Long-Term Carbapenems Antimicrobial Stewardship Program.

OBJECTIVE: To evaluate clinical and antibiotic resistance impact of carbapenems stewardship programs. METHODS: descriptive study, pre-post-intervention, between January 2012 and December 2019; 350-bed teaching hospital. Prospective audit and feedback to prescribers was carried out between January 2015 and December 2019. We evaluate adequacy of carbapenems prescription to local guidelines and compare results between cases with accepted or rejected intervention. Analysis of antibiotic-consumption and hospital-acquired multidrug-resistant (MDR) bloodstream infections (BSIs) was performed. RESULTS: 1432 patients were followed. Adequacy of carbapenems prescription improved from 49.7% in 2015 to 80.9% in 2019 (p < 0.001). Interventions on prescription were performed in 448 (31.3%) patients without carbapenem-justified treatment, in 371 intervention was accepted, in 77 it was not. Intervention acceptance was associated with shorter duration of all antibiotic treatment and inpatient days (p < 0.05), without differences in outcome. During the period 2015-2019, compared with 2012-2014, decreased meropenem consumption (Rate Ratio 0.58; 95%CI: 0.55-0.63), candidemia and hospital-acquired MDR BSIs rate (RR 0.62; 95%CI: 0.41-0.92, p = 0.02), and increased cefepime (RR 2; 95%CI: 1.77-2.26) and piperacillin-tazobactam consumption (RR 1.17; 95%CI: 1.11-1.24), p < 0.001. CONCLUSIONS: the decrease and better use of carbapenems achieved could have clinical and ecological impact over five years, reduce inpatient days, hospital-acquired MDR BSIs, and candidemia, despite the increase in other antibiotic-consumption.

A multicentre prospective study evaluating the impact of proton-pump inhibitors omeprazole and pantoprazole on voriconazole plasma concentrations.

Voriconazole is an antifungal metabolised by CYP2C19 enzyme, which can be inhibited by proton-pump inhibitors (PPIs). A prospective observational study was carried out to determine the influence of PPIs on voriconazole pharmacokinetic. The 78 patients included were divided into 4 groups: omeprazole (n = 32), pantoprazole (n = 25), esomeprazole (n = 3) and no PPI (n = 18). Patients with no PPI had no significant difference in plasma voriconazole concentration when compared with those with PPI (2.63 ± 2.13 µg/mL [95% confidence interval {CI} 1.57-3.69] vs 2.11 ± 1.73 µg/mL [95%CI 1.67-2.55], P > .05). However, voriconazole plasma concentration was significantly lower in patients treated with pantoprazole vs those treated with omeprazole (1.44 ± 1.22 µg/mL [95%CI 0.94-1.94) vs 2.67 ± 1.88 µg/mL [95%CI 2.02-3.32], P = .013) suggesting a greater CYP2C19 enzyme inhibitory effect of omeprazole. This study demonstrates the greater CYP inhibition capacity of omeprazole and should be helpful for the choice of PPIs for patients treated with voriconazole.

Impact of CYP2C19 Genotype and Drug Interactions on Voriconazole Plasma Concentrations: A Spain Pharmacogenetic-Pharmacokinetic Prospective Multicenter Study.

BACKGROUND: Voriconazole, a first-line agent for the treatment of invasive fungal infections, is mainly metabolized by cytochrome P450 (CYP) 2C19. A significant portion of patients fail to achieve therapeutic voriconazole trough concentrations, with a consequently increased risk of therapeutic failure. OBJECTIVE: To show the association between subtherapeutic voriconazole concentrations and factors affecting voriconazole pharmacokinetics: CYP2C19 genotype and drug-drug interactions. METHODS: Adults receiving voriconazole for antifungal treatment or prophylaxis were included in a multicenter prospective study conducted in Spain. The prevalence of subtherapeutic voriconazole troughs was analyzed in the rapid metabolizer and ultra-rapid metabolizer patients (RMs and UMs, respectively), and compared with the rest of the patients. The relationship between voriconazole concentration, CYP2C19 phenotype, adverse events (AEs), and drug-drug interactions was also assessed. RESULTS: In this study 78 patients were included with a wide variability in voriconazole plasma levels with only 44.8% of patients attaining trough concentrations within the therapeutic range of 1 and 5.5 µg/ml. The allele frequency of *17 variant was found to be 29.5%. Compared with patients with other phenotypes, RMs and UMs had a lower voriconazole plasma concentration (RM/UM: 1.85 ± 0.24 µg/ml vs other phenotypes: 2.36 ± 0.26 µg/ml). Adverse events were more common in patients with higher voriconazole concentrations (p<0.05). No association between voriconazole trough concentration and other factors (age, weight, route of administration, and concomitant administration of enzyme inducer, enzyme inhibitor, glucocorticoids, or proton pump inhibitors) was found. CONCLUSION: These results suggest the potential clinical utility of using CYP2C19 genotype-guided voriconazole dosing to achieve concentrations in the therapeutic range in the early course of therapy. Larger studies are needed to confirm the impact of pharmacogenetics on voriconazole pharmacokinetics.