Methimazole-induced urticaria in hyperthyroid patients: A safe re-administration protocol.

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 Cetirizine was added at the time of reintroduction and withdrawn 2 weeks later.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 CONCLUSION: Given the importance of this drug in the management of hyperthyroidism, MMI should not be withdrawn in cases of urticaria.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.

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 DRESS was suspected, and ATD were withdrawn.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.

A prospective validation of a population pharmacokinetic model of tacrolimus in Tunisian kidney transplant patients.

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.

An unusual occurrence of autoimmune pancreatitis after gam-Covid-Vac (Sputnik V): A case report and literature review.

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.

Beta-lactam hypersensitivity in children: Frequency and risk factors.

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.

Erythema nodosum induced by Covid-19 Pfizer-BioNTech mRNA vaccine: A case report and brief literature review.

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.

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.

Cross-reactivity between nonsteroidal anti-inflammatory drugs in fixed drug eruption: Two unusual cases and a literature review.

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.

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.

Betalactam hypersensitivity: The importance of delabelling in primary care.

PATIENTS AND METHODS: An allergy work-up was performed on adult patients with a history of a penicillin allergy seen by primary medical care in Monastir (Tunisia) between July 2016 and February 2018. Patients with negative skin tests were challenged with amoxicillin. Patients who were delabelled were contacted by phone after 6 months to determine outcomes after any therapeutic penicillin-class antibiotic intake. RESULTS: A total of 39 patients were evaluated and 33 (84.6%) were delabelled. Five patients were penicillin skin-test positive and one was oral challenge positive. We succeeded in contacting 33 delabelled patients at 6 months. Twenty-two patients tolerated a subsequent therapeutic course of amoxicillin, eight patients did not retake penicillin due to a lack of therapeutic indication, and three patients refused an indicated penicillin use fearful of another reaction. CONCLUSION: This study highlights the importance of allergy work-up in the diagnosis of beta-lactam hypersensitivity. Most patients were excessively labelled as beta-lactam allergic and this mislabelling could increase healthcare costs and lead to the development of drug resistance by the use of wide-spectrum antibiotics.

Clinical and genetic influencing factors on clozapine pharmacokinetics in Tunisian schizophrenic patients.

Clozapine (Clz) is an atypical antipsychotic, which its pharmacokinetics can be influenced by several factors. The CYP1A2 and CYP2C19, major enzymes implicated in Clz metabolism, present an interethnic variation on their activity caused by single nucleotide polymorphisms (SNPs). The present study investigated the influence of genetic and nongenetic factors on Clz pharmacokinetics in a southern Mediterranean population. We included adult Tunisian schizophrenic patients having received Clz and undergone a therapeutic drug monitoring (TDM) of Clz by morning C0 monitoring. The genomic DNA was extracted using a salting-out procedure. CYP1A2*1F (rs762551;-163C>A), CYP1A2*1C (rs2069514;-3860 G>A) and CYP 2C19*2 (rs4244285; 681G>A) was analyzed using PCR-RFLP. Fifty-one patients were enrolled in the study. The mutant allele (CYP1A2*1F) was the most frequently detected (58.8%). For CYP1A2*1F, Clz dose-normalized (C0/D ratio) was as high as 1.28 ± 0.37 in CC versus 0.67 ± 0.32 ng mL-1 per mg day-1 in AA group (p < 0.001). The influence of genetic (CYP1A2*1F, CYP1A2*1C and CYP2C19*2) and nongenetic parameters (age, weight, gender, tobacco, coffee, and alcohol consumption) on the variation of the Clz C0/D ratio was investigated. Only the CYP1A2*1 F polymorphism correlates significantly with the Clz C0/D variation and could explain 24% of its variability. Our data support a critical role of the CYP1A2 -163C>A on the variation of Clz exposure in Tunisian schizophrenic patients. Considering its narrow therapeutic range, CYP1A2 genotyping combined with TDM of Clz may improve efficacy and safety of this drug. Further studies are needed to investigate this issue.

Development of a population pharmacokinetic model and Bayesian estimators for isoniazid in Tunisian tuberculosis patients.

This study aimed to develop a population pharmacokinetic model using full pharmacokinetic (PK) profiles of isoniazid (INH) taking into account demographic and genetic covariates and to develop Bayesian estimators for predicting INH area under the curve (AUC) in Tunisian tuberculosis patients. The INH concentrations in the building data set were fitted using a one- to three-compartment model. The impact of the different covariates was assessed on the PK parameters of the best model. The best limited sampling strategy (LSS) for estimating the INH AUC was selected by comparing the predicted values to an independent data set. INH PK was best described using a three-compartment model with lag-time absorption. The different studied covariates did not have any impact on the PK parameters of the building model. The Bayesian estimation using one-point concentrations gave the lowest values of prediction errors for the C3 LSS model. This model could be sufficient in routine activity for INH monitoring in this population.

Influence of CYP3A polymorphisms on tacrolimus pharmacokinetics in kidney transplant recipients.

Tacrolimus is characterized by a highly variable pharmacokinetics (PK) and a small therapeutic window. It is metabolized specifically by the CYP3A isoenzymes. This study aimed to determine, in kidney transplant patients, the influence of different genotypic clusters involving these SNPs CYP3A4*1B, CYP3A4*22, and CYP3A5*3 on Tacrolimus bioavailability during the first (PTP1) and the second (PTP2) posttransplant phase (PT). We included kidney transplant patients who received Tacrolimus and underwent drug monitoring by C0 monitoring. CYP3A4 and CYP3A5 genotyping were performed using PCR-RFLP. We classified the patients into four groups: Slow, Intermediate, rapid, and ultra-rapid metabolizers. We included 80 patients. The Tacrolimus dose-normalized C0 (C0/D ratio) was significantly decreased in intermediate, rapid, and ultra-rapid comparing with slow metabolisers. During PTP1 only CYP3A5*3 and CYP3A4*22 polymorphisms correlate significantly with C0/D ratio. Regardless of the PT phase and during the late one, only the CYP3A4 polymorphisms correlate significantly with the C0/D ratio. We identified that these SNPs are all associated independently with Tacrolimus exposure in different PT phases. Moreover, we are the first to define a genotypic cluster including the three CYP3A SNPs.

Dosing algorithm for Tacrolimus in Tunisian Kidney transplant patients: Effect of CYP 3A4*1B and CYP3A4*22 polymorphisms.

Prescribing appropriate Tacrolimus (Tac) dosing is still a challenge for clinicians due to the interindividual variability in dose requirement and the narrow therapeutic index. Our objective is to identify potential factors that affects Tac exposure in Tunisian Kidney patients and to develop and validate a Tac dose requirement algorithm including genetic and nongenetic variables. A cross-sectional study was performed. To assess the implication of each covariate on Tac exposure, we classified the patients according to quartiles of exposure index (trough Tac concentration/Dose: C0/D). The total population was divided into the building (75%) and validation (25%) groups. Multiple linear regression was applied to determine the algorithm of Tac dose including the patient's genetic and nongenetic variables. A total of 685 samples issued from 102 kidney transplant patients were included in the study. The post-transplant time (PT), ATG therapy, CYP3A4, and CYP3A5 polymorphisms were significantly associated with trough Tac C0/D. However, the age, sex, body weight, and induction by basiliximab did not show any effect on C0/D. Predicted Tac dose was calculated as follows: Tac Dose = - 2,725 - (10-3 * PT day) + (0,09*weight) + (1,40*ATG) + (2,09* CYP3A4*1B allele) + (0,88*gender) + (0,05*Age) + (1,10*CYP3A4*22 allele) + (2,30* target ranges). Our study designed the first algorithm that predicts the Tac dose requirement in Tunisian Kidney transplant patients including genetic and non-genetic factors. The application of such an algorithm should reduce the number of patients with Tac trough concentration outside the target range and could minimize the time to reach a therapeutic C0.

Effect of CYP3A4*22 and CYP3A4*1B but not CYP3A5*3 polymorphisms on tacrolimus pharmacokinetic model in Tunisian kidney transplant.

The pharmacokinetics of Tacrolimus is characterized by a high interindividual variability that is mainly explained by pharmacogenetics biomarkers. The aims were to develop a population pharmacokinetic model (Pk pop) taking into account post-transplant phases (PTP), CYP3A4*1B, CYP3A4*22 and CYP3A5*3 polymorphisms on Tac pharmacokinetics in adult kidney transplant patients. The Pk pop study was performed using a nonparametric approach (Pmetrics*). The influence of covariates (age, weight, sex, hematocrit and CYP3A4*1B, CYP3A4*22 and CYP3A5*3 polymorphisms) was tested on the model's Pk parameters. The performance of the final model was assessed using an external dataset. A one-compartment model (Vd: volume of distribution, CL: Tac Clearance) was found to correctly describe the evolution of the C0/D regardless of the PTP. The influence of the covariates has shown that only the CYP3A4*1B and CYP3A4*22 polymorphisms were significantly associated only with CL, regardless of PTP (p = .04 and 0.02, respectively). Only the CYP3A4*22 polymorphism influenced CL during early PTP (P1: the first three months, p = .02). During the late PTP (P2: >3 months), only CYP3A4 polymorphisms were found to affect CL (p = .03 for both). The external validation of the final model, including both CYP3A4 polymorphisms, showed an acceptable predictive performance during P1 and P2. We developed and validated a tac Pk pop model including both CYP3A4*22 and CYP3A4*1B polymorphisms, taking into account PTP. This model was very useful in the Tac dose proposal in this population on any PT day but could not be used in other organ transplants due to pharmacokinetic differences.