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.

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.

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.

Effects of sodium nitroprusside on mouse erythrocyte catalase activity and malondialdehyde status.

There is controversy about the anti- or pro-oxidative effects of the nitric oxide (NO)-donor sodium nitroprusside (SNP). Hence, the activity of the antioxidant enzyme catalase (CAT) and the status of malondialdehyde (MDA) were investigated after a 2.5 mg/kg dose of SNP had been i.p. administered to different and comparable groups of mice (n = 48). The drug was administered at two different circadian times (1 and 13 h after light onset [HALO]). There were, irrespectively of sampling time, no significant differences in the means of CAT activity and MDA status between control and SNP-treated groups, no matter the treatment time. However, CAT activity was significantly (Student's t-test, p < 0.001) increased 1 h following SNP administration at 1 HALO, whereas the significant (p < 0.001) increase in the enzyme activity was found only 3 h after injection at 13 HALO. The drug dosing either at 1 or 13 HALO resulted in no significant differences of MDA status between control and treated groups regardless to the sampling time. Two-way analysis of variance (ANOVA) detected a significant (F0.05(7,88)= 5.3; p < 0.0006) interaction between sampling time and treatment in mice injected at 1 HALO, suggesting the influence of treatment on sampling-time-related changes in CAT activity. However, ANOVA validated no interaction between the two factors in mice treated at 13 HALO, illustrating that the sampling-time differences in enzyme activity were greater. Furthermore, two-way ANOVA revealed no interaction in the variation of MDA status in animals treated either at 1 or 13 HALO. This study indicates that SNP significantly affected the anti-oxidant system.

Development of Limited Sampling Strategies for the Estimation of Tacrolimus Area Under the Curve in Adult Kidney Transplant Recipients According to the Posttransplantation Time.

BACKGROUND: Limited sampling strategies (LSS), using few sampling times after dosing, have been used to reliably predict tacrolimus area under the 12-hour concentration-time curve (AUC). Because the pharmacokinetics of tacrolimus is subject to significant changes over the exposure time to this drug, it can be hypothesized that the reliability of the LSS would also change. This study aimed to develop a reliable and practical LSS allowing the estimation of tacrolimus AUC in Tunisian kidney transplant recipients taking into account the posttransplantation time. METHODS: Thirty Tunisian patients were enrolled into 3 groups (10 in each group) according to the posttransplantation period: period 1: between 1 day and 3 months, period 2: between 3 and 12 months and period 3 over 12 months, as defined by the European consensus conference on the therapeutic drug monitoring of tacrolimus. Samples were collected just before and 0.5, 1, 2, 4, 6, 8, and 12 hours after tacrolimus administration. The full pharmacokinetic profiles obtained from these timed concentration data were used to choose the best sampling times. Error indices (mean absolute prediction error and the root mean squared prediction error) were used to evaluate the predictive performance. RESULTS: Among the 1-point estimations, the C4-predicted AUC showed the highest correlation with the measured one during period 1 and period 2 (r = 0.94 and 0.91, respectively) but not period 3 (r = 0.76). The C0-predicted and the measured AUC become less and less correlated from period 1 to period 3 (r = 0.81, 0.75, and 0.66), respectively. Only the model including the C0/C2 provided a high correlation between predicted and measured tacrolimus AUC regardless of the posttransplant period (r = 0.95, 0.96, 0.98 and root mean squared prediction error = 4.1, 5.8, 4.2 during periods 1, 2, and 3, respectively). CONCLUSIONS: Our data clearly indicate that the predictive performance of LSS is prone to change according to the posttransplantation time. A 2-time point LSS was found to be sufficient to predict tacrolimus AUC. The LSS using C0 and C2 is reliable, accurate, and practical to estimate the AUC of tacrolimus regardless of the posttransplantation time.

Albendazole-induced associated acute hepatitis and bicytopenia.

Acute hepatitis induced by albendazole is rarely reported. We describe herein an original case of acute hepatitis associated with bicytopenia after albendazole intake. This paper is the first to describe a possible association of a hematologic disorder and acute hepatitis, both induced by albendazole therapy.

Antihyperglycemic and antihyperlipidemic activities of ethanolic extract of Zygophyllum album in streptozotocin-induced diabetic mice.

Zygophyllum album has been mentioned in Tunisian system of folk medicine to be of value in the treatment of diabetes mellitus. The present study was designed to investigate the possible antihyperglycemic effects of ethanolic extracts of the whole plant of Z. album on blood glucose, plasma insulin, serum lipids and hepatic glycogen and metabolism enzymes of carbohydrate in streptozotocin (STZ)-induced diabetic mice. Administration of the ethanolic extract from plant (100 and 300 mg/kg body weight) for 14 days resulted in significant reduction in plasma glucose, cholesterol, triglycerides, low-density lipoprotein, very-low-density liprotein, hepatic glucokinase and glycogen in STZ diabetic mice. In addition to that, significant increase in plasma high-density lipoprotein, hepatic phosphofructokinase and glucose-6 phosphate dehydrogenase was observed in STZ diabetic mice. After administration of the ethanolic extract, the increased level of plasma insulin is not significant in diabetic mice. In conclusion, the present results showed that the ethanolic extract of Z. album possesses significant antihyperglycemic and antihyperlipidemic effects in experimental model of diabetes mellitus.

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.

Drug rash with eosinophilia and systemic symptoms (DRESS) probably induced by cefotaxime: a report of two cases.

We report two cases, one of a 52-year-old man and one of a 32-year-old man, who were treated with cefotaxime. On day 23 and day 28 of the treatment, respectively, the patients manifested clinically with fever, pruriginous skin rash, and facial edema. Blood tests showed marked eosinophilia and atypical lymphocytosis for both patients, and hepatic cytolysis only in the second patient. Cefotaxime was discontinued in both patients; the clinico-biological picture improved gradually and completely disappeared approximately 4 weeks later. Six weeks after complete recovery, both patients underwent intradermal testing which was positive to cefotaxime (2 mg/ml) at the 48-hour reading and negative to benzylpenicillin, amoxicillin, and cefazolin at the 20-minute and 48-hour readings. These clinical pictures suggest drug rash with eosinophilia and systemic symptoms (DRESS) induced by cefotaxime. To the best of our knowledge, only one case of cefotaxime-induced DRESS has been reported in the medical literature. Thus, we add two new cases of cefotaxime-induced DRESS and emphasize the usefulness and safety of intradermal testing in establishing the diagnosis.