Comparative activity of tedizolid and glycopeptide combination therapies for the treatment of Staphylococcus aureus infections: an in vitro and in vivo evaluation against strains with reduced susceptibility to glycopeptides.

PURPOSE: Glycopeptides are widely used for the treatment of meticillin-resistant Staphylococcus aureus (MRSA) infections. Although difficult to detect, isolates with reduced (GISA), hetero (hGISA) or complete (GRSA) resistance to glycopeptides are increasingly reported. Optimal therapy for such strains is unknown. We compared the in vitro and in vivo activity of tedizolid (TED), a recently licensed oxazolidonone, with vancomycin (VAN) and teicoplanin (TEIC) combined with fusidic acid (FD) or rifampicin (RIF) against S. aureus (SA) with reduced susceptibility to glycopeptides. METHODS: Susceptibility was determined for six (GISA, hGISA and GRSA) reference strains and 72 clinical MRSA isolates screened for hGISA/GISA-like phenotypes. Synergy and bactericidal activity were assessed using chequerboard and time-kill assays. The G. mellonella wax moth caterpillar model was used to measure the activity of TED and the combinations in vivo. RESULTS: Glycopeptide MICs (VAN/TEIC) ranged from 0.5-8/4 and 0.125-1 for TED. No significant synergy was noted when VAN/TEIC were combined with either RIF or FD. Time-kill assays confirmed that TED was bacteriostatic but superior to VAN and TEIC against GISA strains. In G. mellonella TED was more effective than TEIC monotherapy versus GISA strains. The combination of TEIC with RIF was the most effective combination overall, both in vitro and in vivo. CONCLUSIONS: TED had good in vitro activity versus MRSA including those with reduced susceptibility to glycopeptides. Although bacteriostatic, it was effective in the G. mellonella model and superior to TEIC in the treatment of GISA. Although this supports the use of TED for MRSA and GISA, the TEIC/RIF combination also warrants further study.

Rifaximin combined with polymyxins: A potential regimen for selective decontamination of multidrug-resistant bacteria in the digestive tract?

Selective decontamination of the digestive tract (SDD) using combinations of oral non-absorbable antibiotics has been proposed as a means of preventing multidrug-resistant (MDR) infections. The minimum inhibitory concentrations (MICs) of rifaximin (RIFAX) were determined against 262 Gram-negative and Gram-positive bacterial isolates by broth microtitre assay. Rifampicin (RIF) was used as a comparator in the analysis. Synergistic interactions between RIFAX and polymyxin B (PMB) were assessed by using the chequerboard method and calculating the fractional inhibitory concentration index (FICI). The antimicrobial activities of both RIFAX and RIF were similar with little variation in the overall MIC distributions for Gram-negative non-fermenters and Gram-positive bacteria. However, against Enterobacteriaceae higher MICs (>16mg/L) were observed for RIFAX than for RIF (50% vs 27%). Amongst the 262 isolates tested, 100 could be considered resistant to RIFAX. Overall, the combination of RIFAX and PMB was more active against all of the isolates tested compared with either drug alone, with reductions of 2-11 doubling dilutions in individual MICs. Potent synergy was observed with the RIFAX+PMB combination using FICI criteria (FICI range 0.02-0.5). The data presented here suggest that combination therapy may be significantly more effective against isolates with RIFAX and/or PMB resistance and could be considered as part of a SDD regimen aimed at reducing enteric carriage of MDR pathogens in colonised and infected patients.