Drug-Drug Interaction between Tacrolimus and Fluconazole in a Kidney Transplant Recipient.

We report a case of tacrolimus and fluconazole drug-drug interaction in a 20-year-old female kidney transplant recipient with stable kidney function. The patient's tacrolimus blood concentrations were in the therapeutic range until fluconazole was administrated for Candida albicans infection, on day 58 posttransplant. Tacrolimus blood concentration increased by 125% (18.4 ng/mL) on day 79 and by 212% (25.4 ng/mL) on day 84 posttransplant. On day 92, tacrolimus trough blood concentration returned to the therapeutic range (5.6 ng/mL), with decrease of tacrolimus daily dose by 50% (to 4 mg). After fluconazole withdrawal, the patient was returned to the initial tacrolimus daily dose (8 mg) to maintain a tacrolimus trough blood concentration in the therapeutic range. Fluconazole coadministration with tacrolimus shows a significant clinical effect on tacrolimus trough blood concentration in kidney transplant patients. Maintaining a tacrolimus trough blood concentration in the therapeutic range is crucial for these patients; therefore, physicians should be aware of fluconazole prescriptions.

Interaction Between Tacrolimus and Proton Pump Inhibitor in a Kidney Transplant Recipient.

We aimed to present a drug monitoring profile of tacrolimus and proton pump inhibitor coadministration in a 23-year-old male patient with a history of high blood pressure who underwent kidney transplant. The patient's serum trough levels of tacrolimus were in the therapeutic range until omeprazole 20 mg daily was prescribed. Tacrolimus trough serum level increased to 29.5 ng/mL under the same daily dose and to 13.9 ng/mL after tacrolimus daily dose was decreased to 6 mg/day. This increase in tacrolimus serum level was behind a renal function alteration. After withdrawal of omeprazole, tacrolimus trough serum level returned to the therapeutic range. Because interactions between tacrolimus and omeprazole could result in toxicities, careful monitoring of tacrolimus serum levels should be considered to adjust the dosage.

Cutaneous adverse effects of antiepileptic drugs.

Antiepileptic drugs (AED) are widely used in therapy. They are mainly indicated in the treatment of epilepsy and some psychiatric pathologies as well as for their analgesic action. Their cutaneous adverse effects (CAE) are common, often mild but sometimes serious. The aim of this work was to study the epidemiological and clinical features of CAE occurring in adults and elderly patients (aged over 20 years-old) and to identify the most implicated AED. We conducted a descriptive retrospective study over a period of five years from January 2017 to December 2022 about CAE of AED in adults and elderly patients notified to The National Center Chalbi Belkahia of Pharmacovigilance (Tunis,Tunisia). All cases were analyzed according to the updates French methods of imputability. We collected 71 cases of patients aged over 20 years old who presented CAE to AED. The age ranged from 20 to 79 years (mean age=44.8 years). The sex ratio F/M was 0.7. AED were indicated for neurological pathology in 70.5% of cases, for psychiatric pathology in 15.9% of cases and for their analgesic action in 12.9% of cases. Epilepsy was the first indication (51.1% of cases). The most notified CAE in our study were drug reaction with eosinophilia and systemic symptoms (DRESS syndrome; 34% of cases), maculopapular exanthema (MPE; 26% of cases), erythematous rash (8% of cases) and photosensitivity in 5% of cases. Severe cutaneous adverse reactions were accounted for 37% of all CAE. The most implicated AED were carbamazepine (52%), phenobarbital (24%) and lamotrigine (18%). However, further study with a larger number of patients and in collaboration with prescribing physicians are needed to better clarify features of CAE associated with AED intake and specify the risk factors, specific to our Tunisian population.

Erythema multiforme reactions following Pfizer/BioNTech (tozinameran) vaccination: two case-reports with positive rechallenge and review of the literature.

AIM: Pfizer/BioNTech (BNT162b2) is a COVID-19 vaccine with a reassuring safety profile. The main adverse reactions are mild local reactions. Cutaneous reactions are generally minor. The most common cutaneous reaction reported was a local injection-site reaction. CASE STUDY: Here we present 2 cases of erythema multiform (EM) following BNT162b2 vaccination with positive rechallenge. The 1st case was about a 51-year-old woman who developed 5 days after the 1st dose of the mRNA Pfizer/BioNTech (BNT162b2) a macular, erythematous, round-shaped lesions on the hands, knees and soles. She experienced a positive rechallenge one month later. In the 2nd case, a 55-year-old man presented 6 days following the 2nd shot of the mRNA Pfizer/BioNTech (BNT162b2), targetoid eruption on the upper and lower members. The patient reported that he had the same skin lesions in ankles and soles few days following the 1st shot of the same vaccine. CONCLUSION: Few cases of EM following COVID-19 vaccination were reported in the literature and positive rechallenge in only one case. Rechallenge was not performed in most cases. Our two cases are particular because of the positive rechallenge in both patients. This is the gold standard to confirm that the vaccine was the culprit agent in inducing EM.

Therapeutic Drug Monitoring of Tacrolimus in Tunisian Renal Transplant Patients during the Tuberculosis Infection: A Retrospective, Observational, Single-centre Analysis.

Tuberculosis is a challenge in organ transplantation due to the interaction between Anti- Tuberculosis Treatment (ATT) and immunosuppressive drugs, such as Tacrolimus (TAC). This study aimed to assess this interaction and discuss the guidelines used in this specific case. METHODS: A retrospective, observational, single-center analysis was performed at the Department of Clinical Pharmacology (National Centre of Pharmacovigilance, Tunisia). We analyzed the database of patients who received TAC from 2009 until 2018. We included samples provided from renal transplant patients infected by Mycobacterium tuberculosis after transplantation. Trough blood levels (C0) were determined using an immunoassay analyzer. The Therapeutic Range (TR) of TAC was considered between 5 and 10 ng/mL. Pharmacokinetic parameters were compared between the period of co-administration of TAC/ATT (period A) and the period during which patients received only TAC (period B). RESULTS: Seven renal transplant patients treated by TAC were included. 41 samples were analyzed (16; period A, 25; period B). Only 6 % of C0 values were found within TR during period A, while this rate was 44% during period B. During period A, 88% of TAC C0 was under the lower limit of TR, indicating a high risk of transplant rejection. The mean C0 and C0/D were significantly lower during period A (3.11±1.53 ng/mL vs 7.11 ± 3.37 ng/mL; p = 0.001 and 33.06 ± 24.89 vs 83.14 ± 44.46; p = 0.0006, respectively), without difference in doses between periods. CONCLUSION: Considering the results of this study, clinicians are suggested to monitor TAC closely in this particular circumstance.

DRESS Syndrome Associated with Liposomal Amphotericin-B in a Kidney Transplant Patient: A Case Report.

INTRODUCTION: Liposomal amphotericin B is a widely used broad-spectrum antifungal drug. It was developed to reduce nephrotoxicity and maximize the therapeutic utility of amphotericin B in the treatment of invasive fungal infections. Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) syndrome is a severe drug-induced hypersensitivity syndrome commonly associated with aromatic antiepileptic drugs. Liposomal amphotericin-B was associated with DRESS syndrome in only one case. CASE REPORT: We report an exceptional case of possible DRESS syndrome associated with liposomal amphotericin B in a 31-year-old male renal transplant recipient. Seventeen days after starting liposomal amphotericin B for visceral leishmaniosis, he developed a skin rash with elevated liver tests. Liposomal amphotericin B was then discontinued. A favourable outcome was slowly observed in one month. RESULTS AND CONCLUSION: This case scored two (possible case) based on the criteria adopted by the European group RegiSCAR. The Naranjo score for liposomal amphotericin B was four (possible).

Guillain-Barré syndrome after COVID-19 vaccines: A Tunisian case series.

As the COVID-19 vaccination campaign progresses worldwide, Guillain-Barré syndrome (GBS) vaccine-related cases have been reported. We carried out a retrospective, descriptive study of GBS patients following COVID-19 vaccine, submitted to the National Pharmacovigilance Center of Tunis during the period between March 2021 and May 2022. Our study aimed to identify epidemiological and clinical features of COVID-19 vaccine-associated GBS. We found 9 cases of GBS post COVID-19 vaccination; 5 of them were excluded due to the lack of information, whereas 4 cases were included in this study. Men represented 75% (3/4) of the cases. The most frequently reported vaccine type was ChAdOx1 nCoV-19 vaccine (n = 2 reports [50%]), Ad26.COV2.S vaccine and BNT162b2 vaccine in 1. The mean time interval from vaccination to symptom onset was 15.3 days. Clinical manifestations were different: classical GBS in two cases and GBS with unilateral facial palsy in the other 2 cases. All patients were treated with a course of intravenous immunoglobulin for 5 days. Three patients reported clinical improvement while one case (25%) showed treatment-related fluctuations. Our observations suggest that COVID-19 vaccines may be associated with GBS. Continuous surveillance and further studies are warranted to assess the significance of the association.

Humoral and Cellular Immunogenicity of Six Different Vaccines against SARS-CoV-2 in Adults: A Comparative Study in Tunisia (North Africa).

BACKGROUND: The mass vaccination campaign against SARS-CoV-2 was started in Tunisia on 13 March 2021 by using progressively seven different vaccines approved for emergency use. Herein, we aimed to evaluate the humoral and cellular immunity in subjects aged 40 years and over who received one of the following two-dose regimen vaccines against SARS-CoV-2, namely mRNA-1273 or Spikevax (Moderna), BNT162B2 or Comirnaty (Pfizer-BioNTech), Gam-COVID-Vac or Sputnik V (Gamaleya Research Institute), ChAdOx1-S or Vaxzevria (AstraZeneca), BIBP (Sinopharm), and Coronavac (Sinovac). MATERIAL AND METHODS: For each type of vaccine, a sample of subjects aged 40 and over was randomly selected from the national platform for monitoring COVID-19 vaccination and contacted to participate to this study. All consenting participants were sampled for peripheral blood at 3-7 weeks after the second vaccine dose to perform anti-S and anti-N serology by the Elecsys® (Lenexa, KS, USA) anti-SARS-CoV-2 assays (Roche® Basel, Switzerland). The CD4 and CD8 T cell responses were evaluated by the QuantiFERON® SARS-CoV-2 (Qiagen® Basel, Switzerland) for a randomly selected sub-group. RESULTS: A total of 501 people consented to the study and, of them, 133 were included for the cellular response investigations. Both humoral and cellular immune responses against SARS-CoV-2 antigens differed significantly between all tested groups. RNA vaccines induced the highest levels of humoral and cellular anti-S responses followed by adenovirus vaccines and then by inactivated vaccines. Vaccines from the same platform induced similar levels of specific anti-S immune responses except in the case of the Sputnik V and the AstraZeneca vaccine, which exhibited contrasting effects on humoral and cellular responses. When analyses were performed in subjects with negative anti-N antibodies, results were similar to those obtained within the total cohort, except for the Moderna vaccine, which gave a better cellular immune response than the Pfizer vaccine and RNA vaccines, which induced similar cellular immune responses to those of adenovirus vaccines. CONCLUSION: Collectively, our data confirmed the superiority of the RNA-based COVID-19 vaccines, in particular that of Moderna, for both humoral and cellular immunogenicity. Our results comparing between different vaccine platforms in a similar population are of great importance since they may help decision makers to adopt the best strategy for further national vaccination programs.

Seizures after vaccines.

Immunization plays an important role in achieving global health goals. Thus, vaccination is one of the essential means of preventing infectious and viral diseases. The onset of adverse events following immunization (AEFI) is common and most of the time it is a mild effect. However, stimulating the immune system during critical periods of brain development can lead to neurological effects. Among the neurological effects, we were interested in this work by seizures appearing following vaccination.

Phylogenetic and amino acid signature analysis of the SARS-CoV-2s lineages circulating in Tunisia.

Since the beginning of the Coronavirus disease-2019 pandemic, there has been a growing interest in exploring SARS-CoV-2 genetic variation to understand the origin and spread of the pandemic, improve diagnostic methods and develop the appropriate vaccines. The objective of this study was to identify the SARS-CoV-2s lineages circulating in Tunisia and to explore their amino acid signature in order to follow their genome dynamics. Whole genome sequencing and genetic analyses of fifty-eight SARS-CoV-2 samples collected during one-year between March 2020 and March 2021 from the National Influenza Center were performed using three sampling strategies.. Multiple lineage introductions were noted during the initial phase of the pandemic, including B.4, B.1.1, B.1.428.2, B.1.540 and B.1.1.189. Subsequently, lineages B1.160 (24.2%) and B1.177 (22.4%) were dominant throughout the year. The Alpha variant (B.1.1.7 lineage) was identified in February 2021 and firstly observed in the center of our country. In addition, A clear diversity of lineages was observed in the North of the country. A total of 335 mutations including 10 deletions were found. The SARS-CoV-2 proteins ORF1ab, Spike, ORF3a, and Nucleocapsid were observed as mutation hotspots with a mutation frequency exceeding 20%. The 2 most frequent mutations, D614G in S protein and P314L in Nsp12 appeared simultaneously and are often associated with increased viral infectivity. Interestingly, deletions in coding regions causing consequent deletions of amino acids and frame shifts were identified in NSP3, NSP6, S, E, ORF7a, ORF8 and N proteins. These findings contribute to define the COVID-19 outbreak in Tunisia. Despite the country's limited resources, surveillance of SARS-CoV-2 genomic variation should be continued to control the occurrence of new variants.

Comparing real-life carbamazepine exposure between innovator and generic formulation.

BACKGROUND: Carbamazepine is an anticonvulsant largely used in the treatment of epilepsy. The use of generic antiepileptic drugs (AEDs) is controversial because of the eventual possibility to loss seizures control. The aim of our study was to compare the concentration over dose ratio of two products containing carbamazepine, the innovator (Tégrétol®-NOVARTIS) and the generic (Taver®-MEDOCHEMIE). METHODS: It is a retrospective study (2009-2016) including 32 patients treated with carbamazepine. Patients were treated initially by innovator then switched to generic or vice versa. All patients have at least one level of carbamazepine plasma concentration (C0) with the innovator or the generic formulation. Monitoring of carabamazepine was made using immunoassay method (ARCHITECT-ABOTT®). RESULTS: The mean age of our patients was 28.4 years and ranged from 2 to 55 years. The sex ratio M/F was 1.46. The mean ratio C0/dose for the innovator group was 0.723 (min/max: 0.017/1.73), and the mean ratio C0/dose for the generic group was also 0.607 (min/max: 0.064/1.68). There was no statistically significant difference between both groups (P=0.16). CONCLUSION: Our results confirm the difference between the innovator and the generic formulation of carbamazepine. So, switching from innovator to generic seems to be safe and exposure to carbamazepine remains the same.

Is there a ceiling lamotrigine serum level in epileptic children in remission?

INTRODUCTION: Seizure control, in patients with epilepsy, is proportionally associated with health-related quality of life. Antiepileptic therapy leads to seizure remission in most cases. However, some patients are resistant to treatment despite achieving high doses which can be explained by interindividual variability of antiepileptic drugs' metabolism. A ceiling exposure, in epilepsy, helps to adapt the therapeutic strategy in a faster way and to prevent unnecessary exposure to adverse drug reactions. Due to the increasing use of new generations of antiepileptic drugs, we aimed to explore the distribution of lamotrigine (LMT) trough serum levels in epileptic children, stratified between remission and ongoing seizures, in order to determine whether there is a ceiling effect associated with remission. METHODS: We conducted a retrospective study (2012-2021) including children, with generalized epilepsy (2-18 years), addressed for a therapeutic drug monitoring of LMT trough serum levels. Patients in remission, should have as lasting three times the longest pre-treatment seizure-free interval and more than one year. RESULTS: The population of 114 children with generalized epilepsy was divided in to groups: epileptic children in remission (36) and epileptic children with ongoing seizures (78). There was no significant difference in age and sex in the two groups. Median LMT daily dose and trough serum levels were significantly higher in group 2. The highest LMT serum trough level was 11µg/mL in group 1 and 23.1µg/mL in group 2. Valproate was associated in 29%. There was no significant difference of the distribution of valproate in the two groups (P=0.08). CONCLUSIONS: Children in remission had a LMT trough serum levels under 11µg/mL and a daily dose of 3.36mg/kg/day or less. These results suggest that this LMT serum level and daily dose might be associated with a ceiling effect in epileptic children.