Movement Disorders Secondary to Novel Antiseizure Medications in Pediatric Populations: A Systematic Review and Meta-analysis of Risk.

Novel antiseizure medications are thought to be safer than their conventional counterparts, though no dedicated analysis of movement disorder risk among pediatric populations using novel antiseizure medications has been completed. We report a systematic review with meta-analysis describing the relationship between novel antiseizure medications and movement disorders in pediatrics.MEDLINE, EMBASE, and the World Health Organization's International Clinical Trials Registry Platform were searched up to October 2020 for randomized controlled trials investigating novel antiseizure medications in pediatric populations. Antiseizure medications included lacosamide, perampanel, eslicarbazepine, rufinamide, fenfluramine, cannabidiol, and brivaracetam. Outcomes were pooled using random effects models; risk difference (RD) and 95% confidence intervals (CIs) were calculated.Twenty-three studies were selected from 1690 nonredundant manuscripts (n = 1912 total). There was a significantly increased risk of movement disorders associated with perampanel (RD 0.07, 95% CI 0.01-0.13; n = 133), though only 1 relevant trial was found. No increased risk of movement disorders was found with other antiseizure medications.Our findings indicate most novel antiseizure medications are safe to use in pediatric populations with respect to movement disorders. However, findings were limited by quality of adverse event reporting.

The Global Regulatory Cyclic AMP Receptor Protein (CRP) Controls Multifactorial Fluoroquinolone Susceptibility in Salmonella enterica Serovar Typhimurium.

Fluoroquinolone antibiotics are prescribed for the treatment of Salmonella enterica infections, but resistance to this family of antibiotics is growing. Here we report that loss of the global regulatory protein cyclic AMP (cAMP) receptor protein (CRP) or its allosteric effector, cAMP, reduces susceptibility to fluoroquinolones. A Δcrp mutation was synergistic with the primary fluoroquinolone resistance allele gyrA83, thus able to contribute to clinically relevant resistance. Decreased susceptibility to fluoroquinolones could be partly explained by decreased expression of the outer membrane porin genes ompA and ompF with a concomitant increase in the expression of the ciprofloxacin resistance efflux pump gene acrB in Δcrp cells. Expression of gyrAB, which encode the DNA supercoiling enzyme GyrAB, which is blocked by fluoroquinolones, and expression of topA, which encodes the dominant supercoiling-relaxing enzyme topoisomerase I, were unchanged in Δcrp cells. Yet Δcrp cells maintained a more relaxed state of DNA supercoiling, correlating with an observed increase in topoisomerase IV (parCE) expression. Surprisingly, the Δcrp mutation had the unanticipated effect of enhancing fitness in the presence of fluoroquinolone antibiotics, which can be explained by the observation that exposure of Δcrp cells to ciprofloxacin had the counterintuitive effect of restoring wild-type levels of DNA supercoiling. Consistent with this, Δcrp cells did not become elongated or induce the SOS response when challenged with ciprofloxacin. These findings implicate the combined action of multiple drug resistance mechanisms in Δcrp cells: reduced permeability and elevated efflux of fluoroquinolones coupled with a relaxed DNA supercoiling state that buffers cells against GyrAB inhibition by fluoroquinolones.