Methicillin resistant Staphylococcus aureus-importance of appropriate empirical therapy in serious infections

India has been titled the capital of antimicrobial resistance in the world with the centre for disease dynamics, economics andpolicy (CDDEP) predicting two million deaths in India by 2050. As per the World Health Organisation抯 global priority pathogen list of 2017, methicillin resistant Staphylococcus aureus(MRSA)has been classified as a 慼igh priority� pathogen due to its association with increased mortality rate, rising prevalence of resistance and increased burden on healthcare settings. A recent report by Indian Council of Medical Research signifies the exponential rise in the prevalence of MRSA in India, from 29% in 2009 to 39% in 2018. Serious MRSA infections are commonly associated with poor clinical outcomes coupled with increased hospitalisation stay and cost. Therefore, early identification and appropriate empiric treatment of MRSA plays a crucial role in healthcare settings. However, the constant rise in multi-drug resistance to the currently available anti-MRSA agents as well as their compromised safety profile limits its clinical use to manage severe MRSA infections. This review article explores the implications of severe MRSA infections and inappropriate empirical therapy on the clinical as well as economic outcomes. In addition, it also highlights limitations of the currently available anti-MRSA agentsand the need for newer agents to manage multi drug resistant (MDR)gram positive infections.

Anti-Staphylococcus aureus Methicillin-Resistant (MRSA) activity of a novel 3-Chalcogenyl Indole / Atividade Anti-Staphylococcus aureus Meticilina Resistente (MRSA) de um novo composto 3-Calcogenil Indol

Objective: the development of new drugs against Methicillin-resistant Staphylococcus aureus is a priority to the World Health Organization. So, the objective of this study was to evaluate the antibacterial activity and toxicity of 5-bromo-3-((4-methoxyphenyl) sulfenyl)-1H-indole (3b) against MRSA. Methods: minimum inhibitory concentration (MIC) of 3b was determined against S. aureus ATCC 29213 and 43 clinical isolates. The time-kill assay was performed for 9 isolates. Analysis of variance followed by the post hoc Bonferroni test was used for the statistical tests. Results and conclusions: the MIC50 and MIC90 of 3b were 4 µg.mL-1 and 16 µg.mL-1 respectively. In time-kill assay, the 3b showed bactericidal activity to all evaluated isolates at concentrations of 1xMIC and 2xMIC and the re-growth effect was not observed. About the toxicity tests, 3b has not presented cytotoxicity, mutagenicity, or allergenicity. 3b had particularly good activity against MRSA demonstrating high potential for the development of new antimicrobials products.

Objetivo: o desenvolvimento de novos antimicrobianos contra Staphylococcus aureus resistentes à meticilina (MRSA) é uma prioridade para a Organização Mundial da Saúde. Então, o objetivo desse estudo foi avaliar a atividade antibacteriana e a toxicidade do 5-bromo-3-((4-metoxifenil) sulfenil)-1H-indol (3b) contra MRSA. Métodos: a concentração inibitória minima de 3b foi determinada contra S. aureus ATCC 29213 e 43 isolados clínicos. O ensaio de curva de morte foi realizado para nove isolados. Análise de variância seguida pelo teste post hoc Bonferroni foi usada para testes estatísticos. Resultados e conclusões: a MIC50 e MIC90 do 3b foi 4 µg.mL-1 e 16 µg.mL-1, respectivamente. No ensaio de curva de morte, o 3b demonstrou atividade bactericida contra todos os isolados avaliados na concentração de 1xMIC e 2xMIC e o recrescimento não foi observado. Em relação aos testes de toxicidade, 3b não apresentou citotoxicidade, mutagenicidade ou alergenicidade. 3b apresentou atividade particularmente interessante contra MRSA, demonstrando alto potencial para o desenvolvimento de novos produtos antimicrobianos.

Management of acute bacterial skin and skin structure infections in India: are we equipped to meet the challenges of the growing menace of methicillin-resistant Staphylococcus aureus?

Staphylococcus aureus (S. aureus) is a Gram-positive facultative anaerobic bacterium that colonizes the skin and nasal passages of humans. The incidence of invasive S. aureus infections has increased over the past decades and is associated with poor outcomes and high mortality rates. S. aureus is responsible for almost one-third of acute bacterial skin and skin structure infections with methicillin-resistant Staphylococcus aureus (MRSA) accounting for a large proportion of these. The S. aureus strains prevalent inIndia are more aggressive and there are recent reports of the emergence of the more virulent multidrug resistant lineages ST2371 and ST8. Management of these infections is complicated by the fact that antimicrobial stewardship is non-existent, the choice of treatment is often empirical and available treatment options are limited due to a high prevalence of resistance strains. Currently available anti-MRSA agents include vancomycin, teicoplanin, linezolid, daptomycin, tigecycline, and clindamycin. However, the emergence of resistant strains and several undesirable features related to the safety and tolerability of these agents have limited the options available for the management of MRSA infections. A newer, safe and efficacious antibiotic is thus an unmet need for the management of MRSA in patients with acute bacterial skin and skin structure infections. In this review we explore the current and future trends in the management of acute bacterial skin and skin structure infections highlighting the challenges in their management in India, and current progress in the development of some novel drugs for the management of MRSA infections.

Evaluating the ototoxicity of an anti-MRSA peptide KR-12-a2 / Avaliando a ototoxicidade de um peptídeo anti-MRSA KR-12-a2

Abstract Introduction Methicillin-resistant staphylococcus aureus is an emerging problem for the treatment of chronic suppurative otitis media, and also for pediatric tympanostomy tube otorrhea. To date, there are no effective topical antibiotic drugs to treat methicillin-resistant staphylococcus aureus otorrhea. Objective In this study, we evaluated the ototoxicity of topical KR-12-a2 solution on the cochlea when it is applied topically in the middle ear of guinea pigs. Methods The antimicrobial activity of KR-12-a2 against methicillin-resistant staphylococcus aureus strains was examined by using the inhibition zone test. Topical application of KR-12-a2 solution, gentamicin and phosphate buffered saline were applied in the middle ear of the guinea pigs after inserting ventilation tubes. Ototoxicity was assessed by auditory brainstem evoked response and scanning electron microscope examination. Results KR-12-a2 produced an inhibition zone against methicillin-resistant staphylococcus aureus from 6.25 µg. Hearing threshold in the KR-12-a2 and PBS groups were similar to that before ventilation tube insertion. However, the gentamicin group showed elevation of the hearing threshold and there were statistically significant differences compared to the phosphate buffered saline or the KR-12-a2 group. In the scanning electron microscope findings, the KR-12-a2 group showed intact outer hair cells. However, the gentamicin group showed total loss of outer hair cells. In our experiment, topically applied KR-12-a2 solution did not cause hearing loss or cochlear damage in guinea pigs. Conclusion In our experiment, topically applied KR-12-a2 solution did not cause hearing loss or cochlear damage in guinea pigs. The KR-12-a2 solution can be used as ototopical drops for treating methicillin-resistant staphylococcus aureus otorrhea; however, further evaluations, such as the definition of optimal concentration and combination, are necessary.

Resumo Introdução O staphylococcus aureus resistente à meticilina é um problema emergente não só para a otite média supurativa crônica, mas também para casos de otorreia crônica em crianças com tubo de ventilação. Até o momento, não há antibióticos tópicos efetivos para a otorreia causada por staphylococcus aureus resistente à meticilina. Objetivo Nesse estudo, avaliamos a ototoxicidade da solução tópica de KR-12-a2 na cóclea quando aplicada topicamente na orelha média de cobaias. Método A atividade antimicrobiana de KR-12-a2 contra cepas de staphylococcus aureus resistente à meticilina foi avaliada utilizando-se o teste de zona de inibição de crescimento. Foram aplicados na orelhas médias de 3 grupos de cobaias, ou solução tópica de KR-12-a2, ou gentamicina ou solução salina tamponada com fosfato após timpanostomia. A ototoxicidade foi avaliada através do exame auditivo de potencial evocado auditivo de tronco encefálico e por microscopia eletrônica de varredura. Resultados O KR-12-a2 produziu uma zona de inibição contra o staphylococcus aureus resistente à meticilina a partir de 6,25 µg. Alterações do limiar de audição no grupo KR-12-a2 e no grupo com solução salina foram semelhantes aos observados antes da inserção do tubo de ventilação. No entanto, o grupo gentamicina apresentou um limiar auditivo mais elevado, estatisticamente significativo em comparação ao grupo solução salina ou ao grupo KR-12-a2. Nos achados da microscopia eletrônica, o grupo KR-12-a2 apresentou células ciliadas externas intactas. No entanto, o grupo gentamicina apresentou perda total das células ciliadas externas. Em nosso experimento, a solução de KR-12-a2 aplicada topicamente não causou perda auditiva ou dano coclear em cobaias. Conclusão Em nosso experimento, a solução de KR-12-a2 aplicada topicamente não causou perda auditiva ou dano coclear em cobaias. A solução de KR-12-a2 pode ser utilizada como gotas otológicas para o tratamento da otorreia causada por staphylococcus aureus resistente à meticilina; no entanto, são necessárias outras avaliações, para a definição da concentração e das associações ideais.

In vitro antibacterial effects of Zanthoxylum tingoassuiba root bark extracts and two of its alkaloids against multiresistant Staphylococcus aureus

ABSTRACT The emergence of multiresistant strains of bacteria reinforces the need to search for new compounds able to combat resistant organisms. Medicinal plants are a great resource of bioactive substances, providing the possibility of obtaining molecules with potential antimicrobial activity. The aim of the present study is the evaluation of the antibacterial activity of extracts and alkaloids isolated from the root bark of Zanthoxylum tingoassuiba A. St.-Hil., Rutaceae, against four resistant clinical isolates and Staphylococcus aureus ATCC 25923. The dichloromethane and methanol extracts were fractionated by chromatography on silica gel, leading to the isolation of dihydrocheleryhtrine and N-methylcanadine, identified by Nuclear Magnetic Resonance spectroscopy. The antibacterial activity of the extracts and isolated compounds was evaluated by the disc diffusion method and the minimum inhibitory concentration was determined. The dichloromethane extract was the most active against all the tested strains and the two pure alkaloids were more active than the extracts. The anti-MRSA activity of the two benzophenanthridine alkaloids is demonstrated for the first time in this study. These compounds appear as potential leads for the development of new anti-MRSA compounds and could be responsible for the antibacterial activity, justifying the ethnobotanical use of Z. tingoassuiba and other species for the treatment of various infectious diseases.

Advances in the study of anti-MRSA natural products / 药学学报

Methicillin-resistant Staphylococcus aureus (MRSA) is a multi-drug resistant pathogenic bacteria, which has seriously threatened human health for a long time. Discovery of novel anti-MRSA lead compounds with high efficiency and low toxicity represents an important research focus in the realm of antibiotic studies. Owing to their structural diversity and complexity, natural products have exhibited unique advantages and great potential in the development of anti-MRSA new drugs. This review summarizes the studies of anti-MRSA natural products and their relevant medicinal chemistry reported since 2010.

Screening of Endophytic Bacteria Isolated from Marine Sponge Haliclona fascigera for Inhibition against Clinical Isolates of Methicillin Resistant Staphylococcus aureus (MRSA).

Marine endophytic bacteria are a valuable source of novel antibacterial in combating pathogenic isolates of methicillin-resistant Staphylococcus aureus (MRSA), a global nosocomial problem today. The aim of this study was to assess in vitro anti-MRSA activity of extracts from bacteria endophyte of marine sponge Haliclona fascigera collected from Setan Island, South Coast of West Sumatra, Indonesia. Anti-MRSA activity test carried out by the agar diffusion method using paper disk. The endophytic bacteria from sponge were isolated using dilution method and pour plate method on NA media. From the sponge were obtained 26 isolates of bacterial endophytic then propagated in NB media. The liquid media was then extracted using ethyl acetate solvent. Antimicrobial activity test carried out by the agar diffusion method using paper disk. The antibacterial activity assay was conducted with the extract concentrations of 5 %. Chloramphenicol was used as a positive control agent. The zone of inhibition was measured and expressed in millimeters. There were 12 isolates of the bacteria that considered active to MRSA. Mean of inhibition zones ranged from 11.1±0.17 to 15.17±0.76. Characterization and identification of endophytic bacteria were conducted to several bioactive bacteria. The identification method was performed using Gram staining and biochemical test.

Production of a compound against methicillin resistant Staphylococcus aureus (MRSA) from Streptomyces rubrolavendulae ICN3 & its evaluation in zebrafish embryos.

Background & objectives: Antibiotic resistance in pathogens has become a serious problem worldwide. Therefore, the search for new antibiotics for drug resistanct pathogens is an important endeavor. The present study deals with the production of anti-methicillin resistant Staphylococcus aureus (MRSA) potential of Streptomyces rubrolavendulae ICN3 and evaluation of anti-MRSA compound in zebrafish embryos. Methods: The antibiotic production from S. rubrolavendulae ICN3 was optimized in solid state fermentation and extracted. The antagonistic activity was confirmed against MRSA and purified in silica gel column and reverse phase - HPLC with an absorption maximum at 215 nm. Minimal inhibitory concentration of the compound was determined by broth microdilution method. zebrafish embryos were used to evaluate the extract/compound for its minimal inhibition studies, influences on heart beat rates, haematopoietic blood cell count and lethal dose values. Results: Streptomyces rubrolavendulae ICN3 showed potent antagonistic activity against MRSA with a zone of 42 mm. The minimum inhibitory concentration was calculated as 500 μg/ml of the crude extract and the purified C23 exhibited 2.5 μg/ml in in vitro assay. The LC50 value of the anti MRSA compound C23 was calculated as 60.49 μg/ml and the MRSA treated embryos survived in the presence of purified compound C23 at a dose of 10 μg/ml. Interpretation & conclusions: our results suggested that the compound was potent with less toxic effects in zebrafish embryonic model system for MRSA infection. Further structural evaluation and analysis in higher mammalian model system may lead to a novel drug candidate for drug resistant Staphylococcus aureus.

Clinical Evaluation of Therapeutic Drug Monitoring (TDM) on Antibiotic Therapy for Methicillin-resistant Staphylococcus aureus (MRSA) Infection with the Diagnosis Procedure Combination (DPC) System / 医薬品情報学

<b>Objective: </b>The purpose of this study was to clarify the importance of therapeutic drug monitoring (TDM) at acute care hospitals using Diagnosis Procedure Combination (DPC) data.<br><b>Methods: </b>We used DPC data from about 3,500,000 inpatients at about 950 acute care hospitals.  The investigation period was from July 2010 to December 2010.  Patients were divided into 2 groups: TDM intervention (<i>n</i>=22,012); and non-TDM intervention (<i>n</i>=26,400).  We compared the clinical indicators (length of hospital stay, payment based on performance and drug costs) and use of antimicrobials.<br><b>Results: </b>TDM intervention was carried out in 45.5% patients for whom an anti-MRSA agent was prescribed.  The duration of anti-MRSA agent administration was significantly longer in the TDM intervention group than in the non-TDM intervention group.  The total daily cost of anti-MRSA agents was significantly lower in the TDM intervention group than in the non-TDM intervention group.<br><b>Conclusion: </b>Our results suggest that TDM intervention is often performed for seriously ill patients who require continuous treatment.  TDM intervention may prevent adverse reactions as a result of adjusting the dosage of the anti-MRSA agent.

Isolation and identification of anti-methicillin resistant Staphylococcus aureus compounds from Phyllanthus columnaris stem bark

Aim: Phyllanthus columnaris Müll.Arg. was found to possess anti-methicillin resistant Staphylococcus aureus (antiMRSA) activities. This study aimed at isolating, identifying and evaluating the active compounds from the stem bark of Phyllanthus columnaris Müll.Arg. against MRSA. Methodology and results: Stem bark extracts (methanol, acetone and aqueous) of Phyllanthus columnaris were subjected to anti-MRSA screening by disc diffusion method. MIC and MBC tests were carried out to compare the lowest concentration to inhibit and kill the sixteen MRSA tested among the three extracts. TLC bioautography were performed to detect the bioactive compounds. Isolation of the two active compounds was performed by means of preparative TLC. Morphological and ultra-structure alterations of the MRSA treated with bioactive compounds after 24 h were revealed by scanning and transmission electron microscopy. Both methanol and acetone extracts exhibited good anti-MRSA activity with the lowest minimum inhibitory concentration (MIC) value for both extracts were 0.78 mg/mL and the lowest minimum bactericidal concentration (MBC) were 1.56 mg/mL. Bioassay-guided chromatography by bioautography revealed two active anti-MRSA compounds from both tannin-free methanol and acetone extracts and characterized as stigmasterol and lupeol by nuclear magnetic resonance (NMR) spectral data. Scanning and transmission electron microscopy of MRSA treated with stigmasterol and lupeol showed cell wall disruption, release of cytoplasmic compounds and decreased in cellular volume. Conclusion, significance and impact of study: Results obtained herein, may suggest that the stem bark of Phyllanthus columnaris possess anti-MRSA and the two of the active compounds isolated were stigmasterol and lupeol. Their anti-MRSA effects up to the morphological and ultra-structure studies were not reported earlier

Anti-methicillin-resistant Staphylococcus aureus assay of azalomycin F5a and its derivatives / 中国天然药物

AIM@#To discover anti-methicillin-resistant Staphylococcus aureus (anti-MRSA) microbial natural products or their derivatives.@*METHOD@#Azalomycin F5a (1) was prepared through fermentation of Streptomyces hygroscopicus var. azalomyceticus, and its derivatives were synthesized through hydrocarbylation in hydrocarbyl alcoholic-AcOH (4 : 1) and subsequent demalonylation with 2 mol·L(-1) KOH in MeOH-H2O (7 : 3). Their activities against MRSA ATCC 33592 and three clinical MRSA isolates were evaluated by the agar diffusion and broth microdilution methods.@*RESULTS@#Four demalonylazalomycin F5a derivatives 2 to 5 were synthesized. The anti-MRSA activity assay indicated that compounds 1 to 5 showed remarkable activity against MRSA, and their minimum inhibitory concentrations (MICs) were respectively 3.0-4.0, 0.5-1.0, 0.67-1.0, 0.67-0.83, and 0.5-0.83 μg·mL(-1).@*CONCLUSION@#Azalomycin F5a and the demalonylazalomycin F5a derivatives 2-5 showed remarkable anti-MRSA activity, and the anti-MRSA activities of 2 to 5 were higher than that of 1, while the anti-MRSA activities of 2 to 5 showed no obvious differences. It was also shown that the malonyl monoester group of azalomycin F5a was less important for its anti-MRSA activity.

Anti-methicillin-resistant Staphylococcus aureus activities of three main components of azalomycin F / 中国药学杂志

OBJECTIVE: To research the anti-methicillin-resistant Staphylococcus aureus (anti-MRSA) activities of azalomycins F5a, F4a and F3a and their potential synergistic anti-MRSA activities combined with other compounds. METHODS: Against a reference strain MRSA ATCC 33592 and eight clinical isolates MRSA 01-08, the minimum inhibitory concentrations (MICs) and minimum bactericidal concentrations (MBCs) of three main components of azalomycin F were determined by broth microdilution method, and daptomycin was used as positive control. The anti-MRSA effects of them combined with carnosic acid or trimethylhydroquinone were designed with checkerboard method, and determined by broth microdilution method. RESULTS: Their MICs of azalomycins F5a, F4a and F3a against all nine MRSA strains were successively 4-8, 4 and 4-8 μg · mL-1, and all their MBCs were 8-16 μg · mL-1. All the fractional inhibitory concentration indices (FICIs) of them combined with carnosic acid or trimethylhydroquinone were 0.75-1.25 (indifference) or 0.25-0.50 (synergism). CONCLUSION: Three main compounds of azalomycin F have remarkable anti-MRSA activities, and the anti-MRSA effect of azalomycins F5a, F4a or F3a combined with trimethylhydroquinone was synergistic. As new anti-MRSA macrocyclide, azalomycin F is worthy of further research and development.