Amel Chaabane

Les effets indésirables des antituberculeux : épidémiologie, mécanismes et conduite à tenir

Tuberculosis, what ever its localization, is an infectious disease which can be totally cured by combining antitubercular drugs. Current therapeutic regimens with isoniazid, rifampicin, pyrazinamide, ethambutol, and streptomycin have proved successful in treating tuberculosis. However, they are associated to a high rate of adverse effects that can lead to therapeutic failure. Understanding the nature and the severity of these adverse effects allows for their appropriate management. Toxic neuropathy and hepatitis are the most common adverse reactions to isoniazid. Rifampicin is generally well tolerated but some severe immuno-allergic reactions may occur in case of intermittent regimen. Pyrazinamide-induced liver injury is rare but sometimes lethal. Joint affections, usually due to hyperuricemia, are more frequent but easily manageable. The major adverse effect related to ethambutol is ocular optic neuropathy. It occurs dose-dependently and can be irreversible. Finally, administration of streptomycin is potentially associated with renal and cochleo-vestibular toxicity that might be milder than when induced by other aminoglycosides. The management of antituberculosis-induced adverse effects depends on parameters related to the adverse effect itself and to the administrated drug.

Carbamazepine-induced DRESS and HHV6 primary infection : The importance of skin tests

A 34‐year‐old male with a 20‐year history of epilepsy was treated with valproic acid and phenobarbital. As he had frequent convulsive fits, carbamazepine (CBZ) was added. Thirty‐four days later, the patient developed hyperthermia, (39.5°C), cervical lymphadenopathy and generalized cutaneous exfoliated maculae and papulae. Biochemical investigation was characterized by a white cell count of 16.1 × 103/μl (17% eosinophils) and increased levels of aspartate aminotransferase and alanine aminotransferase (50 and 116 IU/L, respectively). HHV6 serological tests performed on day 21, detected anti HHV6 IgM, suggesting a HHV6 primary infection. Hence, CBZ was discontinued. One month later, the skin eruption, fever, lymph node swelling, liver dysfunction, and eosinophilia were progressively relieved. Six weeks after complete recovery, prick and patch skin tests were performed. They were strongly positive at 48‐h reading. This report suggests the usefulness of skin tests in diagnosing CBZ‐induced‐DRESS, as well as s possible association between DRESS and HHV6 primary infection.

Revue généraleLes effets indésirables des antituberculeux : épidémiologie, mécanismes et conduite à tenirAdverse effects of antitubercular drugs: epidemiology, mechanisms, and patient management

Tuberculosis, what ever its localization, is an infectious disease which can be totally cured by combining antitubercular drugs. Current therapeutic regimens with isoniazid, rifampicin, pyrazinamide, ethambutol, and streptomycin have proved successful in treating tuberculosis. However, they are associated to a high rate of adverse effects that can lead to therapeutic failure. Understanding the nature and the severity of these adverse effects allows for their appropriate management. Toxic neuropathy and hepatitis are the most common adverse reactions to isoniazid. Rifampicin is generally well tolerated but some severe immuno-allergic reactions may occur in case of intermittent regimen. Pyrazinamide-induced liver injury is rare but sometimes lethal. Joint affections, usually due to hyperuricemia, are more frequent but easily manageable. The major adverse effect related to ethambutol is ocular optic neuropathy. It occurs dose-dependently and can be irreversible. Finally, administration of streptomycin is potentially associated with renal and cochleo-vestibular toxicity that might be milder than when induced by other aminoglycosides. The management of antituberculosis-induced adverse effects depends on parameters related to the adverse effect itself and to the administrated drug.

Hypersensitivity Syndrome Induced by Anticonvulsants: Possible Cross-Reactivity Between Carbamazepine and Lamotrigine

A 14‐year‐old male presents with erythroderma and fever 44 days after carbamazepine intake. Laboratory exams show eosinophilia and elevated liver enzymes, and thoracic imaging reveals interstitial pneumonitis. All symptoms disappear after carbamazepine withdrawal. A patch test to carbamazepine performed 6 weeks after recovery is positive. About 8 months later, the patient exhibits the same clinical and biological picture 52 days after lamotrigine intake. Lamotrigine is stopped and all symptoms disappear. A patch test to LMG is positive. This case illustrates a possible cross‐reactivity between carbamazepine and lamotrigine, which are aromatic and nonaromatic anticonvulsants, respectively.

Acute generalized exanthematous pustulosis (AGEP) induced by cefotaxime

We report a case of acute generalized exanthematous pustulosis (AGEP) after cefotaxime use confirmed by a positive patch test. A 30‐year‐old woman received cefotaxime, fosfomycin and ciprofloxacin for sinusitis. Twelve days after drug initiation, she developed an extending pustular erythema associated with fever. Laboratory investigations showed marked leukocytosis. His blood chemistry was normal. The histological examination showed parakeratosis, spongiosis and nonfollicular intra‐epidermal pustules consistent with AGEP. All medications were withdrawn. The symptoms resolved within 11 days after cefotaxime discontinuation. Patch tests were positive to cefotaxime after 48 h, while ciprofloxacin and fosfomycin yielded negative findings. Based on the Naranjo algorithm, it is probable that AGEP reaction was caused by cefotaxime. To our knowledge, this is the first reported case of AGEP associated with positive cefotaxime patch testing.

Hypersensitivity to amoxicillin after drug rash with eosinophilia and systemic symptoms (DRESS) to carbamazepine and allopurinol: a possible co‐sensitization

Hypersensitivity syndrome, also known as drug rash with eosinophilia and systemic symptoms (DRESS), is a serious idiosyncratic drug reaction. It is associated with fever, skin eruption, eosinophilia and multiple organ involvement (lymph node enlargement, hepatitis, pneumonitis, renal dysfunction, pancreatitis, myositis, myocarditis, central nervous system manifestations and hyper- and/or hypothyroidism) [1].

Severe ranitidine-induced anaphylaxis: a case report and literature review

What is known and Objective:  Ranitidine is a generally well‐tolerated drug, and serious side effects are rare. However, ranitidine‐induced anaphylaxis has been reported on rare occasions. We report on such a case and review other cases reported in the literature.

Allergie aux bêtalactamines : mythe et réalités

Allergic reactions to penicillins have been reported since the 1950s, shortly after their introduction as therapeutic agents. An increasing number of reported anaphylactic reactions and other adverse effects proved this to be a serious public health problem. Fifty years later, betalactam-induced hypersensitivity is the most frequent cause of drug reaction and has been the source of a great number of publications. Clinically, betalactam-induced allergic reactions may be immediate or non-immediate according to the time interval between drug intake and the occurrence of symptoms. The diagnosis of betalactam hypersensitivity is based on skin tests methods, in vitro tests and drug provocation test. There are three classical methods for skin testing: prick, intradermal, and patch. These tests are still the most sensitive techniques. In vitro tests, mainly based on the quantification of IgE antibodies to betalactams by immunoassay (Fluorescent Enzyme Immunoassay [FEIA]), may sometimes yield useful complementary information. Drug provocation tests must be performed with the required caution and the adequate indication. Algorithms are available for both immediate and non-immediate reactions to provide a practical approach for patient evaluation. They are based on the following data: clinical history, skin tests, FEIA, and drug provocation tests. Finally, cross reactivity between betalactams has been reported, especially between penicillins and cephalosporins. Their frequency was long over-estimated, but recent evidence, indicates that cross reactivity between betalactams has become rare. Administration of cephalosporins in patients with a history of penicillin allergy requires performing skin testing with penicillin, the probably allergenic drug, and the cephalosporin to be prescribed.

Influence of combined CYP3A4 and CYP3A5 single-nucleotide polymorphisms on tacrolimus exposure in kidney transplant recipients: a study according to the post-transplant phase

AIM The present study investigated in Tunisian renal transplant patients, genetic polymorphisms of CYP3A4 -392A>G and CYP3A5 6986A>G and their influence on tacrolimus (Tac) pharmacokinetics during early and late post-transplant (PT) phases and established customized ranges of Tac doses matching the C0 target levels according to CYP3A4 and CYP3A5 genotype combination and the PT phase. PATIENTS & METHODS We included adult Tunisian patients having received Tac for de novo kidney grafts and undergone a therapeutic drug monitoring of Tac by morning C0 monitoring during early (1 to 90 days) and late (over 90 days) PT phases. The genomic DNA was extracted from peripheral blood mononuclear cells using a salting-out procedure. CYP3A4 promoter (rs2740574; -392A>G) and CYP3A5 (rs776746; 6986A>G) SNP genotyping was analyzed using PCR-RFLP. RESULTS Fifty-two patients were enrolled in the study. During the early PT phase, the CYP3A5 polymorphism but not that of CYP3A4, correlates significantly with Tac dose-normalized C0 (C0/D ratio). During the late PT phase, the effect of CYP3A4 polymorphism becomes significant and that of CYP3A5 becomes nonsignificant on Tac C0/D Tac. The mean daily doses (mg/kg) matching therapeutic C0, regardless of the CYP3A genotypes, were 0.16 ± 0.05 and 0.10 ± 0.05 during early and late PT phase, respectively. Carriers of the CYP3A4*1B allele require higher doses to maintain the C0 in the therapeutic range during the two PT phases. However, patients carrying the CYP3A5*1 require significant higher Tac doses, only during the early phase. CONCLUSION Our data support a critical role of the CYP3A5 6986A>G and CYP3A4 -392A>G polymorphisms on the variation of Tac exposure during the early and the late PT phase, respectively. The establishment of customized Tac doses, according to CYP3A4/CYP3A5 genotype combination and the PT time, may allow preventing graft rejection and improving the safety profile of this drug. Further studies are needed to investigate this issue.

Albendazole-induced associated acute hepatitis and bicytopenia

Abstract 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.