scholarly journals Combinations of (lipo)glycopeptides with β-lactams against MRSA: susceptibility insights

2020 ◽  
Vol 75 (10) ◽  
pp. 2894-2901
Author(s):  
Razieh Kebriaei ◽  
Seth A Rice ◽  
Nivedita B Singh ◽  
Kyle C Stamper ◽  
Logan Nguyen ◽  
...  
Keyword(s):  
Single Agent ◽  
Synergistic Activity ◽  
Bacterial Strains ◽  
Fold Reduction ◽  
High Prevalence ◽  
Mrsa Strains ◽  
Susceptibility Tests ◽  
Time Kill ◽  
The Impact ◽  
Microbroth Dilution

Abstract Background Increasing application of vancomycin due to the high prevalence of MRSA infections has led to the emergence of vancomycin intermediate-resistant Staphylococcus aureus (VISA) and heterogeneous VISA (hVISA). Consequently, the need for alternative therapies that target MRSA has become evident. Objectives To evaluate the synergy between (lipo)glycopeptides (LGP/GPs) (vancomycin, teicoplanin, telavancin, dalbavancin and oritavancin) and β-lactams (ceftaroline, cefepime, cefazolin and oxacillin) against MRSA, hVISA, VISA and daptomycin non-susceptible (DNS) phenotypes. Methods Twenty randomly selected clinical MRSA strains (i.e. 5 MRSA, 5 hVISA, 5 VISA and 5 DNS) were assessed versus LGP/GPs alone and LGP/GPs in combination with β-lactams for MICs. Although verification of antibiotic potency against bacterial strains is assessed by the microbroth dilution (MBD) MIC method recommended by the CLSI, some antibiotics need modified assay conditions in order to demonstrate their optimal activity. Results Addition of β-lactams reduced MIC values of LGP/GPs against all strains (up to 160-fold reduction). In general, LGPs (dalbavancin, oritavancin and telavancin) were more active (significant differences in MIC values, up to 8-fold) compared with vancomycin and teicoplanin. The majority of these combinations were bactericidal and superior to any single agent. Conclusions This report has examined the susceptibility patterns of LGP/GPs and their combination with β-lactams. Of interest, the impact of susceptibility tests (in terms of MIC plates and their surface area) on the synergistic activity in 24 h time–kill experiments was apparent for LGPs. Further clinical research is required to investigate synergy with LGP/GPs and β-lactams against these Staphylococcus strains.

scholarly journals β-Lactam Combinations with Vancomycin Show Synergistic Activity against Vancomycin-SusceptibleStaphylococcus aureus, Vancomycin-IntermediateS. aureus(VISA), and Heterogeneous VISA

2018 ◽  
Vol 62 (6) ◽  
Author(s):  
Kieu-Nhi Tran ◽  
Michael J. Rybak
Keyword(s):  
Staphylococcus Aureus ◽  
Single Agent ◽  
Synergistic Activity ◽  
Beta Lactam ◽  
Beta Lactams ◽  
Content Type ◽  
Fold Reduction ◽  
Mrsa Strains ◽  
Time Kill

ABSTRACTIncreasing utilization of vancomycin due to the high prevalence of methicillin-resistantStaphylococcus aureus(MRSA) infections has led to the emergence of vancomycin-intermediateS. aureus(VISA) and heterogeneous VISA (hVISA) strains.In vitrodata suggest the potential for potent synergy between several beta-lactams and vancomycin. The objective of this study is to evaluate the synergy between beta-lactams and vancomycin against MRSA that is vancomycin susceptible, vancomycin-susceptibleStaphylococcus aureus(VSSA), hVISA, and VISA. Fifty randomly selected clinical MRSA strains with various susceptibility levels to vancomycin were evaluated for vancomycin alone and vancomycin in combination with various concentrations of cefazolin (CFZ), cefepime (FEP), ceftaroline (CPT), and nafcillin (NAF). The potential for synergy was assessed by 24-h time-kill studies. Beta-lactams reduced vancomycin MIC values against all strains (4- to 16-fold reduction). In time-kill studies against MRSA, CFZ, FEP, CPT, and NAF all demonstrated similar degrees of killing at 24 h, and all showed synergistic activity with vancomycin against VSSA, hVISA, and VISA. Each of these combinations was also superior to any single agent against isolates of all three phenotypes, and each was bactericidal (P< 0.001 for all comparisons). All single-agent exposures demonstrated no activity at 24 h. The combination of vancomycin and beta-lactams significantly improved antibacterial activity against VSSA, hVISA, and VISA strains compared to the activity of any agent alone, supporting the potential use of vancomycin–beta-lactam combination therapy in infections caused by MRSA. Further clinical research is warranted to investigate the synergy of vancomycin against theseStaphylococcusstrains.

scholarly journals MDM2 Antagonists Induce a Paradoxical Activation of Erk1/2 through a P53-Dependent Mechanism in Dedifferentiated Liposarcomas: Implications for Combinatorial Strategies

Cancers ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2253
Author(s):  
Shomereeta Roy ◽  
Audrey Laroche-Clary ◽  
Stephanie Verbeke ◽  
Marie-Alix Derieppe ◽  
Antoine Italiano
Keyword(s):  
Tyrosine Kinases ◽  
Mapk Pathway ◽  
Single Agent ◽  
Immunoblot Analysis ◽  
Mek Inhibitor ◽  
Mitogen Activated Protein Kinase ◽  
Synergistic Activity ◽  
Mdm2 Gene ◽  
Mdm2 Antagonist ◽  
The Impact

The MDM2 gene is amplified in dedifferentiated liposarcoma (DDLPS). Treatment with MDM2 antagonists is a promising strategy to treat DDLPS; however, drug resistance is a major limitation when these drugs are used as a single agent. This study examined the impact of MDM2 antagonists on the mitogen-activated protein kinase (MAPK) pathway in DDLPS and investigated the potential synergistic activity of a MAPK kinase (MEK) inhibitor in combination with MDM2 antagonists. We identified a synergistic effect and identified the mechanism behind it. Combination effects of MDM2 antagonists and a MEK inhibitor were analyzed in a patient-derived xenograft mouse model and in DDLPS and leiomyosarcoma cell lines using different cell proliferation assays and immunoblot analysis. MDM2 antagonist (RG7388)-resistant IB115 [P4] cells and p53-silenced DDLPS cells were also established to understand the importance of functional p53. We found that MDM2 antagonists induced an upregulation of phosphorylated extracellular signal-regulated kinase (p-ERK) in DDLPS cells. The upregulation of p-ERK occurred due to mitochondrial translocation of p53, which resulted in increased production of reactive oxygen species, causing the activation of receptor tyrosine kinases (RTKs). Activated RTKs led to the activation of the downstream MEK/ERK signaling pathway. Treatment with a MEK inhibitor resulted in decreased expression of p-ERK, causing significant anti-tumor synergy when combined with MDM2 antagonists. Our results provide a framework for designing clinical studies of combination therapies in DDLPS patients.

Preclinical Approach to Sensitize Multiple Myeloma Cells: Combination of the MEK Inhibitor PD0325901 with ABT-737 or Mevinolin.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1842-1842
Author(s):  
Maria Rosaria Ricciardi ◽  
Elisabetta Calabrese ◽  
Michele Milella ◽  
Paola Bergamo ◽  
Samantha Decandia ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cell Growth ◽  
Cell Lines ◽  
Molecular Mechanisms ◽  
Clinical Investigation ◽  
Single Agent ◽  
Mek Inhibitor ◽  
Synergistic Activity ◽  
Mitochondrial Membrane Depolarization ◽  
The Impact

Abstract Abstract 1842 Poster Board I-868 Multiple myeloma (MM) is a plasma cell malignancy incurable with existing conventional therapies. However, the increased understanding of the molecular mechanisms underlying the growth, progression and drug resistance of MM cells is allowing the development of novel therapies based on target-specific drugs. These agents have shown promising results in pre-clinical trials and some are already in early phase of clinical investigation. However, limitations of this approach are represented by the existence of cross-talking signals among different pathways which results in ineffective inhibition of a single pathway. Therefore, targeted therapy based on the multiple inhibition of key signal transduction pathways represents the present focus of translational research. We have already demonstrated (Haematologica 2008;93[suppl.2]:P195) the potent growth-inhibitory effects of the specific MEK inhibitor PD0325901 and the marked pro-apoptotic activity of the Bcl2/BclXL inhibitor ABT-737 (kindly provided by Abbott Laboratories) on MM cell lines and primary CD138+ cells from MM patients at different disease stages (smoldering, diagnosis, relapse, refractory/resistant). Since it has already been reported that the inhibitor of the mevalonate pathway, Mevinolin, strikingly induces apoptosis by regulating different pathways, including the MEK/ERK module, we aimed in the present study to analyze the impact of the simultaneous inhibition of both pathways on apoptosis and cell growth of MM cell lines and primary samples. We exposed the KMS18, KMS27 and ARH-77 MM cell lines to increasing concentrations of PD0325901 (1–100 nM) and ABT-737 (1–100 nM) or Mevinolin (1–100 μM), alone and in combination. When used as single agents the inhibition of cell-growth was dose-dependent, while if used in combination it was synergistic, with combination indexes (CI) of 0.12 and 0.15 for PD0325901 plus ABT-737 and the same plus Mevinolin, respectively (Chou-Talalay method). We then investigated the effects of these agents on apoptosis, as determined by the sub-G1 DNA peak, and found that PD0325901 mainly showed cytostatic effects, while ABT-737 and Mevinolin needed high concentrations to affect apoptosis. The simultaneous exposure to PD0325901 plus ABT-737 or Mevinolin at lower concentrations, induced apoptosis with highly synergistic effects, as demonstrated by a CI of 0.2 (KMS18) and 0.17 (KMS27) for PD0325901 plus ABT-737 and of 0.135 (KMS18) and 0.128 (KMS27) for PD0325901 plus Mevinolin. Similarly, mitochondrial membrane depolarization was greatly induced with the combination approach. Preliminary experiments performed on primary MM samples confirmed the pro-apoptotic synergistic activity of combination strategies. On the contrary, when we used the MEK-inhibitor resistant MM cell line ARH-77, the effects of ABT-737 and Mevinolin were not potentiated by MEK inhibition with PD0325901. In conclusion, we demonstrated that the simultaneous disruption of the MEK/ERK and Bcl2/BclXL or Mevalonate signalling is effective on apoptosis induction and growth inhibition of MM cells at a greater degree than single agent therapy. Additional ongoing studies on primary samples from MM patients at different stages of the disease will help to determine the feasibility and efficacy of these combinations for clinical use. Disclosures: Petrucci: Celgene: Honoraria; Janssen Cilag: Honoraria.

The role of mprF mutations in “see-saw effect” of Daptomycin-resistant methicillin-resistant Staphylococcus aureus isolates

2021 ◽  
Author(s):  
Shengnan Jiang ◽  
Hemu Zhuang ◽  
Feiteng Zhu ◽  
Xiang Wei ◽  
Junxiong Zhang ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Novel Mutation ◽  
Point Mutations ◽  
Synergistic Activity ◽  
Beta Lactam ◽  
Beta Lactams ◽  
Methicillin Resistant ◽  
Beta Lactam Antibiotics ◽  
Mrsa Strains ◽  
The Impact

The emergence of daptomycin-resistant (DAP-R) Staphylococcus aureus strains has become a global problem. Point mutations in mprF are the main cause of daptomycin (DAP) treatment failure. However, the impact of these specific point-mutations in methicillin-resistant S. aureus (MRSA) strains associated with DAP resistance and the “see-saw effect” of distinct beta-lactams remains unclear. In this study, we used three series of clinical MRSA strains with three distinct mutated mprF alleles from clone complexes (CC) 5 and 59 to explore the “see-saw effect” and the combination effect of DAP plus beta-lactams. Through construction of mprF deletion and complementation strains of SA268, we determined that mprF -S295A, mprF -S337L and one novel mutation of mprF- I348del within the bifunctional domain lead to DAP resistance. Compared with wild-type mprF cloned from a DAP-susceptible (DAP-S) strain, these three mprF mutations conferred the “see-saw effect” to distinct beta-lactams in the SA268Δ mprF strains and mutated- mprF (I348del and S337L) did not alter the cell surface positive charge ( P > 0.05). The susceptibility to beta-lactams increased significantly in DAP-R CC59 strains and the “see-saw effect” was found to be associated with distinct mutated mprF alleles and the category of beta-lactams. The synergistic activity of DAP plus oxacillin was detected in all DAP-R MRSA strains. Continued progress in understanding the mechanism of restoring susceptibility to beta-lactam antibiotics mediated by the mprF mutation and its impact on beta-lactam combination therapy will provide fundamental insights into treatment of MRSA infections.

scholarly journals Oritavancin Combinations with β-Lactams against Multidrug-Resistant Staphylococcus aureus and Vancomycin-Resistant Enterococci

2016 ◽  
Vol 60 (4) ◽  
pp. 2352-2358 ◽  
Author(s):  
Jordan R. Smith ◽  
Juwon Yim ◽  
Animesh Raut ◽  
Michael J. Rybak
Keyword(s):  
Staphylococcus Aureus ◽  
Single Agent ◽  
Multidrug Resistant ◽  
Content Type ◽  
Vancomycin Resistant Enterococci ◽  
Complex Models ◽  
Vancomycin Resistant ◽  
Mrsa Strains ◽  
Time Kill

ABSTRACTOritavancin possesses activity against vancomycin-resistant enterococci (VRE) and methicillin-resistantStaphylococcus aureus(MRSA).In vitrodata suggest synergy between beta-lactams (BLs) and vancomycin or daptomycin, agents similar to oritavancin. We evaluated the activities of BLs combined with oritavancin against MRSA and VRE. Oritavancin MICs were determined for 30 strains, 5 each of MRSA, daptomycin-nonsusceptible (DNS) MRSA, vancomycin-intermediate MRSA (VISA), heteroresistant VISA (hVISA), vancomycin-resistantEnterococcus faecalis, and vancomycin-resistantEnterococcus faecium. Oritavancin MICs were determined in the presence of subinhibitory concentrations of BLs. Oritavancin combined with ceftaroline, cefazolin, or nafcillin was evaluated for lethal synergy against MRSA, and oritavancin combined with ceftaroline, ampicillin, or ertapenem was evaluated for lethal synergy against VRE in 24-h time-kill assays. Oritavancin at 0.5× the MIC was combined with BLs at 0.5× the MIC or the biological free peak concentration, whichever one was lower. Synergy was defined as a ≥2-log10-CFU/ml difference between the killing achieved with the combination and that achieved with the most active single agent at 24 h. Oritavancin MICs were ≤0.125 μg/ml for all MRSA isolates except three VISA isolates with MICs of 0.25 μg/ml. Oritavancin MICs for VRE ranged from 0.03 to 0.125 μg/ml. Oritavancin in combination with ceftaroline was synergistic against all MRSA phenotypes and statistically superior to all other combinations against DNS MRSA, hVISA, and MRSA isolates (P< 0.02). Oritavancin in combination with cefazolin and oritavancin in combination with nafcillin were also synergistic against all MRSA strains. Synergy between oritavancin and all BLs was revealed against VRE strain 8019, while synergy between oritavancin and ampicillin or ertapenem but not ceftaroline was demonstrated against VRE strain R7164. The data support the potential use of oritavancin in combination with BLs, especially oritavancin in combination with ceftaroline, for the treatment of infections caused by MRSA. The data from the present study are not as strong for oritavancin in combination with BLs for VRE. Further study of both MRSA and VRE in more complex models is warranted.

scholarly journals In VitroSynergistic Effect ofPsidium guineense(Swartz) in Combination with Antimicrobial Agents against Methicillin-ResistantStaphylococcus aureusStrains

2012 ◽  
Vol 2012 ◽  
pp. 1-7 ◽  
Author(s):  
Tiago Gomes Fernandes ◽  
Amanda Rafaela Carneiro de Mesquita ◽  
Karina Perrelli Randau ◽  
Adelisa Alves Franchitti ◽  
Eulália Azevedo Ximenes
Keyword(s):  
Staphylococcus Aureus ◽  
Aqueous Extract ◽  
Antimicrobial Agents ◽  
Diffusion Method ◽  
Synergistic Activity ◽  
Disk Diffusion Method ◽  
Microdilution Method ◽  
Fold Reduction ◽  
Amoxicillin Clavulanic Acid ◽  
Mrsa Strains

The aim of this study was to evaluate the antimicrobial activity of aqueous extract ofPsidium guineenseSwartz (Araçá-do-campo) and five antimicrobials (ampicillin, amoxicillin/clavulanic acid, cefoxitin, ciprofloxacin, and meropenem) against twelve strains ofStaphylococcus aureuswith a resistant phenotype previously determined by the disk diffusion method. FourS. aureusstrains showed resistance to all antimicrobial agents tested and were selected for the study of the interaction between aqueous extract ofP. guineenseand antimicrobial agents, by the checkerboard method. The criteria used to evaluate the synergistic activity were defined by the fractional inhibitory concentration index (FICI). AllS. aureusstrains were susceptible toP. guineenseas determined by the microdilution method. The combination of theP. guineenseextract with the antimicrobial agents resulted in an eight-fold reduction in the MIC of these agents, which showed a FICI ranging from 0.125 to 0.5, suggesting a synergistic interaction against methicillin-resistantStaphylococcus aureus(MRSA) strains. The combination of the aqueous extract ofP. guineensewith cefoxitin showed the lowest FICI values. This study demonstrated that the aqueous extract ofP. guineensecombined with beta lactamics antimicrobials, fluoroquinolones, and carbapenems, acts synergistically by inhibiting MRSA strains.

scholarly journals Evaluation of the Bactericidal Activity of Fosfomycin in Combination with Selected Antimicrobial Comparison Agents Tested against Gram-Negative Bacterial Strains by Using Time-Kill Curves

2019 ◽  
Vol 63 (5) ◽  
Author(s):  
Robert K. Flamm ◽  
Paul R. Rhomberg ◽  
Jill M. Lindley ◽  
Kim Sweeney ◽  
E. J. Ellis-Grosse ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Species Complex ◽  
Antimicrobial Agents ◽  
Acinetobacter Calcoaceticus ◽  
Synergistic Activity ◽  
Bacterial Strains ◽  
Gram Negative ◽  
Content Type ◽  
Time Kill

ABSTRACT The effects of combining fosfomycin with various antimicrobial agents were evaluated in vitro by broth microdilution checkerboard and time-kill kinetic studies. Checkerboard analyses were used to evaluate the following 30 Gram-negative isolates: 5 Pseudomonas aeruginosa, 5 Acinetobacter baumannii-Acinetobacter calcoaceticus species complex, and 20 Enterobacteriaceae isolates. No isolate exhibited antagonism when fosfomycin was tested in combination, and synergy was observed in more than 25% of the drug combinations tested. The most frequent instances of synergy occurred when testing fosfomycin with β-lactams. Two isolates of Pseudomonas aeruginosa, 2 of Klebsiella pneumoniae, and 1 of the A. baumannii-A. calcoaceticus species complex that exhibited synergy when fosfomycin was tested in combination were subjected to time-kill kinetic analyses for confirmation. Time-kill assays confirmed synergistic activity. These data indicated that combination therapy with fosfomycin may be beneficial.

scholarly journals 1295. Activity of SPR206, a Polymyxin B Derivative, Compared to Colistin Alone and in Combination Against Multidrug-Resistant Pseudomonas aeruginosa Strains

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S662-S663
Author(s):  
Jacinda C Abdul-Mutakabbir ◽  
Logan Nguyen ◽  
Kyle Stamper ◽  
Philip Maassen ◽  
Katherine Lev ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Triple Therapy ◽  
Bactericidal Activity ◽  
Dual Therapy ◽  
Polymyxin B ◽  
Multidrug Resistant ◽  
Synergistic Activity ◽  
Fold Reduction ◽  
Time Kill

Abstract Background The emergence of multidrug-resistant (MDR) Pseudomonas aeruginosa strains, has resulted in the use of previously discarded antibiotics, such as the polymyxins (polymyxin B and colistin (COL)). Consequently, the polymyxins are continually characterized by the cytotoxicity associated with their use. SPR206 is a polymyxin analogue, however the N-terminal lipophilic side chain has been extensively modified, decreasing the potential for adverse events. SPR206 has reduced minimum inhibitory concentrations (MIC) MIC50 and MIC90 in P. aeruginosa strains when compared to COL. The objective of this study was to compare the in-vitro activity of SPR206 to COL both alone and in combination with other antimicrobials against MDR P. aeruginosa. Methods MIC susceptibility testing was performed against 15 carbapenem-resistant P. aeruginosa strains via broth microdilution. SPR206, COL, aztreonam (AZT) and ceftazidime/ avibactam (CAZ/AVI) were evaluated against the P. aeruginosa strains. Dual therapy and triple therapy combinations, either COL or SPR206-based, were tested against four representative strains in 24h time-kill experiments (TKE). Each antibiotic was tested at both 0.5 and 1x the MIC. A &gt;2 log10 and a &gt;3log10 reduction in CFU/ml were defined as synergistic and bactericidal activity, respectively. Results The MIC testing revealed a lower range of MIC values for SPR206 compared to all agents tested, including COL, for the 15 MDR P. aeruginosa strains. A mean 2-fold reduction in MIC values was observed when comparing the activity of SPR206 to COL. Neither the SPR206 nor COL+CAZ/AVI combinations presented with synergistic activity in the TKEs. SPR206 or COL + CAZ/AVI +AZT, showed synergistic activity against each strain, irrespective of COL or SPR206 base and the tested concentration. At 0.5x MIC bactericidal activity was observed in two of the strains with either COL or SPR206 + AZT. However, at 1xMIC the SPR206+AZT combination exhibited bactericidal activity, equal to that of the triple therapy regimens, against each strain. Conclusion The combination of SPR206 with other antibiotic agents showed promise in eradicating MDR P. aeruginosa. Further research is warranted to solidify the role of SPR206 in the current antibiotic armamentarium. Disclosures Michael J. Rybak, PharmD, MPH, PhD, Paratek (Grant/Research Support)

Comparing the Impact of Religious Discourse on HIV/AIDS in Islam and Christianity in Africa

2012 ◽  
Vol 8 ◽  
Author(s):  
Sloane Speakman
Keyword(s):  
Social Factors ◽  
Negative Relationship ◽  
Hiv Prevalence ◽  
Religious Discourse ◽  
Prevalence Rates ◽  
The Social ◽  
High Prevalence ◽  
Islam And Christianity ◽  
Sub Saharan ◽  
The Impact

In examining the strikingly high prevalence rates of HIV in many parts of Africa, reaching as high as 5% in some areas, how does the discourse promoted by the predominant religions across the continent, Islam and Christianity, affect the outlook of their followers on the epidemic? This question becomes even more intriguing after discovering the dramatic difference in rate of HIV prevalence between Muslims and Christians in Africa, confirmed by studies that have found a negative relationship to exist between HIV prevalence and being Muslim in Africa, even in Sub-Saharan African nations. Why does this gap in prevalence rates exist? Does Islam advocate participating in less risky behavior more so than Christianity? By comparing the social construction, epidemiological understanding and public responses among Muslim populations in Africa with Christian ones, it becomes apparent that many similarities exist between the two regarding discourse and that, rather than religious discourse itself, other social factors, such as circumcision practices, contribute more to the disparity in HIV prevalence than originally thought.

THE EFFECT OF BACTERIAL STRAINS ON THE ENZYMATIC ACTIVITY OF SOILS IN IMPACT ZONE OF ATAMAN LAKE

2020 ◽  
Author(s):  
V.V. Zinchenko ◽  
◽  
E.S Fedorenko ◽  
A.V Gorovtsov ◽  
T.M Minkina ◽  
...  
Keyword(s):  
Enzymatic Activity ◽  
Dehydrogenase Activity ◽  
Contaminated Soil ◽  
Model Experiment ◽  
Impact Zone ◽  
Bacterial Strains ◽  
The Impact

As a result of the model experiment, an increase in the enzymatic activity of meadow chernozem of the impact zone of Ataman Lake with the introduction of a strains mixture of metal-resistant microorganisms into the soil was established. The experiment has shown that the application of bacterial strains increases the dehydrogenase activity of contaminated soil by 51.8% compared to the variant without remediation

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