Synergy between phenothiazines and oxacillin against clinical isolates of methicillin-resistant <i>Staphylococcus aureus</i>

Abstract

Purpose: To evaluate the antimicrobial and resistance-reversal activities of seven phenothiazine derivatives against one standard methicillin-sensitive and ten methicillin-resistant Staphylococcus aureus (MRSA) strains originating from human infections. Methods: Minimum inhibitory concentrations (MIC) of the compounds were determined by agar dilution method, and synergy between phenothiazines and oxacillin was investigated using Checkerboard (microbroth dilution) technique. Results: We found that all S. aureus strains, regardless of their susceptibility to oxacillin, were inhibited by phenothiazines at a concentration of 8 -256 µg/mL, with thioridazine being the most potent inhibitory agent. Phenothiazines at sub-inhibitory concentrations lowered the MIC of oxacillin from 256 to 2 µg/mL, which is a clinically significant level. The highest number of synergistic combinations, i.e., fractional inhibitory concentration (FIC) index less than 0.5, was seen with chlorpromazine and perphenazine. However, thioridazine reversed antibiotic resistance at a concentration as low as 4 µg/mL. Conclusion: Although synergy was observed at concentrations higher than those that phenothiazines usually attain in vivo, the potential offered by non-antibiotics justifies further animal experiments as well as clinical trials to establish their clinical relevance.

Antibacterial Activity of Trifluoperazine; In Vitro Susceptibility of Mrsa Staphylococcus Aureus, Pseudomonas Aeruginosa and E. Coli, and in Vivo Evaluation Against Methicillin Resistant Staphylococcus Aureus in Surgical Wound Infection Model

“…Regarding zones of growth inhibition against MRSA, trifluoperazine produced 0, 13, 18-and 26-mm zone of growth inhibition at 25, 50, 75 and 100 µg/disc potency respectively. These findings are in line with the studies conducted previously (Hadji-nejad et al, 2010 andAmaral et al, 2004). This antimicrobial activity of trifluoperazine against this MRSA isolate is attributed to property of phenothiazine to inhibit ABC type efflux pumps that account for the antibiotic resistance of the organism.…”

“…MICs determined against the said isolates were 50µg/ml for MRSA and P. aeruginosa, whereas it was 100 µg/ml for E. coli. This MICs obtained for trifluoperazine are in line with the studies conducted previously (Hadji-nejad et al, 2010;Advani et al, 2012).…”

Thioridazine affects transcription of genes involved in cell wall biosynthesis in methicillin-resistant Staphylococcus aureus

“…We have previously shown that thioridazine can reverse resistance to oxacillin (a methicillin analogue), if the two drugs are used in combination against MRSA in vitro (Klitgaard et al ., 2008). This synergy, which restores susceptibility to oxacillin, has been confirmed in 10 clinical isolates by others (Hadji‐nejad et al ., 2010). Thioridazine is a phenothiazine derivate, which has been shown to have therapeutic applications in problematic infections caused by antibiotic‐resistant bacteria (Amaral et al ., 2004).…”

Evaluating the Performance of the Location-Aided Routing-1p Route Discovery Algorithm

“…Such as the LAR-1 algorithm (Hnatyshin, 2013;Husain et al, 2010;Deb et al, 2009) and probabilistic broadcast (Hadji-nejad et al, 2010;Nand and Sharma, 2012;Al-Bahadili, 2010a;AlBahadili and Kaabneh, 2010).…”

“…The performance of the new model was compared against pure and probabilistic algorithms. Hadji-nejad et al (2010) introduced a routing scheme for MANETs, which works well under a wide range of network topologies, nodes-density, coverage area size Science Publications JCS and nodes-mobility. The scheme is based on a novel enhancement of the hint-based probabilistic protocol.…”