Association of prior fluoroquinolone treatment with survival outcomes of immune checkpoint inhibitors in Asia.

WHAT IS KNOWN AND OBJECTIVE: Gut microbiota plays an important role in shaping immune responses. Several studies have reported that antibiotics may alter gut microbiota diversity and compromise the therapeutic response to immune checkpoint inhibitors (ICIs). Nevertheless, the impact of a specific class of antibiotics on ICIs therapy is still not known. The aim of this study was to analyse the influence of antibiotics on the clinical outcomes of non-small cell lung cancer (NSCLC) patients treated with ICIs and to compare the effects of fluoroquinolones vs. other broad-spectrum antibiotics. METHODS: This retrospective cohort study (n = 340) analysed data from Chang Gung Research Database, which comprises work from seven medical institutions in Taiwan. Patients with NSCLC who received ICIs between January 2016 and March 2019 were evaluated. The data of patients who received antibiotics (ie fluoroquinolone) within 30 days prior to ICIs therapy were analysed. Overall survival (OS) was the goal of our study and was calculated from the time the ICIs therapy start. Survival analysis was estimated using the Kaplan-Meier and Cox statistics. RESULTS: A total of 340 patients were identified for analysis. Of the 340 patients, only over one third (38%) of patients received antibiotics 30 days prior to ICI therapy. These patients exhibited a shorter OS compared with those not receiving antibiotics (median OS, 266 days vs. 455 days; hazard ratio (HR), 2.9; 95% confidence interval (CI), 1.1-8.1, p = 0.003). In this study, 127 out of 128 patients who were exposed to antibiotics had received at least one broad-spectrum antibiotic. We observed patients who had received fluoroquinolone had a shorter OS compared with those receiving other broad-spectrum antibiotics (median OS, 121 days vs. 370 days; HR, 1.582; 95% CI 1.007-2.841; p = 0.047). WHAT IS NEW AND CONCLUSION: Antibiotic treatment, especially fluoroquinolone, prior to ICIs therapy was associated with poorer clinical efficacy in NSCLC patients. Antibiotics should not be withheld when there is a clear need for them despite the possibility of interfering with the microbiome, which may, in turn, adversely affect the ICI's effectiveness. However, one should consider avoiding the use of fluoroquinolones antibiotics.

The efficacy and safety of elbasvir/grazoprevir treatment in HCV genotype 1 patients in Taiwan.

BACKGROUND: Elbasvir/grazoprevir (EBR/GZR) is a new generation, fixed-dose, combination antiviral drug used in chronic hepatitis C virus (HCV) genotype (GT) 1 or 4 infection. Our study evaluates the clinical efficacy and safety of EBR/GZR after its launch in Taiwan. METHODS: This is a retrospective observational study. Patients who had received EBR/GZR for chronic HCV GT 1 between June 2017 and April 2018 were recruited. Patients' age, sex, HCV GT, changes in HCV RNA level before and after treatment, sustained virologic response 12 weeks (SVR12) after the cessation of drug administration, side effects, and interaction effects were used to evaluate the clinical efficacy and safety. RESULTS: A total of 149 patients were recruited. Of them, 145 (97.3%) had HCV GT 1b, and the rest had HCV GT 1a; most of the EBR/GZR-related side effects in this study were mild. Three participants were discontinued because their alanine transaminase levels were elevated to over 10 times the upper limit of normal. The therapeutic effect analyses revealed a rapid virologic response rate of 95.3% and an SVR12 rate of 98%. Subgroup analyses performed using SVR12 as the outcome variable revealed three demographic factors HCV GT 1, hepatocellular carcinoma medical history, and noncirrhosis plus HCV RNA level. CONCLUSIONS: This study confirmed that EBR/GZR is safe and effective for treating patients with HCV GT 1 and exhibited excellent overall clinical efficacy in Taiwan. The therapeutic effects are unrelated to factors such as sex, HCV RNA level before treatment, and history of liver cirrhosis.

Factors associated with adverse drug reaction occurrence and prognosis, and their economic impacts in older inpatients in Taiwan: a nested case-control study.

OBJECTIVE: Older patients are likely to have higher disease complexity and more drug prescriptions of which are associated with a higher incidence of adverse drug reactions (ADR). This study aimed to investigate factors associated with ADR occurrence, prognosis and medical expenses in older inpatients. DESIGN: A nested case-control study. SETTING: A medical centre located in north Taiwan. PARTICIPANTS: 539 reported ADR cases from a patient cohort containing 108 548 older inpatients were collected from 2006 to 2012. There were 1854 non-ADR matched controls; a maximum of 1:5 matched by age, sex and principal diagnosis were collected. EXPOSURE: Polypharmacy, the number of drugs prescribed, comorbidities and the admission department were factors associated with ADRs, as well as subsequent poor prognosis, length of stay and medical expenses. PRIMARY AND SECONDARY OUTCOME MEASURES: ADR occurrence and poor prognosis (mortality, discharge against medical advice in critical conditions, or admitted to intensive care unit) were the primary outcomes. Additional medical expenses and the length of hospital stay were the secondary outcomes. RESULTS: The admission department, number of comorbidities and number of drug prescriptions before ADRs were associated with ADR occurrence among older inpatients. ADR severity was a significant prognostic factor among ADR cases. The multivariate-adjusted OR of 1.63 (95% CI 1.36 to 1.95) for poor prognosis was found as the number of comorbidities increased. Patients prescribed ≥11 drugs including psychoactive drugs showed 2.45-fold (95% CI 1.40 to 4.28) poorer prognosis than other patients. ADRs caused the addition of US$1803.8, US$360.8 and 5.6 days in total medical expenses, drug expenses and length of stay among affected older inpatients, respectively. CONCLUSIONS: The number of comorbidities and polypharmacy including the use of psychoactive drugs has significant impacts on ADR occurrence and prognosis among older inpatients. The findings provide clues for future prescription modification and patient's safety improvement in geriatric care.

Risk factors and outcomes of Clostridium difficile infection in hospitalized patients.

BACKGROUND: The aim of this study was to identify risk factors for Clostridium difficile infection (CDI) and its attributable mortality and to propose methods to prevent CDI and improve patients' outcomes. METHODS: CDI was defined as diarrheal patients with stool samples that were positive for C. difficile toxin. Clinical presentations of all patients with CDI and two times as many age- and sex-matched culture-negative controls at the Chang Gung Memorial Hospital in 2014 were identified and compared by multivariate, nonparametric, and Kaplan-Meier survival analysis. RESULTS: There were no significant differences in ages, sex, or Charlson comorbidity indexes between the CDI group (n = 42) and the control group (n = 86). The multivariate analysis indicated that underlying peptic ulcer disease and previous use of gastric acid inhibitors or third-generation cephalosporins for at least 3 days were significantly more common in patients with CDI than in the controls. Charlson scores were associated with mortality due to CDI. Recommended treatment using oral vancomycin to treat patients with Charlson score ≥ 5 and oral metronidazole or vancomycin to treat those with moderate underlying disease (Charlson score ≥ 2 and ≤ 5) significantly increased survival in these patients (p = 0.001). CONCLUSIONS: Oral vancomycin given to patients with high Charlson scores and oral metronidazole or vancomycin to patients with moderate Charlson scores decreased mortality due to CDI. Restricting the use of third-generation cephalosporins and gastric acid inhibitors is recommended to prevent CDI in hospitalized patients.

Allopurinol Use and Risk of Fatal Hypersensitivity Reactions: A Nationwide Population-Based Study in Taiwan.

IMPORTANCE: Allopurinol, a first-line drug used for treating gout, is increasingly prescribed worldwide to patients with asymptomatic hyperuricemia and comorbid renal or cardiovascular diseases. Nevertheless, allopurinol use has been associated with fatal hypersensitivity reactions, including drug rash with eosinophilia and systemic symptoms, Stevens-Johnson syndrome, and toxic epidermal necrolysis. The overall risks of allopurinol use remain unclear. OBJECTIVE: To investigate the incidence of, risk factors for, and mortality associated with allopurinol hypersensitivity in new users of allopurinol. DESIGN, SETTING, AND PARTICIPANTS: A retrospective nationwide population study was conducted using data from the Taiwan National Health Insurance Research Database, which includes detailed medical records of more than 23 million insured enrollees. Data were collected from January 1, 2005, through December 31, 2011, using the Anatomical Therapeutic Chemical classification system and International Classification of Diseases, Ninth Revision, Clinical Modification codes. Among 1,613,719 patients receiving allopurinol prescriptions, 495,863 were identified as new users. MAIN OUTCOMES AND MEASURES: Allopurinol hypersensitivity was identified within 3 months since the first prescription. The period for measuring related hospitalizations was 1 month since the episode, and the period for measuring renal complications or mortality was 2 months since the episode. Poisson regression test and multivariable logistic regression analysis were performed, and P < .01 was considered statistically significant. RESULTS: Among the more than 23 million insured enrollees, the annual incidence rates were 4.68 per 1000 new users for allopurinol hypersensitivity, 2.02 per 1000 new users for related hospitalization, and 0.39 per 1000 new users for related mortality. The annual incidence of allopurinol hypersensitivity rose statistically significantly during the study period (P < .001). Risk factors for allopurinol hypersensitivity included female sex, age 60 years or older, initial allopurinol dosage exceeding 100 mg/d, renal or cardiovascular comorbidities, and use for treating asymptomatic hyperuricemia. Patients with asymptomatic hyperuricemia and renal or cardiovascular diseases had statistically significantly increased risk of allopurinol hypersensitivity (odds ratio [OR], 1.61; 95% CI, 1.33-1.94; P < .001 for renal diseases and OR, 1.52; 95% CI, 1.19-1.93; P < .001 for cardiovascular diseases). They also had statistically significantly increased risk of mortality (OR, 5.59; 95% CI, 2.61-11.94; P < .001 for renal diseases and OR, 3.57; 95% CI, 2.31-5.51; P < .001 for cardiovascular diseases). CONCLUSIONS AND RELEVANCE: The use of allopurinol in patients with asymptomatic hyperuricemia accompanied by renal or cardiovascular diseases statistically significantly increased the risk of hypersensitivity reactions. Physicians should be cautious when prescribing allopurinol to high-risk populations and should consider the potential risks of fatal adverse reactions.

Blood culture-guided de-escalation of empirical antimicrobial regimen for critical patients in an online antimicrobial stewardship programme.

A blood culture-guided review strategy was applied to a hospital-wide computerised antimicrobial approval system (HCAAS) at a medical centre in Taiwan. The study aimed to evaluate the impact of this deployment on prescribers' behaviours, antimicrobial consumption, antimicrobial expenditure and healthcare quality in adult intensive care units (ICUs). The HCAAS automatically identifies patients with positive blood cultures and notifies the pre-assigned infectious diseases (ID) physicians for an online second review of the current antimicrobial regimen. Patients from 16 adult ICUs were selected as a focus group. Descriptive analysis, McNemar's test, interrupted time-series analysis and univariate regression analysis were applied. The number of prescriptions assigned for second review increased from 304 in 2010 to 682 in 2012. The approval rate for the antimicrobial regimen in the second review exceeded 70%. In disapproved cases, prescribers accepted the recommendation from ID physicians in 66.1% of cases in the first year; the acceptance rate increased to 80.6% in 2012. Among the restricted antimicrobial agents, consumption gradients decreased for all eight drug classes. The overall antimicrobial expenditure gradient declined significantly following deployment of the second review strategy. The healthcare-associated infection rate continued to decrease over time, and the mortality and ICU re-admission rates remained stable after deployment. A blood culture-guided review of antimicrobial use based on clinical and microbiological evidence improves accuracy in choosing appropriate antimicrobial agents and encourages de-escalation. Consumption and expenditure gradients of antimicrobial agents decreased after the intervention, and healthcare quality was not compromised.

HLA associations and clinical implications in T-cell mediated drug hypersensitivity reactions: an updated review.

T-cell mediated drug hypersensitivity reactions may range from mild rash to severe fatal reactions. Among them, drug reaction with eosinophilia and systemic symptoms (DRESS) or drug-induced hypersensitivity syndrome (DIHS), Stevens-Johnson syndrome/ toxic epidermal necrolysis (SJS/TEN), are some of the most life-threatening severe cutaneous adverse reactions (SCARs). Recent advances in pharmacogenetic studies show strong genetic associations between human leukocyte antigen (HLA) alleles and susceptibility to drug hypersensitivity. This review summarizes the literature on recent progresses in pharmacogenetic studies and clinical application of pharmacogenetic screening based on associations between SCARs and specific HLA alleles to avoid serious conditions associated with drug hypersensitivity.

Implementation and outcomes of a hospital-wide computerised antimicrobial stewardship programme in a large medical centre in Taiwan.

Antibiotic stewardship is important to address the problem of antimicrobial resistance, but a practical and sustainable strategy to provide stewardship in a large hospital setting is lacking. We developed a hospital-wide computerised antimicrobial approval system (HCAAS) to guide the use of antimicrobial agents in late 2004 in a 3500-bed medical centre in Taiwan. The objective of this study was to evaluate the impacts of HCAAS on the hospital from 2003 to 2009. Following HCAAS deployment, the gradients of consumption over time during the study period of third- and fourth-generation cephalosporins, fluoroquinolones and glycopeptides fell significantly, whilst that of carbapenems increased. The amount and expenditure of antimicrobial use did not increase with the overall healthcare-associated infection rate, and inpatient mortality rate remained stable with a slight decreasing trend. The rate of meticillin-resistant Staphylococcus aureus started to decline in 2002 and continued after HCAAS deployment. There was an increasing isolation of extended-spectrum ß-lactamase-producing Escherichia coli and Klebsiella pneumoniae, presumably leading to the increased use of carbapenems. The isolation rate of Clostridium difficile from patients who developed diarrhoea after antimicrobial therapy did not change over the years, with a mean annual rate of 10.0% after the implementation of HCAAS. HCAAS along with strict infection control measures is necessary to reduce the spread of resistant organisms within the hospital. HCAAS is a sustainable system for providing antibiotic stewardship and exerts a positive impact on the hospital by reducing antimicrobial consumption and expenditure whilst not compromising healthcare quality.

Cisplatin-induced acute hyponatremia leading to a seizure and coma: a case report.

We report a rare case of cisplatin-induced acute hyponatremia leading to a seizure and coma. A 66-year-old woman with breast cancer received adjuvant chemotherapy with docetaxel and cisplatin. She had no nausea, vomiting, or diarrhea during or after chemotherapy administration. She had an acute onset of a generalized seizure and coma on the fourth day after chemotherapy. On arrival in the emergency department, she was unconscious with a Glasgow Coma Score of 6 (eyes 1, verbal 1, motor 4). Computed tomography of the brain did not show any lesions. She had no underlying diseases except breast cancer. The laboratory studies showed severe hyponatremia (Na 113 mmol/L) with low plasma osmolality, and elevation of both urinary sodium and urinary osmolality. In addition, polyuria (about 4 L/day) was also noted. Her consciousness level gradually improved the next day with a rise in serum sodium after 3% NaCl infusion. She recovered fully with no sequelae. Assessment using the Naranjo probability scale suggested that cisplatin was the probable cause for the adverse event. The mechanism of hyponatremia induced by cisplatin in our case was thought to be renal salt wasting syndrome (RSWS). In conclusion, cisplatin-induced acute hyponatremia leading to seizures and coma is seen rarely. When RSWS is suspected, hypertonic saline should be administered.

Modified vancomycin dosing protocol for treatment of diabetic foot infections.

PURPOSE: The clinical efficacy of a modified vancomycin dosing protocol with a conventional regimen for managing patients with diabetic foot infections caused by methicillin-resistant Staphylococcus aureus (MRSA) was evaluated. METHODS: This prospective study was conducted from January 2002 to December 2004 at the diabetic ward of Chang Gung Memorial Hospital--Linkou in Taiwan. All diabetic patients with MRSA-related diabetic foot infections confirmed by wound cultures were enrolled in this study. Patients treated with the conventional protocol (from 2002 to 2003) received vancomycin 10-15 mg/kg (up to 1 g) over 60 minutes every 12 hours if their serum creatinine (SCr) concentration was 0.4-1.4 mg/dL according to the estimation of creatinine clearance (CL(cr)). Patients treated with the modified vancomycin dosing protocol (from 2003 to 2004) received vancomycin according to their SCr level, age, and concurrent gentamicin dosage. Data analyzed included patients' age, sex, body weight, SCr level, CL(cr), serum vancomycin peak and trough levels, vancomycin dosage, treatment period, and duration of hospital stay. RESULTS: A total of 85 patients were enrolled in this study. The conventional protocol group achieved substantially higher serum vancomycin levels than those recommended by the British National Formulary (BNF). Although the vancomycin dosage in the modified protocol was lower than that in the conventional protocol, trough and peak vancomycin levels remained within the range recommended by the BNF. The duration of hospitalization and treatment did not significantly differ between the two groups. CONCLUSION: A modified vancomycin dosing protocol for treating diabetic foot infections caused by MRSA was superior to the conventional dosing regimen in achieving therapeutic serum levels of vancomycin.

Pharmacokinetics and bioequivalence study of a generic desloratadine tablet formulation in healthy male volunteers.

The pharmacokinetic profiles and relative bioavailability of desloratadine (CAS 100643-71-8, Denosin as test and another commercially available preparation as reference) tablets from two different pharmaceutical manufacturers were carried out. A single oral dose (10 mg/2 tablets) of desloratadine was administered to 8 healthy young Chinese males in a completely double-blind cross-over design with a two-week washout period between each dose. Plasma samples were obtained before and at various appropriate intervals after dosing up to 120 h. The plasma concentrations were then analyzed by a liquid chromatography/tandem mass spectrometric (LC/MS/MS) method. The limit of quantitation of this LC/MS/MS method was 0.05 ng/mL. The coefficients of variation of the within-day and between-day calibration curves (n = 6) range from 0.05 ng/mL to 10 ng/mL and were less than 10%. The accuracy of this method was verified. Values for the area under the plasma concentration-time curve (AUC), peak concentration (Cmax), time to peak concentration (Tmax), elimination rate constant, half-life, oral clearance were estimated and compared for each preparation. By ANOVA, 90% confidence interval, Mann-Whitney test, and paired t-test, the two desloratadine products can be considered bioequivalent for both the extent and the rate of absorption.