Linezolid and Rifampicin Combination to Combat cfr-Positive Multidrug-Resistant MRSA in Murine Models of Bacteremia and Skin and Skin Structure Infection.

Linezolid resistance mediated by the cfr gene in MRSA represents a global concern. We investigated relevant phenotype differences between cfr-positive and -negative MRSA that contribute to pathogenesis, and the efficacy of linezolid-based combination therapies in murine models of bacteremia and skin and skin structure infection (SSSI). As a group, cfr-positive MRSA exhibited significantly reduced susceptibilities to the host defense peptides tPMPs, human neutrophil peptide-1 (hNP-1), and cathelicidin LL-37 (P < 0.01). In addition, increased binding to fibronectin (FN) and endothelial cells paralleled robust biofilm formation in cfr-positive vs. -negative MRSA. In vitro phenotypes of cfr-positive MRSA translated into poor outcomes of linezolid monotherapy in vivo in murine bacteremia and SSSI models. Importantly, rifampicin showed synergistic activity as a combinatorial partner with linezolid, and the EC50 of linezolid decreased 6-fold in the presence of rifampicin. Furthermore, this combination therapy displayed efficacy against cfr-positive MRSA at clinically relevant doses. Altogether, these data suggest that the use of linezolid in combination with rifampicin poses a viable therapeutic alternative for bacteremia and SSSI caused by cfr-positive multidrug resistant MRSA

Vasopressin and epinephrine versus epinephrine in management of patients with cardiac arrest: a meta-analysis

Objective. A combination of vasopressin and epinephrine may be more effective than epinephrine alone in cardiopulmonary resuscitation (CPR), but evidence is lacking to make clinical recommendations. This meta-analysis compares the efficacy of vasopressin and epinephrine used together versus epinephrine alone in cardiac arrest (CA). Methods. We searched MEDLINE and EMBASE for randomized trials comparing the efficacy of vasopressin and epinephrine versus epinephrine alone in adults with cardiac arrest. The primary outcome was the return of spontaneous circulation (ROSC) and the survival rate on admission and discharge .We also analyzed ROSC in subgroups of patients presenting with different arrest rhythms, such as asystole, pulseless electrical activity (PEA), ventricular fibrillation (VF). Results. We analyzed 6 randomized trials out of 485 articles. We did not find evidence supporting the superiority of vasopressin and epinephrine used in combination, except for the survival rate at 24h 2.99 95% CI(1.43,6.28). No evidence supports the conclusion that vasopressin combined with epinephrine is better than epinephrine alone for ROSC, even amongst subgroups of patients. Conclusion. This systematic review of the efficacy of vasopressin and epinephrine use found that its combined use is better for 24h survival rate but only in one study which included 122 patients. Further investigation will be needed to support the use of this combination for cardiac arrest management

Efflux Pump Overexpression Contributes to Tigecycline Heteroresistance in Salmonella enterica serovar Typhimurium

Bacterial heteroresistance has been identified in several combinations of bacteria and antibiotics, and it complicated the therapeutic strategies. Tigecycline is being used as one of the optimal options for the treatment of infections caused by multidrug-resistant Salmonella. This study investigated whether heterorresistance to tigecycline exists in a Salmonella enterica serovar Typhimurium strain harboring the oqxAB-bearing IncHI2 plasmid pHXY0908. MIC and population analyses were performed to evaluate population-wide susceptibility to tigecycline. The effects of efflux pumps on MIC levels were assessed using the efflux pump inhibitor Phe-Arg-β-naphthylamide, measuring intracellular tigecycline accumulation as well as mRNA levels of regulatory and efflux pump genes. DNA sequencing of regulatory regions were performed and plasmid curing from a resistant strain provided an appropriate control. Results showed that MICs of a parental strain with and without pHXY0908 as well as a plasmid-cured strain 14028/Δp52 were 0.5, 1, and 1 μg/mL, respectively. Population analysis profiling (PAP) illustrated that only the pHXY0908-containg strain was heteroresistant to tigecycline. A fraction of colonies exhibited stable profiles with 4- to 8-fold increases in MIC. The frequencies of emergence of these isolates were higher in the plasmid-containing strain pHXY0908 than either the parental or the 14028/Δp52 strain. Phe-Arg-β-naphthylamide addition restored tigecycline susceptibility of these isolates and intracellular tigecycline accumulation was reduced. Heteroresistant isolates of the strain containing pHXY0908 also had elevated expression of acrB, ramA, and oqxB. DNA sequencing identified numerous mutations in RamR that have been shown to lead to ramA overexpression. In conclusions, heteroresistance to tigecycline in Salmonella enterica serovar Typhimurium was manifested in a plasmid-bearing strain. Our results suggest that this phenotype was associated with overexpression of the AcrAB-TolC and OqxAB efflux pumps

3-(4-Bromo­phen­yl)-4-[2-(4-nitro­phen­yl)hydrazin­yl]furan-2(5H)-one

In the title compound, C16H12BrN3O4, the furan-2(5H)-one ring forms a dihedral angle of 33.19 (9)° with the 4-bromo­benzene unit and is nearly perpendicular to the 4-nitro­benzene segment, making a dihedral angle of 89.93 (10)°. In the crystal, N—H⋯O hydrogen bonds link the mol­ecules, generating an infinite chain along [010]. The chains are linked into a three-dimensional network by C—H⋯O, C—H⋯π and π–π contacts [centroid–centroid separation = 3.805 (2) Å]

Pharmacodynamic Evaluation and PK/PD-Based Dose Prediction of Tulathromycin: A Potential New Indication for Streptococcus suis Infection

Tulathromycin is the first member of the triamilide antimicrobial drugs that has been registered in more than 30 countries. The goal of this study is to provide a potential new indication of tulathromycin for Streptococcus suis infections. We investigated the pharmacokinetic and ex vivo pharmacodynamics of tulathromycin against experimental S. suis infection in piglets. Tulathromycin demonstrated a relatively long elimination half-life (74.1 h) and a mean residence time of 97.6 h after a single intramuscular administration. The minimal inhibitory concentration (MIC) and bactericidal concentration in serum were markedly lower than those in broth culture, with Mueller–Hinton broth/serum ratios of 40.3 and 11.4, respectively. The post-antibiotic effects were at 1.27 h (1× MIC) and 2.03 h (4× MIC) and the post-antibiotic sub-MIC effect values ranged from 2.47 to 3.10 h. The ratio of the area under the concentration–time curve divided by the MIC (AUC/MIC) correlated well with the ex vivo antimicrobial effectiveness of tulathromycin (R2 = 0.9711). The calculated AUC12h/MIC ratios in serum required to produce the net bacterial stasis, 1-log10 and 2-log10 killing activities were 9.62, 18.9, and 32.7, respectively. Based on the results of Monte Carlo simulation, a dosage regimen of 3.56 mg/kg tulathromycin was estimated to be effective, achieving for a bacteriostatic activity against S. suis infection over 5 days period. Tulathromycin may become a potential option for the treatment of S. suis infections

Combination therapy strategies against multiple-resistant streptococcus suis

<p>Streptococcus suis is a major swine pathogen, an emerging zoonotic agent responsible for meningitis, endocarditis and septicaemia followed by deafness in humans. The development of antimicrobial resistance in S. suis increases the risk for therapeutic failure in both animals and humans. In this study, we report the synergism of combination therapy against multi-resistant S. suis isolates from swine. Twelve antibiotic profiles were determined against 11 S. suis strains. To investigate their synergistic/antagonistic activity, checkerboard assay was performed for all the possible combinations. In-vitro killing curves and in-vivo treatment trials were used to confirm the synergistic activity of special combinations against S. suis dominant clones. In this study, 11 S. suis isolates were highly resistant to erythromycin, clindamycin, trimethoprim/sulfamethoxazole, and tetracycline with ratios of 80–100%, and the resistance percentages to enrofloxacin, florfenicol, and spectinomycin were ~50%. The checkerboard data identified two combination regimens, ampicillin plus apramycin and tiamulin plus spectinomycin which gave the greatest level of synergism against the S. suis strains. In-vitro kill-curves showed a bacterial reduction of over 3-logCFU with the use of combination treatments, whilst the application of mono-therapies achieve less than a 2-logCFU cell killing. In-vivo models confirm that administration of these two combinations significantly reduced the number of bacterial cells after 24 h of treatment. In conclusions, the combinations of ampicillin plus apramycin and tiamulin plus spectinomycin showed the greatest synergism and may be potential strategies for treatment of multi-resistant S. suis in animal.</p

(E)-Ethyl 2-cyano-3-[4-(4,5-diphenyl-1H-imidazol-2-yl)phen­yl]acrylate dihydrate

In the title compound, C27H21N3O2·2H2O, the three benzene rings attached to the heterocyclic imidazole ring are not coplanar with the latter, making dihedral angles of 14.8 (2), 31.4 (2), and 37.5 (2)°, respectively, for the benzene ring planes in the 2-, 4- and 5-positions. In the crystal, there are two water mol­ecules which serve as connectors between the acrylate mol­ecules and stabilize the structure via N—H⋯O, O—H⋯N, C—H⋯O and O—H⋯O hydrogen bonding