Concordance of sustained virologic response at weeks 4, 12 and 24 post-treatment of hepatitis c in the era of new oral direct-acting antivirals: A concise review.

The goal of treatment for chronic hepatitis C viral (HCV) infection is to cure the infection rather than suppress the virus. Historically, a sustained virological response (SVR) defined as undetectable HCV RNA at 24 weeks following the completion of treatment was considered the gold standard to define successful eradication of the virus as a primary endpoint in clinical trials. SVR measured at 12 weeks post-treatment has been shown to be highly concordant with SVR24 in trials of pegylated interferon and ribavirin. The appropriateness and durability of SVR12 as the efficacy endpoint with new oral direct-acting antivirals is less established. A literatura search was performed using PubMed, EMBASE and CENTRAL databases to identify any studies that examined the concordance between SVR24 and earlier time points. Two studies and 4 abstracts were found that performed concordance analyses using positive and negative predictive values. Overall, SVR4 and SVR12 were highly concordant with SVR24 with high positive (> 97%) and negative (> 94%) predictive values; however there was a higher risk of HCV relapse occurring after post-treatment week 4. The majority of the data focused on SVR12 and demonstrated that SVR12 reliably predicted SVR24 in several populations infected with HCV (treatment-naïve, prior null responders, different genotypes) using various new oral direct-acting antiviral regimens. In conclusion, the available data suggests that SVR12 is a reliable assessment of HCV eradication and could be used instead of SVR24 for drug development clinical trials assessing efficacy of new direct-acting antivirals. Data on the long-term durability of SVR12 is still needed.

Evaluating outcomes of alternative dosing strategies for cefepime: a qualitative systematic review.

OBJECTIVE: To perform a qualitative systematic review of the evidence comparing traditional with prolonged intermittent or continuous infusions of cefepime based on clinical and pharmacodynamic outcomes. DATA SOURCES: PubMed (1946 to October 2014), EMBASE (1980 to October 2014), CENTRAL, Cochrane Database of Systematic Reviews, Web of Science, and International Pharmaceutical Abstracts (1970 to October 2014) were searched using the terms cefepime, pharmacokinetics, pharmacodynamics, drug administration, intravenous infusions, intravenous drug administration, continuous infusion, extended infusion, and intermittent therapy. Reference lists from relevant materials were reviewed. STUDY SELECTION AND DATA EXTRACTION: Articles evaluating administration regimens of cefepime, one of which included the traditional, manufacturer-recommended 0.5-hour infusion and the other a prolonged or continuous infusion were included. Prespecified clinical outcomes of interest included all-cause mortality, length of hospital stay, clinical cure, and adverse events. The primary pharmacodynamic outcome was percentage time of unbound drug concentration remaining above the minimum inhibitory concentration. DATA SYNTHESIS: In all, 18 studies were included; 6 studies assessed clinical outcomes, and 12 assessed pharmacodynamic outcomes. Prolonged or continuous infusions of cefepime achieved the pharmacodynamic targets more often than traditional infusions. The association of improved clinical outcomes with prolonged or continuous infusions is unclear. All-cause mortality was significantly decreased with the use of a prolonged cefepime infusion in a retrospective study. Two prospective, randomized studies demonstrated no statistically significant difference in mortality between prolonged and intermittent infusions. CONCLUSIONS: The available literature on prolonged and continuous infusions of cefepime demonstrated an improved achievement of pharmacodynamic targets; however, the effect on clinical outcomes is inconclusive. Well-designed prospective studies are required to determine optimal dosing and administration strategies.

Comparison of nimodipine formulations and administration techniques via enteral feeding tubes in patients with aneurysmal subarachnoid hemorrhage: A multicenter retrospective cohort study.

BACKGROUND: Nimodipine improves outcomes following aneurysmal subarachnoid hemorrhage (aSAH) and current guidelines suggest that patients with aSAH receive nimodipine for 21 days. Patients with no difficulty swallowing will swallow the whole capsules or tablets; otherwise, nimodipine liquid must be drawn from capsules, tablets need to be crushed, or the commercially available liquid product be used to facilitate administration through an enteral feeding tube (FT). It is not clear whether these techniques are equivalent. The goal of the study was to determine if different nimodipine formulations and administration techniques were associated with the safety and effectiveness of nimodipine in aSAH. METHODS: This was a retrospective multicenter observational cohort study conducted in 21 hospitals across North America. Patients admitted with aSAH and received nimodipine by FT for ≥3 days were included. Patient demographics, disease severity, nimodipine administration, and study outcomes were collected. Safety end points included the prevalence of diarrhea and nimodipine dose reduction or discontinuation secondary to blood pressure reduction. Predictors of the study outcomes were analyzed using regression modeling. RESULTS: A total of 727 patients were included. Administration of nimodipine liquid product was independently associated with higher prevalence of diarrhea compared to other administration techniques/formulations (Odds ratio [OR] 2.28, 95% confidence interval [CI] 1.41-3.67, p-value = 0.001, OR 2.76, 95% CI 1.37-5.55, p-value = 0.005, for old and new commercially available formulations, respectively). Bedside withdrawal of liquid from nimodipine capsules prior to administration was significantly associated with higher prevalence of nimodipine dose reduction or discontinuation secondary to hypotension (OR 2.82, 95% CI 1.57-5.06, p-value = 0.001). Tablet crushing and bedside withdrawal of liquid from capsules prior to administration were associated with increased odds of delayed cerebral ischemia (OR 6.66, 95% CI 3.48-12.74, p-value <0.0001 and OR 3.92, 95% CI 2.05-7.52, p-value <0.0001, respectively). CONCLUSIONS: Our findings suggest that enteral nimodipine formulations and administration techniques might not be equivalent. This could be attributed to excipient differences, inconsistency and inaccuracy in medication administration, and altered nimodipine bioavailability. Further studies are needed.

Prescribing Patterns and Patient Outcomes for Bone and Joint Infections Treated with Cefazolin and Probenecid: A Retrospective Observational Study.

BACKGROUND: Previous studies have described the use of cefazolin with probenecid to treat uncomplicated skin and soft-tissue infections. Some prescribers are extrapolating from this evidence to treat more invasive infections, which have a greater potential for poor outcomes, including treatment failure that could lead to increased morbidity and mortality. Information supporting cefazolin with probenecid as effective treatment in this context is needed. OBJECTIVES: To describe prescribing patterns and outcomes for patients who received cefazolin with probenecid for the treatment of bone and joint infections. METHODS: This single-centre retrospective study involved adult outpatients for whom cefazolin and probenecid were prescribed for bone and joint infections between April 1, 2012, and March 31, 2017. Patient charts were reviewed, and data were collected for clinical and microbiological variables using a standardized data collection form. RESULTS: In a total of 80 cases, the patient received cefazolin and probenecid for treatment of a bone or joint infection, of which 69 cases met the inclusion criteria. In most cases (n = 67), the patients were treated with cefazolin 2 g IV plus probenecid 1 g PO, both given twice daily. Completion of prescribed treatment occurred in 56 patient cases (81%), resolution of signs and symptoms in 53 (77%), readmission to hospital in 11 (16%), recurrence of infection in 6 (9%), and treatment failure requiring a change in therapy in 7 (10%). CONCLUSIONS: The effectiveness of cefazolin and probenecid for the treatment of bone and joint infections appears to be similar to that of standard treatment, as reported in the literature. Antibiotic effectiveness is difficult to determine conclusively in a retrospective analysis, so these results should be interpreted with caution, but they may stimulate further research.

CONTEXTE: Des études précédentes ont décrit l'utilisation de la céfazoline et du probénécide pour traiter les infections cutanées et les infections de tissus mous. Quelques prescripteurs extrapolent ces éléments probants pour traiter des infections plus invasives, dont les résultats risquent d'être défavorables, comme un échec du traitement pouvant entraîner une morbidité et une mortalité accrues. De l'information supplémentaire étayant l'efficacité du traitement à l'aide de la céfazoline et du probénécide dans ce contexte est nécessaire. OBJECTIFS: Décrire les modes de prescription et les résultats obtenus par des patients ayant reçu de la céfazoline et du probénécide pour traiter des infections osseuses et articulaires. MÉTHODES: Cette étude rétrospective unicentrique porte sur des patients ambulatoires adultes à qui on a prescrit de la céfazoline et du probénécide pour traiter des infections osseuses et articulaires entre le 1er avril 2012 et le 31 mars 2017. L'examen des dossiers médicaux des patients a permis la récolte de données sur les variables cliniques et microbiologiques à l'aide d'un formulaire de recueil de données standard. RÉSULTATS: Les patients, soit 80 cas en tout, ont reçu de la céfazoline et du probénécide pour traiter une infection osseuse ou articulaire et 69 de ces cas répondaient aux critères d'inclusion. Dans la plupart des cas (n = 67), les patients étaient traités avec de la céfazoline IV dosée à 2 g et du probénécide dosé à 1 g PO, les deux produits étant administrés deux fois par jour. Le traitement a été appliqué au complet dans 56 cas (81 %), la résolution des signes et des symptômes a eu lieu dans 53 cas (77 %), la réadmission à l'hôpital s'est produite dans 11 cas (16 %), les infections ont récidivé dans 6 cas (9 %) et le traitement s'est soldé par un échec et a nécessité un changement de thérapie dans 7 cas (10 %). CONCLUSIONS: L'efficacité de la céfazoline et du probénécide dans le traitement des infections osseuses et articulaires semble être similaire à celle des traitements standard, comme le rapporte la littérature scientifique. L'efficacité des antibiotiques est difficile à déterminer de façon concluante dans une analyse rétrospective, ces résultats doivent donc être interprétés avec prudence, mais ils pourraient stimuler des recherches supplémentaires.