Emergence of dalbavancin non-susceptible, vancomycin-intermediate Staphylococcus aureus (VISA) after treatment of MRSA central line-associated bloodstream infection with a dalbavancin- and vancomycin-containing regimen.

OBJECTIVES: Dalbavancin is a long-acting lipoglycopeptide with activity against gram-positives, including methicillin-resistant Staphylococcus aureus (MRSA). The potential for lipoglycopeptides, with half-lives greater than 1 week, to select for resistance is unknown. Here we explore a case of MRSA central line-associated bloodstream infection in which dalbavancin and vancomycin non-susceptibility emerged in a urine isolate collected after the patient was treated with vancomycin and dalbavancin sequentially. METHODS: Isolates from blood and urine underwent susceptibility testing, and whole genome sequencing (WGS). The blood isolate was subjected to successive passage in vitro in the presence of escalating dalbavancin concentrations and the emergent isolate was subjected to repeat susceptibility testing and WGS. RESULTS: The blood isolate was fully susceptible to vancomycin; however, MICs of the urine isolate to dalbavancin, vancomycin, telavancin, and daptomycin were at least fourfold higher than the blood-derived strain. Both strains were indistinguishable by spa and variable number tandem repeat (VNTR) typing, and WGS revealed only seven variants, indicating clonality. Four variants affected genes, including a 3bp in-frame deletion in yvqF, a gene which has been implicated in glycopeptide resistance. Vancomycin and dalbavancin non-susceptibility emerged in the blood isolate after successive passage in vitro in the presence of dalbavancin, and WGS identified a single non-synonymous variant in yvqF. CONCLUSIONS: This is the first case in which VISA has emerged in the context of a dalbavancin-containing regimen. The selection for cross-resistance to vancomycin in vitro by dalbavancin exposure alone is troubling. Clinicians should be aware of the possibility for emergence of dalbavancin non-susceptibility and glycopeptide cross-resistance arising following therapy.

Effects of zolmitriptan (Zomig) on central serotonergic neurotransmission as assessed by active oddball auditory event-related potentials in volunteers without migraine.

In this randomized, double-blind, three-period crossover trial, 24 healthy volunteers without migraine received zolmitriptan 5 mg, dexfenfluramine 15 mg or placebo orally. At 2, 6, and 24 h postdose, auditory stimuli of 1000 Hz (nontarget tone) and 2000 Hz (target tone) were randomly and binaurally presented in an active oddball paradigm (4:1 ratio). Cortical auditory evoked responses were recorded for 500 msec poststimulus. Plasma concentrations of zolmitriptan and a 17-lead quantitative EEG were assessed at the same timepoints. Relative to placebo, zolmitriptan reduced the maximum absolute amplitude, amplitude difference (from nontarget tone noise) and area under the curve of the cortical auditory target tone event-related potential (P300 ERP). The most dramatic effect of zolmitriptan was to diminish the point estimate of noise during the 200-400 msec poststimulus epoch. The effect of zolmitriptan appeared concentration dependent. The latency of the P300 ERP was unaffected by zolmitriptan and there was no clinically significant effect on the EEG. Modification by zolmitriptan of the cortical electrical activity evoked by auditory stimuli confirms a central action of this drug in humans, which appears to affect cortical information processing without global alteration of the quantitative EEG.