Axitinib pharmacologic therapeutic monitoring reveals severe under-exposure despite titration in patients with metastatic renal cell carcinoma.

Introduction New therapeutic strategies combining axitinib and immune checkpoint blockers are ongoing in metastatic renal cell carcinoma (mRCC). These strategies do not consider the pharmacokinetic variability of axitinib. We aimed to describe the risk of axitinib under-exposure using routine pharmacologic therapeutic monitoring (PTM). Methods We analyzed axitinib dosage in nine patients with mRCC. Routine axitinib concentration measurements were centralized at Henri Mondor University Hospital (Créteil, France) using a validated method. The primary objective was to describe the evolution of Cmax dosages (1 to 6 h after oral intake) during routine axitinib titration. Results Nine patients with available Cmax axitinib dosages were included. Four out of the nine patients had axitinib titration and Cmax dosages were performed before and after titration. All but one corrected their plasma axitinib exposure after titration, suggesting of a titration success. The last patient was monitored in the Henri Mondor Hospital routine PTM program and a pharmacokinetic profiling was performed after controlled oral intake. Results suggested a poor axitinib absorption. This patient experienced early tumor progression as best response. Conclusion We report a patient with significant axitinib under-exposure, possibly due to a poor absorption. PTM should be evaluated and considered in drug developments evaluating combination therapies based on axitinib.

Probenecid, an old ß-lactams pharmacokinetic enhancer for a renewed use: A retrospective study.

BACKGROUND: Optimized antibiotic plasma predictor efficacy is essential in systemic infections. The uricosuric agent probenecid inhibits tubular excretion of antibiotics and may be used as ß-lactam pharmacokinetic enhancer (BLPKE), even though few data are currently available for this purpose. METHODS: We conducted a monocentric and retrospective observational study including all patients who received probenecid in combination with parenteral ß-lactam antibiotics for systemic infections from Jan 1, 2014 to Dec 31, 2019. Demographics, infection characteristics, treatment and ATC (antibiotics trough concentration) were investigated. RESULTS: All in all, 38 patients were included. Eight patients had a history of sickle cell disease. Hyperfiltration (defined as eGFR>130mL/min/1.73m2) was detected in twenty-one patients including six with sickle cell disease. Probenecid (500mg q6h orally) was added to antibiotics for a median (IQR) of 13 days (6.75-21.75), after a median (IQR) time lapse of 7 days (4-16) following the initiation of antibiotics. Probenecid was administered for low antibiotic trough concentration in 29 patients, for increased renal clearance in 5 patients and for persisting fever despite antibiotic therapy in 4 patients (including 1 infective relapse). A second plasma trough concentration, following probenecid administration, was available in 19 patients within a median (IQR) 3 days (2-5). Probenecid induced increased ATC in 18/19 patients (94.7%), with a median (IQR) change of +228.4% (IQR 38.7-633). No major adverse effects were reported. CONCLUSION: Probenecid could be a BLPKE. Our data suggest this drug should be used more often to optimize ß-lactam pharmacokinetics in clinical practice.

Mycophenolate mofetil monotherapy for severe side effects of calcineurin inhibitors following liver transplantation.

Withdrawal of calcineurin inhibitors (CNI) followed by mycophenolate mofetil (MMF) monotherapy after liver transplantation (LT) remains controversial due to the increased risk of acute rejection and graft loss. The aim of the present study, performed in a large cohort of liver-transplanted patients with severe CNI-induced side effects, was to assess renal function recovery, and safety in terms of liver function, of complete CNI withdrawal and replacement by MMF monotherapy. Fifty-two patients treated with MMF monotherapy for CNI-induced toxicity were analyzed. Mean estimated glomerular filtration rate (eGFR) increased significantly during the period of MMF monotherapy, from 37 +/- 10 to 44.7 +/- 15 mL/min/1.73 m(2) at 6 months (p = 0.001) corresponding to a benefit of +17.4% in renal function. eGFR stabilized or improved in 86.5%, 81% and 79% of cases, and chronic renal dysfunction worsened in 13.5%, 19% and 21% of cases, at 6, 12 and 24 months after CNI withdrawal, respectively. Only two patients experienced acute rejection. MMF monotherapy may be efficient at reversing/stabilizing CRD, and appears relatively safe in terms of liver graft function in long-term liver-transplanted patients. However, clinicians must bear in mind the potential risk of rejection and graft loss, and should be very cautious in the management of such 'difficult-to-treat patients'.

[Myxomatous mitral valve degeneration: biochemical aspects and physiopathological considerations]. / L'insuffisance mitrale par dégénerescence myxoïde: aspect biochimique et considérations physiopathologiques.

Mitral valve is a complex structure which is submitted to repeated mechanical constraints. In clinical practice, an increasing incidence of mitral insufficiency resulting from myxomatous degeneration is observed. Since myxomatous degeneration is also observed in defined genetic diseases of connective tissues, we propose the hypothesis that idiopathic mitral insufficiency might result from a minor alteration of the interstitial valvular cells and/or their interactions with their support. After a brief review of the role of the extracellular matrix in the heart, some histopathological and biochemical aspects of myxomatous degeneration are presented. Our data and those of the literature will be summarized and a physiopathological hypothesis proposed for myxomatous mitral valve degeneration.

[Today in molecular mechanisms of immunosuppressive drugs actions: roles of pharmacist]. / Mécanismes moléculaires de l'activité des immunosuppresseurs actuels en transplantation : rôles du pharmacien.

Immunosuppressive drugs modulate cellular and humoral immune response in the acute allograft rejection. The panel of drugs, which has been recently extended, allowed a significant progress for immunosuppressive treatment. These drugs help us to improve our knowledge of lymphocyte activation pathways. Corticoids, the oldest immunosuppresive drugs, inhibit many cytokines such as interleukin 2 (IL2) and interleukin 6. They represent the treatment of acute rejection. The other immunosuppressive drugs are used for preventing acute rejection. After binding to a specific immunophillin, cyclosporin and tacrolimus inhibit calcineurine, a serine/threonine phosphatase which plays a major role in cytokines transcription notably IL2 after T-cell activation. Anti-IL2 receptor monoclonal antibodies block IL2 activity following T-cell activation. Protein mammalian target of rapamycin inhibitors avoid the transcription of different mRNA involved in the regulation of the cellular cycle. These new agents are rapamycin or sirolimus and everolimus. The inhibitors of pyrimidic and puric bases synthesis, mycophenolic acid and azathioprin, inhibit T- and B-cell proliferation. The wide variety of immunosuppressive drugs permits the use of combinations, which aims at decreasing the immunologic risk and their own toxicities, notably nephrotoxicity. Before transplant, the pharmacist plays an important role in the prevention of initial pathologies and in the politic of organ donation. After transplant, the pharmacist has a role in the pharmacological and biological monitoring of immunosuppressive drugs. But the pharmacist must be involved in the optimization of therapeutics and in the education of transplant patients.

Does fine sediment source as well as quantity affect salmonid embryo mortality and development?

Fine sediments are known to be an important cause of increased mortality in benthic spawning fish. To date, most of the research has focussed on the relationship between embryo mortality and the quantity of fine sediment accumulated in the egg pocket. However, recent evidence suggests a) that the source of fine sediment might also be important, and b) that fitness of surviving embryos post-hatch might also be impacted by the accumulation of fine sediments. In this paper, we report an experiment designed to simulate the incubation environment of brown trout (Salmo trutta) and Atlantic salmon (Salmo salar). During the experiment, the incubating embryos were exposed to different quantities of fine (<63 µm) sediment derived from four different sources; agricultural topsoils, damaged road verges, eroding river channel banks and tertiary level treated sewage. Results showed that mass and source are independently important for determining the mortality and fitness of alevin. Differences between species were observed, such that brown trout are less sensitive to mass and source of accumulated sediment. We demonstrate for the first time that sediment source is an additional control on the impact of fine sediment, and that this is primarily controlled by the organic matter content and oxygen consumption of the catchment source material.

Plasmodium falciparum parasites in French Guiana: limited genetic diversity and high selfing rate.

The genetic characteristics of Plasmodium falciparum isolates collected in French Guiana, where malaria transmission is low and occurs in isolated foci, were studied. Blood samples were collected from 142 patients with symptomatic malaria and typed using a polymerase chain reaction-based strategy for merozoite surface protein-(MSP-1) block 2, the MSP-2 central domain, and glutamate-rich protein (GLURP) repeat domain polymorphism. This showed that the parasite population circulating in French Guiana presented a limited number of allelic forms (4, 2, and 3 for MSP-1 block 2, MSP-1, and GLURP, respectively) and a small number of mixed infections, contrasting with the large genetic diversity of parasite populations and infection complexity reported for Africa, Asia, and other parts of South America. Two groups of isolates displaying identical 3 loci allele combinations were further studied for the Pf332 antigen, histidine-rich protein-1, thrombospondin-related anonymous protein, and Pf60 multigene family polymorphism. Within each group, most isolates were identical for all markers tested. This suggests a high rate of self-fertilization of P. falciparum parasites in French Guiana, resulting in homogenization of the population. The implications of these findings for malaria control in areas of low endemicity are discussed.

Tonate virus infection in French Guiana: clinical aspects and seroepidemiologic study.

Two recent cases of human infection with Tonate virus, one of which was a fatal case of encephalitis, have renewed interest in these viruses in French Guiana. The clinical aspects of confirmed and probable cases of infection with this virus indicate that it has pathogenic properties in humans similar to those of other viruses of the Venezuelan equine encephalitis complex. To determine the prevalence of antibodies to Tonate virus in the various ethnic groups and areas of French Guiana, 3,516 human sera were tested with a hemagglutination inhibition test. Of these, 11.9% were positive for the virus, but significant differences in seroprevalence were found by age, with an increase with age. After adjustment for age, significant differences were found between places of residence. The prevalence of antibody to Tonate virus was higher in savannah areas, especially in the Bas Maroni (odds ratio [OR] = 22.2, 95% confidence interval [CI] = 15.2-32.4) and Bas Oyapock areas (OR = 13.4; 95% CI = 9.8-18.4). The ethnic differences observed in this study were due mainly to differences in place of residence, except that whites were significantly less frequently infected than other ethnic groups. This study indicates that Tonate virus infection is highly prevalent in French Guiana, especially in savannah areas.

Study of the bioequivalence of two controlled-release formulations of morphine.

The management and treatment of chronic pain in cancer patients is a clear priority for practitioners regularly confronted by the situation. This investigation was carried out to evaluate the bioavailability of a recent sustained-release (SR) formulation of morphine sulphate (30 mg), Skenan, consisted of capsules, relative to a recognized product, Moscontin which is a matrix tablet SR form. The bioavailability was carried out on 12 healthy male volunteers who received a single dose (30 mg) of the test (T) and the recognized (R) products in a randomized balanced 2-way crossover design. After dosing, serial blood samples were collected for a period of 24 hours. Morphine and its main metabolites (i.e. glucuronides M6G and M3G) were assayed by high-performance liquid chromatography using a ion-pair formation. Data were analyzed by a noncompartmental method and were compared by ANOVA method and, each subject taken as his own control, by the Wilcoxon T test. Mean bioavailability of the T formulation was greater than that of R. The parametric confidence intervals (90%) of the mean values of the pharmacokinetics characteristics for T:R ratio were in each case without the bioequivalence acceptable ranges of 0.8-1.25 and 0.70-1.43 respectively for AUCs (i.e. AUCo-->24h and AUCo-->infinity) and Cmax, while confidence intervals symmetric of Westlake (CIW90%) was invariably greater than 20%, i.e. 62.8, 71.1 and 39.3% respectively. Further, the test formulation was not found bioequivalent to the reference formulation by Schuirmann's 2 one-sided t-test. These results justify the conclusion of the non-bioequivalence of the two forms at the unit dose of 30 mg. This information must be considered above all as a dosage adjustment tool enabling use of the two forms by application of a correction factor of the order of 15% when prescribing Skenan in comparison with Moscontin. Assessment is needed of the possible clinical consequences of this finding.

Perioperative pharmacokinetics of piperacillin during liver transplantation.

There have been few evaluations of the perioperative pharmacokinetics of antibiotics. Piperacillin (PPR) is a widely prescribed ureidopenicillin of established efficacy against enterobacteria and P. aeruginosa. The serum pharmacokinetics and perioperative safety of PPR were evaluated in 8 patients hospitalized for an orthotopic liver transplantation. The subjects were given a 60 mg/kg infusion of PPR once every 8 hours. PPR was assayed by HPLC and data were analyzed by a noncompartmental method. There were no adverse events during surgery. It seems that kinetics of PPR showed no variation during the anhepatic period. However, transplants notably modified the kinetics of PPR in comparison with data previously published in healthy volunteers. Trends were as follows: flattening of Cmax and prolongation of T1/2 (2.2 h vs 0.92 h). This phenomenon seems to be due to a marked increase in V(area) (44.0 1 vs 16.2 1) while C1 were similar. The increase in V(area) is probably the combined results of multiple factors including blood loss, vascular filling, combined prescription of vasoactive drugs, and, obviously, the surgical procedure itself. Concentrations of PPR were after 4 hours below (i.e. 5/8 patients) the MIC of P. aeruginosa (i.e. < or = 16 micrograms/ml). From 6 hours onwards antibacterial cover was insufficient against the majority of enterobacteria (i.e. < or = 8 micrograms/ml). This inadequate protection included the critical anhepatic period. Measured concentrations achieved by the initial dosage regimen were compared to those obtained by simulation using modified dosing pattern in order to ensure circulating levels constantly of 16 micrograms/ml or more. This leads to a suggested modified dosage pattern in which PPR would be given as 1 dose of 60 mg/kg every 4 hours. Under these conditions the expected concentrations should be constantly over 16 micrograms/ml and any risk of systemic accumulation is excluded.

Influence of acute renal failure on FPIA rapid serum assay of midazolam and its main metabolite.

We recently developed a simple and fast assay technique, providing the possibility of monitoring of midazolam (M) during sedation. We compared HPLC vs FPIA for the measurement of the sum M plus alpha 1-hydroxymidazolam (OM), its main and pharmacologically active metabolite, in the serum of sedated ICU patients; this activity referred to as M-like. We identified certain patients in whom M-like activity appeared abnormally high in comparison with HPLC assays. Their common denominators were: long-term sedation with M, and seriously impaired renal function. Further, the conjugates of OM (OMG) accumulated in patients with acute renal failure could contribute to the sedation. We compared the metabolic and analytic behavior of M, OM, and OMG in 2 groups of sedated patients either presenting with normal renal functions (group 1) or with a picture of acute renal failure (group 2). Blood samples were assayed by HPLC and by FPIA and analysis was performed before and after hydrolysis of OMG. Before hydrolysis there was a dramatic accumulation of OMG in the patients of group 2, HPLC vs FPIA results were not different within group 1, while in group 2 the FPIA response exceeded that of HPLC. After hydrolysis, measurement by HPLC was greatly increased in group 2, in each group (vs HPLC) and from one group to another, the FPIA signal (the M-like activity) showed a significant increase. It would be important to take OMG into account as a coprotagonist in sedation whenever circumstances predispose to its accumulation.

Influence of pregnancy on the pharmacokinetic behaviour and the transplacental transfer of the piperacillin-tazobactam combination.

The safety/acceptability, blood pharmacokinetics and urinary excretion of the piperacillin-tazobactam (PPR-TZB) combination were studied in six patients between 25 1/7 and 31 5/7 weeks of amenorrhea. The combination was given for a materno-fetal infection due to susceptible organisms i.e. 4/0.5 g/6 h. Whenever possible, the trans-placental transfer (TPT) of the combination was assessed in several sub-compartments of the feto-placental unit i.e. maternal blood sample, cord blood, amniotic fluid, placenta tissue and fetal urine. Two series of nine blood samples were scheduled for each patient, i.e. on D1 (first dose) and D3 (at plateau). Samples were assayed by HPLC and data were analyzed by a non-compartmental method. Safety/acceptability of the treatment proved to be good. The kinetic behavior of both beta-lactams appeared to be identical. Evidence was found during pregnancy of an increase in Vss and Cl of the combination. These increases can be linked to a notable decrease in AUCs. The TPT of the combination was significant. Regarding other accessible compartments (i.e. placenta tissue, amniotic fluid and fetal urine), the ratio of PPR-TZB concentrations was invariably about 8. Maternal circulating levels of PPR-TZB were, by 4 h, less than the MIC of target organisms (i.e. < or = 8 micrograms/ml), both on D1 and at steady state. This raises the question of the pertinence of the dosage regimen. Regarding PPR, it is accepted that antibacterial protection is satisfactory when circulating concentrations are kept at a Css (steady state concentration) of the order of 20 micrograms/ml or more. PPR-TZB combination would be administered by continuous infusion i.e. 8 mg/min to obtain 3 h later a Css of more than 20 micrograms/ml. The daily dosage would then be 12/1.5 g instead of 16/2 g, which is also more satisfactory from a pharmaco-economic standpoint. This proposal must be validated in a sufficient number of patients and, could avoid disqualification of the combination PPR-TZB in the treatment of serious infections during certain pathological pregnancies.

Evaluation of the new heterogeneous ACMIA immunoassay for the determination of whole-blood cyclosporine concentrations in bone marrow, kidney, heart, and liver transplant recipients.

Cyclosporine (CyA) has a narrow therapeutic index. Determination of CyA concentrations correlate with rejection or adverse effects like nephropathy. Cyclosporine is assayed based on either chromatographic or many different immunoenzymologic techniques. The investigators evaluated a new heterogeneous immunoassay of CyA on RxL Dimension. The pretreatment step is automatically performed in the apparatus. Linearity, intra- and interday precision, limit of quantification, dilutions, and stability of the equipment were compared with the EMIT method for patient determinations. The heterogeneous immunoassay showed a good linearity between 0 and 500 ng/mL, and intra- and inter-day precision with a coefficient of variation below 9.2%. The investigators observed reproducible and accurate dilutions of high concentrations (500 to 2000 ng/mL). The correlation with the EMIT technique was valid: ACMIA = 0.964 EMIT + 0.156 (r = .96) for different types of transplant (n = 116). Finally, this new system improves the determination of CyA concentrations.

[Morvan's fibrillary chorea and acrodynic syndrome following mercury treatment]. / Chorée fibrillaire de Morvan et syndrome acrodynique après un traitement mercuriel.

A 31 year-old inhabitant of French Guiana was prescribed mercuric iodide per os for two and a half months. Shortly before the end of the treatment he developed fasciculations in the trunk and particularly the lower limb muscles, distal painful paresthesias with vasomotor disorders, episodes of excessive perspiration and palmoplantar erythema, moderate fluctuating hypertension, progressive loss of weight and irritability with insomnia. Clinical and electrical signs of neuropathy were lacking. The clinical picture was that of Morvan's fibrillary chorea with acrodynia, the conditions of onset strongly suggesting a mercurial intoxication. Blood and particularly urine mercury levels were elevated. Administration of dimercaprol (BAL) considerably increased urinary excretion of mercury and there was progressive improvement and finally recovery after two months of BAL treatment. This case exemplifies the possible co-existence of fibrillary chorea and acrodynia. Whereas in many cases of fibrillary chorea a precise etiology cannot be determined, the affection can be induced by mercury as by gold administration. The fact that cases of fibrillary chorea due to mercury poisoning are rarely reported may be the result of individual patient hypersensitivity or particular metabolic absorption and excretion features of mercury. This case cannot be included within the continuous activity syndrome of muscle fibers described by Isaacs, since muscle contractures were absent and there was associated acrodynia. Moreover, there was no latent polyneuropathy, in spite of the intense fasciculations. It must be concluded, therefore, that in spite of its rarity fibrillary chorea should keep its semiologic autonomy.

Disposition of a new rate-controlled formulation of prazosin in the treatment of hypertension during pregnancy: transplacental passage of prazosin.

Prazosin (PRZ) in conventional tablet form (P-CT) has the disadvantages of a relatively short terminal half-life, a slight solubility in water and the well-recognized adverse effect of symptomatic orthostatic hypotension. The pharmacokinetic study of a new rate-controlled formulation of prazosin (Prazosin-Gastrointestinal System: P-GS) was performed in 9 pregnant women during the third trimester of pregnancy. Patients had persistent elevation of blood pressure. The subjects gave their informed consent for oral administration of 1 daily dose of 5 mg P-GS at 8 a.m. A first analysis period on day 1 enabled definition of the initial pharmacokinetic behavior of the drug, while the aim of a second was to evaluate its fate at plateau. The clinical course of both mother and fetus was subsequently monitored. This was an open, non-randomized study, each patient serving as her own control. For 3 patients, we aimed to determine the possible transplacental passage of PRZ at delivery. PRZ levels were measured by HPLC and data were analysed by noncompartmental linear pharmacokinetic methods. The data show: (i) P-GS was well tolerated by all patients and there were no significant changes in fetal heart rate during the study. (ii) A significant decrease in diastolic blood pressure was observed after the 36th hour following the first dose of P-GS while a reduction in systolic blood pressure was observed on day 4. (iii) An approximated relative bioavailability (f'P-GS) of 36.5% was calculated. P-GS appears to have a lower bioavailability than P-CT in women of similar gestational age. (iv) Both Cmax and AUC0-->infinity are significantly increased at plateau. Further, terminal half-life is increased with regard to the value determined with P-CT. No accumulation of PRZ was noted at steady-state. (v) P-GS is an example of an oral zero-order absorption product that offers one approach to control and improve the outcome of hypertensive therapy during pregnancy. This treatment could represent an alternative to methyldopa as a first treatment of pregnancy-associated hypertension. (vi) There is a slight transplacental passage of the drug (of the order of 10-20%).

[Pharmacokinetics of antibiotics in burn patients]. / Pharmacocinétique des antibiotiques chez le sujet brûlé.

The pathophysiology associated with major burns is complex and subject to a state of flux (coexistence of pain, infectious diseases, multiple trauma, disturbances of metabolism and acid-base status, etc) which could affect the disposition and the pharmacokinetic behaviour of drugs. In current clinical practice, practitioners often use powerful antimicrobial agents; however, few pharmacokinetic studies are available in burns patients (of the order of 30 studies). Furthermore, the methods used are sometimes questionable. After dealing with the ethical and physiological context in which such research is undertaken, the authors report a review of the pharmacokinetic studies done during the last 15 years. Concerning both aminoglycosides and glycopeptides, no therapeutic recommendations are available (therapeutic schedules). However, in this case, therapeutic monitoring is available and represents a suitable tool to better master their use. In the case of beta-lactam antibiotics and quinolones, more data are available. Some investigations have shown the possibility of translesional diffusion of certain agents in burns (such as gentamicin, piperacillin/tazobactam combination, or fosfomycin). This phenomenon could be a co-factor of success in treatment. Considering the relatively meager pharmacokinetic and pharmacodynamic data available in burns, it is important in the future to refine our knowledge of the distribution and metabolism of drugs in burns patients in order to better master their use. Finally, ethical and methodological considerations need to be taken in account.

[Re-emergence of Venezuelan equine encephalitis virus in French Guiana. Apropos of 1 confirmed case]. / Ré-émergence d'un virus du complexe de l'encéphalomyélite équine vénézuélienne en Guyane française. A propos d'un cas confirmé.

Venezuelan equine encephalitis (VEE) is a mosquito-borne viral disease that occurs in equine species and in man. The strains can be grouped epidemiologically into two major categories: enzootic and epizootic. Enzootic strains cause sporadic human disease and are not associated with disease among equines. These strains are found throughout Florida. Central America, northern South America and Brazil. Epizootic strains are associated with enormous morbidity and mortality in equine species. In man, VEE virus infections are largely asymptomatic and in children and young adults there is an increased risk of encephalitis and dead. We report the first case in French Guiana of Venezuelan equine encephalitis. Clinical examination and biological studies showed encephalitis, interstitial pneumonia and acute liver failure. Despite an adequate symptomatic treatment, the young patient died five days after her admission in multiple organ dysfunction syndrome. Diagnosis is establishing by virologic test: VEE virus is isolated from the blood. These example of re-emerging infectious disease vividly illustrate that we remains vulnerable and emphasizes the need for an active surveillance system.

[Evaluation of the heterogeneous immunoassay (ACMIA) for the measurement of blood cyclosporin on the Behring dimension RXL clinical chemistry analyzer]. / Evaluation du réactif immunologique hétérogène (ACMIA) pour le dosage sanguin de ciclosporine sur RXL HM Dimension.

We propose an evaluation of a new heterogeneous immunoassay of cyclosporin on RXL HM Dimension (Dade Behring) for therapeutic cyclosporin monitoring in whole-blood patients transplant. The pretreatment step is performed automatically into the apparatus while it is a manual step with EMIT. Linearity, intra- and inter-day precision, limit of quantification, precision and accuracy of dilution steps and stability into the equipment were studied. We realized the comparison between ACMIA and EMIT methods on whole-blood patients transplant recipients. Heterogeneous immunoassay showed a good linearity between 0 and 500 ng/mL, intra- and inter-day precision with coefficient of variation inferior to 7.2%. We observed reproducible and accurate dilutions of high concentrations (500 to 2,000 ng/mL). The correlation with EMIT technique was correct for different type of transplant (n=55).

[Antibiotic therapy in cystic fibrosis. I. Pharmacologic specifics of antibiotics]. / L'antibiothérapie dans la mucoviscidose. I. Particularités pharmacologiques des antibiotiques.

Antibiotherapy is one of the main treatment in cystic fibrosis. Antibiotic administration schedules are different from normal patients because of pharmacokinetic and pharmacodynamic particularities. In moderate disease, the digestive resorption of antibiotics is delayed and their half-life is reduced due to an increase in total clearance. In severe disease, the volume of distribution of antibiotics is increased due to the higher proportion of lean mass in these malnourished patients. Other particularities limit the action of antibiotics such as thick sputum, which limits drug penetration; the property of Pseudomonas aeruginosa to be surrounded by a biofilm; alteration of local antibacterial defense; and inhibition of antibiotics by local factors. Systematic prescription of a biotherapy beta-lactam-aminoglycoside and obtaining high antibiotic concentration in situ might limit this antagonism. In spite of particular therapeutic schedules such as single daily dose for aminoglycoside and continuous infusion for beta-lactams, the intervals between administrations must be narrowed for time-dependent antibiotics, and the total daily dose increased by 20 to 30% for concentration-dependent antibiotics.