Observational and experimental studies of drug treatment of infection and myocardial infarction/depression in a hospital in St Petersburg

Abstract: Introduction: Treatment of infectious and cardiac diseases represents subjects of great concern for health care all over the world, e.g. in Russia. Major problems may occur in routine use of the drugs that need to be timely considered. Different methodological approaches may be utilized to investigate and constrain the problems depending on its character. Aims: To: (I) test a method of combining routine aggregate antibiotic utilization and resistance data from two different sources as a quality of antibiotic use indicator; (II) assess occurrence and clinical importance of the beta-blocker metoprolol and the antidepressant paroxetine interaction in patients with acute myocardial infarction and depression. Methods: (I) We applied the ATC/DDD methodology on antibacterials for systemic use (ATC: J01) delivered by St Petersburg City hospital N2 pharmacy for the years 2003-2005. Microbial resistance data obtained from the microbiology department were presented within the range of drugs accounting for 90% of the volume in DDDs (the Drug Utilization 90% - DU90% segment). Antibiotic utilization quality was assessed and changes were followed. (II) All consecutive AMI patients receiving metoprolol on clinical grounds were screened for depressive symptoms. Those, in whom depression was diagnosed and paroxetine was prescribed for its management, were genotyped for CYP2D6'3,'4, and gene duplication. Metoprolol and α-hydroxy metoprolol concentrations were measured in blood; heart rate (HR) and blood pressure (BP) changes were registered concomitantly during one dosing interval after steady state concentrations were achieved and repeatedly after a week of paroxetine treatment with additional measurement of paroxetine concentrations. Results: (I) In 2003, 12 of 25 antibiotics accounted for 90% of all antibiotic DDDs. For six of the most commonly used antibiotics a significant part of the strains tested were resistant, including the two cheapest drugs (gentamicine, ampicillin). No resistance data were available for the remaining antibiotics. These data were presented and discussed in early 2004. A general decrease of antibiotic use and resistance was subsequently seen in 2005 with a concomitant decrease in expenditures. (II) Among 115 AMI patients receiving metoprolol routinely, twenty six patients (23%) were depressed and seventeen were prescribed paroxetine (all were genotypically extensive metabolizers (EMs)). After paroxetine administration mean metoprolol areas under concentration-time curve (AUC) increased (1064±1213 to 4476±2821 nM'h/mg/kg, p=0.0001), while metabolite AUCs decreased (1492±872 to 348±279 nM'h/mg/kg, p <0.0001). Mean area under HR versus time curve decreased (835±88 to 728±84 beats'h/min; p= 0.0007). Metoprolol AUCs correlated with patients areas under effect curve (AUEC) at the baseline (Spearman r = -0,64, p<0,01), but not on the 8th day of the study. Reduction of metoprolol dose was required in two patients due to excessive bradycardia and severe orthostatic hypotension. Conclusion: The thesis supports the notion that different methods observational for antibiotic hospital use and experimental for AMI medicines interaction can be effectively utilized in close relation to clinical practice in order to ensure safe and effective drug use.