ABSTRACT
In light of rising antimicrobial resistance and a decreasing number of antibiotics with novel modes of action, it is of utmost importance to accelerate development of novel treatment options. One aspect of acceleration is to understand pharmacokinetics (PK) and pharmacodynamics (PD) of drugs and to assess the probability of target attainment (PTA). Several in vitro and in vivo methods are deployed to determine these parameters, such as time-kill-curves, hollow-fiber infection models or animal models. However, to date the use of in silico methods to predict PK/PD and PTA is increasing. Since there is not just one way to perform the in silico analysis, we embarked on reviewing for which indications and how PK and PK/PD models as well as PTA analysis has been used to contribute to the understanding of the PK and PD of a drug. Therefore, we examined four recent examples in more detail, namely ceftazidime-avibactam, omadacycline, gepotidacin and zoliflodacin as well as cefiderocol. Whereas the first two compound classes mainly relied on the 'classical' development path and PK/PD was only deployed after approval, cefiderocol highly profited from in silico techniques that led to its approval. Finally, this review shall highlight current developments and possibilities to accelerate drug development, especially for anti-infectives.
ABSTRACT
Background: Cytokine release syndrome (CRS) significantly contributes to the pathophysiology and progression of COVID-19. It is speculated that therapeutic plasma exchange (TPE) can dampen CRS via elimination of pathogenic cytokines. Objectives: The study is intended to compare the outcomes of COVID-19 patients with CRS treated with TPE and standard care (SC) to their counterparts receiving SC alone. Methodology: A retrospective cohort study of severe COVID-19 confirmed patients presenting with CRS and admitted to the medical ICU was conducted between March and August 2021. Using case-control (CC) matching 1:1, 162 patients were selected and divided into two equal groups. The primary outcome was 28-day in-hospital survival analysis in severe COVID-19 patients with CRS. However, secondary outcomes included the effect of plasmapheresis on inflammatory markers, the need for mechanical ventilation, the rate of extubation, and the duration of survival. Results: After CC matching, the study cohort had a mean age of 55.41 (range 56.41±11.56 in TP+SC and 54.42±8.94 in SC alone; p=0.22). There were 25.95% males and 74.05% females in both groups. The mean time from first day of illness to hospitalization was 6.53±2.18 days. The majority of patients with CRS had comorbid conditions (75.9%). Diabetes mellitus was the most common comorbidity (40.1%), followed by hypertension (25.3%), and chronic kidney disease (21%). Notable reduction in some inflammatory markers (D-dimers, LDH, CRP and serum ferritin) (p<0.0001) was observed in the group that received TPE+SC. Moreover, the patients in the plasmapheresis plus standard care group required relatively less mechanical ventilation as compared to the group receiving SC alone (46.9% vs 58.1%, respectively; p>0.05). The rate of extubation in the TP+SC group vs SC alone was 60.5% vs 44.7%, respectively (p>0.05). Similarly, the mortality percentages in both groups were 19.8% and 24.7%, respectively. Conclusion: For this particular group of matched patients with COVID-19-induced CRS, TPE+SC was linked with relatively better overall survival, early extubation, and earlier discharge compared to SC alone. As these results were not statistically significant, multi-centered randomized control trials are needed to further elaborate the role of therapeutic plasmapheresis in COVID-19 induced CRS.
ABSTRACT
(1) Background: Immune compromised hemodialysis patients are more likely to develop COVID-19 infections, which increase the risk of mortality. The benefits of Remdesivir, despite less literature support on its effectiveness in dialysis patients due to renal toxicity, can outweigh the risks if prescribed early. The aim of this study was to evaluate the efficacy of Remdesivir on the 30-day in-hospital clinical outcome of hemodialysis population with COVID-19 infection and safety endpoints of adverse events. (2) Study design: A prospective quasi-experimental study design was used in the study. (3) Methods: The sample population consisted of 83 dialysis patients with COVID-19 who were administered Remdesivir at a dose of 100 mg before hemodialysis, as per hospital protocol. After the treatment with Remdesivir, we assessed the outcomes across two endpoints, namely primary (surviving vs. dying) as well as clinical and biochemical changes (ferritin, liver function test, C-reactive protein, oxygen requirements, and lactate dehydrogenase levels) and secondary (adverse effects, such as diarrhea, rise in ALT). In Kaplan-Meier analysis, the survival probabilities were compared between patients who received Remdesivir within 48 h of diagnosis and those who received it after 48 h. Cox regression analysis was employed to determine the predictors of outcome. (4) Results: Of the 83 patients, 91.5% survived and 8.4% died. Remdesivir administration did not reduce the death rate overall. Hospital stays were shorter (p = 0.03) and a nasopharyngeal swab for COVID-19 was negative earlier (p = 0.001) in survivors who had received Remdesivir within 48 h of diagnosis compared to those who had received Remdesivir after 48 h. The only variables linked to the 30-day mortality were serum CRP (p = 0.028) and TLC (p = 0.013). No major adverse consequences were observed with Remdesivir. (5) Conclusions: Remdesivir has the potential to shorten the recovery time for dialysis patients if taken within 48 h of onset of symptoms, without any adverse effects.