Repositioning of Disulfiram in Association with Vancomycin Against Enterococcus spp. MDR and XDR.

The identification of molecules that exhibit potent antibacterial activity and are capable of circumventing resistance mechanisms is an unmet need. The repositioning of approved drugs is considered an advantageous alternative in this case, and has gained prominence. In addition, drug synergism can reduce morbidity and mortality in the treatment of nosocomial infections caused by multi-drug resistant microorganisms (MDR). Whole cell growth inhibition assays were used to define the in vitro antibacterial activity of disulfiram against two standard American Type Culture Collection (ATCC) strains and 35 clinical isolates of vancomycin-resistant enterococci (VRE). The ability of disulfiram to synergize with vancomycin was determined by fractional inhibitory concentration index, preceded by the checkerboard test. The cytotoxicity of drugs alone and in combination was tested against Raw 264.7 cells. Disulfiram exhibited potent antibacterial activity against VRE (MIC 16-64 µg mL-1). Results: Associated with vancomycin, disulfiram it had a reduction in MIC of up to 64 times, with values of 0.5-4 µg mL-1. Vancomycin had a MIC of 128-1024 µg mL-1; combined, reduced this value by up to 124 times (8 µg mL-1), with synergy occurring against all strains. Disulfiram and vancomycin alone and in combination did not show cytotoxicity against the eukaryotic cell line. Based on these results, we suggest that the redirection of disulfiram may be promising in the treatment of infections caused by VRE, since it was able to potentiate the activity of vancomycin against the strains, being able to act as an adjuvant in cases of serious infections caused by Enterococcus.

Anti-infective properties of proton pump inhibitors: perspectives / Propiedades antiinfecciosas de los inhibidores de la bomba de protones: perspectivas

Infectious diseases are among the main causes of morbidity and mortality today. In facing this crisis, the development of new drug options and combat strategies is necessary. In this sense, drug repositioning or drug redirection has emerged for the faster identification of effective drugs. In this “Commentary,” the anti-infective properties of the class of proton pump inhibitors (PPIs) are emphasized. Studies report activities against bacterial, fungal, parasitic, and viral agents. In addition, we have provided in a table a summary of the specific characteristics of PPIs and some of their anti-infective activities.(AU)

Anti-infective properties of proton pump inhibitors: perspectives.

Infectious diseases are among the main causes of morbidity and mortality today. In facing this crisis, the development of new drug options and combat strategies is necessary. In this sense, drug repositioning or drug redirection has emerged for the faster identification of effective drugs. In this "Commentary," the anti-infective properties of the class of proton pump inhibitors (PPIs) are emphasized. Studies report activities against bacterial, fungal, parasitic, and viral agents. In addition, we have provided in a table a summary of the specific characteristics of PPIs and some of their anti-infective activities.

Repositioning of non-antibiotic drugs as an alternative to microbial resistance: a systematic review.

The global spread of microbial resistance coupled with high costs and slow pace in the discovery of a new antibiotic have made drug repositioning an attractive and promising alternative in the treatment of infections caused by multidrug resistant (MDR) microorganisms. The reuse involves the production of compounds with lower costs and development time, using diversified production technologies. The present systematic review aimed to present a selection of studies published in the last 20 years, which report the antimicrobial activity of non-antibiotic drugs that are candidates for repositioning, which could be used against the current microbial multidrug resistance. A search was performed in the PubMed, SciELO and Google Scholar databases using the following search strategies: [(drug repurposing) OR (drug repositioning) OR (repositioning) AND (non-antibiotic) AND (antibacterial activity) AND (antimicrobial activity)]. Overall, 112 articles were included, which explored the antimicrobial activity in antidepressants, antihypertensives, anti-inflammatories, antineoplastics, hypoglycemic agents, among other drugs. It was concluded that they have significant antimicrobial activity in vitro and in vivo, against standard strain and clinical isolates (Gram-negative and Gram-positive) and fungi. When associated with antibacterials, most of these drugs had their antibacterial activity enhanced. It was also a consensus of the studies included in this review that the presence of aromatic rings in the molecular structure contributes to antimicrobial activity. This review highlights the potential repositioning of several classes of non-antibiotic drugs as promising candidates for repositioning in the treatment of severe bacterial infections of MDR bacteria, extensively resistant (XDR) and pan-resistant (PDR) to drugs.

Repositioning of antidepressant drugs and synergistic effect with ciprofloxacin against multidrug-resistant bacteria.

The repositioning of drugs has been shown to be an advantageous alternative for treating diseases caused by multidrug-resistant (MDR) microorganisms. The study aimed to investigate the in vitro antibacterial activity of the antidepressants fluoxetine and paroxetine alone and in combination with the antibacterial ciprofloxacin against standard strains and clinical isolates to explore the repositioning of these drugs in severe bacterial infections. Minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC), tolerance level, fractional inhibitory concentration index (FICI) and interaction of antidepressants with the ciprofloxacin antibiotic were determined using the Checkerboard method against six American Type Culture Collection (ATCC) standard strains and seventy MDR clinical isolates. Both antidepressants showed better antibacterial activity than ciprofloxacin, in addition to being separately bactericidal against all tested Gram-negative and Gram-positive strains. When associated with ciprofloxacin, fluoxetine and paroxetine exhibited significant synergism compared to seventy ciprofloxacin-resistant clinical isolates, demonstrating that these antidepressants were able to increase the antibacterial activity of the antibiotic by eight times. The combination of antidepressants with ciprofloxacin showed relatively better activity against Acinetobacter baumannii, Enterococcus faecium and Klebsiella pneumoniae, strains in which the FICI value obtained was 0.008. The MDR isolates tested in this study ratify the antibacterial properties of the non-antibiotic fluoxetine and paroxetine. In addition, synergism when associated with ciprofloxacin is an alternative for treating serious infections in hospitalized patients. However, additional in vivo studies must be conducted to elucidate the mechanisms of action of these drugs.

Repurposing of escitalopram oxalate and clonazepam in combination with ciprofloxacin and sulfamethoxazole-trimethoprim for treatment of multidrug-resistant microorganisms and evaluation of the cleavage capacity of plasmid DNA.

Bacterial resistance has become one of the most serious public health problems, globally, and drug repurposing is being investigated to speed up the identification of effective drugs. The aim of this study was to investigate the repurposing of escitalopram oxalate and clonazepam drugs individually, and in combination with the antibiotics ciprofloxacin and sulfamethoxazole-trimethoprim, to treat multidrug-resistant (MDR) microorganisms and to evaluate the potential chemical nuclease activity. The minimum inhibitory concentration, minimum bactericidal concentration, fractional inhibitory concentration index, and tolerance level were determined for each microorganism tested. In vitro antibacterial activity was evaluated against 47 multidrug-resistant clinical isolates and 11 standard bacterial strains from the American Type Culture Collection. Escitalopram oxalate was mainly active against Gram-positive bacteria, and clonazepam was active against both Gram-positive and Gram-negative bacteria. When associated with the two antibiotics mentioned, they had a significant synergistic effect. Clonazepam cleaved plasmid DNA, and the mechanisms involved were oxidative and hydrolytic. These results indicate the potential for repurposing these non-antibiotic drugs to treat bacterial infections. However, further studies on the mechanism of action of these drugs should be performed to ensure their safe use.

Drug Repositioning in Oncology.

BACKGROUND: The worldwide increase in the occurrence of cancer associated with the limitations of immunotherapy and the emergence of resistance have impaired the prognosis of cancer patients, which leads to the search for alternative treatment methods. Drug repositioning, a well-established process approved by regulatory agencies, is considered an alternative strategy for the fast identification of drugs, because it is relatively less costly and represents lower risks for patients. AREAS OF UNCERTAINTY: We report the most relevant studies about drug repositioning in oncology, emphasizing that its implementation faces financial and regulatory obstacles, making the creation of incentives necessary to stimulate the involvement of the pharmaceutical industry. DATA SOURCES: We present 63 studies in which 52 non-anticancer drugs with anticancer activity against a number of malignancies are described. THERAPEUTIC INNOVATIONS: Some have already been the target of phase III studies, such as the Add-Aspirin trial for nonmetastatic solid tumors, as well as 9 other drugs (aprepitant, artesunate, auranofin, captopril, celecoxib, disulfiram, itraconazole, ritonavir, and sertraline) in the CUSP9* clinical trial for the treatment of recurrent glioblastoma. Others have already been successful in repositioning such as thalidomide, zoledronic acid, celecoxib, methotrexate, and gemcitabine. CONCLUSIONS: Therefore, drug repositioning represents a promising alternative for the treatment of oncological disorders; however, the support from funding agencies and from the government is still needed, the latter regarding regulatory issues.

Alternatives for the treatment of infections caused by ESKAPE pathogens.

WHAT IS KNOWN AND OBJECTIVE: The widespread use of antibiotics as therapeutic agents caused an increase of multidrug resistant bacteria (MDR) appearance. Regarding MDRs, we highlight the Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter spp.., which are the ESKAPE group. COMMENT: New treatment alternatives for infections caused by ESKAPE are under current scientific research. The main suggestions are the use of actinomycetes that produce promising substances with antibiotic activity, the synergistic effect between antimicrobials and peptides, photoinactivation, peptide rich in cationic histidine, association of new antimicrobials; besides the repositioning of drugs already approved for the treatment of other diseases. WHAT IS NEW AND CONCLUSION: These selected studies showed that researchers from many countries are focused on the development of effective alternative strategies for the treatment of infections caused by these microorganisms.

Drug repositioning is an alternative for the treatment of coronavirus COVID-19.

Given the extreme importance of the current pandemic caused by COVID-19, and as scientists agree there is no identified pharmacological treatment, where possible, therapeutic alternatives are raised through drug repositioning. This paper presents a selection of studies involving drugs from different pharmaceutical classes with activity against SARS-CoV-2 and SARS-CoV, with the potential for use in the treatment of COVID-19 disease.

Synergistic effect of sertraline and disulfiram against multidrug resistant bacteria as a new alternative to drug repositioning

The repositioning of approved drugs is atopic of interest for the academy and the pharmaceutical industry. The synergistic combination of these drugs can be successful in the treatment of infections caused by resistant bacteria. This study aimed to assess the in vitro synergistic antibacterial activity of sertraline and disulfiram and their interaction with ciprofloxacin and sulfamethoxazole/trimethoprim. We determined the minimum inhibitory concentration, the minimum bactericidal concentration and the fractional inhibitory concentration index. Eighteen bacterial strains were used, being nine American Type Culture Collection reference strains and nine multidrug resistant clinical isolates. Synergy was detected between sertraline and disulfiram against a strain of Staphylococcus aureusATCC 25923 and a clinical isolate of S. aureus. When associated to sulfamethoxazole/trimethoprim and ciprofloxacin, sertraline and disulfiram showed eight synergistic events, which occurred against three different standard strains and two multidrug resistant clinical isolates. When the minimum bactericidal concentration was determined, the bactericidal activity of sertraline was enhanced with disulfiram. Our results suggest that these drugs, widely used to treat depression and chronic alcoholism, have antibacterial potential individually, in association, and combined with antimicrobials, what makes their repositioning a promising therapeutic alternative for the effective treatment of infections caused by multidrug resistant bacteria.

Prevalência e perfil de sensibilidade de bactérias isoladas da urina de gestantes atendidas no serviço de obstetrícia de um hospital terciário / Prevalence and susceptibility profile of bacteria isolated from urine of pregnant women seen at the department of obstetrics of a tertiary hospital

OBJETIVOS: Avaliar a prevalência e o perfil de sensibilidade aos antimicrobianos de bactérias isoladas de uroculturas de gestantes atendidas no ambulatório do Serviço de Obstetrícia do Hospital Universitário de Santa Maria, Brasil. MÉTODOS: Foi realizado um estudo retrospectivo dos laudos emitidos pelo Laboratório de Análises Clínicas do Hospital Universitário de Santa Maria. Foram incluídas no estudo todas as uroculturas positivas de gestantes atendidas no ambulatório do Serviço de Obstetrícia deste hospital, no período de janeiro a dezembro de 2014. Os testes de identificação dos micro-organismos isolados e os perfis de sensibilidade frente aos antimicrobianos foram efetuados por meio de um sistema automatizado. RESULTADOS: No período do estudo foram identificadas neste laboratório 423 uroculturas positivas provenientes de gestantes. A bactéria Gram negativa Escherichia coli foi a mais prevalente (46,50% das culturas positivas). A segunda bactéria mais frequente foi a Gram positiva Staphylococcus saprophyticus (6,2%). O fungo Candida spp. foi isolado de 94 (21,8%) amostras de urina. Nitrofurantoína e amoxicilina/ácido clavulânico foram os antimicrobianos com menor taxa de resistência por parte de E. coli (91,33% e 90,77% de sensibilidade, respectivamente). Já frente às bactérias Gram positivas prevalentes, ampicilina foi a que mostrou maior sensibilidade. CONCLUSÕES: O perfil de suscetibilidade apresentado neste estudo indica que a escolha para o tratamento da ITU na gestação pode recair em nitrofurantoína e/ou amoxicilina/ácido clavulânico para as bactérias Gram negativas. Tendo em vista a prevalência encontrada, esses antimicrobianos podem ser iniciados empiricamente antes do resultado da urocultura, nos casos de ITU sintomática. Este estudo ratifica, entretanto, a importância da realização da urocultura entre os exames pré-natais e sua repetição no terceiro trimestre da gravidez, tendo em vista a variedade de micro-organismos identificados e os diferentes perfis de sensibilidade aos antimicrobianos testados.

AIMS: To evaluate the prevalence of bacteria in urine cultures of pregnant women seen at the outpatient clinic of the Department of Obstetrics at the University Hospital of Santa Maria, Brazil, and to determine the antibiotic sensitivity profile of these bacteria. METHODS: The reports issued by the Laboratory of Clinical Analysis of the University Hospital of Santa Maria were retrospectively analyzed. All positive urine cultures of pregnant women seen at the Department of Obstetrics from January to December 2014 were included in the study. The tests for the identification of bacterial isolates and their sensitivity profiles were assessed by an automated system. RESULTS: A total of 423 positive urine cultures were detected in the pregnant women. Gram-negative Escherichia coli was the most prevalent microorganism (46.50%). Gram-positive Staphylococcus saprophyticus was the second most prevalent bacterium (6.2%). Candida spp. was isolated from 94 (21.8%) urine samples. Nitrofurantoin and amoxicillin/clavulanic acid showed the lowest antimicrobial resistance against E. coli (91.33% and 90.77%, respectively). Ampicillin had the highest sensitivity among prevalent Gram-positive bacteria. CONCLUSIONS: The sensitivity profile found in this study allows us to suggest nitrofurantoin and/or amoxicillin/clavulanic acid for the treatment of urinary tract infection caused by Gram-negative bacteria during pregnancy. Given the prevalence rates detected in this study, these antimicrobials can be initiated empirically before the urine culture results are known, in the cases of symptomatic urinary tract infection. This study underscores the importance of urine culture in the prenatal period and in the third trimester because of the different microorganisms identified and the different sensitivity to the antimicrobials tested.

Fasciite necrosante por Aeromonas hydrophila e Staphylococcus epidermidis ­ relato de caso / Necrotizing fasciitis caused by Aeromonas hydrophil a and Staphylococcus epidermidis ­ case report

Introdução: Fasciite necrosante (FN) é uma infecção rara dos tecidos subcutâneos e fáscia superficial, geralmente confundida com infecção benigna. Entretanto, apresenta enorme potencial para o desenvolvimento de complicações graves que contribuem para os elevados índices de mortalidade. Objetivos: Descrever um caso de FN polimicrobiana ocasionada por Aeromonas hydrophila e Staphylococcus epidermidis em paciente portador de síndrome da imunodeficiência adquirida, hepatite C e diabetes mellitus. Métodos: Analisaram-se dados de prontuário e resultados de exames laboratoriais de paciente internado no Hospital Universitário de Santa Maria, Santa Maria, Rio Grande do Sul. Resultados: Paciente do sexo masculino, 47 anos, com relato de fratura exposta em membro inferior esquerdo, desenvolvendo infecção no ferimento. Após desbridamento de tecido desvitalizado, identificaram-se A. hydrophila e S. epidermidis. Paciente continua em tratamento e aguarda cirurgia para enxerto. Conclusões: A FN é uma enfermidade rara que merece toda a atenção médica, pois a identificação e tratamento precoces são fundamentais para a recuperação física do paciente.

Introduction: Necrotizing fasciitis (NF) is a rare infection of the subcutaneous tissue and superficial fascia, usually confused with benign infection. However, it has tremendous potential for the development of serious complications which contribute to the high mortality rates. Objectives: To describe a case of FN caused by Aeromonas hydrophila polymicrobial and Staphylococcus epidermidis in patient immunodeficiency syndrome carrier acquired hepatitis C and diabetes mellitus. Methods: We analyzed data from medical records and laboratory test results of inpatient at the University Hospital of Santa Maria, Santa Maria, Rio Grande do Sul. Results: Male patient, 47 years of age, with compound fracture reporting in the left lower limb, developing infection in the wound. After debridement of devitalized tissue, A. hydrophila and S. epidermidis were identified. Patient continues processing and waits for grafting surgery. Conclusions: The FN is a rare disease that deserves medical attention, for the early identification and treatment are essential for the physical recovery of the patient.

Análise do Perfil de Sensibilidade frente aos antimicrobianos de bactérias isoladas de bacteremias em um hospital universitário / Análisis de la susceptibilidad de los antimicrobianos frente a bacterias aisladas de bacteriemias en un hospital universitario / Analysis of the antimicrobial susceptibility profile of bacteria isolated from bacteriemias in a university hospital

Introdução: bacteremia é uma das complicações mais frequentes e graves que acometem, principalmente pacientes imunodeprimidos. É responsável por prolongar o período de hospitalização e está associada com elevadas taxas de morbidade e mortalidade dos pacientes internados. Objetivo: identificar os microrganismos associados à bacteriemia e analisar seu perfil de sensibilidade frente aos antimicrobianos em um Hospital Terciário. Métodos: foi realizado um estudo retrospectivo e transversal, no qual foram incluídas todas as hemoculturas em que houve o crescimento de microrganismos viáveis. Resultados: um total de 1080 amostras foram avaliadas neste estudo. O patógeno mais isolado foi o Staphylococcus epidermidis (24 por cento/n=259), seguido do Staphylococcus hominis (6,8 por cento/n=74). Todas as bactérias Gram-positivas foram sensíveis frente à daptomicina, tigeciclina, linezolida e vancomicina. Além do mais, 42,31 por cento dos isolados do gênero Staphylococcus foram caracterizados fenotipicamente como Staphylococcus coagulase negativa resistentes à meticilina (MRSCoN). Conclusão: a maioria das bacteremias foram ocasionadas por Staphylococcus coagule negativos (SCoN). Entre esses, uma taxa considerável foi resistente à meticilina. Dessa forma, o antibioticoterapia deveriam ser reconsiderados, principalmente nos pacientes que sobem a bordo escolas nas unidades críticas(AU)

Introducción: La bacteriemia es una de las complicaciones más comunes y graves que afectan principalmente a pacientes inmunocomprometidos. Incrementa la hospitalización y se relaciona con una alta morbilidad y mortalidad. Objetivo: identificar los microorganismos asociados con bacteriemia y analizar su perfil de susceptibilidad antimicrobiana en un hospital de tercer nivel. Métodos: estudio retrospectivo y transversal que incluyó todos los hemocultivos que mostraron crecimiento de microorganismos viables. Se estudiaron 1080 cultivos. Resultados: El organismo más aislado fue Staphylococcus epidermidis (24 por ciento / n = 259), seguido por Staphylococcus hominis (6,8 por ciento / n = 74). Todas las bacterias grampositivas fueron susceptibles a la daptomicina, tigecyline, vancomicina y linezolid. Por otro lado, el 42,31 por ciento de Staphylococcus coagulasa negativos aislados se caracterizaron fenotípicamente como resistente a la meticilina (MRSCon). Conclusiones: la mayoría de las bacteriemias fueron causadas por Staphylococcus coagulasa negativo con una importante resistencia a la meticilina; en consecuencia, la institución debe volver a analizar el tratamiento antibiótico principalmente para pacientes hospitalizados en unidades de cuidados críticos(AU)

Introduction: bacteremia is one of the most common and serious complications that mainly affect immunocompromised patients. It accounts for the extension of hospitalization and is related to high morbidity and mortality rates in inpatients. Objective: to identify microorganisms associated with bacteremia and to analyze their antimicrobial susceptibility profile in a tertiary hospital. Methods: retrospective and cross-sectional study including all the hemocultures that showed viable microorganism growth. Results: one thousand eighty samples were evaluated in this study. The most isolated pathogen was Staphylococcus epidermidis (24 percent/n=259), followed by Staphylococcus hominis (6.8 percent/n=74). All Gram-positive bacteria were susceptible to Daptomycin, Tigecyline, Vancomycin and Linezolid. On the other hand, 42.31 percent of the isolated Coagulase-negative Staphylococcus were phenotipically characterized as methicillin-resistant (MRSCon). Conclusions: the majority of bacteriemias was caused by Coagulase negative Staphylococcus with significant methicillin-resistance; consequently, the institution must reanalyze the antibiotic treatment mainly for hospitalized patients in critical care units(AU)