Risk factors of allopurinol-induced severe cutaneous adverse reactions in a Thai population.

BACKGROUND: Allopurinol is one of the most common causes of severe cutaneous adverse drug reactions (SCARs) including drug reactions with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN). This study identified the risk factors associated with the development of allopurinol-induced SCARs in a Thai population. PATIENTS AND METHODS: Eighty-six allopurinol-induced SCARs (i.e. 19 DRESS and 67 SJS/TEN) and 182 allopurinol-tolerant patients were enrolled in the study. The HLA-B*58:01 allele was determined. Clinical and medicinal data were collected. RESULTS: Results from multivariate analysis showed that only the HLA-B*58:01 and female sex were identified as risk factors of allopurinol-induced SCARs in this Thai population. Patients who carried the HLA-B*58:01 allele were at a higher risk of allopurinol-induced DRESS [odds ratio (OR)=149.2, 95% confidence interval (CI)=24.0-∞, P<1.00×10]. Similar results were observed in allopurinol-induced SJS/TEN (OR=175.0, 95% CI=44.3-690.9, P=1.69×10). The risk of allopurinol-induced SCARs in women was higher than that in men (OR=4.6, 95% CI=1.4-15.6, P=1.44×10). The overall mortality rate of allopurinol-induced SCARs was 11.39% and a higher mortality rate was observed in elderly women. CONCLUSION: Among the risk factors identified, the HLA-B*58:01 allele had the greatest impact on the development of both phenotypes of allopurinol-induced SCARs in this studied Thai population. In case HLA-B*58:01 genotyping cannot be accessed, close monitoring of allopurinol usage, especially in elderly women with impaired renal function, is necessary to reduce the mortality rate of these life-threatening SCARs.

External Validation and Updating of Published Models for Predicting 7-day Risk of Symptomatic Intracranial Hemorrhage after Receiving Alteplase for Acute Ischemic Stroke: A Retrospective Cohort Study.

Background: Prediction scores for symptomatic intracranial hemorrhage (sICH) in acute ischemic stroke patients receiving thrombolytic therapy have been widely developed, but the external validation of these scores, especially in the Thai population, is lacking. This study aims to externally validate existing models and update the selected model to enhance its performance in our specific context. Methods: This cohort study retrospectively collected data from medical records between 2013 and 2022. Acute ischemic stroke patients who received thrombolysis were included. All predictors were gathered at admission. External validation was performed on eight published prediction models; in addition, the observed and expected probabilities of sICH were compared. The most effective model for discrimination was then chosen for further updating using multivariable logistic regression and was bootstrapped for internal validation. Finally, a points-based system for clinical practice was developed from the optimism-corrected model. Results: Fifty patients (10% of the 502 included cohort members) experienced sICH after undergoing thrombolysis. The SICH score outperformed the other seven models in terms of discrimination (area under the receiver operating characteristic [AuROC] curve = 0.74 [95% confidence interval {CI} 0.67 to 0.81]), but it still overstated risk (expected-to-observed outcomes [E/O] ratio = 1.7). Once updated, the optimism-corrected revised SICH model showed somewhat better calibration (E/O = 1 and calibration-in-the-large = 0), slightly worse underprediction in the moderate-to-high risk group (calibration slope = 1.152), and marginally better discrimination (AuROC = 0.78). The points-based system also demonstrated substantial agreement (88.1%) with the risk groups predicted by the logistic regression model (kappa statistic = 0.78). Conclusion: Since the SICH score outperformed seven models in terms of discrimination, it was then modified to the Revised-SICH score, which predicted that patients with at least 5.5 points were at high risk of having sICH.

Use of Andrographis paniculata (Burm.f.) Wall. ex Nees and risk of pneumonia in hospitalised patients with mild coronavirus disease 2019: A retrospective cohort study.

Background: Andrographis paniculata (Burm.f.) Wall. ex Nees (AP) has been widely used in Thailand to treat mild COVID-19 infections since early 2020; however, supporting evidence is scarce and ambiguous. Thus, this study aimed to examine whether the use of AP is associated with a decreased risk of pneumonia in hospitalised mild COVID-19 patients. Materials and methods: We collected data between March 2020 and August 2021 from COVID-19 patients admitted to one hospital in Thailand. Patients whose infection was confirmed by real-time polymerase chain reaction, had normal chest radiography and did not receive favipiravir at admission were included and categorised as either AP (deriving from a dried and ground aerial part of the plant), given as capsules with a total daily dose of 180 mg andrographolide for 5 days or standard of care. They were followed for pneumonia confirmed by chest radiography. Multiple logistic regression was used for the analysis controlling for age, sex, diabetes, hypertension, statin use, and antihypertensive drug use. Results: A total of 605 out of 1,054 patients (mostly unvaccinated) were included in the analysis. Of these, 59 patients (9.8%) developed pneumonia during the median follow-up of 7 days. The incidence rates of pneumonia were 13.93 (95% CI 10.09, 19.23) and 12.47 (95% CI 8.21, 18.94) per 1,000 person-days in the AP and standard of care groups, respectively. Compared to the standard of care group, the odds ratios of having pneumonia in the AP group were 1.24 (95% CI 0.71, 2.16; unadjusted model) and 1.42 (95% CI 0.79, 2.55; fully adjusted model). All sensitivity analyses were consistent with the main results. Conclusion: The use of AP was not significantly associated with a decreased risk of pneumonia in mild COVID-19 patients. While waiting for insights from ongoing trials, AP's use in COVID-19 should be done with caution.

Fosfomycin Dosing Regimens based on Monte Carlo Simulation for Treated Carbapenem-Resistant Enterobacteriaceae Infection.

BACKGROUND: Infections by Carbapenem-Resistant Enterobacteriaceae (CRE) remain a leading cause of death in critically ill patients. Fosfomycin has been regarded as an alternative therapy for treatment of infections caused by CRE organisms. The purpose of this study is to evaluate clinical outcomes amongst patients with CRE infection who are receiving a fosfomycin dosing regimen using a Monte Carlo simulation and fosfomycin minimum inhibitory concentration (MIC). MATERIALS AND METHODS: Fosfomycin MIC was defined by the E-test method. We used Fosfomycin pharmacokinetic parameters from a previously published study. The percent of the time period in which the drug concentration exceeded the MIC, or %T>MIC, used in this study were determined to be 70% of T>MIC and 100% of T>MIC, respectively. All dosing regimens were estimated for the probability of target attainment using a Monte Carlo simulation. RESULTS: In this study, we found the MIC's of fosfomycin against CRE isolates ranged from 8 mg/L to 96 mg/L. The total daily dose of fosfomycin ranged from 16 - 24 g and was administered utilizing various fosfomycin dosing regimens to achieve the pharmacokinetic/pharmacodynamic (PK/PD) target in pathogens with a MIC of 32 mg/L for 70%T>MIC and a MIC of 12 mg/L for 100%T>MIC, respectively. For the twelve patients who received the recommended fosfomycin dosing regimen, eleven achieved bacterial eradication for a microbiological cure rate of 91%; and of those patients achieving eradication, two died despite having negative cultures for CRE; the one remaining patient had bacterial persistence. The most commonly observed adverse drug reactions were hypernatremia (3 cases) and hypokalemia (3 cases) and acute kidney injury (3 cases). CONCLUSION: Our findings suggest fosfomycin has tended to good efficacy when using dosing regimens that achieve the PK/PD target. Nonetheless, further validation of these regimens in larger populations is needed.