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INTRODUCTION: Administration of vancomycin dose by continuous infusion (CI) according to population pharmacokinetic (Pop Pk) models is highly recommended in critically ill patients who exhibit pathophysiological changes. OBJECTIVE: to develop and validate a Pop Pk model of vancomycin administered by CI in critically ill patients with normal and impaired renal functions. METHODS: The Pop Pk study was performed using a nonparametric approach (Pmetrics*). The influence of covariates (gender, age, weight, height, and creatinine clearance Cr-Cl) was tested on the model's Pk parameters. The performance of the final model was assessed using an external dataset. RESULTS: A one-compartment model (Volume of distribution; Vd, Elimination from compartement; Ke) was found to show a good prediction performance. The influence of covariates has shown that age and Cr-Cl affected significantly Vd and Ke respectively. The distribution of simulated vancomycin clearance (CLv) according to different renal function levels showed anegative correlation between CLv and the severity of the renal impairment. The Internal validation of the final model showed that the plot of individual predicted concentration versus observed concentration resulted in r² = 0.86 in the final model.The external validation of the final model showed an acceptable predictive performance. CONCLUSION: We developed a Pop Pk model for vancomycin administered by CI in critically ill patients. A significant impact of Cr-Cl and different stages of renal failure on CLv has been demonstrated. The establishment of an individualized proposal dose based on this model may be helpful to achieve the therapeutic target range which is critical in optimizing the efficacy and safety of this antibiotic.
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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.
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Antipsicóticos , Clozapina , Citocromo P-450 CYP1A2 , Citocromo P-450 CYP2C19 , Esquizofrenia , Humanos , Clozapina/farmacocinética , Clozapina/sangre , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/genética , Masculino , Femenino , Túnez , Citocromo P-450 CYP1A2/genética , Citocromo P-450 CYP1A2/metabolismo , Adulto , Antipsicóticos/farmacocinética , Estudios Transversales , Persona de Mediana Edad , Citocromo P-450 CYP2C19/genética , Modelos Biológicos , Fumar , Adulto Joven , Polimorfismo GenéticoRESUMEN
PURPOSE: The safety profile of methimazole (MMI) seems to be better than propylthiouracil in the management of hyperthyroidism. It is therefore advisable to use IMM as the first choice in Graves' patients. It is important to keep this drug in patients regardless of minor side effects. We report a case series of MMI-induced urticaria and provide a stepwise protocol for the safe re-administration of MMI. METHODS: It was a retrospective case series including all patients having manifested urticaria following MMI intake for hyperthyroidism; notified to the Pharmacovigilance Unit of the Clinical Pharmacology Department (March 2013-January 2022). RESULTS: We have included 11 patients (SR: 0.22). The median time interval between the start of MMI and the onset of urticaria averaged 14.5 days. The median daily dose of MMI was 40mg. MMI was interrupted in all patients. Urticaria has progressively resolved after drug interruption and antihistamine intake. Reintroduction of MMI was performed in 10/11 patients as follows: one quarter of the daily dose on the first day, half of the daily dose on the 4th day, the three quarters of the daily dose on the 7th day, to reach the scheduled total dose on the 10th day. Cetirizine was added at the time of reintroduction and withdrawn 2 weeks later. All the patients were successfully controlled. CONCLUSION: Given the importance of this drug in the management of hyperthyroidism, MMI should not be withdrawn in cases of urticaria. After the resolution of urticaria, a gradual reintroduction of MMI should be attempted with concomitant antihistamine therapy.
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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.
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BACKGROUND: Drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe adverse drug reaction. It is uncommon in the paediatric population and can be difficult to diagnose as its initial symptoms may mimic a viral infection. OBJECTIVE: To analyse the features of paediatric DRESS and to evaluate the interest of skin tests in identifying the causative drugs. METHODS: It is a retrospective analysis (2004-2021) of DRESS cases diagnosed in paediatric patients. The DRESS diagnosis was defined using the RegiSCAR scoring. The skin tests were performed according to the ENDA recommendations. RESULTS: We included 19 cases of DRESS occurred in 18 patients. Common clinical symptoms were exanthema and fever in 94.7% of cases each. The most commonly affected organ was the liver (84.2%). Among the implicated drugs, 16 were tested and skin tests were positive in 75%. To assess cross-reactivity and co-sensitization, skin tests with related and/or co-administered drugs were performed in eight patients. Among them, only one child had positive results. CONCLUSION: Early diagnosis of DRESS and discontinuation of the incriminated drug might reduce the incidence of mortality in the paediatric population. Skin tests could be a safe and useful tool to identify the causative drug and assess cross-reactivity.
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Dermatitis Alérgica por Contacto , Síndrome de Hipersensibilidad a Medicamentos , Eosinofilia , Humanos , Niño , Síndrome de Hipersensibilidad a Medicamentos/diagnóstico , Estudios Retrospectivos , Pruebas CutáneasRESUMEN
BACKGROUND: A prospective validation of pharmacokinetic population (Pk pop) of Tacrolimus (Tac) for dose adjustment in kidney transplant patients was assessed in only one study. The present study was aimed at prospectively evaluating the performance of our previously developed Tac- Pk pop model in predicting trough concentration (C0) in Tunisian kidney transplant patients. PATIENTS AND METHOD: It was a prospective study including patients who had undergone kidney transplantation at Monastir-Nephrology Department. The population study was divided into adherence and control groups. RESULTS: A total of 198 C0 (30 patients) were analyzed. The proportion of C0 within TR was 63.9% and 38.0% in the adhesion and control group, respectively. The percentage of C0 within TR was significantly higher in the adherence group during both early and late post-transplant period (p = 0.03 and 0.04, respectively). This percentage was found to be significantly higher during the third C0 monitoring and thereafter in the adherence group compared with the control group (65.8% vs 41%, respectively). CONCLUSION: Tac dose proposal based on this model could be helpful to improve clinical outcomes in our population by reducing the risk of acute rejection and this immunosuppressant's toxic side effects.
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Trasplante de Riñón , Tacrolimus , Humanos , Tacrolimus/uso terapéutico , Inmunosupresores/uso terapéutico , Estudios ProspectivosRESUMEN
The safety profile of the Sputnik V vaccine is generally reassuring. Nevertheless, an enhanced risk of new-onset of immune-mediated diseases has been increasingly reported following the adenoviral-based Covid-19 vaccine, including inflammatory arthritis, Guillain-Barré syndrome, optical neuromyelitis, acute disseminated encephalomyelitis, subacute thyroiditis and acute liver injury as well as glomerulopathy. However, no case of autoimmune pancreatitis has been reported yet. Herein, we describe a case of type I autoimmune pancreatitis that may be due to the Sputnik V Covid-19 vaccine.
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Pancreatitis Autoinmune , COVID-19 , Humanos , Vacunas contra la COVID-19 , InflamaciónAsunto(s)
Síndrome de Hipersensibilidad a Medicamentos , Eosinofilia , Linfohistiocitosis Hemofagocítica , Humanos , Linfohistiocitosis Hemofagocítica/inducido químicamente , Linfohistiocitosis Hemofagocítica/diagnóstico , Estudios Retrospectivos , Síndrome de Hipersensibilidad a Medicamentos/diagnóstico , Síndrome de Hipersensibilidad a Medicamentos/etiología , Eosinofilia/inducido químicamenteRESUMEN
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.
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Enfermedades Autoinmunes del Sistema Nervioso , COVID-19 , Encefalitis , Humanos , Vacunas contra la COVID-19/efectos adversos , COVID-19/prevención & control , Encefalitis/diagnóstico , Encefalitis/etiología , Prueba de COVID-19RESUMEN
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.
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Síndrome de Hipersensibilidad a Medicamentos , Eosinofilia , Masculino , Adulto , Niño , Humanos , Preescolar , Cefotaxima/efectos adversos , Teicoplanina/efectos adversos , Cefalosporinas/efectos adversos , Vancomicina/efectos adversos , Síndrome de Hipersensibilidad a Medicamentos/diagnóstico , Síndrome de Hipersensibilidad a Medicamentos/etiología , Metronidazol , Eosinofilia/inducido químicamente , Eosinofilia/diagnósticoRESUMEN
AIMS: To determine the frequency of an authentic ß-lactam (BL) hypersensitivity (HS) amongst a large number of children and to identify clinical risk factors that predict this hypersensitivity. METHODS: All children with suspected BL allergy were evaluated by skin tests (ST) with the suspected BL. A 1-day oral provocation test (OPT) was performed in children with negative ST. We defined an authentic BL-HS case if the child exhibited a positive ST or a positive OPT. Risk factors associated with BL-HS were assessed using a univariate analysis. Covariates showing a P-value <.2 were included in the multivariate logistic regression analysis to determine independent predictors. RESULTS: A total of 354 patients reporting 368 suspected BL reactions were included. The diagnosis of BL-HS was established in 24 children (6.7%). All these children had a positive ST. OPT was performed in 30 patients and was negative in all of them. In 110 children with a negative ST, BL was tolerated. In the risk factors analysis, 164 children were included. Older age (>5 years) at the reaction (odds ratio = 1.11; 95% confidence interval, 1.01-1.22; P = .02) and BL administered (odds ratio = 7.7; 95% confidence interval, 2.76-21.8; P < .001) were significantly associated with authentic BL-HS. CONCLUSION: BL-HS should be evaluated with an appropriate allergy work-up before strict prohibition is made. In addition, age of patient and BL involved can be used as predictive factors of developing BL-HS in this population.
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Hipersensibilidad a las Drogas , Hipersensibilidad , Humanos , Niño , Antibacterianos/efectos adversos , beta-Lactamas/efectos adversos , Hipersensibilidad a las Drogas/epidemiología , Hipersensibilidad/complicaciones , Factores de RiesgoRESUMEN
Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the main causes of fixed drug eruption (FDE). Cross-sensitivity between chemically unrelated NSAIDs has been rarely described in FDE. We report herein two cases of NSAID-induced FDE confirmed by oral provocation test (OPT) with a literature review. Case 1 is a 49-year-old woman who took mefenamic, naproxen and acetaminophen for lumbago. On the second day, she noticed three erythematous plaques, located in the upper lip, chin and the right hand, which faded spontaneously, leaving residual patches. Three months later, she took mefenamic acid with reactivation of the same plaques. She received naproxen. On the same day, she exhibited a reactivation of lesions with the development of a new one. These lesions have disappeared leaving hyperpigmented sequelae. After negative patch test to naproxen, an OPT was performed with positive reaction, observed on the third day. To establish the cross-reactivity, she underwent OPTs, which gave positive results to indomethacin, ketoprofen and tiaprofenic acid. Case 2 is a 52-year-old woman who presented painful dusky-red macules, located in the right and left wrists, 24 hours after taking mefenamic acid. She described two similar events that occurred in the past with an undefined drug and piroxicam. Patch tests to lysine acetylsalicylate, mefenamic acid, piroxicam, naproxen and celecoxib were negative. OPTs to the same NSAIDs gave positive results to lysine acetylsalicylate, piroxicam and mefenamic acid. Thirteen case reports, seven case series and one retrospective analysis, including cases with confirmed cross-reactivity between NSAIDs, were reported in literature. Clinicians should be aware of such phenomenon.
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Erupciones por Medicamentos , Naproxeno , Femenino , Humanos , Persona de Mediana Edad , Naproxeno/efectos adversos , Piroxicam , Ácido Mefenámico/efectos adversos , Estudios Retrospectivos , Antiinflamatorios no Esteroideos/efectos adversos , Erupciones por Medicamentos/diagnóstico , Erupciones por Medicamentos/etiología , Erupciones por Medicamentos/patologíaRESUMEN
Erythema nodosum (EN), the most common form of panniculitis, is a reactive inflammation of the subcutaneous fat clinically presented with a sudden onset of painful, erythematous, nodular, subcutaneous lesions, typically localized to the pretibial area. EN is commonly caused by numerous infections (especially beta-haemolytic streptococcal infections), autoimmune diseases (sarcoidosis), inflammatory bowel conditions and drugs. EN induced by Covid-19 vaccines is rarely reported. We describe an original clinical observation of a 75-year-old woman who presented with EN after receiving the second dose of BNT162b2, an mRNA vaccine.
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Enfermedades Autoinmunes , COVID-19 , Eritema Nudoso , Anciano , Femenino , Humanos , Enfermedades Autoinmunes/complicaciones , Vacuna BNT162 , COVID-19/prevención & control , COVID-19/complicaciones , Vacunas contra la COVID-19/efectos adversos , Eritema Nudoso/inducido químicamente , Eritema Nudoso/diagnósticoRESUMEN
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.