones de tecnología sanitaria: no se identificó alguna evaluación del medicamento de linezolid como tratamiento antituberculoso. Revisiones sistemáticas: se identificaron tres revisiones sistemáticas que examinaron los efectos de beneficio y de daño del uso de linezolid en pacientes con TB-DR. Ensayos clínicos: se incluyó un ensayo controlado aleatorizado que evaluó la eficacia y seguridad del uso de linezolid en pacientes adultos con TB-XDR. Otros estudios: se incluyeron una revisión narrativa que describió los resultados de reportes de casos del uso de linezolid en pacientes pediátricos con TB-DR. Ensayos Clínicos registrados en www.clinicaltrials.gov: no se identificaron estudios registrados que tengan como objetivo evaluar los efectos del linezolid en pacientes con TB-XDR. CONCLUSIONES: En la presente evaluación de tecnología sanitaria se identificó evidencia de baja calidad respecto a los efectos de beneficio y de daño de los regímenes que contienen linezolid comparado con los regímenes sin linezolid. El Instituto de Evaluación de Tecnologías en Salud e Investigación-IETSI, aprueba temporalmente el uso del linezolid para el tratamiento de pacientes con TB-XDR. Dado que la evidencia que respalda este uso de linezolid dentro de los esquemas \r\nantituberculosos para casos de TB-XDR es aún limitada, se establece que el efecto de la aprobación del linezolid para su uso en el tratamiento de TB-XDR se evaluará con los datos de los pacientes que hayan recibido el esquema por el lapso de dos años para determinar el impacto de su uso en varios desenlaces \r\nclínicos. Esta información será tomada en cuenta en la re-evaluación de este medicamento para efectos de un nuevo dictamen al terminar la vigencia del presente Dictamen Preliminar.

The challenge of managing extensively drug-resistant tuberculosis at a referral hospital in the state of São Paulo, Brazil: a report of three cases / O desafio do tratamento da tuberculose extensivamente resistente em um hospital de referência no estado de São Paulo: um relato de três casos

ABSTRACT Here, we report the cases of three patients diagnosed with extensively drug-resistant tuberculosis and admitted to a referral hospital in the state of São Paulo, Brazil, showing the clinical and radiological evolution, as well as laboratory test results, over a one-year period. Treatment was based on the World Health Organization guidelines, with the inclusion of a new proposal for the use of a combination of antituberculosis drugs (imipenem and linezolid). In the cases studied, we show the challenge of creating an acceptable, effective treatment regimen including drugs that are more toxic, are more expensive, and are administered for longer periods. We also show that treatment costs are significantly higher for such patients, which could have an impact on health care systems, even after hospital discharge. We highlight the fact that in extreme cases, such as those reported here, hospitalization at a referral center seems to be the most effective strategy for providing appropriate treatment and increasing the chance of cure. In conclusion, health professionals and governments must make every effort to prevent cases of multidrug-resistant and extensively drug-resistant tuberculosis.

RESUMO Relatamos aqui os casos de três pacientes portadores de tuberculose extensivamente resistente, internados em um hospital de referência no estado de São Paulo, e mostramos sua evolução clínica, radiológica e laboratorial pelo período de um ano. O tratamento instituído foi baseado nas diretrizes da Organização Mundial da Saúde, com a inclusão de uma nova proposta de uso de uma associação de drogas antituberculose (linezolida e imipenem). Nos casos estudados, demonstrou-se o desafio de construir um esquema terapêutico aceitável e eficiente com drogas mais tóxicas, mais dispendiosas e que foram utilizadas por períodos mais prolongados. Mostramos também o importante acréscimo nos custos do tratamento desses pacientes, com possíveis impactos no sistema de saúde mesmo após a alta hospitalar. Ressaltamos que, em casos extremos como os apresentados neste estudo, a hospitalização em centros de referência mostrou-se o caminho mais efetivo para oferecer tratamento adequado com possibilidade de cura. Em conclusão, todos os esforços dos profissionais da saúde e do poder público devem ser direcionados a evitar casos de tuberculose multirresistente e extensivamente resistente.

Cost-minimization analysis of oral and intravenous administration of linezolid in a public hospital in southern Brazil / Análise de custo-minimização entre as vias de administração oral e endovenosa de linezolida em um hospital público da região sul do Brasil

Due to the paucity of cost-minimization studies about linezolid, the aim of this study was to estimate the cost differential between intravenous and oral administration. A retrospective cohort study and costminimization analysis was conducted between August 2009 and August 2013 in a public hospital in southern Brazil. Inpatient records were evaluated for 152 patients who received linezolid intravenously or orally. Over two-thirds of the patients (103, 67.8%) received the antibiotic by the intravenous route only (IV group), and the remainder received the antibiotic both routes sequentially (mixed group). In the IV group, 33 patients (31.7%) were eligible to receive the antibiotic orally. The total cost per patient (mean) after changing from intravenous to oral administration was significantly lower than the real cost paid per patient (mean) (p<0.001). The cost savings associated with switching to oral linezolid administration would be US$14,328.32 over four years. Pharmacoeconomic analyses of linezolid therapy can inform hospitals' decisions about the rational use of therapeutics and economic resources.

Devido à escassez de estudos de custo-minimização a cerca da linezolida, o objetivo deste estudo foi estimar a diferença de custo entre a administração intravenosa e oral desse antibiótico. Um estudo de coorte retrospectiva e uma análise de custo-minimização foram realizados entre agosto de 2009 e agosto de 2013, em um hospital público do sul do Brasil. Foram avaliados os prontuários médicos de 152 pacientes que receberam linezolida por via intravenosa e / ou oralmente. Mais de dois terços dos pacientes (103, 67.8%) receberam o medicamento exclusivamente por via intravenosa (grupo IV), e o restante (grupo misto) recebeu o antibacteriano por via intravenosa e por via oral sequencialmente. No grupo IV, 33 pacientes (31.7%) eram elegíveis para receber o antibiótico por via oral. O custo médio total por paciente após a troca hipotética da via de administração intravenosa para oral foi significativamente mais baixo do que o custo médio real pago por cada tratamento com linezolida (p <0.001). A economia de custos associados com a mudança para a administração oral de linezolida seria de US $ 14,328.32 ao longo de quatro anos. A análise farmacoeconômica da terapia com linezolida pode orientar as decisões dos hospitais quanto ao uso racional de terapêuticas e de recursos econômicos.