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Background In complicated endovascular infections by methicillin-resistant Staphylococcus aureus (MRSA) or Staphylococcus epidermidis (MRSE), when first-line therapy with vancomycin (VAN) or daptomycin (DAP) fails, combination therapy with ceftaroline (CFT) and DAP has been shown to be a useful approach as salvage therapy for persistent MRSA bacteremia. Objectives This study aimed to describe experience with daptomycin and ceftaroline combination therapy in MRSE-complicated endovascular infections. Methods A single-center retrospective review of consecutive patients with MRSE-complicated endovascular infections treated with ≥72 hours of DAP+CFT at any time during the course of treatment, from January 1, 2016 to December 31, 2020, at Centro Hospitalar Universitário São João (CHUSJ), Porto, Portugal, was conducted. The exclusion criteria were known resistance to daptomycin or ceftaroline, total time of combination therapy <72 hours and loss to follow-up. Results We identified seven cases that matched our criteria: five endocarditis and two central venous catheter infections. Six patients switched to combination therapy due to treatment failure with first-line agents - three due to persistent bacteremia and three due to progression of infection despite negative blood cultures. Effective surgical source control took one to four weeks to occur. Three patients died during the treatment, one from progression of the disease and two due to another infection. Conclusions We consider the DAP+CFT combination therapy to be a valid and safe therapeutic choice in complicated patients, such as those with severe infection, poor functional status, and impossibility or delay of surgical source control. However, conclusions on the role of combination therapy should be careful due to the low number of patients and the several confounding factors.

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In contrast to the checkerboard method, bactericidal experiments [time-kill curves (TKCs)] allow an assessment of pharmacodynamic (PD) interactions over time. However, TKCs in combination pose interpretation problems. The objective of this study was to characterize the PD interaction over time between ceftazidime/avibactam (CZA) and colistin (CST) using TKC against four multidrug-resistant Klebsiella pneumoniae susceptible to both antibiotics and expressing a widespread carbapenemase determinant KPC-3. In vitro TKCs were performed and analyzed using pharmacokinetic/pharmacodynamic (PKPD) modeling. The general pharmacodynamic interaction model was used to characterize PD interactions between drugs. The 95% confidence intervals (95%CIs) of the expected additivity and of the observed interaction were built using parametric bootstraps and compared to evaluate the in vitro PD interaction over time. Further simulations were conducted to investigate the effect of the combination at varying concentrations typically observed in patients. Regrowth was observed in TKCs at high concentrations of drugs alone [from 4 to 32× minimum inhibitory concentrations (MIC)], while the combination systematically prevented the regrowth at concentrations close to the MIC. Significant synergy or antagonism were observed under specific conditions but overall 95%CIs overlapped widely over time indicating an additive interaction between antibiotics. Moreover, simulations of typical PK profile at standard dosages indicated that the interaction should be additive in clinical conditions. The nature of the PD interaction varied with time and concentration in TKC. Against the four K. pneumoniae isolates, the bactericidal effect of CZA + CST combination was predicted to be additive and to prevent the emergence of resistance at clinical concentrations.

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AIMS: The combination of daptomycin and ceftaroline used as salvage therapy is associated with higher survival and decreased clinical failure in complicated methicillin-resistant Staphylococcus aureus (MRSA) infections that are resistant to standard MRSA treatment. This study aimed to evaluate dosing regimens for coadministration of daptomycin and ceftaroline in special populations including paediatrics, renally impaired (RI), obese and geriatrics that generate sufficient coverage against daptomycin-resistant MRSA. METHODS: Physiologically based pharmacokinetic models were developed from pharmacokinetic studies of healthy adults, geriatric, paediatric, obese and RI patients. The predicted profiles were used to evaluate joint probability of target attainment (PTA), as well as tissue-to-plasma ratios. RESULTS: The adult dosing regimens of 6 mg/kg every (q)24h or q48h daptomycin and 300-600 mg q12h ceftaroline fosamil by RI categories achieved ≥90% joint PTA when the minimum inhibitory concentrations in the combination are at or below 1 and 4 µg/mL against MRSA. In paediatrics, wherein there is no recommended daptomycin dosing regimen for S. aureus bacteraemia, ≥90% joint PTA is achieved when the minimum inhibitory concentrations in the combination are up to 0.5 and 2 µg/mL for standard paediatric dosing regimens of 7 mg/kg q24h daptomycin and 12 mg/kg q8h ceftaroline fosamil. Model predicted tissue-to-plasma ratios of 0.3 and 0.7 in the skin and lung, respectively, for ceftaroline and 0.8 in the skin for daptomycin. CONCLUSION: Our work illustrates how physiologically based pharmacokinetic modelling can inform appropriate dosing of adult and paediatric patients and thereby enable prediction of target attainment in the patients during multitherapies.

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It is accepted that the medicinal use of complex mixtures of plant-derived bioactive compounds is more effective than purified bioactive compounds due to beneficial combination interactions. However, synergy and antagonism are very difficult to study in a meticulous fashion since most established methods were designed to reduce the complexity of mixtures and identify single bioactive compounds. This study represents a critical review of the current scientific literature on the combined effects of plant-derived extracts/bioactive compounds. A particular emphasis is provided on the identification of antimicrobial synergistic or antagonistic combinations using recent metabolomics methods and elucidation of approaches identifying potential mechanisms that underlie their interactions. Proven examples of synergistic/antagonistic antimicrobial activity of bioactive compounds are also discussed. The focus is also put on the current challenges, difficulties, and problems that need to be overcome and future perspectives surrounding combination effects. The utilization of bioactive compounds from medicinal plant extracts as appropriate antimicrobials is important and needs to be facilitated by means of new metabolomics technologies to discover the most effective combinations among them. Understanding the nature of the interactions between medicinal plant-derived bioactive compounds will result in the development of new combination antimicrobial therapies.

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Acinetobacter spp., the nosocomial pathogen, forms strong biofilms and is resistant to numerous antibiotics, causing persistent infections. This study investigates the antibacterial and anti-biofilm activity of polymyxin E alone and in combination with the cell-free supernatants (CFS) of the tested probiotic bacilli, Bacillus subtilis KATMIRA1933 and Bacillus amyloliquefaciens B-1895 against the selected Acinetobacter spp. starins. Three isolates of Acinetobacter spp., designated as Acinetobacter spp. isolate 1; Acinetobacter spp. isolate 2, and Acinetobacter spp. isolate 3, were collected from patients with burns, wounds, and blood infections, respectively. Bacterial identification and antibiotic susceptibility testing were conducted using the VITEK2 system. Auto-aggregation and coaggregation of the tested bacilli strains with the selected Acinetobacter spp. isolates were evaluated. A disk diffusion assay was used to identify the microorganism's susceptibility to the selected antibiotics, alone and in combination with the CFS of the bacilli. The MIC and MBIC (minimum inhibitory and minimum biofilm inhibitory concentrations) of polymyxin E combined with bacilli CFS were determined. Acinetobacter spp. isolates were (i) sensitive to polymyxin E, (ii) able to form a strong biofilm, and (iii) resistant to the tested antibiotics and the CFS of tested bacilli. Significant inhibition of biofilm formation was noticed when CFS of the tested bacilli were combined with polymyxin E. The bacilli CFS showed synergy with polymyxin E against planktonic cells and biofilms of the isolated pathogens.

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Quorum sensing (QS) plays an essential role in the production of virulence factors, in biofilm formation and antimicrobial resistance. Consequently, inhibiting QS is being considered a promising target for antipathogenic/anti-virulence therapies. This study aims to screen 2-nitrovinylfuran derivatives structurally related to Furvina (a broad-spectrum antibiotic already used for therapeutic purposes) for their effects on QS and in biofilm prevention/control. Furvina and four 2-nitrovinylfuran derivatives (compounds 1-4) were tested to assess the ability to interfere with QS of Staphylococcus aureus using bioreporter strains (S. aureus ALC1742 and ALC1743). The activity of Furvina and the most promising quorum-sensing inhibitor (QSI) was evaluated in biofilm prevention and in biofilm control (combined with fusidic acid). The biofilms were further characterized in terms of biofilm mass, viability and membrane integrity. Compound 2 caused the most significant QS inhibition with reductions between 60% and 80%. Molecular docking simulations indicate that this compound interacts preferentially with the protein hydrophobic cleft in the LytTR domain of AgrA pocket. Metabolic inactivations of 40% for S. aureus ALC1742 and 20% for S. aureus ALC1743 were reached. A 24 h-old biofilm formed in the presence of the QSI increased the metabolic inactivation by fusidic acid to 80%, for both strains. The overall results highlight the effects of compound 2 as well as the potential of combining QSI with in-use antibiotics for the management of skin and soft tissues infections.

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The emergence of methicillin-resistant staphylococci necessitated the search for alternative agents as linezolid, introduced to treat infections due to multidrug-resistant bacteria. Linezolid resistance has since emerged, yet its global prevalence remains low. In Egypt, little is known about the situation. We investigated the prevalence and mechanisms of resistance among Egyptian staphylococcal clinical isolates. Linezolid resistance among 232 staphylococcal isolates obtained from Alexandria Main Hospitals between 2011 and 2016 was assessed using disc diffusion and minimum inhibitory concentration. Resistant isolates were checked for cfr presence using polymerase chain reaction. The V domain of different alleles of 23S rRNA gene was investigated for mutations. Selection for linezolid-resistant mutants was performed in vitro through serial passages in linezolid sub-inhibitory concentrations. Combinations of linezolid with imipenem or anti-inflammatory agents were investigated using time-kill and modified checkerboard assays. Three Staphylococcus haemolyticus isolates (1.3%) from 2015 to 2016 were linezolid-resistant. One isolate carried cfr which was plasmid-borne, and together with another isolate which had a G2603T point mutation in the V domain of 23S rRNA gene. Successive exposure to linezolid sub-inhibitory concentrations was selected for three resistant Staphylococcus aureus mutants out of ten susceptible isolates. These mutants were more resistant towards different antibiotic classes than their susceptible parents. Linezolid combinations with imipenem, ibuprofen, or aspirin were synergistic against the isolates and mutants. Despite unregulated use of linezolid, resistance remains fairly low among the Egyptian isolates. Strict antimicrobial stewardship guidelines are needed in hospitals and the community to guard against further evolution of resistant mutants.

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BACKGROUND: Antimicrobial combinations have been proven as a promising approach in the confrontation with multi-drug resistant bacterial pathogens. In the present study, we identify and characterize a synergistic interaction of broad-spectrum nitroreductase-activated prodrugs 5-nitrofurans, with a secondary bile salt, Sodium Deoxycholate (DOC) in growth inhibition and killing of enterobacteria. RESULTS: Using checkerboard assay, we show that combination of nitrofuran furazolidone (FZ) and DOC generates a profound synergistic effect on growth inhibition in several enterobacterial species including Escherichia coli, Salmonella enterica, Citrobacter gillenii and Klebsiella pneumoniae. The Fractional Inhibitory Concentration Index (FICI) for DOC-FZ synergy ranges from 0.125 to 0.35 that remains unchanged in an ampicillin-resistant E. coli strain containing a ß-lactamase-producing plasmid. Findings from the time-kill assay further highlight the synergy with respect to bacterial killing in E. coli and Salmonella. We further characterize the mechanism of synergy in E. coli K12, showing that disruption of the tolC or acrA genes that encode components of multidrug efflux pumps causes, respectively, a complete or partial loss, of the DOC-FZ synergy. This finding indicates the key role of TolC-associated efflux pumps in the DOC-FZ synergy. Overexpression of Nitric Oxide-detoxifying enzyme Hmp results in a three-fold increase in FICI for DOC-FZ interaction, suggesting a role of nitric oxide in the synergy. We further demonstrate that DOC-FZ synergy is largely independent of NfsA and NfsB, the two major activation enzymes of the nitrofuran prodrugs. CONCLUSIONS: This study is to our knowledge the first report of nitrofuran-deoxycholate synergy against Gram-negative bacteria, offering potential applications in antimicrobial therapeutics. The mechanism of DOC-FZ synergy involves FZ-mediated inhibition of TolC-associated efflux pumps that normally remove DOC from bacterial cells. One possible route contributing to that effect is via FZ-mediated nitric oxide production.

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Candida albicans and Staphylococcus epidermidis are important opportunistic human pathogens, which form mixed-species biofilms and cause recalcitrant device associated infections in clinical settings. Further to many reports suggesting the therapeutic potential of plant-derived monoterpenoids, this study investigated the interaction of the monoterpenoids carvacrol (C) and thymol (T) against mono- and mixed-species growth of C. albicans and S. epidermidis. C and T exhibited synergistic antimicrobial activity. The time-kill study and post-antimicrobial effect results revealed the effective microbicidal action of the C + T combination. Filamentation, surface coating assays and live-dead staining of biofilms determined the anti-hyphal, antiadhesion, and anti-biofilm activities of the C + T combination, respectively. Notably, this combination killed highly tolerant persister cells of mono-species and mixed-species biofilms and demonstrated less risk of resistance development. The collective data suggest that the C + T combination could act as an effective therapeutic agent against biofilm associated mono-species and mixed-species infections of C. albicans and S. epidermidis.

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Aim: The aims of the study are to evaluate the activity of sulbactam, meropenem, and polymyxin B alone and in combination against six isolates of extremely drug resistant Acinetobacter baumannii and to determine dosing regimens that achieve a sufficient joint probability of target attainment (PTA) based on combination antimicrobial pharmacodynamics. Materials and Methods: The combinations were evaluated by the checkerboard method and were considered synergistic when the fractional inhibitory concentration index (FICI) ≤0.5. Pharmacodynamic analyses were carried out by evaluating dosing regimens that achieve ≥90% joint PTA at the percentage of time over a 24-h period wherein the free drug concentration is above the minimum inhibitory concentration (%fT> MIC) of 40% and 60% for meropenem and sulbactam, respectively, and 20 for the ratio of the area under the free drug concentration-time curve over MIC (fAUC/MIC) for polymyxin B. Results: For both polymyxin B-resistant and susceptible isolates, the addition of sulbactam in combination with meropenem and subinhibitory concentration of polymyxin B showed important synergistic activity (five isolates; FICI ≤0.281); the recommended dosing regimens were 2/4 g meropenem/sulbactam q8 hours and 0.5 mg/kg polymyxin B q12 hours. Conclusion: This in vitro study showed that sulbactam can significantly improve the action of meropenem and polymyxin B in OXA-producing A. baumannii isolates, especially when there are no new treatment options available for infections caused by these microorganisms.

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In this study, the activity of meropenem (MEM), fosfomycin (FOF) and polymyxin B (PMB), alone and in combination, was analysed. In addition, optimisation of the pharmacodynamic index of MEM and FOF against six isolates of OXA-23-producing Acinetobacter baumannii (including three resistant to PMB) that were not clonally related was assessed. Antimicrobial combinations were evaluated by chequerboard analysis and were considered synergistic when the fractional inhibitory concentration index (FICI) was ≤0.5. Pharmacodynamic analyses of the MEM and FOF dosing schemes were performed by Monte Carlo simulation. The target pharmacodynamic index (%ƒT>MIC) for MEM and FOF was ≥40% and ≥70%, respectively, and a probability of target attainment (PTA) ≥0.9 was considered adequate. Among the PMB-resistant isolates, combinations of PMB+MEM and PMB+FOF+MEM showed the highest synergistic activity (FICI ≤0.125); isolates that were previously PMB-resistant were included in the susceptible category using CLSI interpretive criteria. Pharmacodynamic evaluation found that for a FOF minimum inhibitory concentration (MIC) of ≤16µg/mL, treatment both by bolus dosing and prolonged infusion achieved adequate PTA, whilst for MIC=32µg/mL only infusion achieved adequate PTA. For a MEM MIC of 4µg/mL, only the bolus treatment scheme with 1.5g q6h and the infusion schemes with 1.0g q8h, 1.5g q6h and 2.0g q8h achieved PTA ≥0.9. Results of antimicrobial and pharmacodynamic analyses can assist in treating infections caused by multidrug-resistant A. baumannii. However, in vivo clinical studies are essential to evaluate the true role of these compounds, including intravenous antimicrobial FOF therapy.

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UNLABELLED: Preservative agents determining the shelf life of cosmetic products must have effective antimicrobial activity while meeting safety requirements for topical use. In this study, we determined the antimicrobial activity of 1,2-hexanediol against several Gram-positive and Gram-negative bacteria. Antimicrobial susceptibility tests have shown that 1,2-hexanediol exhibits broad-spectrum activity against Gram-positive and Gram-negative bacteria with MICs of 0·5-2% (v/v). The bactericidal concentration of 1,2-hexanediol was ranging from 1 to 2 × MIC as demonstrated by time-kill curve assay. A membrane depolarization assay showed that 1,2-hexanediol disrupted the cytoplasmic membrane potential. A checkerboard assay indicated that the effective concentration of 1,2-hexanediol was reduced up to 0·25-0·5 × MIC when combined with macelignan and octyl gallate against Gram-positive bacteria. However, this combination was not effective against Gram-negative bacteria. A turbidity reduction assay demonstrated that the combination of a high concentration of 1,2-hexanediol with food-grade antimicrobial compounds could trigger lytic activity towards Bacillus cereus cells. The remaining cell turbidity was 24·6 and 22·2% when 2% of 1,2-hexanediol was combined with 8 mg l(-1) octyl gallate or with 32 mg l(-1) macelignan respectively. This study showed that food-grade antimicrobial compounds may be used in combination with 1,2-hexanediol to increase its efficacy as a preservative agent in cosmetics. SIGNIFICANCE AND IMPACT OF THE STUDY: The antimicrobial activity of 1,2-hexanediol against Gram-positive and Gram-negative bacteria was potentiated with food-grade antimicrobials including xanthorrhizol, macelignan, panduratin A and octyl gallate, which have already been reported to display anti-inflammatory and other beneficial activities related to cosmetics. Therefore, the combination of 1,2-hexanediol and these food-grade antimicrobial agents would have benefits not only for increasing the antimicrobial activity but also in cosmetics use.

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Objective To evaluate the activities of 18 pairs of antimicrobials combinations against non - duplicate clinical isolates of multidrug resistant Acinetobacter baumannii (MDRAB) in vitro.Methods Collect isolates of Acinetobacter baumannii from different patients from October 2009 to May 2010,which were isolated in Clinical Laboratory Center of Beijing Friendship Hospital,Capital Medical University.Use broth microdilution method to detect MIC of mono-antimicrobial,and checkerboard broth microdilution method to detect combinatied MIC,and calculate fractional inhibitory concentration (FIC) index to determine drug combinations effects.When the performance of the same drug combinations conflicted,appropriate strains were selected for screening of drug-resistant mechanisms by polymerase chain reaction( PCR),including efflux pump genes.Results In tests in vitro,rifampicin and polymyxin B,imipenem and gentamicin,cefepime and levofloxacin showed synergy at high proportion,68.1％,45.5％,40.9％,respectively.Minocycline and rifampicin,ampicillin/sulbactam and tobramycin.Ceftazidime and ciprofloxacin showed additive effect at high proportion,81.8％,68.2％,68.2％,respectively.There were several combinations which appeared the opposite effects to tested strains.Strains No.19 corresponding reaction was synergy and No.21,No.26 corresponding reactions were antagonism.The three strains above were selected for screening resistant mechanisms.The difference is that genotypes of adeS were negative in No.19 and positive in No.21 and No.26.Conclusion Rifampicin and polymyxin B combination showed synergy against the MDRAB in vitro,which can be considered as the treatment choice for critical infections caused by MDRAB.Imipenem and gentamicin,cefepime and levofloxacin also showed synergy in vitro,but in some isolates showed antagonism.This phenomenon may be due to the gene adeS activated by certain antibiotics,and the activated adeS drived efflux pump express or overexpress,which made the drugs in bacterial cells pumped out,causing antagonistic effect.The individual differences in strains should be considered when clinic strain apply these two combinations above.

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BACKGROUND: Pseudomonas aeruginosafrequently causes nosocomial infection. Recently, there have been reports of infection with multidrug-resistant P. aeruginosa. The purpose of this study was to evaluate the in vitro effect of antimicrobial combination against multidrug-resistant P. aeruginosa. METHODS: Twenty isolates of imipenem and/or cefepime resistant P. aeruginosa were collected from the microbiology laboratory of Ewha Womans Unversity Mokdong Hospital. Checkerboard titration method was used to assess the activity of ceftazidime or cefepime in combination with amikacin, gentamicin or aztreonam, and colistin in combination with ceftazidime or rifampin. RESULTS: All isolates were resistant to more than 12 antimicrobial agents including imipenem and/or cefepime by broth microdilution method; however, no isolates were resistant to colistin. Most of the isolates showed high level resistance to ceftazidime, cefepime and meropenem, with MIC90 of 128, 512 and 64 microgram/mL, respectively. The MIC90 of colistin was 2 microgram/mL, which is within the su ceptiblerange. Synergistic effect was not detected by the checkerboard titration method with any antimicrobial combinations. However, a partial synergy was observed in 40% of the isolates with the combination of ceftazidime and amikacin, 65% with ceftazidime and gentamicin, 45% with cefepime and amikacin, and 75% with cefepime and gentamicin. Other antimicrobial combinations showed indifference against most strains, and antagonism was not observed. CONCLUSION: Multidrug-resistant P. aeruginosa isolates were all susceptible to colistin. The combined regimens of ceftazidime with amikacin or gentamicin and cefepime with amikacin or gentamicin revealed a partially synergistic effect in 40-75% of the isolates.

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BACKGROUND: Acinetobacter baumannii has been reported as a major cause of nosocomial infections with increasing frequency. Recently, the emergence of carbapenem-resistant strains has become a major problem in treatment. The use of nontraditional agents such as colistin and a combination therapy have been tried. The purpose of this study was to evaluate the activity of antimicrobial combinations against multidrug-resistant (MDR) A. baumannii. METHODS: Twenty-nine strains of MDR A. baumannii, either resistant or intermediate to imipenem, were collected from February 2003 to February 2004. Minimum inhibitory concentrations (MICs) were determined by the agar dilution method. The checkerboard method was used to assess the activity of ampicillin-sulbactam in combination with amikacin, tobramycin or meropenem and colistin in combination with ceftazidime, meropenem, or rifampin. RESULTS: The MIC90 of ceftazidime and cefepime were 2, 048 g/mL and 512 g/mL, respectively, while the MIC90 of colistin was 0.5 g/mL. The antimicrobial combinations that showed an additive effect for one or two strains were colistin with rifampin or ceftazidime and ampicillin-sulbactam with tobramycin or meropenem. Other antimicrobial combinations showed indifferent effects against most strains. There were no synergistic or antagonistic combinations. CONCLUSIONS: These data suggested that colistin may be an alternative drug for MDR A. baumannii. For the effective treatment of patients infected with these resistant strains, further studies are needed to evaluate antimicrobial combinations against a large number of heterogeneous isolates, and these studies must be followed by clinical trials.

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