Chloroquine (CQ) exhibited promising in vitro activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), but the optimal dosage regimens remain unknown. Our objective was to explore the optimal chloroquine phosphate (CQP) dosage regimens for early achievement of virological clearance within 48-72 hours to diminish in-hospital transmission to front-line healthcare workers. A 10,000-subject Monte Carlo simulation was performed to calculate both probability of efficacy and safety attainment (PTA) using pharmacokinetic (PK) parameters obtained from the published population PK study. Dosage regimens that early achieved PTA of efficacy (PTAeff) ≥90% within 48-72 hours, while maintained PTA of toxicity (PTAtox) ≤1% were considered optimal. For the previously proposed regimens in published guidelines and clinical studies, all dosage regimens could not achieve ≥90% PTAeff, except one with the highest dosage regimen. Our simulations suggested that large amount of loading dose was required for the early achievement. We designed three dosage regimens containing high loading dose (2-3 gram per day), which early achieved ≥90% PTAeff within 48-72 hours, while also maintained ≤1% PTAtox throughout the treatment course. Further clinical studies are needed to prove the efficacy and safety of our designed regimens.

Coronavirus disease 2019 (COVID-19) is an outbreak of acute respiratory illness caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Fourteen percent of patients developed severe illness requiring oxygen therapy and approximately 5% have multi-organ dysfunction requiring intensive care unit (ICU) treatment 1 . Multiple host factors were associated with severity including age ≥ 50 years, male sex, cardiovascular disease, diabetes, and malignancy 2 . However, there have not been any medications or other therapeutic options presently approved by the U.S. Food and Drug Administration (FDA) 3 . Hydroxychloroquine (HCQ) is currently being distributed to selected hospitals by the government in several countries, based on in vitro data and clinical studies showing potential benefits [4][5][6] . HCQ effectively inhibits viral replication by elevating the pH of endosomes and lysosomes 7 . Their anti-inflammatory properties that were demonstrated in the treatment of autoimmune diseases, may also reduce the inflammatory response to viral infection 8 .Currently, there is no conclusive evidence to support the optimal dosing and duration of HCQ for the treatment of COVID-19. Several HCQ regimens have been proposed in in vitro studies including 400 mg twice daily followed by 200 mg daily for 4 days 7 . In Thailand, the current national guideline recommended the regimen of 600 mg twice daily on the first day followed by 400 mg daily for 4-9 days 6 . However, these regimens have not been

around 180 million people worldwide were infected by COVID-19, the newly emerged pandemic disease caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), with an overall mortality rate as high as 2 percent 1 . Its major symptoms are fever, cough, sore throat, myalgia, and respiratory tract symptoms 2 . Pediatric COVID-19 cases are less severe than adults, with hospitalization in only 8 versus 165 per 100,000 cases. Despite its low severity among children, drug treatments for severe cases in this population are still needed. Moreover, the rapid viral clearance provided by early antiviral administration is one of the treatment strategies that might prevent multisystem inflammatory syndrome in children (MIS-C). This syndrome is a postinfection consequence that explicitly affects children. It affects about 0.4 percent of all pediatric COVID-19 cases, mainly found in school-aged children, and is relatively severe with a mortality rate of 2 to 4 percent 3 .CQ has been used for nearly a century as an antimalarial agent. It was recommended as part of compassionate use for COVID-19 treatment by early clinical practice guidelines (CPGs) [4][5][6] . Its potency was demonstrated by several in vitro tests 7-8 but efficacy was controversial in clinical trials 9-10 with a higher dose than the usual malaria dose. Consequently, in March 2020, the United States Food Drug Administration (USFDA) approved CQ and hydroxychloroquine (HCQ), its derivative, for Emergency Use Authorization (EUA) 11 . However, the EUA was then revoked in June 2020 12 . Furthermore, the current CPGs 13-14 have discouraged use of CQ/HCQ in adult and pediatric COVID-19 patients because of a lack of efficacy and safety concerns, as shown in some meta-analysis studies

The objective of this study was to determine the optimal dosage regimens of biapenem and fosfomycin combination achieving desirable pharmacodynamic effects against multidrug-resistant Acinetobacter baumannii (MDR-AB) infections in pediatric patients. A total of 120 clinical MDR-AB strains were collected from tertiary hospitals in Thailand. Minimum inhibition concentrations (MICs) of all the isolates were determined by broth microdilution method. Synergy studies were performed using the checkerboard method. The population pharmacokinetic (PK) parameters of biapenem were obtained from a previously published study. PK parameters of fosfomycin were analyzed by using published plasma concentrations of pediatric patients. Then, these PK parameters and MIC after synergy were used in Monte Carlo simulation to find the exposure time during which drug concentration remains above the MIC. MIC for 50% of the isolates (MIC50) of biapenem before and after synergy with fosfomycin were 16 and 2 mcg/mL, respectively, and MIC50 of fosfomycin before and after synergy with biapenem were 256 and 32 mcg/mL, respectively, for MDR-AB. Biapenem 5 mg/kg q8 h 3-h infusion and fosfomycin 100 mg/kg q8 h 8-h infusion could be used for A. baumannii susceptible to biapenem and fosfomycin. For organisms that are resistant to biapenem and fosfomycin, only biapenem can be used. However, biapenem 5, 10 mg/kg q8 h 3-h infusion and fosfomycin 480-600 mg/kg/day with prolonged infusion provided >80% cumulative fraction of response (CFR). In conclusion, extended biapenem infusion combined with prolonged high-dose fosfomycin infusion would be an option for the treatment of MDR-AB infection in pediatric patients.

Coronavirus disease 2019 (COVID-19) is an infectious disease that causes acute respiratory illness. It was first reported in Wuhan, China. The virus has spread rapidly around the world. Epidemiological studies performed in children found that most children infected with COVID-19 were asymptomatic or had mild symptoms. However, about 10% developed severe symptoms, needed oxygen support, and were admitted to critical care units 1 . The most common route of coronavirus transmission to children is via household contact 2 . No specific drugs have been approved to treat COVID-19 infections in children. Many clinical trials of drugs for the treatment of COVID-19 have been conducted. Some drugs were proven their efficacy for adult patients, but none as yet demonstrated satisfactory outcomes for children [3][4][5][6][7][8][9] . Analyses of in vitro data for hydroxychloroquine, an analogue of chloroquine, showed that it effectively inhibited coronavirus replication [10][11][12] . Hydroxychloroquine blocks coronaviral entry by obstructing glycosylation in the host receptor, thereby viral replication is inhibited by increasing endosomal pH. Hydroxychloroquine also has an immunomodulatory effect by decreasing