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 DRESS was suspected, and ATD were withdrawn.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.

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 Metronidazole was withdrawn and vancomycin was changed by teicoplanin 10 and 15 days later, respectively.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.

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.

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.

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.

Drug reaction with eosinophilia and systemic symptoms in a paediatric population: Interest of skin tests.

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.

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.

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.

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.

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.

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.

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.

Limited sampling strategy for predicting isoniazid exposure in patients with extrapulmonary tuberculosis.

WHAT IS KNOWN AND OBJECTIVE: Limited sampling strategies (LSS), using few sampling times after dosing, have been used to reliably predict the isoniazid area under the 24-hour concentration-time curve (AUC). Experience with isoniazid is very limited, and no LSS has been developed in south-Mediterranean populations. Hence, we aimed to develop an accurate and convenient LSS for predicting isoniazid AUC in Tunisian patients with extrapulmonary tuberculosis. METHODS: Pharmacokinetic profiles consisting of six blood samples each, collected during the 24-hour dosing interval, were obtained from 25 (6 men and 19 women) Tunisian patients with extrapulmonary tuberculosis. The AUC was calculated according to the linear trapezoidal rule. The isoniazid concentrations at each sampling time were correlated by a linear regression analysis with the measured AUC. We analysed all the developed models for their ability to estimate the isoniazid AUC. Error indices including the percentage of Mean Absolute Prediction Error (%MAE) and the percentage of Root Mean Squared Prediction Error (%RMSE) were used to evaluate the predictive performance. The agreement between predicted and measured AUCs was investigated using Bland and Altman and mountain plot analyses. RESULTS AND DISCUSSION: Among the 1-time-point estimations, the C3 -predicted AUC showed the highest correlation with the measured one (r2  = .906, %MAE = 10.45% and %RMSE = 2.69%). For the 2-time-point estimations, the model including the C2 and C6 provided the highest correlation between predicted and measured isoniazid AUC (r2  = .960, %MAE = 8.02% and %RMSE = 1.75%). The C0 /C3 LSS model provided satisfactory correlation and agreement (r2  = .930, %MAE = 10.19% and %RMSE = 2.32%). The best multilinear regression model for predicting the full isoniazid AUC was found to be the combination of 3 time points: C0 , C1 and C6 (r2  = .992, %MAE = 4.06% and %RMSE = 0.80%). The use of a 2-time-point LSS to predict AUC in our population could be sufficient. C2 /C6 combination has shown the best correlation but the use of the C0 /C3 combination could be more practical with an accurate prediction. Therapeutic drug monitoring of isoniazid based on the C3 can be used also in daily clinical practice in view of its reliability and practicality. WHAT IS NEW AND CONCLUSION: The LSS using C0 and C3 is reliable, accurate and practical to estimate the AUC of isoniazid. A 1-time-point LSS including C3 had acceptable correlation coefficient and prediction error indicators could be used alternatively.

Piroxicam-induced fixed drug eruption: Cross-reactivity with meloxicam.

BACKGROUND: Non-steroidal anti-inflammatory drugs constitute a main cause of fixed drug eruption (FDE). A few cases of piroxicam-induced FDE have been reported; however, the cross-reactivity among oxicams has rarely been evaluated. OBJECTIVES: To describe a series of patients with piroxicam-induced FDE, mostly confirmed by a positive patch test reaction, in whom cross-reactivity to meloxicam was assessed. METHODS: We included all cases of piroxicam-induced FDE diagnosed in the department of pharmacovigilance of Monastir. Patch tests for piroxicam and meloxicam were performed in the involved skin according to the European Network on Drug Allergy recommendations. Oral provocation tests (OPTs) were performed for patients with negative skin test results. RESULTS: Seven patients were included in this study. FDE was multiple for five patients and solitary for two. Bullous eruption was noticed in two cases. Lesional patch tests for piroxicam gave positive results in six patients. To assess cross-reactivity with meloxicam, this was patch tested. The test gave a positive result in only one patient. OPTs with meloxicam gave positive results in two patients with negative patch test results. CONCLUSION: Meloxicam is not a safe alternative for the treatment of piroxicam-induced FDE, and OPTs can be used to confirm tolerance before this drug is prescribed as a safer alternative.

Clinical features, culprit drugs, and allergology workup in 41 cases of fixed drug eruption.

BACKGROUND: Fixed drug eruption (FDE) represents a drug-related cutaneous reaction. Many drugs been associated with this clinical entity, with continually evolving documentation of implicated agents and clinical presentations. A bullous form can occur although it is rare. OBJECTIVES: To assess the epidemiological and clinical characteristics of FDE. METHODS: We retrospectively analysed all FDE cases who presented to the Clinical Pharmacology Department at the University Hospital, Monastir, Tunisia, for allergy workup. RESULTS: The mean age of the 41 confirmed FDE cases was 43.8 ± 15.5 years. The time between first lesion onset and FDE diagnosis was less than 1 month for 13 patients (31.7%). Fifteen patients had bullous lesions. The upper limbs were the most common location (65.9% of cases). The patch tests were positive in 27 cases; a provocation test yielded a positive response in the four cases tested. Nonsteroidal anti-inflammatory drugs (NSAIDs) were involved in 51.2%, antibiotics in 24.4%, and other analgesics in 19.5%. The most common offending drug was mefenamic acid in 24.4% of cases. Bullous lesions were significantly associated with paracetamol intake (P = .014; odds ratio 16.7; 95% confidence interval: 1.76-158). CONCLUSIONS: NSAIDs and antibiotics were the most implicated in inducing FDE; paracetamol was associated with bullous lesions.

Distribution of Genetic Polymorphisms of Genes Implicated in Thiopurine Drugs Metabolism.

Thiopurine-S-methyltransferase (TPMT) and inosine triphosphate pyrophosphatase (ITPA) are crucial enzymes involved in the metabolism of thiopurine drugs. Significant interethnic variation in the expression of TPMT and ITPA is caused by single nucleotide polymorphisms of genes encoding these proteins. The aim of this study was to describe the distribution of TPMT and ITPA polymorphisms in healthy Tunisian subjects and to establish the metabolizer status of thiopurine drugs in this population. A total of 309 healthy Tunisian subjects were recruited among blood donors of Fattouma Bourguiba Hospital of Monastir. A written informed consent was obtained from all subjects. Whole blood samples were collected from every subject in ethylenediaminetetraacetic acid tubes. TPMT (c.238 G > C, c.460 G > A and c.719A > G) and ITPA (c.94C > A and IVS2+21A > C) mutations were genotyped using polymerase chain reaction-restriction fragment length polymorphism. The observed frequencies of TPMT*3A and TPMT*3C alleles were both 0.8%. The phenotype distribution of TPMT was bimodal: 96.8% of subjects were extensive metabolizers and 3.2% were intermediate metabolizers. Genotyping of ITPA revealed frequencies of 9% and 3% for IVS2+21A > C and c.94C > A mutations, respectively. Accordingly, a trimodal phenotype distribution was found: 75.4% of the subjects were extensive metabolizers, 23.4% were intermediate metabolizers, and 1.2% wereslow metabolizers. Combination of TPMT and ITPA genotyping has revealed that a quarter of the Tunisian Population carries polymorphisms that reduce the metabolic activities of these enzymes.

Therapeutic drug monitoring of caffeine in preterm infants: Could saliva be an alternative to serum?

OBJECTIVE: Evaluate whether saliva could be a useful alternative to serum for routine therapeutic drug monitoring of caffeine in preterm infants using the enzyme multiplied immunoassay technique (EMIT) assay. METHODS: We conducted a prospective study including preterm infants (less than 34 weeks' amenorrhea) admitted to the intensive care and neonatal medicine department. All infants received 5, 10, 15, 20 and 25mg/kg/day of citrate caffeine intravenously from the first to the fifth day of birth, respectively. For each patient, two concomitant blood and saliva samples corresponding to the trough concentrations were collected 24hours after each caffeine dose. The caffeine concentrations were determined using the EMIT®2000 caffeine assay. RESULTS: Thirteen preterm infants were included. The saliva and the serum caffeine concentration increased proportionally to the administered dose. Saliva and serum kinetics were comparable and the saliva caffeine concentrations were correlated to the serum ones (r2=0.76). CONCLUSION: Saliva caffeine monitoring by EMIT is a valid, useful and safe alternative to serum in preterm infants.