favipiravir and Critical-Illness

Influenza represents a significant treatment burden to critical care services. A variety of treatment strategies exist, with more and more therapeutic avenues opening up as research progresses. We examined both pharmacological and supportive treatment strategies currently available to see how they might be applied in an ICU setting.. Supportive care in Influenza centres around optimizing respiratory failure, particularly through well established and recognized ventilatory strategies. Noninvasive ventilation and high-flow nasal oxygen may have a limited role in selected patients under carefully monitored circumstances. Drug therapy exerts only a modest clinical effect and has been poorly studied in the critically ill, though there is some evidence to support the use of neuraminidase inhibitors (NAI) - particularly oseltamivir - as early as possible in this cohort. Newer agents have failed to demonstrate superiority over NAIs but may be useful options if the patient fails to respond or should resistant influenza strains emerge. Steroid therapy, in the absence of another indication, must be recommended against given the repeated trend towards increased mortality in this group.. Influenza management is an evolving field of significant interest to any critical care provider. Currently, good respiratory supportive care and early enteral oseltamivir are the best supported treatment strategies. Further study in the intensive care setting will be needed before the use of novel agents can be recommended.

Topics: Adrenal Cortex Hormones; Amides; Antiviral Agents; Critical Care; Critical Illness; Dibenzothiepins; Enzyme Inhibitors; Humans; Influenza, Human; Morpholines; Neuraminidase; Oseltamivir; Pyrazines; Pyridines; Pyridones; Pyrimidines; Pyrroles; Respiration, Artificial; Triazines; Zanamivir

Since December 2019, a novel coronavirus (severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2)) infection has been rapidly spreading worldwide and causing the respiratory illness, coronavirus disease 2019 (COVID-19). The antiretroviral drug favipiravir (FPV) has been experimentally used for COVID-19 treatment since March 2020 in Japan. However, the pharmacokinetics of FPV in critically ill patients is unknown. We measured the serum concentration of FPV using high-performance liquid chromatography in patients with severe COVID-19 who were admitted to the intensive care unit and placed on mechanical ventilation. The patients were administered 1,600 mg of FPV twice daily on day 1, followed by 600 mg twice daily from day 2 to day 5 (or more if needed). Suspensions of FPV tablets were administered through a nasogastric tube. Seven patients were enrolled in this study. Forty-nine blood samples were obtained from the eligible patients to evaluate FPV concentration. The FPV trough (after 8-12 hours) concentrations of most samples were lower than the lower limit of quantification (1 µg/mL) and half-maximal effective concentration (9.7 µg/mL) against SARS-CoV-2 previously tested in vitro. FPV trough concentration in critically ill patients was much lower than that of healthy subjects in a previous clinical trial, which is a cause for great concern. Further study is required to determine the optimal strategy for treatment of patients with severe COVID-19.

Topics: Adult; Aged; Amides; Betacoronavirus; Coronavirus Infections; COVID-19; COVID-19 Drug Treatment; Critical Illness; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Intubation, Gastrointestinal; Male; Pandemics; Pneumonia, Viral; Pyrazines; Respiration, Artificial; SARS-CoV-2; Severity of Illness Index; Suspensions; Tablets; Treatment Outcome

The Faculty of Pharmaceutical Sciences, Kobe Gakuin University has collaborated in clinical research with Kobe City Medical Center General Hospital. In this university-medical institution collaboration, university faculty members discuss clinical problems with on-site pharmacists and doctors, and carry out clinical research to resolve these problems. During the coronavirus disease 2019 (COVID-19) pandemic, many patients with COVID-19 were treated at Kobe City Medical Center General Hospital. In February 2020, during the first increase in the number of patients with COVID-19 in Japan, treatment for COVID-19 was not established, and some existing anti-viral drugs, such as favipiravir, were experimentally used for COVID-19 treatment. However, since these drugs were not developed specifically for treating COVID-19, their pharmacokinetics have not been sufficiently studied. In particular, the pharmacokinetics of favipiravir in critically ill patients with COVID-19 was of concern, because critically ill patients have an urgent need for life-saving anti-viral drug treatment. Therefore, we conducted a collaborative clinical study to evaluate the pharmacokinetics of favipiravir in patients with COVID-19. The blood concentration of favipiravir in patients with COVID-19 at Kobe City Medical Center General Hospital was measured by lipid chromatography-tandem mass spectrometry at Kobe Gakuin University. Population pharmacokinetics analysis was then performed. In this symposium review, we introduce our pharmacokinetic study of antiviral drugs in patients with COVID-19, focusing on the university-medical institution collaboration. We believe collaborative clinical research will be useful for solving clinical issues and ensuring the effectiveness and safety of pharmacotherapies.

Topics: Antiviral Agents; COVID-19; COVID-19 Drug Treatment; Critical Illness; Humans

Favipiravir is an oral antiviral, that might treat COVID-19 by enhancing viral eradication, particularly in patients with mild-to-moderate disease. Yet, the findings on the use of favipiravir in critically ill patients with COVID-19 are inconsistent. Therefore, this study aimed to assess the effectiveness and safety of favipiravir in critically ill patients with COVID-19.. A multicenter retrospective cohort study includes critically ill adult patients with COVID-19 admitted to the intensive care units (ICUs) was conducted from March 2020 to July 2021. Patients were categorized based on favipiravir use (control vs. favipiravir). The primary outcome was in-hospital mortality. Secondary outcomes included mechanical ventilation (MV) duration, 30-day mortality, ICU length of stay (LOS), hospital LOS, and complications during the stay.. After propensity score (PS) matching (1:1 ratio), 146 patients were included in the final analysis. A higher in-hospital and 30-day mortality were observed in patients receiving favipiravir compared to the control group at crude analysis (65.3% vs. 43.8%; P-value=0.009 and 56.3% vs. 40.3; P-value=0.06, respectively); however, no differences were observed using multivariable Cox proportional hazards regression analysis (HR 1.17; 95% CI 0.73, 1.87; P-value =0.51 and HR 0.86; 95% CI 0.53, 1.39; P-value=0.53, respectively). Conversely, the MV duration and ICU LOS were longer in patients who received favipiravir than the control group (β coefficient 0.51; CI 0.09, 0.92; P-value = 0.02, β coefficient 0.41; CI 0.17, 0.64; P-value = 0.0006, respectively). Complications during the stay were comparable between the two groups.. The use of favipiravir in critically ill patients with COVID-19 did not demonstrate a reduction in mortality; instead, it was linked with longer MV duration and ICU stay. This finding suggests limiting favipiravir use to infections where it is more effective, other than COVID-19. Further randomized clinical trials are needed to confirm these findings.

Topics: Adult; Antiviral Agents; COVID-19; Critical Illness; Humans; Intensive Care Units; Retrospective Studies

Topics: Amides; COVID-19; Critical Illness; Humans; Propensity Score; Pyrazines; Retrospective Studies; SARS-CoV-2

Prior to the availability of the current COVID-19 vaccine, the need to control the pandemic worldwide was focused on management of the disease using previously approved antivirals, including Favipiravir which inhibits viral replication through the RNA dependent RNA polymerase enzyme. Favipiravir's efficacy against different viral infections has made it a potential treatment for COVID-19. We are aiming in this study to assess the therapeutic efficacy and safety of Favipiravir in treating critically ill patients admitted with COVID-19 to Intensive Care Units (ICUs).. This is a retrospective cohort study was conducted in five tertiary hospitals in Riyadh, Kingdom of Saudi Arabia (KSA). The studied sample was randomized from a huge pool of data collected primarily for critically ill COVID-19 patients admitted to (ICUs) during the period between April 2020 to March 2021. Two groups of patients matched 1: 1 for age and body mass index (BMI) was enrolled in the study; one group received Favipiravir and another comparison group received other antimicrobial medications, not including Favipiravir.. A total data of 538 COVID-19 patients were analyzed, 269 (50.%) received Favipiravir and 269 (50%) the control group received different treatments. More than two-thirds 201 (74.7%) were Saudi citizens, the majority 177 (65.8%) were males and the mean age and (BMI) were; (57.23 ± 15.16) years and (31.61 ± 7.33) kg/m2 respectively. The most frequent symptoms of presentation were shortness of breath (SOB), fever, and cough, and the most frequent comorbidity was diabetes mellitus, hypertension, and ischemic heart disease. In the supplemental therapy, corticosteroid, tocilizumab and chloroquine were statistically significant (P = 0.001) when combined in the FVP group more than in the comparison group. Severe acute respiratory distress syndrome (ARDS) was more frequent among Favipiravir group, while the overall mortality rate among the Favipiravir group was not statistically significant (p-value 0.4).. According to the study's results revealing FVP is not superior to other antivirals, patients who received Favipiravir presented with more severe symptoms, more comorbidities, more complications, and is not effective in controlling the cytokine storm which negatively impact the efficacy of Favipiravir. FVP therapy had no influence on ICU and hospital length of stay in comparison with the control group as well as in the overall mortality rate among the FVP group was not statistically significant. further research is needed to understand how FVP along with other treatments can improve the length of stay among COVID-19 patients admitted to the ICU.

Topics: Amides; Antiviral Agents; COVID-19 Drug Treatment; COVID-19 Vaccines; Critical Illness; Humans; Intensive Care Units; Male; Pyrazines; Retrospective Studies; SARS-CoV-2; Saudi Arabia

Topics: Adult; Amides; COVID-19; Critical Illness; Female; Humans; Male; Middle Aged; Pyrazines

In November 2019, several patients were diagnosed with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in Wuhan, China. So far, there are no specific treatments with proven high efficacy in patients with SARS-CoV-2. Presently, several drugs, such as hydroxychloroquine, ribavirin, favipiravir (FVP), lopinavir/ritonavir (LPV/r), remdesivir and oseltamivir, have been suggested as effective treatments for SARS-CoV-2. The aim of this study was to describe the clinical experience with FPV and LPV/r in critically ill patients with COVID-19 at Sakarya University Education and Research Hospital.. The study included 107 consecutive patients who had a laboratory confirmation of COVID-19 and were admitted to the intensive care unit (ICU) between 19 March and 19 May 2020. Follow-up continued through 30 May 2020 when the last observed patients were discharged.. Of the 107 patients, 65 received FPV (Group FPV) and 42 received LPV/r (Group LPV/r). The two groups were similar in terms of demographic data and clinical findings. 43 (66.2%) of the 65 patients in the FPV group and 23 (54.8%) of the 42 patients in the LPV/r group died (p = 0.237). The median ICU stay was 6.6 (IQR, 3-10) days in the FPV group and 9 (IQR, 6-16) days in the LPV/r group, which was a statistically significant difference (p = 0.010).. The length of hospital stay was significantly lower in the FVP group compared to the LPV/r group among patients who were discharged from the ICU. Although the analysis was done with a limited number of patients and the observed difference in mortality rate is of some concern, FVP treatment may be more beneficial than LPV/r in terms of effective use in the ICU.

Topics: Amides; Antiviral Agents; COVID-19; COVID-19 Drug Treatment; Critical Illness; Drug Combinations; Female; Humans; Intensive Care Units; Length of Stay; Lopinavir; Male; Middle Aged; Mortality; Pyrazines; Ritonavir; SARS-CoV-2; Treatment Outcome; Turkey

Favipiravir is a repurposed drug to treat coronavirus 2019 (COVID-19). Due to a lack of available real-world data, we assessed its effectiveness and safety in moderately to critically ill COVID-19 patients.. This retrospective study was conducted in two public/specialty hospitals in Saudi Arabia. We included patients ≥18 years) admitted April-August 2020 with confirmed SARS-CoV-2 diagnosed by real-time polymerase chain reaction (RT-PCR) from nasopharyngeal swab. Patients received either favipiravir (1800 mg or 1600 mg twice daily loading dose, followed by 800 mg or 600 mg twice daily) or supportive-care treatment. Patients were excluded if they were outside the study period, classified as having a mild form of the disease per WHO criteria, or had an incomplete patient file. Kaplan-Meier (KM) models were used to estimate median time to discharge. Discharge ratios, progression to mechanical ventilation, and mortality outcomes were estimated across the severity spectrum using Cox proportional-hazards models. As a sensitivity analysis, we performed propensity score-matching (PSM) analysis.. Overall, median time to discharge was 10 days (95%CI = 9-10) in the favipiravir arm versus 15 days (95%CI = 14-16) in the supportive-care arm. The accelerated discharge benefit was seen across the COVID-19 spectrum of severity. The adjusted discharge ratio was 1.96 (95%CI = 1.56-2.46). Progression to mechanical ventilation was slower with favipiravir (HR. Favipiravir was associated with clinical benefits, including accelerated discharge rate and less progression to mechanical ventilation; however, no overall mortality benefits were seen across the severity spectrum.

Topics: Amides; Antiviral Agents; COVID-19; Critical Illness; Humans; Propensity Score; Pyrazines; Respiration, Artificial; Retrospective Studies; SARS-CoV-2; Saudi Arabia; Sensitivity and Specificity

This report presents a case of a 74-year-old man who showed dramatic therapeutic response to treatment of coronavirus infectious disease-19 (COVID-19) pneumonia. He reported four-day history of sustained fever and acute progressive dyspnea. He developed severe respiratory failure, underwent urgent endotracheal intubation and showed marked elevation of inflammatory and coagulation markers such as c-reactive protein (CRP), ferritin, lactate dehydrogenase (LDH) and D-dimer. Chest computed tomography (CT) demonstrated diffuse consolidation and ground glass opacity (GGO). We diagnosed critical COVID-19 pneumonia with detailed sick contact history and naso-pharyngeal swab of a reverse-transcriptase-polymerase-chain reaction (RT-PCR) assay testing. He received anti-viral drug, anti-interleukin (IL-6) receptor antagonist and intravenous methylprednisolone. After commencing combined intensive therapy, he showed dramatic improvement of clinical condition, serum biomarkers and radiological findings. Early diagnosis and rapid critical care management may provide meaningful clinical benefit even if severe case. J. Med. Invest. 68 : 192-195, February, 2021.

Topics: Aged; Amides; Antibodies, Monoclonal, Humanized; Antiviral Agents; COVID-19; COVID-19 Drug Treatment; Critical Illness; Drug Therapy, Combination; Glucocorticoids; Humans; Lung; Male; Methylprednisolone; Pneumonia, Viral; Pyrazines; Receptors, Interleukin-6; SARS-CoV-2; Tomography, X-Ray Computed; Treatment Outcome

A synergistic effect of combination therapy with favipiravir and oseltamivir has been reported in preclinical models of influenza. However, no data are available on the clinical effectiveness of combination therapy in severe influenza.. Data from 2 separate prospective studies of influenza adults were used to compare outcomes between combination and oseltamivir monotherapy. Outcomes included rate of clinical improvement (defined as a decrease of 2 categories on a 7-category ordinal scale) and viral RNA detectability over time. Subhazard ratios (sHRs) were estimated by the Fine and Gray model for competing risks.. In total, 40 patients were treated with combination therapy and 128 with oseltamivir alone. Clinical improvement on day 14 in the combination group was higher than in the monotherapy group (62.5% vs 42.2%; P = .0247). The adjusted sHR for combination therapy was 2.06 (95% confidence interval, 1.30-3.26). The proportion of undetectable viral RNA at day 10 was higher in the combination group than the oseltamivir group (67.5% vs 21.9%; P < .01). No significant differences were observed in mortality or other outcomes.. Favipiravir and oseltamivir combination therapy may accelerate clinical recovery compared to oseltamivir monotherapy in severe influenza, and this strategy should be formally evaluated in a randomized controlled trial.

Topics: Aged; Amides; Antiviral Agents; Critical Illness; Drug Therapy, Combination; Female; Humans; Influenza, Human; Male; Middle Aged; Oseltamivir; Pyrazines; Retrospective Studies

Topics: Aged; Amides; Benzamidines; Coronavirus Infections; COVID-19 Drug Treatment; Critical Illness; Drug Therapy, Combination; Female; Guanidines; Humans; Male; Middle Aged; Pyrazines; Treatment Outcome

Topics: Amides; Benzamidines; Betacoronavirus; Coronavirus Infections; COVID-19; Critical Illness; Guanidines; Humans; Pandemics; Pneumonia, Viral; Pyrazines; SARS-CoV-2

Topics: Amides; Benzamidines; Betacoronavirus; Coronavirus; Coronavirus Infections; COVID-19; Critical Illness; Disease Progression; Guanidines; Humans; Pandemics; Pneumonia, Viral; Protease Inhibitors; Pyrazines; SARS-CoV-2

Favipiravir is a novel antiviral drug approved for influenza treatment in Japan. Little is known about favipiravir pharmacokinetics in critically ill patients. Here, we report a patient with influenza treated with favipiravir and undergoing continuous venovenous haemofiltration (CVVH) on the Intensive Care Unit of a tertiary hospital in the Netherlands. Pharmacokinetic analyses showed increased clearance and decreased plasma levels compared to healthy volunteers. CVVH has no clinically relevant contribution to total clearance. Despite susceptibility to favipiravir, the influenza virus was not cleared. A multi-disciplinary approach is needed to ensure optimal favipiravir treatment in critically ill patients.

Topics: Amides; Antiviral Agents; Critical Illness; Fatal Outcome; Hemofiltration; Humans; Influenza, Human; Intensive Care Units; Male; Middle Aged; Netherlands; Oseltamivir; Pyrazines; Tertiary Care Centers