Exploring clozapine pharmacokinetics in Tunisian schizophrenic patients: A population-based modelling approach investigating the impact of genetic and non-genetic variables.

Clozapine is characterized by a large within- and between-patient variability in its pharmacokinetics, attributed to non-genetic and genetic factors. A cross-sectional analysis of clozapine trough concentration (Clz C0) issued from Tunisian schizophrenic patients was collected and analysed using a nonparametric modelling approach. We assessed the impact of demographic covariates (age, weight and sex), patient's habits (smoking status, alcohol and caffeine intake) and the genetic factors (CYP1A2*1C, CYP1A2*1F and CYP2C19*2 polymorphisms) on each pharmacokinetic parameter. An external validation of this pharmacokinetic model using an independent data set was performed. Fit goodness between observed- and individual-predicted data was evaluated using the mean prediction error (% MPE), the mean absolute prediction error (% MAPE) as a measure of bias, and the root mean squared error (% RMSE) as a measure of precision. Sixty-three CLz C0 values issued from 51 schizophrenic patients were assessed in this study and divided into building and validation groups. CYP1A2*1F polymorphism and smoking status were the only covariates significantly associated with clozapine clearance. Precision parameters were as follows: 1.02%, 0.95% and 22.4%, respectively, for % MPE, % MAPE and % RMSE. We developed and validated an accurate pharmacokinetic model able to predict Clz C0 in Tunisian schizophrenic patients using the two parameters CYP1A2*1F polymorphism and smoking.

Antituberculosis-Drugs Induced DRESS: A Multidrug Hypersensitivity or Drug Hypersensitivity Relapse? A Case Report.

DRESS related to first-line antituberculosis drugs (ATD) is a challenging diagnosis. With a long-lasting combined treatment of 4-concomitantly administrated drugs, identification of the culprit drug remains difficult and may expose patients to treatment interruption and affect their outcome. A 42-year-old female, treated with isoniazid, rifampicin, pyrazinamide and ethambutol for multifocal tuberculosis, developed, 40 days later, hyperthermia, facial edema, cervical lymphadenopathy and generalized exanthema. Biological test results revealed eosinophilia, atypical lymphocytes, and liver injury. DRESS was suspected, and ATD were withdrawn. As patch tests for the 4 ATD showed negative results, we decided to reintroduce pyrazinamide, ethambutol and rifampicin separately with a 3-day interval. Pyrazinamide and rifampicin were tolerated. However, after receiving ethambutol, she developed fever and generalized rash, with no biological abnormalities. Since ethambutol was claimed to be the culprit drug, isoniazid was added, and 10 hours later, the patient developed fever, facial edema, generalized rash, eosinophilia and liver injury. This clinical and biological pattern resolved 2 weeks later. This report suggests a hypersensitivity relapse to ethambutol after isoniazid-induced DRESS.

Seronegative acute encephalitis following COVID-19 vaccines: a case series of an overlooked diagnosis with literature review.

PURPOSE: Autoimmune encephalitis is a neurological emergency of new-onset altered mental status, caused by an exaggerated immune-mediated response that targets the central nervous system. Autoimmune encephalitis has become an emerging differential diagnosis, when a classical infection cannot explain neurological symptoms. Displaying overlapping clinical presentations, ranging from the insidious onset of cognitive deficiency to more severe forms of encephalopathy with refractory seizures, autoimmune encephalitis can be challenging for clinicians. When evidence of malignancy is absent and pathogenic autoantibodies are undetected, with typical clinical and imaging features of autoimmune encephalitis, seronegative autoimmune encephalitis may be considered. Recently, vaccination-related autoimmune encephalitis and acute encephalitis after COVID-19 vaccination have attracted attention. METHODS AND RESULTS: We report a case series consisting of three patients with autoimmune encephalitis occurring shortly after COVID-19 vaccination and a current review of all previous reported autoimmune encephalitis related to COVID-19 vaccines. CONCLUSION: We emphasise on the prompt diagnosis of autoimmune encephalitis induced by Covid-19 vaccines and its timely treatment to improve the clinical outcome of this severe neurological condition. Post-licencing vaccine safety surveillance for potential adverse events is essential for vaccine safety and public confidence.

Cefotaxime-induced drug reaction with eosinophilia and systemic symptom in a child with cross-reactivity to other cephalosporins and cosensitization to teicoplanin.

Drug reaction with eosinophilia and systemic symptom (DRESS) is a severe adverse drug-induced reaction. Commonly related to anticonvulsant and allopurinol, DRESS can affect both adults and children. Cefotaxime is rarely associated with DRESS, especially with children. We report a cefotaxime-induced DRESS in a child and emphasize the role of allergological work-up to point out the culprit drug in exploring cross-reactivity and identifying a possible cosensitization. A 2-year-old boy was treated with cefotaxime, vancomycin and metronidazole for acute otomastoiditis. Metronidazole was withdrawn and vancomycin was changed by teicoplanin 10 and 15 days later, respectively. Nineteen days after ongoing cefotaxime and 4 days after teicoplanin intake, the patient developed hyperthermia, a widespread exanthema, facial oedema with neither mucosal involvement nor palpable lymphadenopathy. Biological tests revealed eosinophilia, atypical lymphocytes, mild cytolysis and a high lactate dehydrogenase level. Serological tests for viral and bacterial infections were negative. DRESS was suspected and the 2 antibiotics were withdrawn. Intradermal tests (IDT) were carried out 2 months later with cefotaxime and teicoplanin. They revealed a positive result at 48-hour reading. To assess cross-reactivity among ß-lactams, IDT to penicillins (benzylpenicillin, amoxicillin and oxacillin) was performed showing negative results at 48-hour reading. Nevertheless, IDT to cephalosporins (cefazolin, cefuroxime, ceftazidime and ceftriaxone) displayed positive results at 48-hour reading. As a result, IDT are of great interest and should be performed to confirm the role of cefotaxime and detect a potential cross-reactivity with chemically similar drugs and drugs taken before and during the episode of DRESS.

Pristinamycin-induced toxic epidermal necrolysis: A case report.

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are acute, life-threatening and rare severe cutaneous adverse reactions induced by drugs in most cases. The drugs most often reported to be implicated in inducing TEN/SJS are allopurinol, antibacterial sulfonamides, antiepileptic drugs and oxicam. Pristinamycin is an oral streptogramin antibiotic with bactericidal activity against Gram-positive bacteria that is rarely linked to TEN. Typically, this condition develops 4-28 days after drug exposure, Herein, we report a case of a 71-year-old female who developed TEN within 3 days of administration of pristinamycin and was managed successfully with supportive care, including intravenous fluids, pain control, prophylactic antibiotics and intravenous methylprednisolone. This case of rapidly developing SJS/TEN after administration of pristinamycin highlights the possibility that these complications can develop within only a few days following ingestion of drugs thought to be probably safe.

Case series of chronic spontaneous urticaria following COVID-19 vaccines: an unusual skin manifestation.

BACKGROUND: Urticaria following the COVID-19 vaccine was rarely reported and had a short self-limited resolution. However, there has been relatively little literature published on CSU induced by COVID-19 vaccines. PURPOSE: We describe a case series of patients who experienced CSU after SARS-CoV-2 vaccination. METHODS: A retrospective case series of 10 patients referred to the Department of Clinical Pharmacology of the University of Monastir (January 2021-January 2022) and included for evaluation of urticaria after COVID-19 vaccination. RESULTS: The median age was 31 years and patients were mostly female. Atopy was presented in 3 patients and urticaria was accompanied by angioedema in 6 patients. The median time interval between vaccination and the onset of urticaria was 28.5 h. The offended dose was the first one in 8 patients. The resolution of the eruption was observed at least 2 months later, despite the regular use of a full dose of antihistamine in nine patients. Polynuclear leucocytosis was identified in 5 patients. Anti-TPOAb was positive in one patient after receiving the BNT162b2 vaccine. Total serum IgE was elevated in 4 patients. Skin tests for the suspected vaccine as well as the vaccine excipient were negative. CONCLUSION: We add to the medical literature ten new cases of chronic spontaneous urticarial reactions following COVID-19 vaccines uncontrolled with high-dose first-generation H1 antihistamines.