Assessment of current practice for ß-lactam therapeutic drug monitoring in French ICUs in 2021: a nationwide cross-sectional survey.

BACKGROUND: Current guidelines and literature support the use of therapeutic drug monitoring (TDM) to optimize ß-lactam treatment in adult ICU patients. OBJECTIVES: To describe the current practice of ß-lactam monitoring in French ICUs. METHODS: A nationwide cross-sectional survey was conducted from February 2021 to July 2021 utilizing an online questionnaire that was sent as an email link to ICU specialists (one questionnaire per ICU). RESULTS: Overall, 119 of 221 (53.8%) French ICUs participated. Eighty-seven (75%) respondents reported having access to ß-lactam TDM, including 52 (59.8%) with on-site access. ß-Lactam concentrations were available in 24-48 h and after 48 h for 36 (41.4%) and 26 (29.9%) respondents, respectively. Most respondents (n = 61; 70.1%) reported not knowing whether the ß-lactam concentrations in the TDM results were expressed as unbound fractions or total concentrations. The 100% unbound fraction of the ß-lactam above the MIC was the most frequent pharmacokinetic and pharmacodynamic target used (n = 62; 73.0%). CONCLUSIONS: Despite the publication of international guidelines, ß-lactam TDM is not optimally used in French ICUs. The two major barriers are ß-lactam TDM interpretation and the required time for results.

Online SPE UPLC-MS/MS method for the simultaneous determination of 33 psychoactive drugs from swab-collected human oral fluid samples.

Oral fluid is easy and safe to collect and allows the detection of drugs of abuse after local exposure by oral, smoked, and/or inhaled intake, or systemic exposure. A routine online solid-phase extraction UPLC-MS/MS method was developed for the simultaneous determination of 33 psychoactive drugs in oral fluid. The selected drugs were fourteen fentanyl analogs and nineteen other abused psychoactive compounds, including classical narcotics, which were analyzed in a run of 10 min. Limits of detection and of quantification ranged from 0.02 to 1 ng/mL and from 0.02 to 5 ng/mL depending on the analyte, respectively. Matrix effect was in the range - 17 to + 15.7% for all analytes having a deuterated analog. Accuracy ranged from 82.7 to 113.4% and precision CV was at worst of 18.6%. Carryover was below 0.8% for all analytes. Recovery from FLOQSwabs™ showed high variability between analytes with THC, D2FF, 4-ANPP, ocfentanil, and valerylfentanyl being recovered below 40%. A stability study performed over 2 weeks on collecting devices loaded with artificial oral fluid showed huge variation between analytes with morphine, BZE, and norfentanyl being the more stable. Storage at 4 °C allowed drug detection for 1 week except for THC and remifentanil. The method was successfully applied to the detection of abused psychoactive compounds in oral fluid samples from 6 patients admitted to an addiction department.

Temocillin dosage adjustment in a preterm infant with severe renal disease: a case report.

BACKGROUND: Temocillin is a carboxypenicillin antibiotic indicated in complicated urinary tract infections due to susceptible ESBL-producing Enterobacteriaceae. While temocillin therapeutic schemes for adult patients with normal or impaired renal function are evidence based, little is known in paediatric populations. OBJECTIVES: We report herein the management of temocillin treatment in a preterm infant with end-stage renal disease. PATIENTS AND METHODS: The patient was a 7-month-old preterm infant born at 35 weeks gestation and treated by temocillin for 10 days for a bacteraemic urinary tract infection due to a susceptible ESBL-producing Enterobacter cloacae complex strain. Temocillin was administered by continuous infusion using a loading dose of 25 mg followed by a maintenance dose of 70 mg daily. Determination of MIC and temocillin plasma and urinary concentration was performed. RESULTS: Clinical improvement was observed 24 h after the initiation of temocillin treatment. Temocillin concentrations ranged between 21.6 and 35.5 mg/L in urine between the first and the sixth day of treatment and between 47.0 and 61.8 mg/L in plasma after 6 and 10 days of treatment, respectively. Temocillin concentrations were found to be above the determined MIC of 6 mg/L. From the measured concentrations, we can postulate that 100%fT>MIC was achieved in urine and at least equal to 40% in plasma. CONCLUSIONS: Temocillin dosing adjustment performed in the present reported case allowed safe and effective treatment. The strategy described herein could be used as a basis for further clinical studies relative to temocillin use in a paediatric population with renal impairment.

Serum and peritoneal exudate concentrations after high doses of ß-lactams in critically ill patients with severe intra-abdominal infections: an observational prospective study.

BACKGROUND: Critically ill patients with severe intra-abdominal infections (IAIs) requiring surgery may undergo several pharmacokinetic (PK) alterations that can lead to ß-lactam underdosage. OBJECTIVES: To measure serum and peritoneal exudate concentrations of ß-lactams after high doses and optimal administration schemes. METHODS: This observational prospective study included critically ill patients with suspicion of IAI who required surgery and a ß-lactam antibiotic as empirical therapy. Serum and peritoneal exudate concentrations were measured during surgery and after a 24 h steady-state period. The PK/pharmacodynamic (PD) target was to obtain serum ß-lactam concentrations of 100% fT>4×MIC based on a worst-case scenario (based on the EUCAST highest epidemiological cut-off values) before bacterial documentation (a priori) and redefined following determination of the MIC for the isolated bacteria (a posteriori). Registered with ClinicalTrials.gov (NCT03310606). RESULTS: Forty-eight patients were included with a median (IQR) age of 64 (53-74) years and a SAPS II of 40 (32-65). The main diagnosis was secondary nosocomial peritonitis. Piperacillin/tazobactam was the most administered ß-lactam antibiotic (75%). The serum/peritoneal piperacillin/tazobactam ratio was 0.88 (0.64-0.97) after a 24 h steady-state period. Prior to bacterial documentation, 16 patients (33.3%) achieved the a priori PK/PD target. The identification of microorganisms was available for 34 patients (71%). Based on the MIC for isolated bacteria, 78% of the patients achieved the serum PK/PD target. CONCLUSIONS: In severe IAIs, high doses of ß-lactams ensured 100% fT>4×MIC in the serum for 78% of critically ill patients with severe IAIs within the first 24 h. In order to define optimal ß-lactam dosing, the PK/PD target should take into account the tissue penetration and local ecology.

Antibiotic prophylaxis with high-dose cefoxitin in bariatric surgery: an observational prospective single center study.

BACKGROUND: The optimal dose of cefoxitin for antibiotic prophylaxis in obese patients remains uncertain. We evaluated the adequacy of a 4-gram dosing regimen of cefoxitin against the most frequent pathogens that infect patients undergoing bariatric surgery. METHODS: This observational prospective study included obese patients who required bariatric surgery and a 4-gram dose of cefoxitin as an antibiotic prophylaxis. Serum concentrations were measured during surgery (incision, wound closure and in case of reinjection). The pharmacokinetic/pharmacodynamic (PK/PD) target was to obtain free cefoxitin concentrations above 4× MIC, from incision to wound closure (100% ƒT>4xMIC). The targeted MIC was based on the worst-case scenario (the highest ECOFF value of Staphylococcus aureus, Enterobacteriaceae and anaerobic bacteria). The secondary outcomes were the factors related to underdosage. RESULTS: Two hundred patients were included. The mean age of the patients was 46 (±12) years-old, and the mean BMI was 45.8 (±6.9) kg/m2 Bypass surgery was the preferred technique (84%). The percentages of patients who met the PK/PD target (100% fT>4xMIC) of cefoxitin were 37.3%, 1.1% and 0% for S. aureus, Enterobacteriaceae and anaerobic bacteria, respectively. BMIs below 50 kg/m2 (OR 0.29, 95% CI [0.11-0.75], P = 0.0107) and a shorter duration of surgery (OR 0.97, 95% CI [0.95-0.99], P = 0.004) were associated with reaching the target concentrations. CONCLUSIONS: In obese patients undergoing bariatric surgery, a regimen of 4 grams of cefoxitin led to an inadequate coverage for most common pathogens. A longer surgery duration and BMI over 50 kg/m2 increase the risk of underdosage.

Optimization of the treatment with beta-lactam antibiotics in critically ill patients-guidelines from the French Society of Pharmacology and Therapeutics (Société Française de Pharmacologie et Thérapeutique-SFPT) and the French Society of Anaesthesia and Intensive Care Medicine (Société Française d'Anesthésie et Réanimation-SFAR).

BACKGROUND: Beta-lactam antibiotics (ßLA) are the most commonly used antibiotics in the intensive care unit (ICU). ICU patients present many pathophysiological features that cause pharmacokinetic (PK) and pharmacodynamic (PD) specificities, leading to the risk of underdosage. The French Society of Pharmacology and Therapeutics (SFPT) and the French Society of Anaesthesia and Intensive Care Medicine (SFAR) have joined forces to provide guidelines on the optimization of beta-lactam treatment in ICU patients. METHODS: A consensus committee of 18 experts from the two societies had the mission of producing these guidelines. The entire process was conducted independently of any industry funding. A list of questions formulated according to the PICO model (Population, Intervention, Comparison, and Outcomes) was drawn-up by the experts. Then, two bibliographic experts analysed the literature published since January 2000 using predefined keywords according to PRISMA recommendations. The quality of the data identified from the literature was assessed using the GRADE® methodology. Due to the lack of powerful studies having used mortality as main judgement criteria, it was decided, before drafting the recommendations, to formulate only "optional" recommendations. RESULTS: After two rounds of rating and one amendment, a strong agreement was reached by the SFPT-SFAR guideline panel for 21 optional recommendations and a recapitulative algorithm for care covering four areas: (i) pharmacokinetic variability, (ii) PK-PD relationship, (iii) administration modalities, and (iv) therapeutic drug monitoring (TDM). The most important recommendations regarding ßLA administration in ICU patients concerned (i) the consideration of the many sources of PK variability in this population; (ii) the definition of free plasma concentration between four and eight times the Minimal Inhibitory Concentration (MIC) of the causative bacteria for 100% of the dosing interval as PK-PD target to maximize bacteriological and clinical responses; (iii) the use of continuous or prolonged administration of ßLA in the most severe patients, in case of high MIC bacteria and in case of lower respiratory tract infection to improve clinical cure; and (iv) the use of TDM to improve PK-PD target achievement. CONCLUSIONS: The experts strongly suggest the use of personalized dosing, continuous or prolonged infusion and therapeutic drug monitoring when administering ßLA in critically ill patients.

[Good use and knowledge of paracetamol (acetaminophen) among self-medicated patients: Prospective study in community pharmacies]. / Étude prospective en pharmacie du bon usage et de la connaissance du paracétamol pris en automédication.

Acetaminophen (paracetamol), the highest over-the-counter (OTC) selling drug in France, is also the first cause of acute hepatic failure. We aimed to assess the good use and the knowledge of acetaminophen in a setting of urban self-medicated patients. We conducted a prospective observational study in randomly selected community pharmacies of Metz (France) agglomeration. Patients coming to buy OTC acetaminophen for themselves or their family had to answer to an anonymous autoquestionnaire. Responses were individually and concomitantly analyzed through 3 scores: good use, knowledge and overdosage. Twenty-four community pharmacies participated and 302 patients were interviewed by mean of a dedicated questionnaire. Most of patients (84.4%) could be considered as "good users" and independent factors of good use were (i) a good knowledge of acetaminophen (OR=5.3; P<0.0001) and more surprisingly; (ii) the fact of having no children (parentality: OR=0.1; P=0.006). Responses corresponding to involuntary overdosage were mostly due to a too short interval between drug intakes (3hours). Only 30.8% of patients were aware of liver toxicity of acetaminophen and only 40.7% knew the risk of the association with alcohol. Both good use and knowledge were significantly higher in patients looking for information from their pharmacist, physician and package leaflet. Patients should definitely be better informed about acetaminophen to warrant a better safety of its consumption. Pharmacists and physicians have to remind patients the risk factors of unintentional overdose and liver toxicity. Package leaflets have also to be more informative.

[Counterfeit and Falsified Drugs: an Overview]. / Trafic de faux médicaments : panorama 2014.

If the traffic of fake medicines may represent an economic threat for the pharmaceutical industry, it can also be responsible of safety concerns for patients. Despite fake drugs represent a real threat for public health, the intended punishments are until now only based on intellectual property rights. Estimated to generate more than 55 billion euros per year, the traffic of falsified drugs varies from a country to another one. Indeed, the proportion of falsified drugs ranges from 1% in industrialized countries with a regulated and controlled distribution system to 60% of medicines in some developing countries. Currently, the measures developed to limit this traffic concern five main areas: legislation / regulation, cooperation, enforcement, technology and communication. Communication actions should be performed to inform health professionals as the populations about the risks of using drugs purchased outside the legal drug market.

Role of nicotinic acid and nicotinamide in nicorandil-induced ulcerations: from hypothesis to demonstration.

Nicorandil, a nicotinamide ester, was first reported to be involved in the induction of oral ulcers in 1997. Since then, many reports of single or multiple nicorandil-induced ulcerations (NIUs) have been reported. We hypothesised that in the case of high-dosage nicorandil or after an increased dosage of nicorandil, nicotinic acid and nicotinamide (two main metabolites of nicorandil) cannot appropriately merge into the endogenous pool of nicotinamide adenine dinucleotide/phosphate, which leads to abnormal distribution of these metabolites in the body. In recent or maintained trauma, nicotinamide increases blood flow at the edge of the raw area, inducing epithelial proliferation, while nicotinic acid ulcerates this epithelial formation, ultimately flooding the entire scar. We demonstrate, by comparison to a control patient non-exposed to nicorandil, an abnormal amount of nicotinic acid (×38) and nicotinamide (×11) in the ulcerated area in a patient with NIUs. All practitioners, especially geriatricians, dermatologists and surgeons, must be aware of these serious and insidious side effects of nicorandil. It is critical to rapidly reassess the risk-benefit ratio of this drug for any patient, and not only for those with diverticular diseases.

Death of an alcohol-dependent patient following intentional drug intoxication: implication of baclofen?

Used in the treatment of spasticity at low doses, baclofen is also prescribed off-label at high doses for the treatment of alcohol dependence. Several cases of baclofen intoxication have been reported, but only 1 case deals with the treatment of alcohol dependence. Thus, we report the first death in the context of baclofen off-label use of an alcohol-dependent patient with a high blood baclofen concentration after intentional drug intoxication. The safety profile of baclofen in the treatment of alcohol dependence is reviewed and discussed, underlining the obligatory caution that may support any prescription of high doses of baclofen in this off-label indication and especially in patients with concomitant psychiatric disorders.

Population pharmacokinetics of prophylactic cefoxitin in elective bariatric surgery patients: a prospective monocentric study.

BACKGROUND: This study describes the population pharmacokinetics of cefoxitin in obese patients undergoing elective bariatric surgery and evaluates different dosing regimens for achievement of pre-defined target exposures. METHODS: Serial blood samples were collected during surgery with relevant clinical data. Total serum cefoxitin concentrations were measured by chromatographic assay and analysed using a population PK approach with Pmetrics®. The cefoxitin unbound fraction (fu) was estimated. Dosing simulations were performed to ascertain the probability of target attainment (PTA) to achieve cefoxitin fu above minimum inhibitory concentrations (MIC) from surgical incision to wound closure. Fractional target attainment (FTA) was calculated against MIC distributions of common pathogens. RESULTS: A total of 123 obese patients (median BMI 44.3 kg/m2) were included with 381 cefoxitin concentration values. Cefoxitin was best described by a one-compartment model, with a mean clearance and volume of distribution of 10.9 ± 6.1 L/h and 23.4 ± 10.5 L, respectively. In surgery <2 h, a 2 and a 4 g doses were sufficient for an MIC up to 4 and 8 mg/L (fu 50%), respectively. In prolonged surgery (2-4 h), only continuous infusion enabled optimal PTA for an MIC up to 16 mg/L. Optimal FTAs were obtained against Staphylococcus aureus and Escherichia Coli only when simulating with 50% cefoxitin protein binding (intermittent regimen) and regardless of the protein binding for the continuous infusion. CONCLUSION: Intermittent dosing regimens resulted in optimal FTAs against susceptible MIC distributions of S. aureus and E. coli when simulating with 50% cefoxitin protein binding. Continuous infusion of cefoxitin may improve FTA regardless of protein binding. STUDY REGISTRATION: Registration on ClinicalTrials.gov, NCT03306290.

Evaluation of amphetamines diffusion in hair after contact with amphetamines-containing blood.

Amphetamine-type stimulants are the third most widely consumed category of illicit drugs worldwide. Faced with the growing problem of amphetamine-type stimulants, numerous qualitative and quantitative techniques have been developed to detect amphetamine (AMP), methamphetamine (MET), MDMA, MDEA or MDA in biological matrices, including hair. Hair analysis is widely used in forensic medicine, but one of its main drawbacks remains external contamination. In this study, we investigated the possibility of hair contamination through external exposure to blood containing AMP, MET MDMA, MDEA or MDA at 2 ng/mL; 20 ng/mL; 200 ng/mL or 2000 ng/mL after 6 h, 1, 3, 7 or 14 days of contact protected from light at room temperature (RT or 20 °C) or at 4 °C. Dried extracts of hair samples were analyzed by UPLC-MS/MS after extensive washings in several baths of water, methanol and acetone before grounding. At the end of our study, contamination of hair was observed from 6 h of contact with all tested amphetamine-type stimulants. The concentrations found in hair ranged from 3 ± 1 to 1464 ± 10 pg/mg, 5 ± 1 to 5070 ± 160 pg/mg, 3 ± 1 to 1269 ± 60 pg/mg, 4 ± 1 to 1860 ± 113 pg/mg and from 8 ± 1 to 1041 ± 44 pg/mg for AMP, MET, MDMA, MDEA and MDA, respectively. Possibly due to its low polar surface area, MET was the most prone to contaminate. As anticipated, hair contamination was mainly dependent on the concentration of all molecules in the contaminating blood, reaching the SOHT cut-off of 200 pg/mg when amphetamine-type stimulants are at toxic or lethal concentrations in the blood. These observations call for caution in interpreting exposure to these substances in such forensic situations.

In vitro stability study of 10 beta-lactam antibiotics in human plasma samples.

BACKGROUND AND OBJECTIVES: Beta-lactam antibiotics are reported for some of them to be subject to a rapid degradation in infusion solutions and in human blood samples. However, the current data of stability available in blood samples are limited to a few number of beta-lactam antibiotics, and the methodology of the corresponding studies may be discussed. The objective of the present study is to evaluate the stability of 10 beta-lactam antibiotics in human plasma samples. METHODS: Stability of amoxicillin, cefazolin, cefepime, cefotaxime, cefoxitin, ceftazidime, ceftriaxone, imipenem, meropenem, and piperacillin was evaluated at low and high concentrations at 20°C, 4°C, -20°C, and -80°C for 1, 7, 60, and 90 days, respectively. RESULTS: Amoxicillin, cefepime, meropenem, and piperacillin were the least stable antibiotics. The maximum durations allowing the stability for all the evaluated beta-lactams at both tested concentrations were estimated at 3 h, 23 h, 10 days, and 35 days at 20°C, 4°C, -20°C, and -80°C, respectively. CONCLUSION: We recommend to transport antibiotic plasma samples in ice at 4°C and even at -20°C if these samples come from external hospitals. Ideally, plasma samples should be stored at -80°C if possible; if not, the analysis of the samples should be performed as soon as possible in the limit of 10 days after a storage at -20°C.

Rat synovial tissue and blood rapamycin pharmacokinetics after intra-articular injection of free solution or nanoparticles vs free rapamycin intravenous shot.

Intra-articular (IA) injection of a chondroprotective candidate may delay the osteoarthritis (OA) course, but its rapid absorption into systemic circulation may limit efficacy and produce untoward effects. We compared the pharmacokinetics (PK) of IA rapamycin injected as sustained release in nanoparticles (NPs) versus a free rapamycin suspension in the rat knee compared to an intravenous (IV) free rapamycin shot taken as a reference. Rats received either a single IV injection of free rapamycin (10 µM) or an IA of free or NPs-loaded rapamycin. After sequential exsanguination (15, 30, 60, 180, 360 min, D1, and D7), knee synovial tissue (ST) and cartilage histology were performed. Blood and ST concentrations (LC-MS/MS), PK parameters (area under the curve: AUC; mean residence time: MRT; elimination half-life: T1/2), and IA biocompatibility were assessed. AUCIV was significantly higher for IV than for both IA injections (AUCIA free and AUCIA NPs), with 4248 vs 28 and 74 µg.min.L-1. For ST parameters, we observed a significant difference between AUCIA free and AUCIA NPs with 3735 and 10513 µg.min.L-1 correspondingly. Articular T1/2 and MRT were higher after NPs than after free rapamycin injection: 57.8 and 5.0 h for T1/2 and 80.6 and 5.5 h for MRT, respectively. Histological analysis revealed no chondral injuries and slight transient synovitis only 3 h after the administration of NPs. In the rat knee, rapamycin-loaded NPs delivery via a single IA injection is biocompatible and prolongs synovium joint residency, diminishes blood levels, and reduces detrimental systemic exposure.

Impaired Pharmacokinetics of Amiodarone under Veno-Venous Extracorporeal Membrane Oxygenation: From Bench to Bedside.

BACKGROUND: Adjusting drug therapy under veno-venous extracorporeal membrane oxygenation (VV ECMO) is challenging. Although impaired pharmacokinetics (PK) under VV ECMO have been reported for sedative drugs and antibiotics, data about amiodarone are lacking. We evaluated the pharmacokinetics of amiodarone under VV ECMO both in vitro and in vivo. METHODS: In vitro: Amiodarone concentration decays were compared between closed-loop ECMO and control stirring containers over a 24 h period. In vivo: Potassium-induced cardiac arrest in 10 pigs with ARDS, assigned to either control or VV ECMO groups, was treated with 300 mg amiodarone injection under continuous cardiopulmonary resuscitation. Pharmacokinetic parameters Cmax, Tmax AUC and F were determined from both direct amiodarone plasma concentrations observation and non-linear mixed effects modeling estimation. RESULTS: An in vitro study revealed a rapid and significant decrease in amiodarone concentrations in the closed-loop ECMO circuitry whereas it remained stable in control experiment. In vivo study revealed a 32% decrease in the AUC and a significant 42% drop of Cmax in the VV ECMO group as compared to controls. No difference in Tmax was observed. VV ECMO significantly modified both central distribution volume and amiodarone clearance. Monte Carlo simulations predicted that a 600 mg bolus of amiodarone under VV ECMO would achieve the amiodarone bioavailability observed in the control group. CONCLUSIONS: This is the first study to report decreased amiodarone bioavailability under VV ECMO. Higher doses of amiodarone should be considered for effective amiodarone exposure under VV ECMO.

Misuse of acetaminophen in the management of dental pain.

PURPOSE: We highlight the risk associated with acetaminophen misuse in patients having dental pain in France based on a series of cases of unintentional acetaminophen overdose reported by the Emergency Dental Service of Nancy over a 9-month period. METHODS: Data were collected by querying the French Pharmacovigilance database. Each retrieved clinical data were reviewed by a clinician. RESULTS: Thirteen cases of acetaminophen overdose were reported to the Regional Pharmacovigilance Center of Lorraine, Nancy, France. Most cases (10/13) concerned men aged 20-40 years old. Mild, unspecific clinical symptoms were observed in seven of 13 patients. The median value of the supposed ingested dose was 137 mg/kg/24 h. Liver enzyme activity was tested in 10 patients and was abnormal in four patients. N-acetylcysteine treatment was administered to four patients. CONCLUSIONS: We propose that even patients with mild clinical symptoms with a supposed ingested dose of acetaminophen greater than 150 mg/kg/24 h should be referred to an emergency department and that liver enzyme activity should be analyzed. No case of liver failure was observed during our short survey. However, hepatotoxicity of repeated supratherapeutic ingestion of acetaminophen was suspected in four patients. Patients and practitioners should thus be better informed about the risk of unintentional acetaminophen overdose following supratherapeutic acetaminophen ingestion.

[Sarcoïdosis and anti-TNF: a paradoxical class effect? Analysis of the French Pharmacovigilance system database and literature review]. / Sarcoïdose et anti-TNF : un effet paradoxal de classe? Analyse des cas de la base française de Pharmacovigilance et revue de la littérature.

OBJECTIVES: To identify and characterize the observations of sarcoidosis occurring during anti-TNF blockade collected in the French Pharmacovigilance system database and reported in the literature. RESULTS: Seven cases were reported in the French Pharmacovigilance system database and 39 cases (37 original) have been reported internationally. Monoclonal antibodies (infliximab and adalimumab) and fusion protein (etanercept) are equally involved. Sarcoidosis have been confirmed histologically and occurred predominantly in the rheumatoid arthritis (22) and spondylarthropathy (16). CONCLUSION: The lack of protopathic bias suggests that these paradoxical sarcoidosis occurring during treatment with anti-TNF are a class-effect, as with psoriasis, uveitis, and IBD reported under similar conditions. Their pathogenesis remains unclear.

Influence of the Obesity Phenotype on the Adequacy of Antibiotic Prophylaxis with Cefoxitin for Obese Patients Undergoing Bariatric Surgery: Lessons Learnt and Future Considerations.

BACKGROUND AND OBJECTIVES: A high inter-individual variability in pharmacokinetic parameters in obese patients is observed. The objective of this study was to evaluate the effect of obesity parameters on the pharmacokinetics of cefoxitin administered for antibiotic prophylaxis during bariatric surgery. METHODS: This a secondary analysis of a pharmacokinetic study involving 174 obese patients scheduled for bariatric surgery and receiving a 4-g dose of cefoxitin. Blood samples were collected at incision and wound closure. The total plasma concentrations were assessed utilising a validated high-performance liquid chromatography-tandem mass spectrometry method. The pharmacokinetic and pharmacodynamic target was defined as an estimated free concentration of cefoxitin at the time of wound closure >8 mg/L. Specific evaluated obesity parameters were fat body mass, fat body mass/height2, lean body mass, lean body mass/height2, visceral adipose tissue and presence of a metabolic syndrome. RESULTS: A total of 174 patients (median age 47 years) with a majority of women (75.3%) and a median BMI of 44 kg/m2 were analysed. The percentage of patients who met the pharmacokinetic and pharmacodynamic target was 85.1%. In the whole population, a tendency to fail to reach the target was observed with a higher lean mass over height2 [OR = 0.79; 95% CI (0.62-1.01); P = 0.060]. In the female subgroup, higher lean mass over height2 [OR = 0.63; 95% CI (0.41-0.97); P = 0.037] and the presence of a metabolic syndrome [OR = 0.17; 95% CI (0.03-0.83); P = 0.030] were associated with failure to reach the pharmacokinetic and pharmacodynamic target. CONCLUSION: Obese patients with a higher lean mass and a metabolic syndrome could constitute a subgroup at risk for cefoxitin under-dosage.