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The aim was to assess the appropriateness of recommended regimens for empirical MIC coverage in critically ill patients with open-abdomen and negative-pressure therapy (OA/NPT). Over a 5-year period, every critically ill patient who received amikacin and who underwent therapeutic drug monitoring (TDM) while being treated by OA/NPT was retrospectively included. A population pharmacokinetic (PK) modeling was performed considering the effect of 10 covariates (age, sex, total body weight [TBW], adapted body weight [ABW], body surface area [BSA], modified sepsis-related organ failure assessment [SOFA] score, vasopressor use, creatinine clearance [CLCR], fluid balance, and amount of fluids collected by the NPT over the sampling day) in patients who underwent continuous renal replacement therapy (CRRT) or did not receive CRRT. Monte Carlo simulations were employed to determine the fractional target attainment (FTA) for the PK/pharmacodynamic [PD] targets (maximum concentration of drug [Cmax]/MIC ratio of ≥8 and a ratio of the area under the concentration-time curve from 0 to 24 h [AUC0–24]/MIC of ≥75). Seventy critically ill patients treated by OA/NPT (contributing 179 concentration values) were included. Amikacin PK concentrations were best described by a two-compartment model with linear elimination and proportional residual error, with CLCR and ABW as significant covariates for volume of distribution (V) and CLCR for CL. The reported V) in non-CRRT and CRRT patients was 35.8 and 40.2 liters, respectively. In Monte Carlo simulations, ABW-adjusted doses between 25 and 35 mg/kg were needed to reach an FTA of >85% for various renal functions. Despite an increased V and a wide interindividual variability, desirable PK/PD targets may be achieved using an ABW-based loading dose of 25 to 30 mg/kg. When less susceptible pathogens are targeted, higher dosing regimens are probably needed in patients with augmented renal clearance (ARC). Further studies are needed to assess the effect of OA/NPT on the PK parameters of antimicrobial agents.

Objectives To describe the rationale for subcutaneous (SC) administration of antibiotics from available published data and to make propositions to help clinicians in daily practice. Design Narrative review. Setting and Participants Hospitalized patients, persons in long-term care facilities and ambulatory care. Methods We searched the MEDLINE/PubMed electronic database for evidence supporting SC administration of antibiotics up to September 2019; the results of this primary search were supplemented by searching the references of the identified articles, as well as by searching in Google Scholar. Results Regarding tolerability, efficacy, and pharmacokinetic/pharmacodynamic profiles, most studies suggest that the SC route could be an alternative to the intravenous route, particularly for time-dependent antibiotics and among certain patient populations, such as patients with poor venous access, swallowing disorders, or behavioral disturbance. However, clinical evidence of the benefits and risks of SC antibiotic administration is still scarce and of low level. Conclusions and Implications SC administration of antibiotics may be useful in various settings such as in hospitalized patients and among those in long-term care facilities or being cared for at home. However, further clinical studies are needed to assess the pharmacokinetic/pharmacodynamic properties, as well as the risks and benefits of SC administration of antibiotics. In this review, we highlight the potential benefits of SC administration of antibiotics and address practical recommendations for its use. This information will enable improvement of treatment strategies and present the SC route as a potential option in specific situations.

Background Hemofiltration rate, changes in blood and ultrafiltration flow, and discrepancies between the prescribed and administered doses strongly influence pharmacokinetics (PK) and pharmacodynamics (PD) of antimicrobial agents during continuous veno-venous hemofiltration (CVVH) in critically ill patients. Methods Ancillary data were from the prospective multicenter IVOIRE (hIgh VOlume in Intensive caRE) study. High volume (HV, 70 mL/kg/h) was at random compared with standard volume (SV, 35 mL/kg/h) CVVH in septic shock patients with acute kidney injury (AKI). PK/PD parameters for all antimicrobial agents used in each patient were studied during five days. Results Antimicrobial treatment met efficacy targets for both percentage of time above the minimal inhibitory concentration and inhibitory quotient. A significant correlation was observed between the ultrafiltration flow and total systemic clearance (Spearman test: P < 0.005) and between CVVH clearance and drug elimination half-life (Spearman test: P < 0.005). All agents were easily filtered. Mean sieving coefficient ranged from 38.7% to 96.7%. Mean elimination half-life of all agents was significantly shorter during HV-CVVH (from 1.29 to 28.54 h) than during SV-CVVH (from 1.51 to 33.85 h) (P < 0.05). Conclusions This study confirms that CVVH influences the PK/PD behavior of most antimicrobial agents. Antimicrobial elimination was directly correlated with convection rate. Current antimicrobial dose recommendations will expose patients to underdosing and increase the risk for treatment failure and development of resistance. Dose recommendations are proposed for some major antibiotic and antifungal treatments in patients receiving at least 25 mL/kg/h CVVH.

International audience; BACKGROUND:Tobacco smoking is common in people living with HIV, but high-quality evidence on interventions for smoking cessation is not available in this population. We aimed to assess the efficacy and safety of varenicline with counselling to aid smoking cessation in people living with HIV.METHODS:The ANRS 144 Inter-ACTIV randomised, parallel, double-blind, multicentre, placebo-controlled phase 3 trial was done at 30 clinical hospital sites in France. People living with HIV who had smoked at least ten cigarettes per day for 1 year or longer, were motivated to stop smoking, were not dependent on another psychoactive substance, and had no history of depression or suicide attempt were eligible. Using a computer-generated randomisation sequence, we allocated (1:1) the patients to receive either varenicline titrated to two 0·5 mg doses twice daily or placebo twice daily for 12 weeks, plus face-to-face counselling. Patients and investigators were masked to treatment group allocation. Patients who were not abstinent at week 24 were offered open-label varenicline for 12 additional weeks. The primary outcome was the proportion of smokers continuously abstinent from week 9 to week 48. Smoking status was confirmed by carbon monoxide in exhaled air. Primary analyses were done in both the intention-to-treat (ITT) population and modified ITT (mITT) population, which comprised all patients who took at least one tablet of their assigned study treatment. The safety analyses were done in the mITT population. The trial is registered at ClinicalTrials.gov, number NCT00918307. The trial status is complete.FINDINGS:From Oct 26, 2009, to Dec 20, 2012, of 303 patients assessed for eligibility, 248 patients were randomly assigned to the varenicline group (n=123) or the placebo group (n=125). After randomisation, one participant initially assigned to the placebo group was excluded from the ITT analysis for a regulatory reason (no French health-care coverage). 102 patients in the varenicline group and 111 patients in the placebo group received at least one dose of their assigned treatment and were included in the mITT analysis. In the ITT analysis, varenicline was associated with a higher proportion of patients achieving continuous abstinence over the study period (week 9-48): 18 (15%, 95% CI 8-21) of 123 in the varenicline group versus eight (6%, 2-11) of 124 in the placebo group, adjusted odds ratio (OR) 2·5 (95% CI 1·0-6·1; p=0·041). In the mITT analysis, varenicline was also associated with higher continuous abstinence: 18 (18%, 95% CI 10-25) of 102 versus eight (7%, 2-12) of 111 in the placebo group (adjusted OR 2·7, 95% CI 1·1-6·5; p=0·029). The incidence of depression was 2·4 per 100 person-years (95% CI 0·6-9·5; two [2%] of 102) in the varenicline group and 12·4 per 100 person-years (95% CI 6·9-22·5; 11 [10%] of 111) in the placebo group. 14 (7%) of 213 participants had 18 cardiovascular events: six (6%) of 102 people in the varenicline group and eight (7%) of 111 people in the placebo group.INTERPRETATION:Varenicline is safe and efficacious for smoking cessation in people living with HIV and should be recommended as the standard of care.FUNDING:The French National Institute for Health and Medical Research (INSERM)-French National Agency for Research on AIDS and Viral Hepatitis (ANRS) and Pfizer.

This study assessed whether augmented renal clearance (ARC) impacts negatively on antibiotic concentrations and clinical outcomes in patients treated by high-dose β-lactams administered continuously. Over a 9-month period, all critically ill patients without renal impairment treated by one of the monitored β-lactams for a documented infection were eligible. During the first 3 days of antibiotic therapy, every patient underwent 24-h CLCr measurements and therapeutic drug monitoring. The main outcome was the rate of β-lactam underdosing, defined as a free drug concentration

IntroductionSacubitril/valsartan, a new treatment for chronic cardiac failure, has been available only in retrocession from approved pharmacies since it obtained market authorization. A specific communication pathway (pharmaceutic interview and hospital-to-community liaison) has been set up, to optimise the continuity of patient care and to inform community and hospital health professionals.ObjectivesEvaluate the pathway and the tools developed.MethodsEvaluation of pharmaceutical interventions (PI) and patient satisfaction with the process, of the usefulness of hospital-to-community liaison for community health professionals, and of extension of the process to other approved retrocession structures.ResultsEighty-one patients were enrolled; 61 pharmaceutic interviews were carried out at initiation of treatment (75%). Fifty-eight per cent of PIs (15/26) were accepted, avoiding dosage errors. Ninety per cent of patients who responded to the satisfaction survey (20/22) were very satisfied with this process. Only 18% of community health professionals contacted (13/92) were aware of this drug, and 53% (15/28 satisfaction questionnaire respondents) judged hospital-to-community liaison useful. Sixty-eight per cent of retrocession structures contacted (21/31) adopted the process.ConclusionSetting up pharmaceutic interviews and hospital-to-community liaison contributes to optimising patient management.; IntroductionSacubitril/valsartan, nouveau traitement de l’insuffisance cardiaque chronique, n’est disponible qu’en rétrocession depuis sa mise sur le marché. Un circuit spécifique (entretiens pharmaceutiques, lien ville-hôpital) a été mis en place afin d’optimiser la prise en charge des patients et d’informer les professionnels de santé libéraux et hospitaliers.ObjectifÉvaluer le circuit et les outils spécifiques mis en place.MéthodeÉvaluation des interventions pharmaceutiques (IP), de la satisfaction du patient vis-à-vis de cette démarche, de la pertinence du lien ville-hôpital par les professionnels de santé de ville et de la diffusion de la démarche à d’autres rétrocessions de centres hospitaliers.RésultatsQuatre-vingt-un patients ont été inclus. Soixante et un entretiens pharmaceutiques ont été réalisés lors de l’initiation de traitement (75 %). Cinquante-huit pour cent d’IP (15/26) ont été acceptées, évitant des erreurs de posologie. Quatre-vingt dix pour cent des patients ayant répondu au questionnaire de satisfaction (20/22) étaient très satisfaits de la démarche. Dix-huit pour cent des professionnels de santé de ville contactés (13/92) connaissaient ce médicament, et 53 % (15 sur 28 ayant répondu au questionnaire de satisfaction) ont jugé le lien ville/hôpital pertinent. Soixante-huit des rétrocessions contactées (21/31) ont transposé cette démarche.Conclusion La mise en place d’entretiens pharmaceutiques et d’un lien ville-hôpital participe à l’optimisation de la prise en charge des patients.

Resume Introduction L’utilisation de medicaments potentiellement inappropries (MPI) chez la personne âgee est associee a une augmentation de la mortalite et du nombre d’effets indesirables. Objectifs Analyser les prescriptions des personnes âgees hospitalisees dans un service de cardiologie afin de detecter et d’analyser d’eventuelles prescriptions inappropriees, au moyen d’outils existants. Methode Une analyse prospective a ete realisee de juin a septembre 2015, chez les patients âges hospitalises dans le service. La recherche de MPI a l’entree et a la sortie a ete realisee a partir de la liste de Laroche, des criteres STOPP-START et des indicateurs d’alerte de la Haute Autorite de sante. Resultats Cent dix-huit patients ont ete inclus. Parmi les prescriptions a l’entree, 58 possedaient au moins un MPI, majoritairement des medicaments de la liste de Laroche. Chez 35 patients, il s’agissait d’une instauration a l’hopital. L’analyse de l’ordonnance de sortie a montre que 55 d’entre elles possedaient au moins un MPI, majoritairement des medicaments de la liste de Laroche egalement. Conclusion L’hospitalisation est souvent l’objet d’une prise en charge specifique, rendant difficile une optimisation de la prescription chez la personne âgee. Neanmoins, l’intervention du pharmacien hospitalier peut etre une aide a une reevaluation du traitement.

Resume Introduction Les anticoagulants oraux directs (ACOD) sont de plus en plus prescrits en alternative aux anti-vitamine K dans le traitement et la prevention des evenements thromboemboliques. Objectif Decrire et evaluer les modalites de prescription et d’utilisation des ACOD dans des services de medecine de notre etablissement par rapport aux recommandations de bon usage. Methodes Recueil retrospectif des donnees pendant un mois (juin 2014) dans les dossiers informatises des patients traites par un ACOD a l’aide d’une grille de recueil evaluant : la conformite de l’indication et de la posologie, la presence de contre-indications, l’adaptation des posologies au risque hemorragique et la presence d’interactions medicamenteuses. Resultats Les recommandations de prescription sont bien respectees, cependant 11 erreurs de posologie ont ete relevees : sous-dosage non documente en rivaroxaban pour 5 patients et absence d’adaptation de la posologie a la fonction renale pour 6 patients parmi les 17 patients insuffisants renaux de l’echantillon (clairances renales de 26 a 49 mL/min). Les principales interactions medicamenteuses relevees etaient des precautions d’emploi. Conclusion Afin de securiser la prescription, une fiche de bon usage des ACOD a ete realisee par les pharmaciens, les cardiologues et les hemobiologistes.

The objective of the present study was to determine whether augmented renal clearance (ARC) impacts negatively on ceftriaxone pharmacokinetic (PK)/pharmacodynamic (PD) target attainment in critically ill patients. Over a 9-month period, all critically ill patients treated with ceftriaxone were eligible. During the first 3 days of antimicrobial therapy, every patient underwent 24-h creatinine clearance (CL CR ) measurements and therapeutic drug monitoring of unbound ceftriaxone. ARC was defined by a CL CR of ≥150 ml/min. Empirical underdosing was defined by a trough unbound ceftriaxone concentration under 2 mg/liter (percentage of the time that the concentration of the free fraction of drug remained greater than the MIC [ fT \textgreaterMIC ], 100%). Monte Carlo simulation (MCS) was performed to determine the probability of target attainment (PTA) of different dosing regimens for various MICs and three groups of CL CR (\textless150, 150 to 200, and \textgreater200 ml/min). Twenty-one patients were included. The rate of empirical ceftriaxone underdosing was 62% (39/63). A CL CR of ≥150 ml/min was associated with empirical target underdosing with an odds ratio (OR) of 8.8 (95% confidence interval [CI] = 2.5 to 30.7; P \textless 0.01). Ceftriaxone PK concentrations were best described by a two-compartment model. CL CR was associated with unbound ceftriaxone clearance ( P = 0.02). In the MCS, the proportion of patients who would have failed to achieve a 100% fT \textgreaterMIC was significantly higher in ARC patients for each dosage regimen (OR = 2.96; 95% CI = 2.74 to 3.19; P \textless 0.01). A dose of 2 g twice a day was best suited to achieve a 100% fT \textgreaterMIC . When targeting a 100% fT \textgreaterMIC for the less susceptible pathogens, patients with a CL CR of ≥150 ml/min remained at risk of empirical ceftriaxone underdosing. These data emphasize the need for therapeutic drug monitoring in ARC patients.

// Claire Calmettes 1 , Frederic Gabriel 2 , Elodie Blanchard 3 , Vincent Servant 4 , Stephane Bouchet 5 , Nathanael Kabore 6 , Edouard Forcade 1 , Camille Leroyer 7 , Audrey Bidet 8 , Valerie Latrabe 9 , Thibaut Leguay 1 , Stephane Vigouroux 1 , Reza Tabrizi 1 , Dominique Breilh 4 , Isabelle Accoceberry 2 , Manuel Tunon de Lara 3 , Arnaud Pigneux 1 , Noel Milpied 1 and Pierre-Yves Dumas 1 1 Department of Hematology and Cell Therapy, University Hospital, F-33000 Bordeaux, France 2 Laboratory of Mycology, University Hospital, F-33000 Bordeaux, France 3 Department of Respiratory Diseases, University Hospital, F-33000 Bordeaux, France 4 Pharmacy, University Hospital, F-33000 Bordeaux, France 5 Department of Clinical Pharmacology, University Hospital, F-33000 Bordeaux, France 6 Medical Information Department, University Hospital, F-33000 Bordeaux, France 7 Department of Infection Control, University Hospital, F-33000 Bordeaux, France 8 Laboratory of Hematology, University Hospital, F-33000 Bordeaux, France 9 Thoracic and Cardiovascular Imaging Department, University Hospital, F-33000 Bordeaux, France Correspondence to: Pierre-Yves Dumas, email: pierre-yves.dumas@u-bordeaux.fr Keywords: acute myeloid leukemia; posaconazole; invasive aspergillosis; galactomannan enzyme immunoassay; sensitivity Received: February 28, 2018 Accepted: May 07, 2018 Published: June 01, 2018 ABSTRACT Posaconazole prophylaxis has demonstrated efficacy in the prevention of invasive aspergillosis during prolonged neutropenia following acute myeloid leukemia induction chemotherapy. Antifungal treatment decreases serum galactomannan enzyme immunoassay diagnostic accuracy that could delay the diagnosis and treatment. We retrospectively studied patients with acute myeloid leukemia who underwent intensive chemotherapy and antifungal prophylaxis by posaconazole oral suspension. Clinical, radiological, microbiological features and treatment response of patients with invasive aspergillosis that occurred despite posaconazole prophylaxis were analyzed. Diagnostic accuracy of serum galactomannan assay according to posaconazole plasma concentrations has been performed. A total of 288 patients with acute myeloid leukemia, treated by induction chemotherapy, who received posaconazole prophylaxis for more than five days were included in the present study. The incidence of invasive aspergillosis was 8% with 12 (4.2%), 8 (2.8%) and 3 (1%), possible, probable and proven invasive aspergillosis, respectively. Posaconazole plasma concentration was available for 258 patients. Median duration of posaconazole treatment was 17 days, and median posaconazole plasma concentration was 0.5 mg/L. None of patients with invasive aspergillosis and posaconazole concentration ≥ 0.5 mg/L had a serum galactomannan positive test. Sensitivity of serum galactomannan assay to detect probable and proven invasive aspergillosis was 81.8%. Decreasing the cut-off value for serum galactomannan optical density index from 0.5 to 0.3 increased sensitivity to 90.9%. In a homogenous cohort of acute myeloid leukemia patients during induction chemotherapy, increasing the posaconazole concentration decreases the sensitivity of serum galactomannan assay.

Resume Introduction Bien que presentes comme plus faciles d’utilisation, les anticoagulants oraux directs (AOD) sont une source potentielle de iatrogenie. Objectifs Evaluer les competences des patients vis-a-vis de leur traitement par AOD. Methode Les patients de plus de 18 ans, sous anticoagulants depuis au moins 7 jours et hospitalises au CHU entre juillet et novembre 2013 ont ete inclus. Un questionnaire a permis d’evaluer les savoirs, les savoir-etre et les savoir-faire. Les reponses des patients mis « directement » sous AOD et de ceux ayant recu un traitement anterieur par AVK ont ete comparees. Un groupe de patients sous AVK a ete constitue comme reference. Resultats Cent patients ont ete inclus. Si les patients sous AVK savent gerer leur traitement, les patients sous AOD ont peu de competences, ce qui est renforce lorsqu’un patient n’a pas d’antecedent de traitement par AVK. Discussion et conclusion Il est necessaire de mettre en place des actions correctrices afin d’eviter la iatrogenie deja si presente pour les medicaments de la precedente generation. Ceci pourrait se faire au moyen d’ateliers educatifs. Il conviendrait probablement de distinguer les patients avec et sans antecedent de traitement par AVK.

A lung transplant offers patients with terminal respiratory failure the hope of a longer life expectancy, as well as a better quality of life and greater autonomy. After the transplant, patients must receive rigorous care and accept that they will have to take medication for the rest of their lives. In this respect, the post-transplant follow-up constitutes a ‘new chronic condition’ to which they must adapt.; La transplantation pulmonaire offre aux malades atteints d’insuffisance respiratoire terminale l’espoir d’une durée de vie augmentée, mais aussi d’une meilleure qualité de vie et d’une autonomie plus grande. Après la greffe, les patients doivent bénéficier d’une prise en charge rigoureuse et accepter de prendre un traitement à vie. En cela, le suivi après la transplantation constitue une véritable “nouvelle maladie chronique” à laquelle ils devront s’adapter.

International audience; Obesity and critical illness modify pharmacokinetics of antibiotics, but piperacillin-tazobactam continuous IV infusion pharmacokinetics has been poorly studied in obese critically ill patients. We aimed to compare pharmacokinetics of piperacillin in severely obese and nonobese patients with severe sepsis or septic shock. We hypothesized that plasma concentration variability would expose the critically ill to both piperacillin under and overdosing.METHODS:Prospective comparative study. Consecutive critically ill severely obese (body mass index, > 35 kg/m) and nonobese patients (body mass index, < 30 kg/m) were treated with 16 g/2 g/24 hr continuous piperacillin-tazobactam infusion. Piperacillin plasma concentration was measured every 12 hours over a 7-day period by high-pressure liquid chromatography. Unbound piperacillin plasma concentration and fractional time of plasma concentration spent over 64 mg/L (4-fold the minimal inhibitory concentration for Pseudomonas aeruginosa) were compared between the two groups. We performed 5,000 Monte Carlo simulations for various dosing regimens and minimal inhibitory concentration and calculated the probability to spend 100% of the time over 64 mg/L.RESULTS:We enrolled 11 severely obese and 12 nonobese patients and obtained 294 blood samples. We did not observe a statistically significant difference in piperacillin plasma concentrations over time between groups. The fractional time over 64 mg/L was 64% (43-82%) and 93% (85-100%) in obese and nonobese patients, respectively, p = 0.027 with intra- and intergroup variability. Five nonobese and two obese patients experienced potentially toxic piperacillin plasma concentrations. When 64 mg/L was targeted, Monte Carlo simulations showed that 12 g/1.5 g/24 hr was inadequate in both groups and 16 g/2 g/24 hr was adequate only in nonobese patients.CONCLUSION:Using a conventional dosing of 16 g/2 g/24 hr continuous infusion, obese patients were more likely than nonobese patients to experience piperacillin underdosing when facing high minimal inhibitory concentration pathogens. The present study suggests that piperacillin drug monitoring might be necessary in the sickest patients who are at the highest risk of unpredictable plasma concentration exposing them to overdose, toxicity, underdosing, and treatment failure.

International audience; The quantification of monoclonal antibodies (mAbs) such as bevacizumab, a recombinant humanized immunoglobulin G1 (hIgG1), in biological fluids, is an essential prerequisite to any pharmacokinetic preclinical and clinical study. To date, reference techniques used to quantify mAbs rely on enzyme-linked immunosorbent assay (ELISA) lacking specificity. Furthermore, the commercially available ELISA kit to quantify bevacizumab in human plasma only assesses the free fraction of the drug. However, the conditions of storage and analysis of plasma samples could alter the physiological equilibrium between the free, bound and partially bound forms of bevacizumab and this could result in over- or underestimation of drug concentration. We developed a new assay for absolute quantification of total fraction of bevacizumab by liquid chromatography tandem mass spectrometry (LC-MS/MS) basing identification and quantification of bevacizumab on two specific peptides. In this report we compare our assay with two internal standard (IS) calibration approaches: one using a different human mAb (Trastuzumab) and the other using a stable isotope labeled specific peptide. After enrichment by affinity chromatography on protein A and concentration by ultrafiltration, human plasma samples were proteolyzed by trypsin. Linearity was established from 12.5 to 500μg/mL with an interday accuracy ranging from 101.7 to 110.6% and precision from 7.0% to 9.9%. This study demonstrates the importance of the choice of the IS in quantifying bevacizumab in human plasma and highlights the difficulty of reaching a reliable proteolysis with a sufficient recovery. We developed a reliable and cost-effective LC-MS/MS method to quantify total plasmatic fraction of bevacizumab in human plasma. Through our development we proposed a generic methodology easily transposable to quantify all IgG1 subclass very useful for clinical pharmacokinetics studies.

Aim To date, neither the benefit of mycophenolic acid (MPA) therapeutic drug monitoring (TDM), the prodrug of mycophenolate mofetil (MMF), nor the optimal monitoring technique have been established in autoimmune diseases. This study was undertaken to confirm, in a cohort of new patients, the plasma MPA thresholds previously published in patients with systemic lupus erythematosus (SLE) or vasculitis. Methods MPA areas under the concentration–time curves between 0 and 12 h, 12 h trough concentrations and pre-dose concentrations (C0) were determined for 23 patients with SLE and 21 with systemic vasculitis. The relationship between patients' pharmacokinetic (PK) variables and their clinical outcomes during follow-up were analyzed. Results In both autoimmune diseases, at PK assessment, median MPA C0 for patients with uncontrolled disease was significantly lower than that of patients with stable disease or in remission, 1.6 mg l–1 (IQR 0.9–2.1 mg l–1) vs. 2.95 mg l–1 (IQR 1.38–3.73 mg l–1) for SLE (P = 0.048) and 1.55 mg l–1 (IQR 0.98–2.18 mg l–1) vs. 3 mg l–1 (IQR 2.2–4.4 mg l–1) for vasculitis (P = 0.016). According to our receiver operating characteristics curve analysis, a C0 threshold of 2.5–3 mg l–1 was best able to discriminate a flare (SLE: 88% sensitivity, 80% specificity; vasculitis: 100% sensitivity, 90% specificity). Patients with C0 ≥ 2.5–3 mg l–1 at inclusion had better clinical outcomes during the 12 months following PK assessment. Conclusion Provided that the benefit of TDM in patients with autoimmune diseases could be confirmed by randomized, controlled trials, it might be based on the C0 measured approximately 12 h post-dose.

Resume La selection des doses durant les dernieres phases cliniques de developpement d’un antibiotique represente une etape cruciale dans la possibilite d’individualisation des traitements et la prise en charge du risque permanent de resistance lie a la pression de selection face a des expositions infra-therapeutiques. Cet article decrit les principaux resultats recemment publies dans le domaine de la pharmacocinetique clinique, les etudes pharmacocinetique/pharmacodynamique (PK/PD) ainsi la modelisation in silico (Monte Carlo simulations) permettant de maximiser la probabilite de reussite du traitement et de minimiser le risque d’observer des effets indesirables graves. Dans le contexte actuel de penurie de developpement de nouveaux antibiotiques, la mise en application de ces resultats permettrait de contribuer a ne pas se trouver dans un defaut d’efficacite chez des patients fragilises pour des infections severes et profondes a bacteries multiresistantes.

Introduction Liquid chromatography coupled with mass spectrometry for the quantification of raltegravir in human plasma and peripheral blood mononuclear cells has been developed. Methods Sample preparations were based on a fully automated solid-phase extraction process. Mass spectrometric data were acquired in a single-ion monitoring method. Raltegravir and quinoxaline, the internal standard, were well separated in a gradient mode over 15 min. Key findings Validation study exhibited excellent linearity, with good intra- and inter-day precision and accuracy. Conclusions The assay was successfully applied to the raltegravir quantification in HIV-infected patients.

Introduction of new agents for the treatment for colorectal cancer (CRC) has been accompanied by the publication of guidelines. The COLCHIC cohort was set up to evaluate CRC treatment practices and the use of these innovative and expensive agents. Patients initiating CRC treatment at the Bordeaux teaching hospital between 1 March 2005 and 1 March 2006 were identified, and treatment courses from 1 March 2005 to 31 December 2006 were studied; 192 patients were included, 188 with analysable data: 43 patients initiated 51 courses for non-metastatic cancer, 153 initiated 366 courses for metastatic cancer, eight patients initiated courses for both non-metastatic and metastatic cancer. Most treatments were used for indications found in guidelines published during the study (83.9%). Of the others, nearly half were approved in guidelines published subsequently. In this teaching hospital, prescribing practice was generally in line with recommendations, with an anticipation of future guidelines. This mostly concerned monoclonal antibodies, which were new at the time of the study.

Introduction L’utilisation de la voie sous cutanee (SC) pour l’administration d’antibiotiques est frequente en France, en particulier en geriatrie, comme alternative a la voie intraveineuse (IV). Il existe cependant tres peu de donnees PKPD dans la litterature validant une telle pratique. L’emergence des enterobacteries secretrices de β-lactamases a spectre etendu (EBLSE) rend parfois necessaire l’emploi de carbapenemes dont l’ertapeneme. L’objectif de cette etude etait de determiner les donnees PK/PD de l’ertapeneme administre par voies sous cutanee et intraveineuse dans une population de patients âges. Materiels et methodes Il s’agit d’une etude observationnelle prospective, monocentrique incluant des patients âges de plus de 75 ans traites par ertapeneme depuis au moins 48 h (etat d’equilibre) par voie IV ou SC. Les concentrations d’ertapeneme serique (H0, H + 0,5 et H + 2,5) ont ete realisee par chromatographie en phase liquide couplee a la spectrometrie de masse. Les aires sous la courbe (ASC) ont ete calculees pour chaque voie et une simulation de Monte Carlo a ete realisee (1000 sujets âges) afin de determiner l’influence de la voie d’administration sur la probabilite de maintenir la concentration libre d’ertapeneme au-dessus de la concentration minimale inhibitrice (CMI) au moins 40 % du temps. Resultats Dix patients (âge moyen 87 ± 7,0 ans) traites par voie SC et 11 patients (88 ± 5,0 ans) par voie IV ont ete inclus dans l’etude. Les concentrations residuelles moyennes (H0) n’etaient pas significativement differentes entre la voie IV (11 ± 8 ug/mL) et la voie SC (11 ± 7 ug/mL) ; en revanche les concentrations maximales a la fin de la perfusion (H + 0,5 ; 186 ± 98 ug/mL versus 29 ± 22ug/mL) 2 h apres (101 ± 34 versus 58 ± 36ug/mL) etaient superieures avec la voie IV. Les ASC n’etaient pas differentes entre les 2 voies (986 ± 302 versus 887 ± 212 ug/mL*h, p = 0,27). La probabilite de maintenir la concentration d’ertapeneme libre au dessus de la CMI au moins 40 % du temps n’etait pas significativement differente entre les voies SC et IV. Il n’y a pas eu d’effets indesirables locaux notables. Conclusion Les premiers resultats de cette etude originale de PK/PD chez le sujet âge sont en faveur d’une utilisation possible de la voie SC pour la delivrance de l’ertapeneme par voie SC en alternative a la voie IV. La simplicite d’utilisation de la voie SC pourrait permettre de raccourcir les durees d’hospitalisation voire de les eviter dans cette population.

Mycophenolic acid (MPA), the active form of mycophenolate mofetil (MMF) and enteric-coated mycophenolate sodium (EC-MPS), is used to treat systemic lupus erythematosus (SLE). MMF and EC-MPS pharmacokinetics were examined to devise guidance for therapeutic drug monitoring (TDM) for SLE patients with normal renal function.This observational study included 21 patients receiving MMF (1000 mg twice daily) and 14 taking EC-MPS (720 mg twice daily). MPA AUC between 0 and 12 h (AUC(0-12h)), C(max), T(max), and 12-h trough concentrations (C(12h)) were determined.Means of dose-normalized MMF- or EC-MPS-MPA C(max) were 64.6 +/- 25 and 61.4 +/- 27.1 h mg/l, respectively. MPA T(max) for EC-MPS was longer and more variable than for MMF. MMF-MPA AUC(0-12h) and C(12h) were correlated (r = 0.78, p = 0.0001), but EC-MPS-MPA C(max) and single concentrations were weakly correlated. A limited-sampling strategy (LSS) combining C(max) and C(12h) gave satisfactory predictive performance to estimate MPA AUC(0-12h) after EC-MPS administration.For TDM in SLE patients with GFR60 ml/min/1.73 m(2), C(12h) after MMF ingestion could predict MPA AUC(0-12h), while an LSS around T(max) should be used for patients on EC-MPS.

Summary Background The main goal of therapy in hepatitis C virus (HCV) infection is to achieve a sustained virological response (SVR). However, the impact of the pharmacological properties of ribavirin on the SVR has not been fully investigated. Aim To evaluate, through a prospective study, the association between ribavirin plasma level and SVR response in HCV patients treated with pegylated interferon (PEG-IFN) and ribavirin. Patients and methods Patients treated with PEG-IFN and ribavirin had plasmatic ribavirin dosage at weeks 4 and 12. SVR was evaluated 6 months after the end of treatment. Results At week 4, a strong correlation was found between HCV-RNA and Cmin of ribavirin plasma level (r = −0.376, P = 0.002) and AUC012h of ribavirin plasma level (r = −0.277, P = 0.018). At week 12, a strong correlation was found between HCV-RNA and Cmin of ribavirin plasma level (r = −0.384, P

Resume Les trois objectifs principaux de la prise en charge therapeutique au cours de la maladie d’Alzheimer, sont d’ameliorer, de retarder ou de stabiliser la progression des deficits cognitifs ainsi que leurs consequences sur la vie quotidienne, et de minimiser les manifestations psychologiques et comportementales qui sont associees. Le traitement repose generalement sur une association de medicaments de classes pharmacologiques specifiques pour la prise en charge des troubles cognitifs et non cognitifs. Naturellement implique dans le bon usage du medicament, l’optimisation et l’individualisation des traitements, le pharmacien clinicien doit connaitre les differents mecanismes d’action ainsi que les proprietes physico-chimiques et pharmacocinetiques des medicaments utilises dans la maladie d’Alzheimer, mais aussi definir les doses efficaces en tenant compte du rapport risque/benefice ce qui revient a definir les doses maximales tolerees propres a chaque individu. Ce dernier point implique une parfaite connaissance du patient et de ses modifications physiopathologiques au cours du temps et leurs principales consequences en termes pharmacodynamiques et pharmacocinetiques, donc une collaboration etroite avec le medecin responsable du patient. Enfin, les conditions reglementaires et economiques d’utilisation des medicaments definissent aujourd’hui un cadre de prescription strict que seule une confrontation argumentee au cours de reunions multidisciplinaires entre medecins, pharmaciens et equipes soignantes peut nuancer.

Liquid chromatography coupled with mass spectrometry for the determination of total and unbound mycophenolic acid and its major metabolite in human plasma has been developed. Sample preparations were based on a fully automated solid-phase extraction process and ultrafiltration. Mass spectrometric data were acquired in a single-ion monitoring method. The analytes and nevirapine (internal standard) were well separated in an isocratic mode over 8 min. Validation study exhibited excellent linearity, with intra- and inter-day precision and accuracy of less than 12%. The assay was successfully applied to the pharmacokinetic study of mycophenolic acid in patients with autoimmune diseases.

International audience; BACKGROUND: The efficacy of raltegravir plus optimized background therapy (OBT) has been demonstrated for antiretroviral (ARV)-experienced HIV-1-infected patients in randomized clinical trials. We studied viro-immunological response, pharmacokinetic parameters and genotypic test results in an observational cohort of multiple ARV class-experienced patients starting a raltegravir-based regimen. METHODS: Already enrolled ANRS CO3 Aquitaine Cohort patients with virological failure were included in this study after starting a raltegravir-based regimen (400 mg twice a day, week 0). Virological success was defined by the plasma HIV-1 RNA level [viral load (VL)] or =1 and or =2 (P = 0.02), respectively. Raltegravir-related mutations emerged in 9 of 11 failing patients (82%): Q148H/R (n = 5), N155S/H (n = 3) and S230N (n = 1). Median CD4 increases from week 0 to week 4 and week 24 were 28 (-4, 85) and 57 (0, 156) cells/mm(3), respectively. A poor immune response was independently associated with a lower VL decline (week 0 to week 12) [odds ratio (OR): 3.5, 95% confidence interval (CI): 1.4, 8.4, for 1 log(10) less] and CD4+% at baseline (OR: 2.6, 95% CI: 0.97, 8.3, for 10% lower). CONCLUSIONS: Raltegravir plus OBT provided a good virological success rate in highly pre-treated patients under clinical routine conditions.

Objectives The degree of penetration of an antibiotic into the infected site is an important criterion for therapeutic success. Ertapenem is a new carbapenem, exhibiting activity against most Gram-positive and Gram-negative aerobic and anaerobic bacteria commonly recovered from community-acquired infections. However, no studies concerning its diffusion into bone and synovial tissue are available. Our objective was to quantify ertapenem bone and synovial tissue penetration and to compare our data with the MIC(90)s for causative pathogens. Patients and methods In an open-label study, 18 patients who were undergoing elective total hip replacement received a single, parenteral, 1 g dose of ertapenem. One serum, one cortical and cancellous bone and one synovial tissue sample was collected per patient a median [interquartile range (IQR)] of 1.6 (1.5-1.7), 12.4 (11.9-13.1) or 23.8 h (22.6-25.2) later and analysed by HPLC. Results The median (IQR) serum concentrations of ertapenem were 70.1 (56.1-75.9), 10.0 (9.1-11.2) and 2.6 mg/L (2.3-3.0), respectively, at the different time points. The median (IQR) cancellous bone tissue concentrations were 13.2 (10.2-14.8), 1.9 (1.7-2.1) and 0.6 microg/g (0.4-0.6) at the different time points, corresponding to a median (IQR) tissue/serum penetration ratio of 0.19 (0.18-0.23). The median (IQR) cortical bone tissue concentrations were 8.0 (6.5-9.5), 1.3 (1.2-1.3) and 0.3 microg/g (0.3-0.4) at the different time points, corresponding to a median (IQR) tissue/serum penetration ratio of 0.13 (0.12-0.14). The median (IQR) synovial tissue concentrations were 26.2 microg/g (22.7-28.4), 4.0 mg/L (3.7-4.4) and 1.0 mg/L (0.9-1.2) at the different time points, corresponding to a median (IQR) tissue/serum penetration ratio of 0.41 (0.39-0.42). Conclusions The concentrations after an ertapenem 1 g dose achieved in cancellous and cortical bone tissue and in synovial tissue were greater than the MIC(90)s for most aerobic organisms for 24 h, and for 12 to 24 h for anaerobic bacteria in healthy volunteers undergoing total hip replacement.

To evaluate the reliability of mini-bronchoalveolar lavage (mini-BAL) for the measurement of tobramycin concentrations in epithelial lining fluid (ELF) in comparison with conventional bronchoscopic bronchoalveolar lavage (BAL).Prospective, open-label study.An intensive care unit and research ward in a university hospital.Twelve critically ill adult patients with ventilator-associated pneumonia (VAP).All subjects received intravenous infusions of tobramycin 7-10 mg/kg once daily. After 2 days of therapy, the steady-state serum and ELF concentrations (obtained from BAL and mini-BAL) of tobramycin were determined by means of high-performance liquid chromatography.We observed poor penetration of tobramycin in ELF of approximately approximately 12% with ELF peak concentrations of approximately approximately 3 mg/l with both methods. Good agreement in Bland-Altman analysis (mean +/- SD bias = 0.04 +/- 0.38 mg/l) was observed between the two methods of sampling.Our results suggest that tobramycin 7-10 mg/kg once daily in critically ill patients with VAP might provide insufficient lung concentrations in the case of difficult-to-treat pathogens. Besides, mini-BAL, which is simple, non-invasive and easily repeatable at the bedside, appears to be a reliable method for the measurement of antibiotic concentrations in ELF in comparison with bronchoscopic BAL in critically ill patients with VAP.

The objectives of the study were to assess the effects of pravastatin on plasma HIV RNA, lipid parameters, and protease inhibitor (PI) concentrations in patients treated with PI-containing regimens and with total cholesterol (TC)or = 5.5 mmol/L.A clinical trial including patients randomized to receive pravastatin or matching placebo for 12 weeks was implemented.Twelve patients were included in the pravastatin group and 9 in the placebo group. At week 12 (W12), no patient had experienced virological failure. Between week 0 (W0) and W12, the median differences for TC were -1.4 mmol/L in the pravastatin group and +0.2 mmol/L in the placebo group (p = .005); for LDL, they were -1.0 mmol/L and +0.3 (p = .007), respectively. A significant decrease of the PI concentration (12 hours after administration) ratio W12 - W0/W0 was noticed in the pravastatin group (-0.2 [interquartile range, -0.3 to -0.1] as compared with the placebo group (0.1 [IQR, 0.0 to 0.3]) (p = .03). When the study was restricted to patients treated with lopinavir/ritonavir, a decrease from 3.8 microg/mL at baseline to 2.9 mug/mL at W12 was noticed in the pravastatin arm (p = .04) but not in the control arm (p = 1.00). No clinical adverse event reached a severity of grade 3.We observed in this study that the use of pravastatin in PI-treated patients was not associated with major change in the plasma HIV RNA on 12 weeks of follow-up. However, we found a trend of decrease of the trough PI concentration at W12, suggesting a possible drug-drug interaction of pravastatin on PI metabolism.

Background: There is insufficient data to reliably assess the benefit of bronchodilators in ventilated premature neonates. Objectives: To compare the efficacy/tolerance of inhaled ipratropium bromide (IB) vs. terbutaline (T) and to describe factors associated with their efficacy. Methods: A cross-over randomized controlled double-blind trial including intubated neonates with respiratory distress syndrome. Two puffs of IB or T were administered at 0, 20, 40 min. Passive respiratory system resistance (Rrs) and compliance (Crs) were measured at 0, 20, 40, 60 min. A positive response was defined as a >2 individual coefficients of variation decrease in Rrs or increase in Crs. Results: Twenty-one infants (gestational age (mean ± SD): 27.3 ± 1.6 weeks; birth weight: 947 ± 250 g; postnatal age: 20 ± 9 days) were included. At 60 min, no treatment effect for Rrs and Crs could be identified (cross-over analysis). Overall data (irrespective of order of administration) showed that after 6 puffs, the decrease in Rrs was greater in the IB vs. T group (–17.0 ± 22.2% vs. –11.3 ± 26.7%, respectively (NS)). Thirty-eight percent of infants responded to IB vs. 43% to T. However, in 19% of patients, decreased Crs was observed after 6 puffs of T. No marker of a positive or paradoxical response could be identified. Treatment was well-tolerated. Conclusion: High doses of bronchodilators are required in ventilated neonates, but the positive response rate was

To assess intracellular and plasma efavirenz concentrations in HIV-infected patients who switched to efavirenz-based highly active antiretroviral therapy (HAART) from successful protease inhibitor-based HAART.A total of 49 patients were included in this observational cohort study. At inclusion, all patients had plasma HIV-RNA levels50 copies/mL and switched to efavirenz combined with two nucleoside reverse transcriptase inhibitors. Intracellular and plasma concentrations were measured 12 h post-dose, 1 month (M1) and 6 months (M6) after starting efavirenz. Virological success (VS) was defined as plasma HIV-RNA level50 copies/mL within the first 12 months and remaining undetectable at the end of the follow-up.VS was documented in 48 patients for at least 12 months (range 12-78 months). High inter-patient variabilities of intracellular and plasma efavirenz concentrations were observed (coefficients of variation40%). At M1 and M6, respectively, median [Q1; Q3] intracellular efavirenz concentrations were 5300 [2830; 11 530] and 6790 [3870; 8790] ng/mL, median plasma efavirenz concentrations were 2050 [1600; 3100] and 2100 [1410; 2500] ng/mL. No correlation was found between intracellular and plasma concentrations. Plasma efavirenz levels exceeded the proposed threshold of 1000 ng/mL in 96% of patients from M1.For moderately pre-treated HIV-infected patients with few mutations who switched to efavirenz from previous successful HAART, the proposed plasma efficacy-threshold was reached without any dosage adaptation. VS was maintained beyond 12 months, despite high inter-patient and intra-patient variabilities of intracellular and plasma efavirenz concentrations.

To determine the steady-state trough serum and epithelial lining fluid (ELF) concentrations of teicoplanin 12 mg/kg per day in critically ill patients with ventilator associated pneumonia.Prospective, pharmacokinetic study in the surgical intensive care unit in a university hospital.Thirteen adult patients with nosocomial bacterial pneumonia on mechanical ventilation were enrolled.All subjects received a 30-min intravenous infusion of 12 mg/kg teicoplanin every 12 h for 2 consecutive days followed by 12 mg/kg once daily. Teicoplanin concentrations in serum and ELF were determined simultaneously 4-6 days after antibiotic administration started.The median total and free concentrations of teicoplanin in serum at trough were 15.9 microg/ml (range 8.8-29.9) and 3.7 (2.0-5.4), respectively. The concentration in ELF was 4.9 (2.0-11.8).In critically ill patients with ventilator-associated pneumonia the administration of high teicoplanin doses is required to reach sufficient trough antibiotic concentrations in lung tissues at steady state. At that time trough-free concentrations of teicoplanin in serum and ELF are comparable.

A sensitive assay for the determination of unbound ertapenem in human plasma and bronchoalveolar lavage (BAL) was developed using ultrafiltration of plasma and BAL samples. A rapid HPLC method was used with ultraviolet detection set at a wavelength of 305 nm and a separation on a Prontosil AQ C18 column, with imipenem used as internal standard. This assay was linear over the concentration range of 0.5-100 microg/mL and 0.25-50 microg/mL in plasma and BAL, respectively. Limits of detection and quantitation were respectively 0.05 and 0.25 microg/mL. Validation data for accuracy and precision were CV

Although it is well accepted that treatment with nucleoside reverse transcriptase inhibitors (NRTIs) modifies fat metabolism and fat distribution in humans, the mechanisms underlying these modifications are not yet known. The present investigation examines the effects of chronic oral administration of 3'-azido-3'-deoxythymidine (AZT) on the mitochondrial metabolism and the redox status management of rat white adipose tissues originating from two anatomical sites, as well as of the rat liver. Results showed that AZT treatment induced differential effects on the mitochondrial functions depending on the anatomical localisation. Indeed, in inguinal adipose tissue, a significant decrease in the cytochrome c oxidase activity and in the mitochondrial DNA (mtDNA) content was observed, whereas the activity of citrate synthase, a mitochondrial protein exclusively encoded by the nucleus, was not affected. In contrast, no significant change in these parameters could be detected for epididymal tissue and for liver. In parallel, no oxidative stress could be detected after treatment, for both white adipose tissues and for liver, even though treated liver exhibited several modifications in redox management. Taken together, these data demonstrate differential mitochondrial effects of AZT on subcutaneous versus visceral white adipose tissue. Moreover, the decrease in mitochondrial oxidative capacity of inguinal adipocyte consecutive to AZT treatment is not primarily due to an oxidative stress per se, but rather to a depletion of the mtDNA content per cell.

Objectives To assess the impact of HIV-1 protease mutations and intracellular and plasma lopinavir minimum concentrations (Cmin) on virological success or failure on lopinavir/ritonavir-containing highly active antiretroviral therapy (HAART). Design HIV-1-infected HAART-experienced patients included in an observational study, received lopinavir/ritonavir (400/100 mg twice a day) plus two to three nucleoside reverse transcriptase inhibitors (NRTI) or one NRTI plus one non-NRTI. A viral load less than 50 copies/ml at month 6 defined virological success. Methods Intracellular and plasma lopinavir concentrations were determined by high-pressure liquid chromatography with mass-spectrometry detection. Reverse transcriptase and protease genes were sequenced at baseline and the time of virological failure. Results When the 38 patients started the lopinavir/ritonavir-based regimen, baseline median (25-75th percentile) values were: CD4 cell count 218 cells/microl (133-477); plasma HIV-1-RNA load 5.3 log10 copies/ml (3.8-5.1); number of lopinavir mutations four per protease gene (two to six). Univariate analysis associated virological success or failure at month 6 (21/38 patients) with the number of baseline lopinavir mutations, intracellular and plasma lopinavir Cmin, and the genotype inhibitory quotient (GIQ) at months 1 and 6. Multivariate analysis showed that the number of baseline lopinavir mutations and intracellular and plasma lopinavir Cmin were independently associated with virological success or failure. We defined the most discriminating intracellular and plasma lopinavir Cmin efficacy thresholds (8 and 4 microg/ml, respectively) and GIQ thresholds (1 and 3, respectively). Conclusion The monitoring of lopinavir/rironavir-based HAART efficacy should include the number of baseline lopinavir/ritonavir mutations, intracellular and plasma lopinavir Cmin and GIQ calculation.

To determine the steady-state plasma and epithelial lining fluid (ELF) concentrations of piperacillin/tazobactam (P/T) administered to critically ill patients with severe bacterial pneumonia.Prospective, open-label study.An intensive care unit and research ward in a university hospital.Ten adult patients with severe nosocomial bacterial pneumonia on mechanical ventilation.All subjects received a 30-min intravenous infusion of P/T 4 g/0.5 g every 8 h. The steady-state plasma and ELF concentrations of P/T were determined by high-performance liquid chromatography.The mean+/-SD steady-state plasma trough, peak, and intermediate concentrations were 8.5+/-4.6 microg/ml, 55.9+/-21.6 microg/ml, and 24.0+/-13.8 microg/ml for piperacillin, and 2.1+/-1.0 microg/ml, 4.8+/-2.1 microg/ml, and 2.4+/-1.2 microg/ml for tazobactam, respectively. The mean+/-SD steady-state intermediate ELF concentrations were 13.6+/-9.4 microg/ml for piperacillin and 2.1+/-1.1 microg/ml for tazobactam, respectively, showing a mean percentage penetration of piperacillin and tazobactam into ELF of 56.8% and 91.3 %, respectively, with a P/T ratio of 6.5:1.Our results show that during the treatment of severe nosocomial pneumonia, a regimen of P/T 4 g/0.5 g every 8 h might provide insufficient concentrations into lung tissue to exceed the MIC of many causative pathogens. This suggests that higher doses of P/T should be administered in order to maximize the antibiotic concentration at the site of infection, or that a second antimicrobial agent should be used in association.

The aim of this study was to develop a specific and sensitive high-performance liquid chromatographic (HPLC) assay for the determination of levofloxacin in human plasma, bronchoalveolar lavage and bone tissues. The sample extraction was based on a fully automated liquid-solid extraction with an OASIS cartridge. The method used ultraviolet detection set at a wavelength of 299 nm and a separation with a Supelcosil ABZ+ column. The assay has been found linear over the concentration range 0.25-25 microg/ml for levofloxacin in plasma, 1-6 microg/ml in bronchoalveolar lavage and 0.5-10 microg/g for bone tissues and it provided good validation data for accuracy and precision. The assay will be applied to determine the penetration of levofloxacin in human bronchoalveolar lavage (BAL) and bone tissues during pharmacokinetic steady state.

The degree of penetration of an antibiotic into the infection site is an important factor for its therapeutic efficacy, particularly in respiratory tract infections. In the present study, we examined the lung tissue diffusion of moxifloxacin at a dose of 400 mg administered intravenously or orally once-daily, and the results were correlated to microbiological data to estimate the clinical efficacy of moxifloxacin in lower community-acquired respiratory infections. This was a prospective, randomized, parallel-group trial, open-label, single-center study. Patients undergoing lung surgery for bronchial cancer which necessitates the removal of an anatomical piece of lung tissue were randomized into twelve treatment groups, dependent upon the time of surgery and the moxifloxacin formulation, i.v. or oral, administered. During surgery, one blood sample was taken at the time of tissue collection to determine moxifloxacin plasma concentration. At the same time, tissue samples were taken by pulmonary exeresis. A validated new high performance liquid chromatography assay was used to determine moxifloxacin concentrations in plasma and lung tissue. A total of 49 patients (25 for i.v. administration, 24 for oral administration, 44 men and 5 women, mean age, 61 years, mean body weight, 72 kg, mean creatinine clearance was 84 ml/min/1.73 m2) were enrolled. The mean +/- SD steady-state moxifloxacin ratios between lung and plasma concentrations were respectively: 3.53 +/- 1.89 and 4.36 +/- 1.48 for i.v. and oral administration. The mean steady-state moxifloxacin maximal lung concentrations (Cmax) were respectively 12.37 microg/g and 16.21 microg/g for i.v. and oral administration. Moxifloxacin both intravenously and orally exhibits high penetration in lung tissue, with tissue concentrations far above the MIC90s for most of the susceptible pathogens commonly involved, thus underlining its suitability for the treatment of community-acquired, lower respiratory tract infections.

To the Editor: Mycophenolic acid (MPA), the active form of mycophenolate mofetil (MMF), is an immunosuppressant increasingly used for remission maintenance after induction therapy for systemic lupus erythematosus (SLE) and antineutrophil cytoplasmic antibody-associated vasculitides (AAV)1,2. However, no recommendations concerning optimal dose of MMF for AAV are available, and a high relapse rate might compromise its use as a first-line remission-maintenance therapy3. An association between SLE activity and the pharmacokinetics of MPA has been described4,5,6. We previously reported that, for patients with SLE without renal manifestations, clinical flares under MMF were associated with 12-h trough concentrations (C12h) of MPA that were < 3 mg/l5. Pertinently, the increasing attention on therapeutic drug-monitoring for SLE raises the question of individualizing MMF therapy for patients with vasculitides based on its pharmacokinetics. Although preliminary results suggest MMF-pharmacokinetic efficacy relationships in AAV4, further confirmatory data are needed. We conducted a single-center observational study to investigate the relationships between plasma MPA exposure and disease activity in 28 patients with only extrarenal manifestations of systemic vasculitides, defined according to the 1992 Chapel Hill … Address correspondence to S. Djabarouti; E-mail: sarah.djabarouti{at}chu-bordeaux.fr

The response to regimens including lopinavir-ritonavir (LPV/r) in patients who have received multiple protease (PR) inhibitors (PI) can be analyzed in terms of human immunodeficiency virus type 1 (HIV-1) genotypic and pharmacokinetic (pK) determinants. We studied these factors and the evolution of HIV-1 resistance in response to LPV/r in a prospective study of patients receiving LPV/r under a temporary authorization in Bordeaux, France. HIV-1 PR and reverse transcriptase sequences were determined at baseline LPV/r for all the patients and at month 3 (M3) and M6 in the absence of response to treatment. pK measurements were determined at M1 and M3. Virological failure (VF) was defined as a plasma viral load ≥400 copies/ml at M3. A multivariate analysis of the predictors of VF, including clinical and biological characteristics and the treatment history of the patients, was performed. The PR gene sequence at M0, including individual mutations or a previously defined LPV mutation score (D. J. Kempf, J. D. Isaacson, M. S. King, S. C. Brun, Y. Xu, K. Real, B. M. Bernstein, A. J. Japour, E. Sun, and R. A. Rode, J. Virol. 75: 7262-7269, 2001), and the individual exposure to LPV were also included covariates. Sixty-eight patients were enrolled. Thirty-four percent had a virological response at M3. An LPV mutation score of >5 mutations, the presence of the PR I54V mutation at baseline, a high number of previous PIs, prior therapy with ritonavir or indinavir, absence of coprescription of efavirenz, and a lower exposure to LPV or lower LPV trough concentrations were independently associated with VF on LPV/r. Additional PI resistance mutations, including primary mutation I50V, could be selected in patients failing on LPV/r. Genotypic and pK parameters should be used to optimize the virological response to LPV/r in PI-experienced patients and to avoid further viral evolution.

Background Increased antibiotic resistance against Staphylococcus aureus and low penetration into bone requires regimen optimization of available drugs. Methods We evaluate pharmoacokinetic and pharmacodynamic parameters (PK/PD) as well as in vivo interactions of continuous flucloxacillin 12 g/d administration combined with high dose oral rifampicin 600 mg bid in the serum of 15 adult patients with bone and soft tissue infections. We use the patient’s own serum directed against his own isolated S. aureus strain to reproduce in vivo conditions as closely as possible. Results The continuous flucloxacillin infusion constantly generated plasma free drug levels largely exceeding the serum minimal inhibitory concentrations (mean 74-fold). Combination with rifampicin significantly increased flucloxacillin levels by 44.5%. Such an increase following rifampicin introduction was documented in 10/15 patients, whereas a decrease was observed in 1/15 patients. Finally, all infections were cured and the combination was well tolerated. Conclusions In this in vivo methodological pilot study among adult patients with orthopaedic infections due to S. aureus, we describe a new method and reveal substantial but inconsistent interactions between flucloxacillin and rifampicin, of which the clinical significance remains unclear.

To date, neither the benefit of mycophenolic acid (MPA) therapeutic drug monitoring (TDM), the prodrug of mycophenolate mofetil (MMF), nor the optimal monitoring technique have been established in autoimmune diseases. This study was undertaken to confirm, in a cohort of new patients, the plasma MPA thresholds previously published in patients with systemic lupus erythematosus (SLE) or vasculitis.MPA areas under the concentration-time curves between 0 and 12 h, 12 h trough concentrations and pre-dose concentrations (C0 ) were determined for 23 patients with SLE and 21 with systemic vasculitis. The relationship between patients' pharmacokinetic (PK) variables and their clinical outcomes during follow-up were analyzed.In both autoimmune diseases, at PK assessment, median MPA C0 for patients with uncontrolled disease was significantly lower than that of patients with stable disease or in remission, 1.6 mg l(-1) (IQR 0.9-2.1 mg l(-1)) vs. 2.95 mg l(-1) (IQR 1.38-3.73 mg l(-1)) for SLE (P = 0.048) and 1.55 mg l(-1) (IQR 0.98-2.18 mg l(-1)) vs. 3 mg l(-1) (IQR 2.2-4.4 mg l(-1)) for vasculitis (P = 0.016). According to our receiver operating characteristics curve analysis, a C0 threshold of 2.5-3 mg l(-1) was best able to discriminate a flare (SLE: 88% sensitivity, 80% specificity; vasculitis: 100% sensitivity, 90% specificity). Patients with C0 ≥ 2.5-3 mg l(-1) at inclusion had better clinical outcomes during the 12 months following PK assessment.Provided that the benefit of TDM in patients with autoimmune diseases could be confirmed by randomized, controlled trials, it might be based on the C0 measured approximately 12 h post-dose.

Background: The degree of penetration of an antibiotic into the site of infection is an important factor in its therapeutic efficacy, particularly in bone and joint infections. Piperacillin/tazobactam, a β-lactam/β-lactamase inhibitor combination, has been widely used in the treatment of serious infections, including bone infections, but few studies have examined the bone diffusion of these antibiotics. Objective: The purpose of this study was to quantify the bone tissue penetration of piperacillin/tazobactam into cancellous and cortical bone tissue and, from these results, estimate the efficacy of this antibiotic combination against microorganisms commonly encountered in bone infections. Methods: In this open-label, single-arm, noncomparative study, subjects of similar age, body weight, height, and creatinine clearance who were undergoing elective total hip replacement received a single, parenteral 4 g/500 mg dose of piperacillin/tazobactam. Approximately 1.5 hours later, plasma and bone tissue samples were collected and analyzed by a validated high-pressure liquid chromatography method. Results: Twelve patients (3 men and 9 women; mean age, 73.5 years; mean body weight, 52.2 kg) were enrolled. The mean concentrations of piperacillin and tazobactam were 18.9 ± 2.3 μg/g and 2.0 ± 0.3 μg/g, respectively, in cancellous bone tissue and 15.1 ± 2.0 μg/g and 2.0 ± 0.3 μg/g in cortical bone tissue. The bone tissue/plasma ratios for piperacillin and tazobactam were both 0.3 in cancellous bone tissue and 0.2 and 0.3, respectively, in cortical bone tissue. The piperacillin/tazobactam concentration ratio was 9.3:1 in cancellous bone tissue and 7.8:1 in cortical bone tissue. Conclusions: The concentrations achieved in both cancellous and cortical bone tissue were greater than the minimum concentrations required to inhibit the growth of 50% of strains (MIC 50 ) of most of the susceptible pathogens commonly involved in bone infections.

The aim of this study (SITEPO) is to evaluate the influence of the intravenous injection site (drip chamber injection site, venous injection site or venous fistula needle) on plasma concentration of epoetin beta (Neorecormon, Roche), a recombinant Human Erythropoietin (rHuEPO), at the end of in vitro hemodialysis sessions. No practical administration guidelines are available. Twenty 1-h dialysis sessions are performed. Before each dialysis, the circuit is filled with 270ml, of heparinized total human blood whose hematocrit is adjusted to 35%. A common dosage of epoetin beta in clinical practice (3000IU) is studied for the three injection sites and for reference experiments in which rHuEPO is not injected into the dialysis circuit. Plasma concentrations of erythropoietin are measured by ELISA. The physiologically endogenous erythropoietin concentration is systematically determined and removed from the total epoetin beta concentration. Average epoetin beta plasma levels returned are not significantly different between the three injection sites and no significant rHuEPO loss is observed after injection into the drip chamber, the venous injection site and the venous fistula needle compared with reference experiments. The three intravenous injection sites of rHuEPO can be used at the end of dialysis without significant epoetin beta loss.

The aim of this study was to describe a high-performance liquid chromatography (HPLC) assay for the determination of cefepime and cefpirome in human serum without changing chromatographic conditions. The assay consisted to measure cefepime and cefpirome which were unbound to proteins having a molecular mass of 10,000 or more by ultrafiltration followed by HPLC with a Supelcosil ABZ+ column and UV detection at a wavelength of 263 nm. The assay was been found to be linear and has been validated over the concentration range 200 to 0.50 microg/ml for both cefepime and cefpirome, from 200 microl serum, extracted. In future, the assay will support therapeutic drug monitoring for cefepime and cefpirome in neutropenic patients in correlation with microbiological parameters such as MIC90 (minimal inhibitory concentration of antibiotic which kills 90% of the initial bacterial inoculum) and clinical efficacy.

OBJECTIVE To evaluate the effect of foscarnet on HIV-1 replication in vivo. PATIENTS AND METHODS Seventeen AIDS patients with cytomegalovirus (CMV), herpes simplex virus (HSV), varicella-zoster virus (VZV) infection, Kaposi's sarcoma (KS), or a combination of these were treated with foscarnet. HIV RNA quantification (bDNA 2.0, Chiron, Emeryville, CA, U.S.A.), CMV pp65 antigenemia (Argene Biosoft, Varilhes, France), and CMV viremia were determined before and during therapy. RESULTS Four patients had CMV retinitis (1 with KS), 2 patients had CMV pneumonia (1 with KS), 1 patient had CMV cholecystitis, 2 patients had VZV infection (1 with KS), 1 patient had HSV-2 infection, and 7 patients had KS alone. The decrease in HIV-1 load was -0.73 +/- 0.39 log copies/ml (p = 2.10(-6)) after 3 days of treatment and -1.15 +/- 0.49 log copies/ml (p < 10(-7)) after 10 days of treatment, compared with day 0. Furthermore, reduction of HIV-1 plasma load during foscarnet therapy did not depend on the presence or absence of CMV disease or on a positive pp65 antigenemia at day 0. CONCLUSION We observed decreased HIV-1 plasma load in all patients treated with foscarnet, regardless of presence or absence of clinical or biologic CMV infection. This decrease supports the proposition that foscarnet anti-HIV-1 activity may be of clinical importance.

The objective of this study was to analyze the pharmacokinetics of cefepime, in six patients with acute renal failure related to septic shock, during continuous venovenous hemodiafiltration (CVVHD) (Hemospal AN 69S hemofilter; Hospal, Lyon, France). Six patients, mean age 65 +/- 4 years (range, 61 to 69), were included and each received 2 g of cefepime by intravenous infusion over a 30-min period every 12 h. Prefilter serum, dialysate outlet (DO), and ultrafiltrate samples were collected 0.47, 0.50, 0.57, 1, 3, 5, 7, and 12 h after the beginning of infusion. The time design of samples was optimized in accordance with the theory of D optimality. The cefepime concentrations were measured by high-performance liquid chromatography. The pharmacokinetics computation was carried out using P-PHARM software. Mean serum concentration peaks were 53 +/- 21.9 mg/liter (range, 13.0 to 68.9) one-half hour after the infusion. The mean elimination half-life was 8.11 +/- 2.22 h (range, 4.76 to 10.84). DO clearance was 66.57 +/- 30.14 ml/min (range, 38.66 to 119.87). The mean volume of distribution was 0.71 +/- 0.37 liters/kg of body weight. CVVHD was effective for cefepime elimination. In these subjects, the elimination half-life and DO clearance were almost constant. The results of this study suggested that a 2-g twice-daily infusion (usual dosage) was required for an effective concentration in this group of patients.