Characteristics of Gram-positive cocci infection and the therapeutic effect after liver transplantation / 中南大学学报(医学版)

OBJECTIVES@#Gram-positive cocci is the main pathogen responsible for early infection after liver transplantation (LT), posing a huge threat to the prognosis of liver transplant recipients. This study aims to analyze the distribution and drug resistance of Gram-positive cocci, the risk factors for infections and efficacy of antibiotics within 2 months after LT, and to guide the prevention and treatment of these infections.@*METHODS@#In this study, data of pathogenic bacteria distribution, drug resistance and therapeutic efficacy were collected from 39 Gram-positive cocci infections among 256 patients who received liver transplantation from donation after citizens' death in the Third Xiangya Hospital of Central South University from January 2019 to July 2022, and risk factors for Gram-positive cocci infection were analyzed.@*RESULTS@#Enterococcus faecium was the dominant pathogenic bacteria (33/51, 64.7%), followed by Enterococcus faecalis (11/51, 21.6%). The most common sites of infection were abdominal cavity/biliary tract (13/256, 5.1%) and urinary tract (10/256, 3.9%). Fifty (98%) of the 51 Gram-positive cocci infections occurred within 1 month after LT. The most sensitive drugs to Gram-positive cocci were teicoplanin, tigecycline, linezolid and vancomycin. Vancomycin was not used in all patients, considering its nephrotoxicity. Vancomycin was not administered to all patients in view of its nephrotoxicity.There was no significant difference between the efficacy of daptomycin and teicoplanin in the prevention of cocci infection (P>0.05). Univariate analysis indicated that preoperative Model for End-Stage Liver Disease (MELD) score >25 (P=0.005), intraoperative red blood cell infusion ≥12 U (P=0.013) and exposure to more than 2 intravenous antibiotics post-LT (P=0.003) were related to Gram-positive cocci infections. Multivariate logistic regression analysis revealed that preoperative MELD score >25 (OR=2.378, 95% CI 1.124 to 5.032, P=0.024) and intraoperative red blood cell transfusion ≥ 12 U (OR=2.757, 95% CI 1.227 to 6.195, P=0.014) were independent risk factors for Gram-positive cocci infections after LT. Postoperative Gram-positive cocci infections were reduced in LT recipients exposing to more than two intravenous antibiotics post-LT (OR=0.269, 95% CI 0.121 to 0.598, P=0.001).@*CONCLUSIONS@#Gram-positive cocci infections occurring early after liver transplantation were dominated by Enterococcus faecalis infections at the abdominal/biliary tract and urinary tract. Teicoplanin, tigecycline and linezolid were anti-cocci sensitive drugs. Daptomycin and teicoplanin were equally effective in preventing cocci infections due to Gram-positive cocci. Patients with high preoperative MELD score and massive intraoperative red blood cell transfusion were more likely to suffer Gram-positive cocci infection after surgery. Postoperative Gram-positive cocci infections were reduced in recipients exposing to more than two intravenous antibiotics post-LT.

Bacteriemia por Enterococcus faeciumresistente a daptomicina / Daptomycin-resistant enterococcus faecium bacteremia

La aparición de cepas de enterococos resistentes a daptomicina es un tema de preocupación clínica y epidemiológica en años recientes. Se presenta el caso de un paciente de 50 años con antecedente de artritis reumatoide e inmunosupresión crónica hospitalizado en contexto de neumonía viral por COVID-19, con sobreinfección bacteriana y choque séptico, en quien se documentó en tres oportunidades diferentes aislamientos de Enterococcus faecium vancomicino-resistente VAN A y B con falla terapéutica a daptomicina, por deterioro clínico y persistencia de hemocultivos positivos. Se inició manejo con linezolid con control de la infección, negativización de hemocultivos y evolución clínica satisfactoria. Se realiza reporte del presente caso para dar a conocer la aparición de enterococos resistentes a daptomicina, la cual es una creciente preocupación epidemiológica, con el fin de realizar identificación temprana, prevenir falla terapéutica y poder conocer la epidemiología local

n recent years, the emergence of daptomycin-resistant enterococcus strains is a growing clinical and epidemio-logical topic of concern. We report the case of a 50 year old patient with an antecedent of rheumatoid arthritis and chronic immunosuppression hospitalized in the con-text of COVID-19 pneumonia with bacterial co-infection and septic shock in which a three different moments an isolate of a "vancomycin-resistant enterococcus faecium"(VRE) Van A and B that presented therapeutic failure with daptomycin was documented after clinical deterioration and persistence of positive blood cultures. Linezolid was initiated, with clinical recovery and negativization of blood cultures following the change in antibiotic treatment. This case is reported in order to expose the ever growing con-cern of daptomycin-resistant enterococcus strains in or-der to prevent therapeutic failure, make early identifica-tion and get to know the local epidemiological status.

Experiencia con el uso de daptomicina en un hospital pediátrico de alta complejidad / Experience with daptomycin in a tertiary pediatric hospital

Resumen Introducción: Vancomicina ha sido considerada como el tratamiento de elección en especial para Staphylococcus aureus resistente a meticilina (SARM); pero su escasa penetración tisular, su toxicidad renal y el requerir monitoreo de su dosis, plantean la necesidad de nuevas alternativas de tratamiento, como daptomicina. Objetivos: Analizar la seguridad y efectividad de daptomicina en niños. Pacientes y Métodos: Se incluyeron, retrospectivamente, niños con infecciones microbiológicamente documentadas, tratados con daptomicina. Resultados: Las infecciones más frecuentes fueron endocarditis en 9 (32%), sepsis de la comunidad en 4 (14%), bacteriemia en 7 (asociada a catéter en 3) (25%), osteomielitis en 3 (10%), peritonitis asociada a diálisis en 3 (10%) y tromboflebitis supurativa en 2 pacientes (7%). Staphylococcus aureus resistente a meticilina fue el patógeno más común en 18 pacientes (64%), Daptomicina fue indicada por el fracaso del tratamiento convencional en 17 (61%), y la toxicidad o intolerancia a vancomicina en 11 pacientes (39%). La duración media de tratamiento fue de 19 días (RIC 95% 7-42 días). Cuatro pacientes (14%) completaron tratamiento ambulatorio. Tuvieron respuesta favorable 22 pacientes (79%) Se reportaron eventos adversos en tres pacientes: dos elevaciones de creatina-fosfocinasa) y una erupción cutánea grave. Conclusiones: Daptomicina demostró una eficacia y seguridad favorables en esta población pediátrica.

Abstract Background: Vancomycin has been considered the treatment of choice especially for methicillin-resistant Staphylococcus aureus (MRSA) infections; but its poor tissue penetration, renal toxicity, and requiring of dosages monitoring, raises the need for new treatment alternatives such as daptomycin. Aims: To analyze the safety and effectiveness of daptomycin in children. Methods: Children with microbiologically documented infections treated with daptomycin were retrospectively included. Results: The most frequent infections were endocarditis in 9 (32%), sepsis in 4 (14%), bacteremia in 7 (associated with catheter in 3) (25%), osteomyelitis in 3 (10%), peritonitis associated with dialysis in 3 (10%) and suppurative thrombophlebitis in 2 patients (p) (7%). Methicillin-resistant Staphylococcus aureus was the most common pathogen in 18 patients (64%). The indications for daptomycin were due to the failure of conventional treatment in 17 (61%), and the toxicity or intolerance to vancomycin in 11 patients (39%). The average duration of treatment was 19 days (95% ICR 7-42 days). Four patients (14%) completed outpatient treatment, 22 patients had a favorable response (79%). Adverse events were reported in 3 patients (2 creatinine-phosfo-kinase increase) and in one severe skin rash. Conclusions: Daptomycin demonstrated a favorable efficacy and safety in this pediatric population.

Nonadherence to treatment recommendations is a factor contributing to the clinical failure of daptomycin: Cohort study in Brazil

To evaluate the clinical outcomes of daptomycin therapy and adherence to treatment recommendations, a retrospective cohort study was conducted with patients that received daptomycin during the period of the study. The adherence and nonadherence to clinical guidelines were assessed through organism identification, dose and time of treatment, management of bacteremia, and vancomycin treatment failure. A multiple logistic regression model analyzed the association between independent variables and clinical success (dependent variable), considering 5% of statistical significance. The study presented 52 patients who received daptomycin for the treatment of bacteremia (21.1%) or infections (osteomyelitis [63.5%], synovial fluid [15.4%]). Most patients (86.5%) received daptomycin as the second line of treatment, and 51.9% achieved clinical success. The patients had a better chance of clinical success when they followed the guideline indications (OR = 16.86; 95% CI = 1.45-195.88) and the medication was prescribed by a specialist in infectious diseases (OR = 4.84; 95% CI = 1.11-21.09). The study demonstrated lower clinical success than that described in the literature because of patients who were not eligible according to the clinical guidelines. Adherence to recommendations and appropriate prescription of reserve antibiotics is important in limiting early resistance, and avoiding clinical failure and unnecessary expenditure.

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.

Daptomycin to bone and joint infections and prosthesis joint infections: a systematic review

ABSTRACT Backgroud: Daptomycin has been used in bone and joint infections (BJI) and prosthesis joint infections (PJI) considering spectrum of activity and biofilm penetration. However, the current experience is based on case reports, case series, cohorts, and international surveys. The aim of this systematic review was to evaluate studies about daptomycin treatment efficacy in BJI/PJI compared to other antibiotic regimens. Methods: PubMed, LILACS, Scielo and Web of Science databases were searched for articles about daptomycin and treatment of BJI and PJI from inception to March 2018. Inclusion criteria were any published researches that included patients with BJI treated with daptomycin. Diagnosis of BJI was based on clinical, laboratory and radiological findings according to IDSA guidelines. Results: From 5107 articles, 12 articles were included. Only three studies described the outcomes of patients with BJI treated with daptomycin with comparator regimen (vancomycin, teicoplanin and oxacillin). Studies presented large heterogeneity regarding device related infections, surgical procedures, and daptomycin regimens (varied from 4 mg/kg to 10 mg/kg). A total of 299 patients have been included in all studies (184 infections associated with orthopedic disposal and 115 osteomyelitis/septic arthritis). Two hundred and thirty-three patients were treated with daptomycin. The clinical cure rates on device related and non-device related infections (i.e. osteomyelitis) were 70% and 78%, respectively. Compared to all regimens evaluated, daptomycin group outcomes were non-inferior. Conclusion: Although a randomized clinical trial is needed, this systematic review tends to support daptomycin usage for bone and joint infections.

Daptomycin and vancomycin non-susceptible methicillin-resistant Staphylococcus aureus clonal lineages from bloodstream infection in a Brazilian teaching hospital

ABSTRACT Introduction: This study aimed to characterize Staphylococcus aureus isolates from bloodstream infections in patients attending a teaching hospital, between 2011 and 2015. Methods: The minimum inhibitory concentration for daptomycin, linezolid, oxacillin, teicoplanin, vancomycin, and trimethoprim/sulfamethoxazole was accessed by broth microdilution. SCCmec type and clonal profile were determined by molecular tests. Vancomycin heteroresistance was evaluated using screening tests and by population analysis profile/area under the curve. Results: Among 200 S. aureus isolates, 55 (27.5%) were MRSA, carrying SCCmec II (45.5%) or IV (54.5%). The most frequent MRSA lineages were USA100 (ST5-II) (45.5%) and USA800 (ST5-IV) (30.9%). Six isolates were confirmed as vancomycin heteroresistant, showing area under the curve ratio 1.1, 1.2 or 1.3 (four USA100, one USA800 and one USA1100 isolates). Conclusions: Daptomycin and vancomycin non-susceptible MRSA clonal lineages were found in bloodstream infections over five years, highlighting the importance of continuous surveillance of multiresistant bacteria in hospitals.

Antimicrobial therapy for methicillin-resistant Staphylococcus aureus

Methicillin-resistant Staphylococcus aureus (MRSA) is a common cause of healthcare-associated infections. Recently, community-associated MRSA has emerged, manifesting as skin and soft tissue infections in patients without any prior healthcare contact. Vancomycin, a glycopeptide in clinical use for more than 50 years, still remains an acceptable treatment option. However, significant concerns have been raised regarding the decreasing susceptibility of S. aureus to this agent. The growing awareness of the limitations of vancomycin has served as an impetus for development of newer agents. There has been an increase in the number of agents available to treat MRSA infections. Linezolid, daptomycin, telavancin, and ceftaroline have received regulatory approval in the last decade for the treatment of MRSA. Although these drugs do have certain differentiating attributes and may offer some advantages over vancomycin, they also have significant limitations.

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.

Tratamiento de la bacteriemia por enterococo resistente a vancomicina con daptomicina versus linezolid: revisión sistemática y metanálisis / Treatment of bacteremia by vancomycin-resistant Enterococcus with daptomycin versus linezolid: asystematic review and meta-analysese / Tratamento da bacteriemia por enterococus resistentea vancomicina com daptomicina versus linezolida: revisão sistemática e metanálise

Introducción: Para el tratamiento de las infecciones por Enterococcus resistente a vancomicina (ERV) se emplean fármacos de segunda línea como daptomicina y linezolid. Objetivo: hacer una revisión sistemática para evaluar el tratamiento de la bacteriemia por ERV, con daptomicina o linezolid. Metodología: búsqueda electrónica en las bases de datos de Pubmed, Embase, Scopus, ScienceDirect, CENTRAL, Lilacs y Google Académico, para identificar estudios anteriores a julio de 2015 que hayan comparado los tratamientos con daptomicina o linezolid de pacientes infectados por ERV. Resultados: se incluyeron 15 estudios de 1307 registros. No hubo diferencias entre daptomicina y linezolid con respecto a la mortalidad a 30 días. Con la daptomicina se logró más tempranamente el control microbiológico (OR: 0,64; IC95 %: 0,45-0,92). No hubo diferencias entre los dos antibióticos en cuanto a la mejoría clínica, la necesidad de admisión a la UCI o la aparición de efectos adversos como trombocitopenia, neutropenia e insuficiencia renal. Conclusiones: no encontramos diferencias entre daptomicina y linezolid en cuanto a la mortalidad de pacientes infectados por ERV, aunque con la daptomicina se logró una cura microbiológica más rápida.

Introduction: Second-line drugs such as linezolid and daptomycin are used for treatment of vancomycin-resistant Enterococcus (VRE) infections. Objective: A systematic review to evaluate treatment of VRE bacteremia with linezolid versus daptomycin. Methods: A search was done in the databases of Pubmed, Embase, Scopus, ScienceDirect, CENTRAL, Lilacs and Google Scholar to identify studies comparing treatment with daptomycin or linezolid of patients infected by VRE up to July 2015. Result: Only 15 studies were included of a total of 1.307 records. There were no differences between daptomycin and linezolid with respect to mortality at 30 days. Microbiological cure was better with daptomycin (OR: 0.64; 95 % CI: 0.45-0.92), whereas there was no difference between the two antibiotics with respect to clinical cure, need to ICU admission, and the occurrence of adverse effects such as thrombocytopenia, neutropenia and renal failure. Conclusions: No significant differences were observed between daptomycin and linezolid in reference to mortality of patients infected with VRE, although daptomycin treatment produced a faster microbiological cure.

Introdução: Para o tratamento das infecções por Enterococcusresistente a vancomicina (ERV) se empregam fármacos de segunda linha como daptomicina e linezolida. Objetivo: fazer uma revisão sistemática para avaliar o tratamento da bacteriemia por ERV, com daptomicina o linezolida. Metodologia: busca eletrônica nas bases de dados de Pubmed, Embase, Scopus, ScienceDirect, CENTRAL, Lilacs e Google Acadêmico, para identificar estudos anteriores a julho de 2015 que foram comparados os tratamentos com daptomicina ou linezolida de pacientes infectados por ERV. Resultados: se incluíram 15 estudos de 1.307 registros. Não houve diferenças entre daptomicina e linezolida com respeito à mortalidade a 30 dias. Com a daptomicina se conseguiu mais precoce o controle microbiológico (OR: 0,64; IC95 %: 0,45-0,92). Não houve diferenças entre os dois antibióticos em quanto à melhoria clínica, a necessidade de admissão à UTI ou a aparição de efeitos adversos como trombocitopenia, neutropenia e insuficiência renal. Conclusões: não encontramos diferenças entre daptomicina e linezolida em quanto à mortalidade de pacientes infectados por ERV, embora com a daptomicina se conseguiu uma cura microbiológica mais rápida.

Molecular Typing and Resistance Profiles of Vancomycin-Intermediate Staphylococcus aureus in Korea: Results from a National Surveillance Study, 2007-2013 / 대한임상미생물학회지

BACKGROUND: To investigate the national molecular epidemiology and resistance profiles of vancomycin-intermediate Staphylococcus aureus (VISA), we analyzed the characteristics of methicillin-resistant Staphylococcus aureus (MRSA) collected from clinical samples at tertiary or general hospitals participating in a nationwide surveillance program for VISA and vancomycin-resistant Staphylococcus aureus (VRSA) in Korea during an 12-week period in each year from 2007 to 2013. METHODS: VISA was defined by agar dilution, broth dilution and E-test methods with vancomycin minimum inhibitory concentrations of >2 μg/mL. All VISA isolates were characterized by multilocus sequence typing, staphylococcal cassette chromosome mec typing, spa typing, accessory gene regulator typing, Diversilab analysis, and antibiogram analysis. RESULTS: Of 109,345 MRSA isolates, 87,354 were screened and 426 isolates were identified as positive on brain heart infusion agar containing 4 μg/mL vancomycin (BHI-V4). Of 426 isolates, 76 isolates were identified as VISA. No VRSA isolates were detected among the isolates. Overall, a total of 6 genotypes were identified among VISA strains and the predominant clones were ST5-II-t2460, ST72-IV-t324, and ST239-III-t037 (44.7%, 15.8%, and 10.5%, respectively). Of note, ST72-IV-t324 clones are known to be a typical community-associated MRSA. ST239-III-t037 strains were more resistant to trimethoprim-sulfamethoxazole than any other type of strain. ST72-IV-t324 strains were susceptible to all of the antimicrobial agents tested except erythromycin and daptomycin. All of the VISA isolates were susceptible to linezolid and quinupristin-dalfopristin. CONCLUSION: Although VRSA is still rare, continuous monitoring of VRSA occurrence is needed, as well as VISA prevalence, epidemic clonal shift, and antimicrobial resistance.

A fully validated microbiological assay for daptomycin injection and comparison to HPLC method

abstract Daptomycin (DPT) was the first lipopeptide antibiotic available for commercialization. It is active against gram-positive bacteria, including resistant strains. This work aimed to develop and validate a turbidimetric microbiologic assay to determine daptomycin in an injectable form. A 3x3 design was employed, at concentrations of 1, 2 and 4.0 µg/mL. The microorganism test used was Staphylococcus aureus ATCC 6538p, and Antibiotic Medium 3 was used as the culture medium. Method validation demonstrated that the bioassay was linear (r=0.9995), precise (RSD=2.58%), accurate (recovery 100.48± 2.11%), and robust. Degradation kinetics was also performed in an alkaline medium, indicating that daptomycin degradation follows first order kinetics under these conditions. The analyses of degraded solutions showed that daptomycin degradation products do not possess bactericidal activity. The bioassay was compared to HPLC method that was previously developed and no significant difference was found between them (p>0.05). The method proved to be appropriate for daptomycin injection quality control.

resumo A daptomicina (DPT) é o primeiro lipopeptídeo cíclico disponível para comercialização. Possui atividade frente a bactérias gram-positivas, incluindo cepas resistentes. O objetivo deste trabalho foi desenvolver e validar um ensaio microbiológico turbidimétrico para quantificar a daptomicina na forma injetável. Empregou-se delineamento 3x3, nas concentrações de 1,0; 2,0 e 4,0 µg/mL. Como micro-organismo teste foi usado Staphylococcus aureus ATCC 6538p, e Meio para Antibióticos nº 3 foi empregado como meio de cultura. A validação do método demonstrou que o ensaio foi linear (r=0,9995), preciso (RSD=2,55%), exato (recuperação de 100,48 ± 2,11%) e robusto. A cinética de degradação em meio alcalino foi avaliada, indicando que a daptomicina segue cinética de primeira ordem nessa condição. A análise das soluções degradadas mostrou que os produtos de degradação da daptomicina não possuem atividade antimicrobiana. O bioensaio foi comparado com o método por CLAE previamente desenvolvido e não houve diferença significativa entre ambos (p<0,05). O método mostrou-se apropriado para o controle de qualidade da daptomicina injetável.

A green approach for the quantification of daptomycin in pharmaceutical formulation by UV spectrophotometry

abstract Daptomycin is the first approved drug from a new class of antimicrobials, the cyclic lipopeptides, and is a very important antimicrobial agent in current clinical practice. Currently, there are no "green" analytical methods described in the literature to analyze the typical pharmaceutical dosage form of daptomycin. Thus, the aim of this work was to validate an environment-friendly spectrophotometric method in the UV region, for the analysis of daptomycin as a lyophilized powder. Water was used as diluent and the analyses were carried out on a spectrophotometer at 221 nm. The method met all validation requirements of the ICH guidelines, over a concentration range of 6-21 µg mL-1. A Student's t-test demonstrated that the proposed method was comparable to an HPLC method previously validated. Thus, the validated spectrophotometric method could quantify daptomycin in a powder form for injectable solutions, while being an economical, rapid, and "green" alternative for routine analysis in quality control.

resumo A daptomicina é o primeiro membro aprovado de uma nova classe de antimicrobianos, os lipopeptídeos cíclicos, e é muito importante para a prática clínica atualmente. Não existem métodos analíticos "verdes" descritos na literatura para a análise da daptomicina na forma farmacêutica. Desta forma, o objetivo deste trabalho foi a validação de método espectrofotométrico na região do UV ambientalmente favorável para análise da daptomicina em pó liofilizado. A água foi escolhida como diluente e as análises foram realizadas em 221 nm. O método atendeu a todas as exigências de validação dos guias do ICH, na faixa de 6-21 µg mL-1. Teste t de Student mostrou que o método proposto é intercambiável com método de HPLC previamente validado. Assim, o método espectrofotométrico validado é capaz de quantificar a daptomicina em pó para solução injetável e é uma opção econômica, rápida e "verde" para análises de rotina do controle de qualidade deste fármaco.

Worrisome trends in rising minimum inhibitory concentration values of antibiotics against methicillin resistant Staphylococcus aureus - Insights from a tertiary care center, South India

ABSTRACT INTRODUCTION: Appearance of isolated reports of resistance to anti-methicillin-resistantStaphylococcus aureus (MRSA) drugs is worrisome underscoring the need to continuously monitor the susceptibility of clinical MRSA isolates to these drugs. Hence, the present study is conducted to determine the susceptibility of MRSA isolates to various classes of anti-MRSA drugs such as vancomycin (glycopeptide), daptomycin (lipopeptide), tigecycline (glycylcycline), and linezolid (oxazolidinone) to determine the MIC50 and MIC90 values, and to observe MIC creep over a three year period, if any, with respect to these drugs. METHODS: A total of 200 isolates of MRSA obtained from clinical specimens were included. MIC was determined by E-test for anti-MRSA antibiotics vancomycin, linezolid, daptomycin, and tigecycline. Non-parametric methods (Kruskal-Wallis and Chi-square test) were used to assess MIC trends over time. In addition, MIC50 and MIC90 values were also calculated. RESULTS: No isolate was found resistant to vancomycin, daptomycin, or linezolid; five isolates were resistant to tigecycline. Seven VISA isolates were encountered with the MIC value for vancomycin of 4 µg/mL. MIC values for vancomycin, tigecycline, linezolid showed a definite increase over a 3-year period which was statistically significant with p-values <0.0001, 0.0032, 0.0242, respectively. When the percentage of isolates with a median MIC value less than or equal to that of the index year was calculated, the change was most striking with vancomycin. The proportion of isolates with higher MIC values was greater in 2014 than 2012 and 2013. CONCLUSION: MIC creep was notably observed with vancomycin, and to some extent with tigecycline and linezolid. Selection pressure may result in creeping MICs, which may herald the emergence of resistant organisms.

Tratamiento de las infecciones invasivas por Staphylococcus aureus meticilino resistente adquirido en la comunidad / Treatment of invasive infections due to community acquired methicillin resistant Staphylococcus aureus

Las infecciones por Staphylococcus aureus meticilino resistente adquirido en la comunidad (SAMR-AC) constituyen un problema emergente debido a su elevada virulencia y gran capacidad de diseminación. Para las infecciones invasivas, las recomendaciones publicadas sugieren vancomicina como droga de elección. Sin embargo, no está claro si otras alternativas pudieran ser mejores en determinadas situaciones, o si el uso de combinaciones de antibióticos sería beneficioso. No se han realizado trabajos que sugieran que alguna alternativa terapéutica sea preferible a otra para el tratamiento de pacientes con infecciones invasivas por SAMR-AC, por lo que las decisiones a tomar se basan en la extrapolación de datos de estudios realizados en otros contextos o en la opinión de expertos. Por tal motivo, se presenta esta revisión, con el objeto de poner en manos de los infectólogos y otros especialistas la evidencia disponible, a fin de intentar encontrar las mejores alternativas de tratamiento para estas infecciones...

Infections caused to community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) is an emerging problem due to its high virulence and large capacity of spread. For invasive infections, published recommendations suggest vancomycin as the drug of choice. However, it is unclear whether other alternatives might be better in certain situations, or if the use of combinations of antibiotics would be beneficial. No studies has been done to suggest that any therapeutic alternative is better than another for the treatment of patients with invasive CA-MRSA infections, so the decisions you make are based on extrapolation of data from studies in other contexts or expert opinion. Therefore, this review is presented, in order to put in the hands of infectologist and others specialists the available evidence, in order to find the best treatmente options for these infections...

Resistencia a antibióticos de última línea en cocos Gram positivos: la era posterior a la vancomicina / Resistance to "last resort" antibiotics in Gram-positive cocci: The post-vancomycin era

En los últimos años se han desarrollado nuevas alternativas para el tratamiento de infecciones por patógenos Gram positivos multirresistentes, entre los cuales Staphylococcus aureus resistente a la meticilina (SARM) y los enterococos resistentes a la vancomicina (ERV) se consideran un verdadero reto terapéutico, y aunque el uso de la vancomicina en infecciones graves causadas por SARM ha generado serias dudas en los últimos años, continúa siendo escasa la información clínica de respaldo al uso de agentes terapéuticos que la superen en eficacia. El linezolid, la daptomicina y la tigeciclina son agentes que tienen actividad contra los cocos Gram positivos y que fueron aprobados e introducidos en la terapia clínica en la década pasada. Además, se han probado o están en las fases finales de desarrollo otros agentes como las cefalosporinas de última generación (ceftarolina y ceftobiprol). El propósito de esta revisión fue describir las nuevas alternativas terapéuticas, particularmente en la era posterior a la vancomicina, y repasar las características químicas más relevantes de los compuestos y su espectro de actividad, haciendo énfasis en sus mecanismos de acción y resistencia.

New therapeutic alternatives have been developed in the last years for the treatment of multidrug-resistant Gram-positive infections. Infections caused by methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE) are considered a therapeutic challenge due to failures and lack of reliable antimicrobial options. Despite concerns related to the use of vancomycin in the treatment of severe MRSA infections in specific clinical scenarios, there is a paucity of solid clinical evidence that support the use of alternative agents (when compared to vancomycin). Linezolid, daptomycin and tigecycline are antibiotics approved in the last decade and newer cephalosporins (such as ceftaroline and ceftobiprole) and novel glycopeptides (dalvavancin, telavancin and oritavancin) have reached clinical approval or are in the late stages of clinical development. This review focuses on discussing these newer antibiotics used in the "post-vancomycin" era with emphasis on relevant chemical characteristics, spectrum of antimicrobial activity, mechanisms of action and resistance, as well as their clinical utility.

Long-circulating liposomal daptomycin enhances protection against systemic methicillin-resistant Staphylococcus aureus infection with improved therapeutic potential / 药学学报

In the face of escalating problems with pathogen control, the development of proper formulations of existing antibiotics is as important as the development of novel antibiotics. Daptomycin is a lipopeptide antibiotic with potent activity against Gram-positive bacteria. Currently, only injectable solution of daptomycin has been approved for clinical use. In the present study, the formulation of PEGylated liposomal daptomycin (PLD) was prepared and optimized, and its efficacy against methicillin-resistant Staphylococcus aureus (MRSA252) strains was investigated. The obtained PLD had a mean vesicle diameter of (111.5 +/- 15.4) nm and a mean percent drug loading of (5.81 +/- 0.19) % with high storage stability. Potent activity of PLD against MRSA was demonstrated in vitro with a more sustained effect than that of conventional liposomal daptomycin and daptomycin solution. In addition, intravenous administration of a single dose (equal to human use) of PLD significantly increased the survival of mice in a MRSA252 systemic infection model compared with other formulations. Drug distribution in the lung was significantly enhanced following administration of PLD, and no measurable tissue lesions or pathological changes were detected during PLD treatment. Taken together, PEGylated liposomes loaded with daptomycin may represent a promising approach to reduce MRSA252 infections, especially those involving bloodstream dissemination, such as hematogenous pulmonary infection.

Susceptibility of Glycopeptide-Resistant Enterococci to Linezolid, Quinupristin/dalfopristin, Tigecycline and Daptomycin in a Tertiary Greek Hospital

We investigated the antibiotic susceptibility of glycopeptide-resistant enterococci (GRE). Seventy consecutive GRE were tested. Sixty-two isolates were identified as Enterococcus faecium (88.6%), and 8 (11.4%) as Enterococcus faecalis. All strains were susceptible to linezolid and daptomycin, while 17.1% (12/70) and 11.4% (8/70) were resistant to quinupristin/dalfopristin (QD) and tigecycline, respectively. All E. faecalis isolates were resistant to QD, while 4 of 62 (6.5%) E. faecium isolates were resistant to QD. All E. faecalis isolates were susceptible to tigecycline, while 14.5% (9/62) E. faecium isolates were resistant. Continued surveillance of GRE antibiotic susceptibilities is important for combating these multi-resistant nosocomial pathogens.

Brazilian experience in EU-CORE: daptomycin registry and treatment of serious Gram-positive infections

OBJECTIVES: To collect data about non-controlled prescribing use of daptomycin and its impact among Brazilian patients with serious Gram positive bacterial infection, as well as the efficacy and safety outcomes. MATERIALS AND METHODS: This is a multi-center, retrospective, non-interventional registry (August 01, 2009 to June 30, 2011) to collect data on 120 patients (44 patients in the first year and 76 patients in the second year) who had received at least one dose of commercial daptomycin in Brazil for the treatment of serious Gram-positive bacterial infection. RESULTS: Right-sided endocarditis (15.8%), complicated skin and soft tissue infections (cSSTI)wound (15.0%) and bacteremia-catheter-related (14.2%) were the most frequent primary infections; lung (21.7%) was the most common site for infection. Daptomycin was used empirically in 76 (63.3%) patients, and methicillin-resistant Staphylococcus aureus (MRSA) was the most common suspected pathogen (86.1%). 82.5% of the cultures were obtained prior to or shortly after initiation of daptomycin therapy. Staphylococcus spp. - coagulase negative, MRSA, and methicillin-susceptible S. aureus were the most frequently identified pathogens (23.8%, 23.8% and 12.5%, respectively). The most common daptomycin dose administered for bacteremia and cSSTI was 6 mg/kg (30.6%) and 4 mg/kg (51.7%), respectively. The median duration of inpatient daptomycin therapy was 14 days. Most patients (57.1%) did not receive daptomycin while in intensive care unit. Carbapenem (22.5%) was the most commonly used antibiotic concomitantly. The patients showed clinical improvement after two days (median) following the start of daptomycin therapy. The clinical success rate was 80.8% and the overall rate of treatment failure was 10.8%. The main reasons for daptomycin discontinuation were successful end of therapy (75.8%), switched therapy (11.7%), and treatment failure (4.2%). Daptomycin demonstrated a favorable safety and tolerability profile regardless of treatment duration. CONCLUSIONS: Daptomycin had a relevant role in the treatment of Gram-positive infections in the clinical practice setting in Brazil.