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.

Optimal detection of carbapenemase-producing Enterobacteriaceae from rectal samples: a role for enrichment?

BACKGROUND: Successful laboratory detection of carbapenemase-producing Enterobacteriaceae (CPE) in patient surveillance samples is a diagnostic challenge. In the absence of a reference standard for screening rectal swabs for CPE, many phenotypic, genotypic, culture- and non-culture-based assays have been proposed for identifying these bacteria. AIM: To develop and optimize a CPE screening protocol capable of identifying all frequently encountered CPE, including those producing OXA-48-like carbapenemases. METHODS: Faropenem susceptibility testing was performed on 507 presumptive CPE isolated from diagnostic samples and CPE rectal screens between March and August 2016. Results from this CPE screening method were compared to those from direct culture on mSuperCARBA™, temocillin enrichment culture, and use of an antibiotic resistance algorithm, to determine the optimal method to employ in the detection of CPE. FINDINGS: Faropenem was a poor predictor of carbapenemase production (58% true positives). The combination of a temocillin enrichment stage and interpretive reading of antibiotic resistance phenotypes improved the recovery and identification of CPE significantly (91% true positives), especially for OXA-48 producers (P = 0.03). CONCLUSION: The combination of temocillin enrichment, a selective chromogenic medium, and an antibiotic resistance-based algorithm significantly improved the detection of all CPE recovered from routine and targeted surveillance samples.

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.

Activity of colistin in combination with tigecycline or rifampicin against multidrug-resistant Stenotrophomonas maltophilia.

The antimicrobial treatment of Stenotrophomonas maltophilia infections is complicated by intrinsic multidrug resistance and a lack of reliable susceptibility data. We assessed the activity of colistin (COL), rifampicin (RIF) and tigecycline (TGC) alone and in combination using a range of in vitro susceptibility testing methodologies and a simple invertebrate model of S. maltophilia infection (Galleria mellonella). Synergy [fractional inhibitory concentration indices (FICIs) ≤0.5] between COL and either RIF or TGC was observed against 92 % and 88 % of 25 S. maltophilia isolates, respectively, despite resistance to one or another of the single agents alone. In time-kill assays, COL combined with either RIF or TGC was superior to single agents, but only the COL/RIF regimen was reliably bactericidal. The in vitro findings correlated with treatment outcomes in G. mellonella, with heightened survival observed for larvae treated with COL/RIF or COL/TGC compared with COL, RIF or TGC alone. COL combined with RIF was the most effective combination overall in both in vitro and in vivo (p < 0.05) assays. Given the difficulty in selecting appropriate therapy for S. maltophilia infections, regimens consisting of COL combined with RIF or TGC could be considered for clinical use.

In vitro activity of daptomycin in combination with low-dose colistin against a diverse collection of Gram-negative bacterial pathogens.

The activity of colistin in combination with daptomycin was assessed using 30 Gram-negative type strains and multidrug-resistant isolates with defined mechanisms of resistance. Daptomycin minimum inhibitory concentrations (MICs) were determined with and without sub-inhibitory concentrations of colistin. The activity of daptomycin was not affected with respect to Escherichia coli, Klebsiella pneumoniae or Pseudomonas aeruginosa. For colistin-susceptible Acinetobacter baumannii, sensitisation factors ranged from 8 to 128 (median 32), with the daptomycin MIC being reduced to the Clinical and Laboratory Standards Institute (CLSI) enterococci susceptibility breakpoint of 4 µg/ml for the ATCC 19606 type strain. A combination of daptomycin and colistin may be useful for the treatment of A. baumannii but not infections due to other Gram-negative species.

Master-slave robotic system for therapeutic gastrointestinal endoscopic procedures.

Flexible endoscopy is used to inspect and treat disorders of the gastrointestinal (GI) tract without the need for creating an artificial opening on the patient's body. Simple surgical procedures (like polypectomy and biopsy) can be performed by introducing a flexible tool via a working channel to reach the site of interest at the distal end. More technically demanding surgical procedures like hemostasis for arterial bleeding, or suturing to mend a perforation cannot be effectively achieved with flexible endoscopy. The proposed robotic system enables the endoscopist to perform technically demanding therapeutic procedures (currently possible only with open surgery) in conjunction with conventional flexible endoscopes. The robotic system consists of a master console and a slave. The latter is a cable driven flexible robotic manipulator that can be inserted into tool channel of existing endoscopes or attached in tandem to the endoscopes. Together with the real time endoscopic view, the endoscopist would be capable of performing more intricate and difficult surgical procedures.