Safety and efficacy of fluoxetine on functional outcome after acute stroke (AFFINITY): a randomised, double-blind, placebo-controlled trial

Background Trials of fluoxetine for recovery after stroke report conflicting results. The Assessment oF FluoxetINe In sTroke recoverY (AFFINITY) trial aimed to show if daily oral fluoxetine for 6 months after stroke improves functional outcome in an ethnically diverse population. Methods AFFINITY was a randomised, parallel-group, double-blind, placebo-controlled trial done in 43 hospital stroke units in Australia (n=29), New Zealand (four), and Vietnam (ten). Eligible patients were adults (aged ≥18 years) with a clinical diagnosis of acute stroke in the previous 2–15 days, brain imaging consistent with ischaemic or haemorrhagic stroke, and a persisting neurological deficit that produced a modified Rankin Scale (mRS) score of 1 or more. Patients were randomly assigned 1:1 via a web-based system using a minimisation algorithm to once daily, oral fluoxetine 20 mg capsules or matching placebo for 6 months. Patients, carers, investigators, and outcome assessors were masked to the treatment allocation. The primary outcome was functional status, measured by the mRS, at 6 months. The primary analysis was an ordinal logistic regression of the mRS at 6 months, adjusted for minimisation variables. Primary and safety analyses were done according to the patient's treatment allocation. The trial is registered with the Australian New Zealand Clinical Trials Registry, ACTRN12611000774921. Findings Between Jan 11, 2013, and June 30, 2019, 1280 patients were recruited in Australia (n=532), New Zealand (n=42), and Vietnam (n=706), of whom 642 were randomly assigned to fluoxetine and 638 were randomly assigned to placebo. Mean duration of trial treatment was 167 days (SD 48·1). At 6 months, mRS data were available in 624 (97%) patients in the fluoxetine group and 632 (99%) in the placebo group. The distribution of mRS categories was similar in the fluoxetine and placebo groups (adjusted common odds ratio 0·94, 95% CI 0·76–1·15; p=0·53). Compared with patients in the placebo group, patients in the fluoxetine group had more falls (20 [3%] vs seven [1%]; p=0·018), bone fractures (19 [3%] vs six [1%]; p=0·014), and epileptic seizures (ten [2%] vs two [<1%]; p=0·038) at 6 months. Interpretation Oral fluoxetine 20 mg daily for 6 months after acute stroke did not improve functional outcome and increased the risk of falls, bone fractures, and epileptic seizures. These results do not support the use of fluoxetine to improve functional outcome after stroke

Impact of metronidazole on Clostridioides difficile, possible consequences for the efficacy of the treatment of infections and optimization of this antibiotic administration by a targeted delivery system.

Clostridioides difficile est une bactérie anaérobie stricte, responsable de divers symptômes intestinaux allant de la diarrhée légère à la colite pseudomembraneuse sévère. Les infections à C. difficile sont devenues un problème majeur de santé publique en raison de leur gravité et de leur incidence croissante. Le métronidazole (MTZ) a été le traitement de première intention des infections légères à modérées liées à C. difficile pendant environ 30 ans. Cependant, plusieurs études cliniques ont montré que les taux d'échec clinique et de récidive du MTZ étaient supérieurs à la vancomycine. En conséquence, la mise à jour en 2018 des lignes directrices américaines et européennes ont recommandé le MTZ uniquement comme alternative à la vancomycine ou à la fidaxomicine, pour une infection initiale non sévère. Nos objectifs étaient d’étudier l’impact du métronidazole sur Clostridioides difficile, d’évaluer les conséquences possibles sur l’efficacité du traitement des infections et enfin d’optimiser l’administration de cet antibiotique par un système de libération ciblée au niveau colique, site de l’infection. Pour cela, dans un premier temps, nous avons étudié l'impact de concentrations sub-inhibitrices de MTZ sur C. difficile, in vitro sur la morphologie, la motilité, la formation de biofilm, l'adhésion sur des cellules intestinales TC7, ainsi que les protéomes et in vivo sur le processus de colonisation dans deux modèles murins. Ces études ont été réalisées avec deux souches de C. difficile la souche VPI 10463 sensible et la souche CD17-146 de sensibilité diminuée au MTZ. Pour la souche CD17-146, les concentrations sub-inhibitrices de MTZ ont induit un allongement cellulaire, la formation d’un biofilm plus épais, une meilleure adhésion sur les cellules TC7 et un niveau de colonisation plus élevé dans les modèles murins comparativement à la souche VPI10463. Compte tenu des faibles concentrations fécales de MTZ, nos résultats suggèrent que des bactéries exposées à des concentrations sub-inhibitrices de MTZ développent des stratégies d'adaptation qui sont souches dépendantes. Dans un second temps, nous avons développé un système d'encapsulation du MTZ fondé sur l’utilisation d’une émulsion multiple et de la coacervation afin d’obtenir un taux d’encapsulation élevé et une libération optimale de cet antibiotique au niveau du site infectieux.Lostridioides difficile is a strictly anaerobic bacterium responsible for a variety of intestinal symptoms ranging from mild diarrhea to severe pseudomembranous colitis. C. difficile infections have become a major public health problem due to their severity and increasing incidence. Metronidazole (MTZ) has been the first-line treatment for mild to moderate C. difficile infections for approximately 30 years. However, several clinical studies have shown that the rates of clinical failure and recurrence of MTZ are higher than vancomycin. As a result, the 2018 update of the US and European guidelines recommended MTZ only as an alternative to vancomycin or fidaxomicin, for an initial non-severe infection. Our objectives were to study the impact of metronidazole on Clostridioides difficile, to assess the possible consequences on the effectiveness of the treatment of infections and finally to optimize the administration of this antibiotic by a targeted delivery system at the colic level, site of infection. To do this, we first studied the impact of sub-inhibitory concentrations of MTZ on C. difficile, in vitro, on morphology, motility, biofilm formation, adhesion on intestinal TC7 cells, as well as as proteomes and in vivo on the colonization process in two mouse models. These studies were carried out with two strains of C. difficile, the susceptible strain VPI 10463 and the strain CD17-146 with reduced susceptibility to MTZ. For strain CD17-146, sub-inhibitory concentrations of MTZ induced cell lengthening, thicker biofilm formation, better adhesion to TC7 cells, and a higher level of colonization in mouse models compared to strain VPI10463. Given the low fecal concentrations of MTZ, our results suggest that bacteria exposed to sub-inhibitory concentrations of MTZ develop adaptation strategies that are strain dependent. Secondly, we developed a MTZ encapsulation system based on the use of a multiple emulsion and coacervation in order to obtain a high level of encapsulation and an optimal release of this antibiotic at the level of the infectious site

Impact of Subinhibitory Concentrations of Metronidazole on Morphology, Motility, Biofilm Formation and Colonization of Clostridioides difficile

Clostridioides difficile infection (CDI) is the primary cause of health-care-associated infectious diarrhea. Treatment requires mostly specific antibiotics such as metronidazole (MTZ), vancomycin or fidaxomicin. However, approximately 20% of treated patients experience recurrences. Treatment with MTZ is complicated by reduced susceptibility to this molecule, which could result in high failure and recurrence rates. However, the mechanism remains unclear. In this study, we investigated the impact of subinhibitory concentrations of MTZ on morphology, motility, biofilm formation, bacterial adherence to the intestinal Caco-2/TC7 differentiated monolayers, and colonization in monoxenic and conventional mouse models of two C. difficile strains (VPI 10463 and CD17-146), showing different susceptibility profiles to MTZ. Our results revealed that in addition to the inhibition of motility and the downregulation of flagellar genes for both strains, sub-inhibitory concentrations of MTZ induced various in vitro phenotypes for the strain CD17-146 exhibiting a reduced susceptibility to this antibiotic: elongated morphology, enhanced biofilm production and increased adherence to Caco-2/TC7 cells. Weak doses of MTZ induced higher level of colonization in the conventional mouse model and a trend to thicker 3-D structures entrapping bacteria in monoxenic mouse model. Thus, sub-inhibitory concentrations of MTZ can have a wide range of physiological effects on bacteria, which may contribute to their persistence after treatment

Impact of subinhibitory concentrations of metronidazole on proteome of Clostridioides difficile strains with different levels of susceptibility

International audienceClostridioides difficile is responsible for various intestinal symptoms from mild diarrhea to severe pseudomembranous colitis and is the primary cause of antibiotic-associated diarrhea in adults. Metronidazole was the first-line treatment for mild to moderate C . difficile infections for 30 years. However, clinical failure and recurrence rates of metronidazole is superior to oral vancomycin and metronidazole is now recommended only as an alternative to vancomycin or fidaxomicin, for an initial non-severe infection. The mechanisms of treatment failure and infection recurrence remain unclear. Given the poor fecal concentrations of metronidazole, the bacteria may be exposed to subinhibitory concentrations of metronidazole and develop adaptation strategy, which is likely to be the origin of an increase in treatment failures. In this study, a proteomic approach was used to analyze changes in the proteome of two strains with different levels of susceptibility to metronidazole in the presence of subinhibitory concentrations of this antibiotic. The two strains were grown to stationary phase: CD17-146, a clinical C . difficile isolate with reduced susceptibility to metronidazole, and VPI 10463, a metronidazole susceptible strain. Our study revealed that, whatever the strain, subinhibitory concentrations of metronidazole modified the amount of proteins involved in protein biosynthesis, glycolysis, and protection against stress induced by metronidazole, as well as in DNA repair. Several proteins involved in stress response are known to be synthesized under the control of Sigma factor B, which suggests a close link between Sigma factor B and metronidazole. Interestingly, impact of metronidazole on protein production for VPI 10463 strain differed from CD17-146 strain, for which the amount of two proteins involved in biofilm formation of CD17-146 were modified by metronidazole

2,4‐Disubstituted 5‐Nitroimidazoles Potent against Clostridium difficile

International audienc

Twelve-Month Outcomes of the AFFINITY Trial of Fluoxetine for Functional Recovery After Acute Stroke: AFFINITY Trial Steering Committee on Behalf of the AFFINITY Trial Collaboration

Background and Purpose: The AFFINITY trial (Assessment of Fluoxetine in Stroke Recovery) reported that oral fluoxetine 20 mg daily for 6 months after acute stroke did not improve functional outcome and increased the risk of falls, bone fractures, and seizures. After trial medication was ceased at 6 months, survivors were followed to 12 months post-randomization. This preplanned secondary analysis aimed to determine any sustained or delayed effects of fluoxetine at 12 months post-randomization. Methods: AFFINITY was a randomized, parallel-group, double-blind, placebo-controlled trial in adults (n=1280) with a clinical diagnosis of stroke in the previous 2 to 15 days and persisting neurological deficit who were recruited at 43 hospital stroke units in Australia (n=29), New Zealand (4), and Vietnam (10) between 2013 and 2019. Participants were randomized to oral fluoxetine 20 mg once daily (n=642) or matching placebo (n=638) for 6 months and followed until 12 months after randomization. The primary outcome was function, measured by the modified Rankin Scale, at 6 months. Secondary outcomes for these analyses included measures of the modified Rankin Scale, mood, cognition, overall health status, fatigue, health-related quality of life, and safety at 12 months. Results: Adherence to trial medication was for a mean 167 (SD 48) days and similar between randomized groups. At 12 months, the distribution of modified Rankin Scale categories was similar in the fluoxetine and placebo groups (adjusted common odds ratio, 0.93 [95% CI, 0.76–1.14]; P =0.46). Compared with placebo, patients allocated fluoxetine had fewer recurrent ischemic strokes (14 [2.18%] versus 29 [4.55%]; P =0.02), and no longer had significantly more falls (27 [4.21%] versus 15 [2.35%]; P =0.08), bone fractures (23 [3.58%] versus 11 [1.72%]; P =0.05), or seizures (11 [1.71%] versus 8 [1.25%]; P =0.64) at 12 months. Conclusions: Fluoxetine 20 mg daily for 6 months after acute stroke had no delayed or sustained effect on functional outcome, falls, bone fractures, or seizures at 12 months poststroke. The lower rate of recurrent ischemic stroke in the fluoxetine group is most likely a chance finding. REGISTRATION: URL: http://www.anzctr.org.au/ ; Unique identifier: ACTRN12611000774921