Sleep and mood changes in advanced age after blue-blocking (yellow) intra ocular lens (IOLs) implantation during cataract surgical treatment: a randomized controlled trial.

OBJECTIVES: Both advanced age and depression are characterized by changes in sleep patterns. Light exposure is one of the main synchronizers of circadian cycles and influences sleep by inhibiting melatonin secretion, which is mostly sensitive to light of low wavelengths (blue). Blue-blocking (yellow) intraocular lenses (IOLs) have supplanted the usual UV-blocking (clear) IOLs during cataract surgery to prevent age-related macular degeneration, however, the impact of yellow IOLs on sleep and mood is unclear. The purpose of this study was to compare the effects of yellow and clear IOLs on sleep and mood in aged patients undergoing bilateral cataract surgery. METHODS: A randomized controlled superiority study was conducted within three ophthalmic surgical wards in France. A total of 204 subjects (mean age 76.2 ± 7.5 years) were randomized into yellow or clear IOLs groups. Patients completed a sleep diary, the pictorial sleepiness scale and the Beck Depression Inventory (BDI) one week before and eight weeks after the last surgical procedure. RESULTS: According to an Intent To Treat (ITT) analysis, no significant difference was found between yellow and clear IOLs groups regarding sleep time, sleep latency, total sleep duration, quality of sleep and BDI scores. The rate of patients whose BDI score increased at the cutoff score of ≥5 after surgery was significantly higher in the yellow IOL group (n = 11, 13.1%) compared with the clear IOL group (n = 4; 4.7%); p = 0.02. CONCLUSIONS: Using yellow IOLs for cataract surgery doesn't significantly impact sleep but may induce mood changes in aging.

[Hydroxychloroquine during pregnancy: a review of retinal toxicity in the newborns]. / Toxicité rétinienne de l'hydroxychloroquine chez le nouveau-né exposé in utero.

OBJECTIVE: The objective of this study is to review the published data on ocular toxicity in newborns after in utero exposure to hydroxychloroquine. METHODS: All publications related ophthalmologic follow-up of newborns or infants who were exposed to hydroxychloroquine during pregnancy were selected. RESULTS: Nine studies were analyzed, concerning 246 infants for which an ophthalmological examination was available. None of the infants had signs of ocular toxicity at the clinical stage. Among the 31 infants having electrophysiologics explorations, 4 had suggestive signs of retinal toxicity at the preclinical stage. This could probably be explained by a low cumulative dose, the immaturity of the fetal retina and the low light stimulation in utero. However, without a remote monitoring of infants, it is difficult to conclude to the absence of functional impairment. CONCLUSION: Data are not for a major risk of retinal toxicity associated with exposure in utero to hydroxychloroquine.

[Neonatal risks of drugs exposure at the end of pregnancy]. / Risque néonatal des médicaments pris à la fin de la grossesse.

Foetal drugs exposure consequences depend according to the drug involved and to the length of the exposure which in the sum of length of treatment and of drug elimination (5 half life). Decisions are based upon risk evaluation and are a compromise between a risk banalisation and an excess of carefully. We described risks management for drugs used for a disease due to the pregnancy (glucocorticoïdes, antibiotics) then for drugs used for a chronic disease often preceding the pregnancy (non steroidal anti-inflammatory, serotonin recapture inhibitors, benzodiazepines, antiepileptics, conversion enzyme inhibitors/renine angiotensine antagonists, betabloquants). We also present the elements to take in account for the best drug choice at the end of pregnancy and/or for an adapted advice if the drug has been already taken: the drug itself (pharmacological effects, kinetics in neonate, toxicity marker, risk detection tool), drug amount possibly received by the neonate and literature data about neonatal manifestations due to the drug.

Drug exposure during the periconceptional period: a study of 1793 women.

BACKGROUND: Many studies have described the prescribing of drugs to pregnant women, but only very few have data concerning the periconceptional period specifically. AIM: The aim of the study was to evaluate the incidence of exposure to teratogenic drugs during early pregnancy and to determine whether a safer drug exists. METHODS: In a French health insurances database, we analyzed drugs prescribed during the period starting 1 month before and ending 2 months after the beginning of pregnancy between 1 January 2006 and 31 December 2007. Based on the Summary of Product Characteristics (SPC), drugs we considered were those 'contraindicated', 'not recommended', 'to be avoided', and 'possible' for use during the first trimester of pregnancy. For drugs 'contraindicated', we established if there were alternatives with similar efficacy for the mother and lower risk for the fetus. RESULTS: Over a period of 2.25 years, 8754 drugs were prescribed to 1793 women starting 1 month prior to and ending 2 months after conception. Among these drugs, 20 (0.2%) were 'contraindicated', 195 (2.2%) were 'not recommended', and 1209 (13.8%) were 'to be avoided' during the first trimester of pregnancy. Twenty (1.1%) women received at least one drug that was 'contraindicated' during the first trimester, 171 (9.5%) received a drug that was 'not recommended' and 768 (42.8%) received a drug that was 'to be avoided'. At least one possible alternative was available for all except one 'contraindicated' drug. CONCLUSIONS: During the highest teratogenic risk period, 1.1% of women received a contraindicated drug, despite existence of a safer alternative drug. This may be partly accounted for by physicians not being aware of the pregnancy at the time the drug was administered and could be reduced by adding a section entitled 'women of child-bearing potential' to the SPC.

[Adverse drug reactions of strontium ranelate(Protelos(®) in France]. / Ranélate de strontium (Protelos®): effets indésirables rapportés en France.

OBJECTIVE: Study of side effects (SE) associated with strontium ranelate required by the French Drug agency (Afssaps). METHOD: SE associated with strontium ranelate and spontaneously reported until March 2009 to the manufacturer or to the French Regional Pharmacovigilance Centers and the periodic safety reports have been analyzed. Utilisation and sales data have been obtained from the manufacturer. RESULTS: During the 3 years of the study, 844 SE have been reported in France in patients treated with strontium ranelate. The 199 severe SE are cardiovascular (52%), cutaneous (26%), hepatodigestive (6%), neurological (5%), haematological (3%), osteomuscular (3%) and various (3%). Venous thromboembolic events (VTEE) are the most frequent cardiovascular SE (93/104) with an incidence of 1/31,052 months of treatment. At least one VTEE risk factor is present in 26 (28%) patients. DRESS syndrome which median delay of advent is 35 days is the most frequent cutaneous SE (19/51 SE) with an incidence of 1/13,725 months of treatment. The 14 severe hepatodigestive SE are hepatitis (n=5), pancreatitis (n=2) and various others SE (n=7). The 10 severe neurological SE are confusion/amnesia (n=5), convulsions (n=4) and parenthesis (n=1). The seven severe haematological SE are pancytopenia (n=5), erythroblastopenia (n=1) and thrombocytopenic purpura (n=1). Among the seven deaths, only three (two pulmonary embolisms, one DRESS syndrome) are attributable to strontium ranelate. Apart from the severe SE, 685 SE have also been reported because strontium ranelate was the only drug with an imputability "suspect". DISCUSSION: Anti-fractural effect of strontium ranelate is at least as equal as those of bisphosphonates. Its usual SE are benign but two severe risks of strontium ranelate i.e. VTEE and DRESS syndrome are confirmed. The profile of tolerability, different from the one of bisphosphonates makes strontium ranelate as an alternative when bisphosphonates are not recommended or contraindicated (renal insufficiency for example). CONCLUSION: If DRESS syndrome is unpredictable, the one of VTEE could be reduced by a strontium ranelate contraindication for patients with a history of VTEE and by stopping the drug if a new VTEE risk situation happens.

Risk of ST versus non-ST elevation myocardial infarction associated with non-steroidal anti-inflammatory drugs.

OBJECTIVE: The objective of this study was to explore the association of non-steroidal anti-inflammatory drugs (NSAID) with ST-segment elevation myocardial infarction (STEMI) and non-ST segment elevation myocardial infarction (NSTEMI). DESIGN, SETTING & PATIENTS: A matched case-control study comparing patients with incident non-fatal myocardial infarction (MI) collected by cardiologists with controls. Cases were retrieved from the Pharmacoepidemiological General Research on Myocardial Infarction (PGRx-MI) registry, a French nationwide registry consisting of 55 cardiology centres, whereas controls were selected from general practice settings. Both cases and controls were recruited from the same geographically diverse areas across continental France. MAIN OUTCOME MEASURES: The association between NSAID and MI was assessed by matched adjusted OR from conditional logistic regression. RESULTS: Between 2007 and 2009, 1125 incident cases were included (67.3% and 32.7% for STEMI and NSTEMI, respectively), with 2790 controls matched to MI cases by age and sex. Current use (previous 2 months) of either diclofenac or naproxen and other arylpropionic acid NSAID was not associated with STEMI (OR 0.9, 95% CI 0.4 to 1.9 and OR 1.0, 95% CI 0.6 to 1.7, respectively), instead it showed significant association with NSTEMI (OR 2.8, 95% CI 1.2 to 6.4 and OR 0.4, 95% CI 0.2 to 0.9, respectively). Our study confirms results from previously published analyses on the association of MI with NSAID (OR 1.5, 0.9, and 1.0 for diclofenac, naproxen and related NSAID, and all NSAID combined, respectively). CONCLUSIONS: Our study shows that the MI risk modification associated with NSAID is limited to NSTEMI.

Heptavalent pneumococcal conjugate vaccine (PCV7): French survey of serious adverse reactions.

PURPOSE: Previous study did not reveal any particular heptavalent pneumococcal conjugate vaccine (PCV7) related risk. However, french drugs agency (Afssaps) requested the continuation of its surveillance. METHODS: All serious PCV7-related adverse drug reactions spontaneously reported between October 1, 2004 and December 31, 2007 to the French pharmacovigilance centers or to Wyeth Pharmaceutical France were included. Vaccine failure was defined as an invasive pneumococcal infection due to vaccine serotype which occurs at least 15 days after the third dose of vaccine. Incidence rates were estimated according to the doses number except for vaccine failure estimated according to the vaccinated children number. RESULTS: During the 39-month follow-up period, 154 serious adverse drug reactions were spontaneously reported: convulsions (17%), fever (13%), hypotonia (10%), sudden death (7%) and thrombopenic purpura (6%). Evolution was recovery in 72% of cases. PCV7 was the only suspect medication in 28% of cases. The median age was 4 months (range 1-108), and the children's sex was male in 53%. The adverse drug reaction recurred after a subsequent injection in six cases. Among the 24 pneumococcal infections PCV7 failure was certain in 4 cases. The incidences of serious adverse drug reactions did not differ from our previous survey, except the incidence of thrombopenic purpura and of PCV7 failure which seems to be increasing. CONCLUSIONS: This new study confirms the risk of vascular purpura, raises the thrombopenic purpura issue, and the emergence of PCV7 failures which will need a strict monitoring of the future 13 valences vaccine.

Isotretinoin exposure during pregnancy: assessment of spontaneous reports in France.

BACKGROUND: In three previous studies, we have shown that pregnant women were still being exposed to isotretinoin and that compliance with recommendations was incomplete. The relaxation of these recommendations (summary of product characteristics 2004), combined with the release of generic brands, encouraged us to carry out a fourth study. OBJECTIVE: To assess isotretinoin exposure during pregnancy following the application of less stringent recommendations and the marketing of generic isotretinoin brands. METHODS: All cases of isotretinoin exposure during pregnancy, between 1 January 2003 and 31 December 2006, spontaneously reported to pharmacovigilance centres, the Teratogenic Agent Information Centre, and pharmaceutical companies in France were assessed. Cases were classified for analysis into the following groups: 'conception <1 month after isotretinoin discontinuation', 'conception during isotretinoin treatment' and 'patient already pregnant when isotretinoin was started'. The rate of spontaneously reported isotretinoin exposure during pregnancy was estimated by dividing the number of isotretinoin-exposed pregnancies by the number of women of childbearing age treated with isotretinoin. RESULTS: Over 4 years, 147 cases of isotretinoin exposure during the teratogenic risk period were spontaneously reported, i.e. 'conception <1 month after isotretinoin discontinuation' (23%), 'conception during isotretinoin treatment' (61%), and 'patient already pregnant when isotretinoin was started' (16%). Nineteen percent of the patients did not use any form of contraception. In 23% of the patients, the method of contraception used did not comply with recommendations, while in 86% of the cases, isotretinoin was prescribed by a dermatologist. Among the 44 pregnancies with available data on fetuses or neonates, there were two (4.5%) malformations compatible with the time of exposure and with isotretinoin embryopathy. The rate of spontaneously reported isotretinoin exposure during pregnancy has increased by approximately 30%, from 0.32 (95% CI 0.26, 0.38) to 0.41 (95% CI 0.34, 0.49) per 1000 women of childbearing age treated since 1999-2002. CONCLUSIONS: We suggest that recommendations be tightened, with specific information regarding the most effective contraceptive method combined with compulsory monthly pregnancy testing during treatment. The French Drug Agency has informed the European Medicines Agency of the need for measures aimed at improving compliance.

[Adverse reactions of atazanavir, fosamprenavir and tipranavir in "real life"]. / Effets indésirables de l'atazanavir, du fosamprénavir et du tipranavir en situation réelle d'emploi.

OBJECTIVE: To precise adverse effects of atazanavir, fosamprenavir and tipranavir "in real life". METHOD: Descriptive study of 3 protease inhibitor adverse effects stored in the French Bank of Pharmacovigilance. RESULTS: Nineteen adverse effects having at least possible links with antiretroviral drugs studied were reported. It was essentially hepatobiliary (atazanavir: 29/59, tipranavir: 4/6) and skin (fosamprenavir: 10/20) adverse reactions. These reactions, relatively "serious" (35.1%) led to the interruption of the person (or persons) medication (s) suspected (s) in 69 folds (82.1%) and evolved to healing without sequelae in 68 folds (81%). CONCLUSION: The drug side effects were for the most expected. However, their frequency and their seriously underline the interest of a post-AMM monitoring to reassess the drugs risk-benefit report.

Clinical features and risk factors for upper gastrointestinal bleeding in children: a case-crossover study.

OBJECTIVE: This population-based survey was conducted to provide a formal description of upper gastrointestinal bleeding (UGIB) in children on a nationwide basis and assess the contribution of risk factors, principally nonsteroidal anti-inflammatory drugs (NSAID). METHODS: A case-crossover study of UGIB patients aged between 2 months and 16 years was conducted in France. Medical data were collected by physicians, and personal risk factors and exposure to drugs during the month preceding the onset of the bleeding was ascertained by a standardised telephone interview with parents. The odds ratios for UGIB and NSAID was assessed by comparing exposure during the 7 days preceding the date of hospitalisation and the 21st to the 28th days before that date. RESULTS: A total of 177 children with UGIB were included over 2 years. Eighty-three children had taken at least one NSAID before the index date, among which 58 were ibuprofen, 26 aspirin and nine others. The adjusted odds ratio (OR) of exposure was 8.2 [95% confidence interval (CI) 2.6-26.0] for NSAIDs altogether, and this was 10.0 (95% CI 2.0-51.0) for ibuprofen and 7.3 (95% CI 0.9-59.4) for aspirin. There was no increased risk associated with NSAIDS for oesophageal lesion [OR = 1.0 [(5% CI:0.2-7.2)]. CONCLUSION: The study confirms that UGIB is rare but that some cases may be avoided, as one third of the cases was attributable to exposure to NSAID at doses used for analgesic or antipyretic purposes, which may be attained with alternative therapy. The findings from this study call for more caution in prescribing NSAIDS to children.

Drug dependence associated with triptans and ergot derivatives: a case/non-case study.

INTRODUCTION: The aim of this case/non-case study was to assess and compare the risk of drug dependence associated with different migraine-specific drugs, i.e., ergot derivatives and triptans, using the French pharmacovigilance database. METHODS: Reports on drug side effects recorded in this database between January 1985 and June 2007 were analyzed, and triptans (almotriptan, eletriptan, naratriptan, sumatriptan, and zolmitriptan) as well as ergot derivatives used in acute migraine were examined. For all reports, cases were defined as those reports corresponding to "drug abuse," "physical or mental drug dependence," and "pharmacodependence," whereas "non-cases" were defined as all the remaining SED reports. The method's reliability was assessed by calculating the risk associated with a negative (amoxicillin) and a positive (benzodiazepines) control. The risk of dependence associated with each drug and control was evaluated by calculating the odds ratio (OR) with a confidence interval of 95%. RESULTS: Among the 309,178 reports recorded in the database, drug dependence accounted for 0.8% (2,489) of the reports, with 10.9% (449) involving a triptan, and 9.33% (332) an ergot derivative. The risk of dependence was similar for triptans and ergot derivatives and did not differ from that of benzodiazepines. In the triptan group, the risk (odds ratio [95% CI]) ranged from 10.3 [4.8-22.3] for sumatriptan to 21.5 for eletriptan [10.1-45.6], while in the ergot derivative group, it ranged from 12 [8-17.9] for ergotamine to 20.6 [8-53] for dihydroergotamine. CONCLUSIONS: These findings confirm the hypothesis that triptans and ergot derivatives are associated with an increased risk of drug dependence.

Avoidability of adverse drug reactions spontaneously reported to a French regional drug monitoring centre.

BACKGROUND: Adverse drug reactions (ADRs) are now recognized as a major category of iatrogenic illness in terms of morbidity and mortality. OBJECTIVE: To describe the type and frequency of avoidable ADRs spontaneously reported to a regional drug monitoring centre following inappropriate prescribing, as a basis for preventive actions. METHODS: A prospective, observational study of ADRs reported to the Regional Drug Monitoring Centre of Tours, France, between 26 November 2002 and 28 November 2003. The outcome measure was ADRs secondary to inappropriate prescribing that were defined as entirely or partly avoidable, i.e. at least one of the recommendations in various sections of the summary of product characteristics (SPC; indication, route of administration, dose, duration of treatment, dose adaptation, precautions for use, monitoring of treatment, absolute contraindications and contraindicated interactions) had not been respected. The link between the lack of conformity of the drug prescription with the SPC and occurrence of the ADR was evaluated by a working group using two criteria: (i) is nonconformity of the prescription of this drug a known and validated risk factor for this ADR?; and (ii) are there other aetiologies or other risk factors for this ADR? RESULTS: Three hundred and sixty ADRs in 294 adults and 66 children were analysed. The prescription was considered inappropriate for 213 of the 659 (32%) drugs implicated in ADRs, corresponding to 161 patients (45%). The ADR was adjudged entirely avoidable for 32 (9%) patients, partly avoidable for 28 (8%) patients and unavoidable for 300 (83%) patients. Not taking into account a history of allergy or altered renal function and not respecting the recommended dose were the most frequent causes of entirely avoidable ADRs. Allopurinol and lamotrigine were the drugs most frequently involved in serious avoidable ADRs. CONCLUSIONS: Preventive actions should focus on more systematic allergy checks when prescribing drugs and on dose adaptation in cases of altered renal function.

A multicentre case-control study of nonsteroidal anti-inflammatory drugs as a risk factor for severe sepsis and septic shock.

INTRODUCTION: We aimed to establish whether the use of nonsteroidal anti-inflammatory drugs (NSAIDs) during evolving bacterial community-acquired infection in adults is associated with severe sepsis or septic shock. METHODS: We conducted a multicentre case-control study in eight intensive care units. Cases were all adult patients admitted for severe sepsis or septic shock due to a bacterial community-acquired infection. Control individuals were patients hospitalized with a mild community-acquired infection. Each case was matched to one control for age, presence of diabetes and site of infection. RESULTS: The main outcome measures were the proportions of cases and controls exposed to NSAIDs or aspirin during the period of observation. In all, 152 matched pairs were analyzed. The use of NSAIDs or aspirin during the observation period did not differ between cases and controls (27% versus 28; odds ratio = 0.93, 95% confidence interval [CI] = 0.52 to 1.64). If aspirin was not considered or if a distinction was made between acute and chronic drug treatment, there remained no difference between groups. However, the median time to prescription of effective antibiotic therapy was longer for NSAID users (6 days, 95% CI = 3 to 7 days) than for nonusers (3 days, 95% CI = 2 to 3 days; P = 0.02). CONCLUSIONS: In this study, the use of NSAIDs or aspirin during evolving bacterial infection was frequent and occurred in one-quarter of the patients with such infection. Although the use of NSAIDs by patients with severe sepsis or septic shock did not differ from their use by those with mild infection at the same infected site, we observed a longer median time to prescription of effective antibiotic therapy in NSAID users.

Prevalence and patterns of methylphenidate use in French children and adolescents.

OBJECTIVE: The aim of the study was to describe the prevalence and utilization patterns of methylphenidate (MPH) in children and adolescents in France. METHODS: This was a population-based retrospective study in which the cohort consisted of patients for whom data were extracted from the dispensation drug claims database of the national health insurance (NHI) fund for self-employed workers. Annual prevalence of MPH use was evaluated on patients aged 6-18 years who were reimbursed for at least one MPH prescription a year. Between January 2004 and June 2005, features of MPH medication and user profile were described for the "new starters" having a screening period of 1 year without receiving a MPH prescription and a follow-up >or=12 months. Time to interruption of MPH regular use was analysed by Kaplan-Meier survival analysis. Mean duration of exposure to MPH treatment was computed with the 95% confidence interval (CI). RESULTS: Annual prevalence of MPH per 1000 persons was 1.1 in 2003, 1.5 in 2004 and 1.8 in 2005 (relative increase of 63.5%). New starters (n = 447) received their first MPH prescription through the hospital (65.1%) or through private practitioners (34.9%). The user profiles were: short (16.6%), occasional (33.8%) and regular (49.6%). Among the new starters, the median time to interruption of MPH regular use was 10.2 months (95% CI: 7.9-12.4). The mean duration of exposure to MPH treatment was: occasional (4.9 months, 95% CI: 4.3-5.5) and regular (25.7 months, 95% CI: 24.6-26.8). CONCLUSION: Although there is a low prevalence of MPH use in France, this survey revealed a wide profile of users and heterogeneous use patterns.

Ibuprofen versus paracetamol in pediatric fever: objective and subjective findings from a randomized, blinded study.

OBJECTIVE: The main objective of this study was to compare the single-dose efficacy of 15 mg/kg paracetamol (acetaminophen) versus 10 mg/kg ibuprofen in a general practice setting. METHODS: Children from the age of 3 months to 12 years with a fever of non-serious origin were randomized to receive either ibuprofen or paracetamol. The first dose was given double-blind, using a double-dummy technique. Tympanic temperature was measured at baseline and over the following 8 hours. The second and subsequent doses were administered open-label for up to 3 days by parents at home. At the end of the double-blind and the open-label periods, parents were asked to subjectively rate the efficacy of the product and state whether they would treat their child with the product again. The primary endpoint of the study was the area under the temperature reduction curve expressed as an absolute difference from baseline, from 0 to 6 hours (AUC(0-6)). Secondary efficacy endpoints included a variety of objective and subjective measures. RESULTS: No statistically significant differences in the primary endpoint or any of the objective secondary endpoints were observed. Both agents were equally well tolerated. Compared with parents in the paracetamol group, significantly more parents in the ibuprofen group rated the drug as very efficacious, and reported that they would use the drug again in both the double-blind and open-label phases of the study. CONCLUSIONS: Ibuprofen at a dose of 10 mg/kg and paracetamol at a dose of 15 mg/kg have equivalent efficacy and tolerability; parental opinion in favor of ibuprofen could be explained by additional benefits of ibuprofen that were not measured in this trial and helped allay their anxiety over the treatment of their child.

Lack of association between rifampicin plasma concentration and treatment-related side effects in osteoarticular infections.

The aim of this study was to assess the frequency of gastrointestinal side effects (GSE) and hepatotoxicity in patients treated with rifampicin for an osteoarticular infection and to determine if there is an association between rifampicin plasma concentrations and side effects. Rifampicin plasma concentrations were prospectively measured before (trough concentration, C(0)) and 2 +/- 0.5 h (peak concentration, C(2)) after drug intake. The presence of GSE, the alanine transferase (ALT) value, and concomitantly administered medications were recorded on the day rifampicin concentrations were measured. C(0) and C(2) were compared for differences regarding the presence or absence of side effects. Multivariate analysis was performed, with associated medications being taken into account. Seventy C(0) and 57 C(2) values were measured in 46 adults after a median treatment of 8 days (range, 1-179). Wide inter-individual variability was observed for C(0) and C(2). Thirteen (28%) patients reported GSE at least once. When GSE occurred, C(0) (median, 1 mg L(-1); range, 0.1-9.9 mg L(-1)) and C(2) (median, 10.3 mg L(-1); range, 1.8-40.3 mg L(-1)) were similar to C(0) (median, 0.6 mg L(-1); range, 0.1-10.3 mg L(-1)) and C(2) (median, 10.9 mg L(-1); range, 2.9-29.0 mg L(-1)) without GSE. The ALT value was more than normal in only three patients (6.5%) after rifampicin treatment began. The patients received no different associated medications whether or not GSE were present. Multivariate analysis showed no association between rifampicin plasma concentrations and GSE. GSE occur frequently in patients receiving rifampicin for osteoarticular infection but without an association with rifampicin plasma concentrations. Thus, therapeutic drug monitoring of rifampicin is irrelevant in the management of GSE.