Tramadol versus codeine and the short-term risk of cardiovascular events in patients with non-cancer pain: A population-based cohort study.

AIMS: The effect of tramadol on the cardiovascular system is largely unknown. There is concern that, with its multimodal mechanism of action to increase serotonin and norepinephrine levels in the body, it could increase the risk of arterial ischaemia and cardiovascular events. We aimed to compare the short-term risk of cardiovascular events with the use of tramadol to that of codeine among patients with non-cancer pain. METHODS: We conducted a retrospective population-based cohort study using data from the Clinical Practice Research Datalink (CPRD) with new users of tramadol or codeine from April 1998 to March 2017. Exposure was defined using an approach analogous to an intention-to-treat, with a maximum follow-up of 30 days. The primary endpoint was myocardial infarction, and secondary endpoints were unstable angina, ischaemic stroke, coronary revascularization, cardiovascular death and all-cause mortality. Hazard ratios (HRs) were estimated using Cox proportional hazards models, adjusted for high-dimensional propensity score. RESULTS: The final cohort included 123 394 tramadol users and 914 333 codeine users. When tramadol was compared to codeine, the adjusted hazard ratio (HR) of myocardial infarction was 1.00 (95% CI 0.81-1.24). There was also no evidence of elevated risks of unstable angina (0.92; 95% CI 0.67-1.27), ischaemic stroke (0.98; 95% CI 0.82-1.17), coronary revascularization (0.97; 95% CI 0.69-1.38), cardiovascular death (1.07; 95% CI 0.93-1.23) or all-cause mortality (1.03; 95% CI 0.94-1.14) when tramadol was compared to codeine. CONCLUSIONS: Short-term use of tramadol, compared with codeine, was not associated with an increased risk of cardiac events among patients with non-cancer pain.

Domperidone and the risks of sudden cardiac death and ventricular arrhythmia: A systematic review and meta-analysis of observational studies.

AIMS: Concerns exist regarding the cardiovascular safety of domperidone. However, many of the previous studies addressing this issue had important limitations. We aimed to examine domperidone and the risks of sudden cardiac death and ventricular arrhythmia through a systematic review and meta-analysis of observational studies, including an in-depth methodological assessment. METHODS: We systematically searched MEDLINE, PubMed, EMBASE, Scopus and CINAHL Plus to identify observational studies examining the association of domperidone and sudden cardiac death and/or ventricular arrhythmia. We assessed study quality in duplicate using the ROBINS-I tool supplemented by an assessment of specific biases and the GRADE (Grading of Recommendations, Assessment, Development and Evaluations) approach. Data were pooled across studies using DerSimonian and Laird random-effects models. RESULTS: Six case-control studies, 1 case-crossover study and 1 retrospective cohort study were included (n = 480 395). Based on ROBINS-I, 3 studies had moderate risk of bias, 4 had serious risk, and 1 had critical risk. The overall GRADE rating is moderate. When data were pooled across nonoverlapping studies, domperidone was associated with an increased risk of composite endpoint of sudden cardiac death or ventricular arrhythmia compared to nonuse (adjusted odds ratio: 1.69; 95% confidence interval: 1.46, 1.95; I2 : 0%; τ2 : 0). This association persisted when restricted to higher-quality studies (odds ratio: 1.60; 95% confidence interval: 1.30, 1.97; I2 : 0%; τ2 : 0). CONCLUSION: Domperidone is associated with an increased risk of sudden cardiac death and ventricular arrhythmia compared to nonuse. Further investigation comparing domperidone to an active comparator and in younger populations are warranted.

Fosfomycin Susceptibility in Multidrug-Resistant Enterobacteriaceae Species and Vancomycin-Resistant Enterococci Urinary Isolates.

BACKGROUND: Broad-spectrum antibiotics are often used to treat urinary tract infections (UTIs) due to drug-resistant species of Enterobacteriaceae and Enterococcus (e.g., organisms producing extended-spectrum ß-lactamase [ESBL] or AmpC ß-lactamase, as well as vancomycin-resistant enterococci [VRE]). However, this type of therapy can promote selection of resistant organisms and may necessitate venous access. Fosfomycin is an orally administered, single-dose antibiotic for the treatment of uncomplicated UTI. Little is known about its microbiologic activity against urinary isolates, including in southwestern Ontario, since fosfomycin susceptibility testing is not routinely performed. OBJECTIVE: To explore a cost-effective alternative for the treatment of lower UTIs caused by multidrug-resistant Enterobacteriaceae and VRE organisms resistant to usual first-line therapies by determining fosfomycin susceptibility rates. METHODS: Urinary isolates were collected prospectively from November 2015 to April 2016 at 3 hospitals in southwestern Ontario. Susceptibility testing was completed according to guidelines of the Clinical and Laboratory Standards Institute, with interpretation by zone of inhibition (as diameter in millimetres). Patients 18 years of age or older with isolation of multidrug-resistant Enterobacteriaceae or VRE were eligible for inclusion. Urinary isolates from these patients were subjected to susceptibility testing. The primary outcome was the rate of fosfomycin susceptibility of these isolates. RESULTS: A total of 137 urinary isolates were tested: 106 positive for ESBL-or AmpC ß-lactamase-producing Enterobacteriaceae (95 Escherichia coli, 11 Klebsiella spp.) and 31 positive for vancomycin-resistant Enterococcus faecium. Susceptibility rates for ESBL- and AmpC ß-lactamase-producing E. coli were 100% for ertapenem, 96% for fosfomycin, 83% for nitrofurantoin, 72% for gentamicin, 56% for trimethoprim-sulfamethoxazole, and 14% for ciprofloxacin. Susceptibility rates of vancomycin-resistant E. faecium urinary isolates were 100% for linezolid, 81% for fosfomycin, 68% for tetracycline, 6% for ampicillin, 3% for penicillin, and 0% for both nitrofurantoin and ciprofloxacin. CONCLUSION: Given susceptibility rates at the study institutions, fosfomycin was deemed the most reliable oral option for the treatment of lower UTI in patients with suspected or documented multidrug-resistant uropathogens.

CONTEXTE: Les antibiotiques à large spectre sont souvent employés pour traiter les infections urinaires causées par des espèces d'entérobactériacées et d'Enterococcus résistantes aux médicaments (par exemple, des organismes qui produisent des ß-lactamases à spectre étendu [BLSE] ou des ß-lactamases AmpC de même que des entérocoques résistants à la vancomycine [ERV]). Or, ce type de traitement peut favoriser la sélection d'organismes résistants et peut nécessiter un accès veineux. La fosfomycine est un antibiotique oral à dose unique servant au traitement d'infections urinaires non compliquées. On connaît peu de choses sur son activité microbiologique contre les isolats urinaires, en l'occurrence dans le sud-ouest de l'Ontario, car on ne teste pas systématiquement la fosfomycine dans les antibiogrammes. OBJECTIF: Chercher une solution ayant un bon rapport coût-efficacité pour le traitement des infections urinaires basses causées par des espèces d'entérobactériacées multirésistantes aux antibiotiques et des ERV qui ne répondent pas aux traitements de première intention normalement utilisés en déterminant les degrés de sensibilité à l'égard de la fosfomycine. MÉTHODES: Des isolats urinaires ont été recueillis de façon prospective entre novembre 2015 et avril 2016 dans trois hôpitaux du sud-ouest de l'Ontario. Des antibiogrammes ont été réalisés selon les lignes directrices du Clinical and Laboratory Standards Institute, et l'interprétation était fondée sur la zone d'inhibition (soit le diamètre en millimètres). Les patients de 18 ans et plus chez qui on avait isolé des entérobactériacées ou des ERV multirésistants aux antibiotiques étaient admissibles à l'étude. Les isolats urinaires provenant de ces patients étaient soumis à un antibiogramme. Le principal paramètre d'évaluation était le taux de sensibilité à la fosfomycine des isolats urinaires. RÉSULTATS: Au total, 137 isolats urinaires ont été testés; 106 étaient positifs pour des espèces d'entérobactériacées produisant des BLSE ou des ß-lactamases AmpC (95 Escherichia coli, 11 espèces de Klebsiella) et 31 étaient positifs pour l'Enterococcus faecium résistant à la vancomycine. Les taux de sensibilité d'E. coli produisant des BLSE et des ß-lactamases AmpC étaient de 100 % pour l'ertapénem, 96 % pour la fosfomycine, 83 % pour la nitrofurantoïne, 72 % pour la gentamicine, 56 % pour le co-trimoxazole et 14 % pour la ciprofloxacine. Les taux de sensibilité pour les isolats urinaires d'Enterococcus faecium résistant à la vancomycine étaient de 100 % pour le linézolide, 81 % pour la fosfomycine, 68 % pour la tétracycline, 6 % pour l'ampicilline, 3 % pour la pénicilline et 0 % pour la nitrofurantoïne et la ciprofloxacine. CONCLUSION: En raison des taux de sensibilité obtenus aux établissements à l'étude, la fosfomycine a été jugée comme le médicament oral le plus fiable pour le traitement des infections urinaires basses chez les patients pour lesquels la présence d'uropathogènes multirésistants aux antibiotiques est soupçonnée ou connue.