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.

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.

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.

[Verification/validation of the performances of analytical method]. / Vérification/validation des performances d'une méthode d'analyse.

The verification and validation of methods consist in evaluating the precision, the analytical range, the accuracy, the trueness and the detection limit, if appropriate. These measurements must follow a standardized protocol and the obtained results must be compared to defined quality criteria. Each chapter includes, the purpose, the material used, the operating procedures, the collection of results, the calculation and is illustrated by an example. This document aims at simplifying, standardizing and optimizing the evaluation in order to allow a comparison between laboratories and to facilitate method assessment.

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'.

[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.

[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.

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.

[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).

Suburban transmission of Q fever in French Guiana: evidence of a wild reservoir.

The annual incidence of Q fever in French Guiana was found to have increased in 1996 and was 37/100,000 population over the last 4 years. Subsequent investigations in Cayenne and its suburbs indicated that a wild reservoir of the bacteria was responsible for the epidemiologic pattern. A case-control study showed that residence near a forest and occupations and activities that result in exposure to aerosols of dusts from the soil are risk factors for Q fever. By means of time-series analysis, a strong positive correlation between rainfall and the incidence of Q fever with a time lag of 1-3 months was found. The spatial distribution of the cases showed that transmission occurs widely throughout greater Cayenne, which is incompatible with a pinpoint source of contamination. Transmission from livestock and dissemination of the bacteria by the wind appeared to be unlikely, which strengthens the hypothesis that a wild reservoir is responsible for transmission.

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.

Association of severe malaria with a specific Plasmodium falciparum genotype in French Guiana.

Why severe Plasmodium falciparum malaria occurs in only a small percentage of patients is unclear. The possibility that specific parasite characteristics contribute to severity has been investigated in French Guiana, a hypoendemic area, where parasite diversity is low and all patients with severe cases are referred to a single intensive care unit. Parasite genotyping in geographically and temporally matched patients with mild and severe disease showed that the association of a specific msp-1 allele (B-K1) with a specific var gene (var-D) was overrepresented among patients with severe versus mild disease (47% vs. 3%, respectively; P<.001). Moreover, this genotype combination was consistently observed in the most severe clinical cases. Reverse-transcription polymerase chain reaction demonstrated programmed expression of var-D in vivo, which is consistent with its potential implication in severe disease. These results provide field evidence of an association of severe malaria with specific genetic characteristics of parasites and open the way for intervention strategies targeting key virulence factors of parasites.

Sputum itraconazole concentrations in cystic fibrosis patients.

Itraconazole diffusion in sputum was studied in 11 cystic fibrosis patients with allergic bronchopulmonary aspergillosis. There was a high interindividual variability in sputum itraconazole concentration and sputum/serum drug concentration ratio. Three children had sputum drug concentrations before oral administration that were lower than the itraconazole MIC at which 90% of Aspergillus fumigatus strains were inhibited, although their serum drug concentrations were within the therapeutic range.

Simultaneous high-performance liquid chromatographic determination of the antiretroviral agents amprenavir, nelfinavir, ritonavir, saquinavir, delavirdine and efavirenz in human plasma.

This article describes a method for the simultaneous determination of four licensed HIV protease inhibitors (amprenavir, nelfinavir, saquinavir and ritonavir) and two novel non-nucleoside reverse transcriptase inhibitors (efavirenz and delavirdine) in human plasma in a single run. Plasma samples (500 microl) were treated by liquid-liquid extraction with methyl tert.-butyl ether. The compounds were separated by reversed-phase liquid chromatography on a C(18) column with spectrophotometric detection at 260 nm. The method is linear over the specific ranges investigated, accurate (inaccuracy <11.7%) and showed intra-day and inter-day precision within the ranges of 0.9-7.0 and 1.9-8.8%, respectively. The six compounds were stable in plasma after 6 months of storage at -20 degrees C and after five freeze-thaw cycles.

[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.

Association of Tonate virus (subtype IIIB of the Venezuelan equine encephalitis complex) with encephalitis in a human.

Tonate virus, subtype IIIB of the Venezuelan equine encephalitis (VEE) complex, was first isolated in 1973 in French Guiana, South America. However, very little is known about its pathogenicity; it was considered to be responsible for only mild dengue-like syndromes. In 1998, a 2-month-old boy living along the Oyapock river in French Guiana was hospitalized for fever and generalized status myoclonus, and despite treatment the patient died 72 h after admission. Testing showed the presence of IgM specific for viruses of the VEE complex. A sensitive seminested polymerase chain reaction derived from a previous study was developed to detect viruses from the VEE complex, since no virus could be recovered from clinical specimens cultured on mosquito cells or from intracerebral inoculation into newborn mice. The genome of a virus from the VEE complex was detected in postmortem brain biopsies, and Tonate virus was identified by direct sequencing. This is the first reported case of human encephalitis due to Tonate virus.

Clinical pharmacokinetics of ciprofloxacin in patients with major burns.

OBJECTIVE: To better master the use of ciprofloxacin (CPF) in burn patients, a clinical study, including pharmacokinetics in serum and urine, was undertaken in a pathophysiologically homogeneous population of major-burn subjects. METHODS: Twelve major-burn patients who were infected with Pseudomonas aeruginosa, enterobacteria and gram-positive cocci, received CPF (600 mg t.i.d.). The mean body surface area affected by third-degree burns was 31.8 +/- 14.5%. Two series of blood samples were drawn after the first and seventh doses; urine was collected during the first infusion. Levels of CPF in serum and urine were measured by means of high-performance liquid chromatography. A non-compartmental method was used for kinetic and graphic analysis of concentration-time pairs. RESULTS: No adverse effects were noted. Trough concentrations measured on day 3 (mean +/- SD) were above the minimum inhibitory concentration (MIC) for the organism responsible for infection; i.e., 2.0 +/- 1.2 microg. ml(-1), and maximum concentrations were high 9. 9 +/- 3.4 microg. ml(-1). An area under the concentration-time curve (AUC)/MIC ratio above 125 SIT(-1) (where SIT is the serum inhibitory titer), which has been strongly correlated with clinical response and time to bacterial eradication, was achieved in 11 patients with a MIC of 0.5 microg. ml(-1). There was a statistically significant difference between C(min) and AUC determined on day 1 and day 3. In contrast to healthy volunteers, CPF clearance rates were notably decreased. CONCLUSION: The pharmacokinetics of CPF was altered in major-burn patients. The recommended dosage regimen for administration of CPF, i.e. 600 mg t.i.d. shows no adverse effects and a good microbiological efficacy.