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Biomedical subjects

A Lefort

Publications and source records attributed to A Lefort.

At least 19 recordsLinked to original sources
PubMed2006

Fluconazole for the management of invasive candidiasis: where do we stand after 15 years?

Candida spp. are responsible for most of the fungal infections in humans. Available since 1990, fluconazole is well established as a leading drug in the setting of prevention and treatment of mucosal and invasive candidiasis. Fluconazole displays predictable pharmacokinetics and an excellent tolerance profile in all groups, including the elderly and children. Fluconazole is a fungistatic drug against yeasts and lacks activity against moulds. Candida krusei is intrinsically resistant to fluconazole, and other species, notably Candida glabrata, often manifest reduced susceptibility. Emergence of azole-resistant strains as well as discovery of new antifungal drugs (new triazoles and echinocandins) have raised important questions about its use as a first line drug. The aim of this review is to summarize the main available data on the position of fluconazole in the prophylaxis or curative treatment of invasive Candida spp. infections. Fluconazole is still a major drug for antifungal prophylaxis in the setting of transplantation (solid organ and bone marrow), intensive care unit, and in neutropenic patients. Prophylactic fluconazole still has a place in HIV-positive patients in viro-immunological failure with recurrent mucosal candidiasis. Fluconazole can be used in adult neutropenic patients with systemic candidiasis, as long as the species identified is a priori susceptible. Among non-neutropenic patients with candidaemia fluconazole is one of the first line drugs for susceptible species. Cases reports and uncontrolled studies have also reported its efficacy in the setting of osteoarthritis, endophthalmitis, meningitis, endocarditis and peritonitis caused by Candida spp. among immunocompetent adults. In paediatrics, fluconazole is a well tolerated and major prophylactic drug for high-risk neonates, as well as an alternative treatment for neonatal candidiasis. Importantly 15 years after its introduction in the antifungal armamentarium, fluconazole is still a first line treatment option in several cases of invasive candidiasis. Its prophylactic use should however be limited to selected high-risk patients to limit the risk of emergence of azole-resistant strains.

Antifungal Agents↗
PubMed2006

Escherichia coli native valve endocarditis.

Among 36 cases of Escherichia coli native valve endocarditis (NVE) that met Duke criteria (31 cases in the literature between 1909 and 2002, and five cases seen in Paris, France), the urinary tract was the most common portal of entry. The majority (72.2%) of cases developed in elderly females. Overall, the proportion of patients aged > 70 years rose from 5.3% in 1982 to 22.9% in 2002. Persistent E. coli bacteraemia in the elderly in the absence of cardiac risk-factors may be a sign of NVE and should prompt an investigation by echocardiography.

Age Factors↗
PubMed2005

Serratia marcescens prosthesis infection successfully treated with meropenem after imipenem failure.

A 78-year-old woman developed an early knee-prosthesis infection due to multiresistant Serratia marcescens that was successfully treated with high-dose meropenem, after failure of a long-term therapy combining imipenem and multiple surgical interventions. Because of its lower neurotoxicity, meropenem might be preferred to imipenem/cilastatin for the treatment of osteo-articular infections due to multiresistant Gram-negative bacilli in the elderly.

Aged↗
PubMed2004

Low seroprevalence and poor specificity of antineutrophil cytoplasmic antibodies in tuberculosis.

OBJECTIVES: Recently published findings suggested that antineutrophil cytoplasmic antibodies (ANCA), particularly those with a cytoplasmic (C-ANCA) labelling pattern and targeting proteinase 3 (anti-PR3), might be markers of tuberculosis (TB). This is a critical issue, because C-ANCA/anti-PR3 were considered to be a highly specific hallmark of Wegener's granulomatosis or microscopic polyangiitis and because TB may clinically mimic Wegener's granulomatosis. We therefore undertook a study with the aim of investigating further the prevalence and specificity of ANCA in TB. METHODS: We evaluated serum samples from 67 patients diagnosed with culture-proven TB and 10 previously untested control samples from patients known to be ANCA positive (four Wegener's granulomatosis and two microscopic polyangiitides) or negative. All 77 sera were screened for ANCA using commercially available indirect immunofluorescence (IIF) and enzyme-linked immunosorbent assay (ELISA) for anti-PR3 and antimyeloperoxidase (MPO). IIF-positive and anti-PR3- and anti-MPO-negative sera were also tested for bactericidal/permeability-increasing protein, lactoferrin, elastase and cathepsin G specificities with commercially available ELISA. RESULTS: IIF detected ANCA in seven (10%) of the TB sera, including three C-ANCA and four atypical perinuclear-labelling ANCA. Only one IIF-negative specimen was anti-PR3 positive in ELISA. ANCA testing of the control sera yielded IIF and ELISA results concordant with previous findings, except for one borderline ELISA. CONCLUSION: Our results indicate that TB is associated with low ANCA seroprevalence and poor specificity, with no test serum showing combined C-ANCA/anti-PR3 activity. In a clinical setting of Wegener's granulomatosis/TB mimicry, such combined reactivity would seem to be more suggestive of Wegener's granulomatosis.

Adult↗
PubMed2004

Simultaneous determination of tryptophan and kynurenine in serum by HPLC with UV and fluorescence detection.

Tryptophan metabolism is disturbed in mental depression, and the induction of indoleamine 2,3-dioxygenase increases kynurenine production. In order to determine this disturbance in patients with chronic hepatitis C and receiving interferon-based immunotherapy, a new and specific HPLC protocol was elaborated. For tryptophan, the assay was linear from 6.25 to 100 micromol L(-1), and the limits of detection (LOD) and quantitation (LOQ) for the method were 0.7 and 8.0 micromol L(-1). For kynurenine, the linearity of calibration was from 0.0625 to 6.25 micromol L(-1), with LOD and LOQ of 2 and 3 nmol L(-1). Reproducibility and repeatability were satisfactory. The method allowed study of human blood serum.

Chromatography, High Pressure Liquid↗
PubMed2003

Two cases of cerebral aspergillosis successfully treated with voriconazole.

Described here are two cases of cerebral aspergillosis successfully treated with voriconazole after the failure of first-line treatment with amphotericin B deoxycholate. In both cases, clinical and radiological cure was achieved within 6 weeks. Voriconazole should be considered as first-line therapy for cerebral aspergillosis.

Administration, Oral↗
PubMed2001

Transport properties in a two-temperature plasma: theory and application.

An alternate derivation of transport properties in a two-temperature plasma has been performed. Indeed, recent works have shown that the simplified theory of transport properties out of thermal equilibrium introduced by Devoto and then Bonnefoi, very often used in two-temperature modeling, is questionable and particularly does not work when calculating the combined diffusion coefficients of Murphy. Thus, in this paper, transport properties are derived without Bonnefoi's assumptions in a nonreactive two-temperature plasma, assuming chemical equilibrium is achieved. The electron kinetic temperature T(e) is supposed to be different from that of heavy species T(h). Only elastic processes are considered in a collision-dominated plasma. The resolution of Boltzmann's equation, thanks to the Chapman-Enskog method, is used to calculate transport coefficients from sets of linear equations. The solution of these systems allows transport coefficients to be written as linear combinations of collision integrals, which take into account the interaction potential for a collision between two particles. These linear combinations are derived by extending the definition and the calculation of bracket integrals introduced by Chapman et al. to the thermal nonequilibrium case. The obtained results are rigorously the same as those of Hirschfelder et al. at thermal equilibrium. The derivation of diffusion velocity and heat flux shows the contribution of a new gradient, that of the temperature ratio straight theta=T(e)/T(h). An application is presented for a two-temperature argon plasma. First, it is shown that the two-temperature linear combinations of collision integrals are drastically modified with respect to equilibrium. Secondly, the two-temperature simplified theory of transport coefficients of Devoto and Bonnefoi underestimates the electron thermal conductivity with respect to the accurate value at T(e)=20 000 K. Lastly, contrary to the simplified theory of transport coefficients, the diffusion coefficients satisfy the symmetry conditions. An example is given at T(e)=6000 K for different values of straight theta for the diffusion coefficient between electrons and heavy species D(e-Ar) as well as for that between argon atoms and argon ions D(Ar-Ar+).

Journal Article↗
PubMed2001

A conserved Asn in transmembrane helix 7 is an on/off switch in the activation of the thyrotropin receptor.

The thyrotropin (TSH) receptor is an interesting model to study G protein-coupled receptor activation as many point mutations can significantly increase its basal activity. Here, we identified a molecular interaction between Asp(633) in transmembrane helix 6 (TM6) and Asn(674) in TM7 of the TSHr that is crucial to maintain the inactive state through conformational constraint of the Asn. We show that these residues are perfectly conserved in the glycohormone receptor family, except in one case, where they are exchanged, suggesting a direct interaction. Molecular modeling of the TSHr, based on the high resolution structure of rhodopsin, strongly favors this hypothesis. Our approach combining site-directed mutagenesis with molecular modeling shows that mutations disrupting this interaction, like the D633A mutation in TM6, lead to high constitutive activation. The strongly activating N674D (TM7) mutation, which in our modeling breaks the TM6-TM7 link, is reverted to wild type-like behavior by an additional D633N mutation (TM6), which would restore this link. Moreover, we show that the Asn of TM7 (conserved in most G protein-coupled receptors) is mandatory for ligand-induced cAMP accumulation, suggesting an active role of this residue in activation. In the TSHr, the conformation of this Asn residue of TM7 would be constrained, in the inactive state, by its Asp partner in TM6.

Animals↗
PubMed2001

[Purulent meningitis].

Purulent meningitis is a bacterial infection of the subarachnoid space. It constitutes a diagnostic and therapeutic emergency. The vital and functional prognosis is always engaged and depends on the rapidity and the adequacy of management. Treatment is based on a bactericidal antibiotic treatment which is at first empirically prescribed, on the basis of the underlying condition, the clinical examination and the epidemiological context, and then adjusted according to the micro-organism isolated from the cerebrospinal fluid. The recent emergence and increase of penicillin-resistant Streptococcus pneumoniae has led to a modification of antibiotic guidelines.

Anti-Bacterial Agents↗
PubMed2001

Consequences of VanE-type resistance on efficacy of glycopeptides in vitro and in experimental endocarditis due to Enterococcus faecalis.

The consequences on glycopeptide activity of low-level resistance to vancomycin due to VanE-type resistance were evaluated in vitro and in experimental endocarditis caused by Enterococcus faecalis BM4405 (MICs of vancomycin and teicoplanin: 16 and 0.5 microg/ml, respectively), its susceptible derivative BM4405-1, and susceptible E. faecalis JH2-2. After 24 h of incubation, vancomycin at 8 microg/ml was not active against E. faecalis BM4405 whereas it was bacteriostatic against strains BM4405-1 and JH2-2. Against all three strains, vancomycin at 30 microg/ml and teicoplanin at 8 or 30 microg/ml were bacteriostatic but bactericidal when combined with gentamicin. In rabbits with aortic endocarditis due to VanE-type resistant strain BM4405, treatment with a standard dose of vancomycin generated subinhibitory plasma concentrations (i.e., peak of 36.3 +/- 2.1 microg/ml and trough of 6.0 +/- 2.2 microg/ml) and led to no significant reduction in mean aortic valve vegetation counts compared to no treatment of control animals. In contrast, a higher dosing regimen of vancomycin (i.e., resulting in a peak of 38.3 +/- 5.2 microg/ml and a trough of 15.0 +/- 8.3 microg/ml), providing plasma concentrations above the MIC for the entire dosing interval, led to significant and similar activities against all three strains, which were enhanced by combination with gentamicin. Treatment with teicoplanin led to results similar to those obtained with vancomycin at a high dose. No subpopulations with increased resistance to glycopeptides were selected in vitro or in vivo. In conclusion, the use of a high dose of vancomycin was necessary for the treatment of experimental enterococcal endocarditis due to VanE-type strains.

Animals↗
PubMed2001

Effects of mutations involving the highly conserved S281HCC motif in the extracellular domain of the thyrotropin (TSH) receptor on TSH binding and constitutive activity.

A model has been proposed in which, in the absence of TSH, the extracellular domain of the TSH receptor would exert a silencing effect on the serpentine domain involved in activation of the G(alpha)(s) protein. Mutation of S281 in the ectodomain is supposed to release this constraint, thereby causing receptor activation. This defines S281 and its neighbors as a segment important in intramolecular signal transduction. The functional importance of this segment was explored by site-directed mutagenesis experiments involving S281, as well as the two cysteine residues (C283, C284) present immediately downstream. S281 was mutated to N, T, G, and A in this study, and the functional characteristics of the mutants were compared. We found that S281N, S281T, and S281G display stronger constitutive activity than S281A mutant, suggesting that increase in constitutive activity is related to the extent of disruption of the local structure of the ectodomain. C283 and C284, the two consecutive cysteines that are highly conserved in glycoprotein hormone receptors, were mutated to serine, either alone (S281HSC or S281HCS) or in combination (S281HSS) and were studied in two different TSH receptor backgrounds. The mutated cysteine ectodomains were either linked to a glycosylphosphatidylinositol anchor or the serpentine domain of the wild-type holoreceptor. Glycosylphosphatidylinositol-anchored ectodomain receptors showed good cell surface expression in CHO cells, but only S281HCS was able to bind TSH specifically, illustrating the importance of C283, or the putative disulphide bond, in maintaining the conformation of the ligand binding site. In contrast, cysteine mutants on an extracellular domain-holoreceptor background displayed severely impaired membrane targeting and were poorly expressed in COS cells. However, basal cAMP production, normalized to expression at the plasma membrane, indicated significant increase in constitutive activity of all three mutants, compared with the wild-type receptor. Altogether, these findings support a model in which the ectodomain would act as a silencer of the basal activity of the serpentine portion of the receptor.

Amino Acid Sequence↗
PubMed2000

Antienterococcal antibiotics.

The treatment of severe enterococcal infections based on the currently available antibacterial agents is difficult. The help of the microbiology laboratory for determining MICs, MBCs, and most effective synergistic combinations is crucial. There is a need for good prospective multicenter clinical trials to improve the prognosis of such infections by defining therapeutic strategies better. Such a requirement is highly suitable for the treatment of infections caused by enterococci exhibiting acquired resistance mechanisms to the available agents. The current clinical development of new compounds looks promising in these persistently life-threatening infections mostly occurring in deficient hosts.

Anti-Bacterial Agents↗
PubMed2000

Streptococcus pneumoniae endocarditis in adults. A multicenter study in France in the era of penicillin resistance (1991-1998). The Pneumococcal Endocarditis Study Group.

To better define the overall characteristics and risk factors for dying of adult pneumococcal endocarditis (PE) focusing on the echocardiographic diagnosis, the impact of surgery, and emergence of penicillin resistance, the medical and microbiologic charts of adult PE cases observed between 1991 and 1998 in university and general hospitals were reviewed through a nationwide retrospective study in France. Thirty cases of PE (22 men, 8 women; median age, 53 yr; range, 27-87 yr) were collected and validated. Twenty patients (66.7%) had no known predisposing cardiopathy; 4 had a bioprosthetic valve. The primary focus of infection was pneumonia in 10 (33.3%), and meningitis was noted in 12 (40.0%). Half the patients suffered from chronic alcoholism. Echocardiography detected vegetation(s) in 29 cases (96.7%), valvular perforation in 6 (20.0%), and/or valve ring abscess in 4 (13.3%). The most frequent complications were congestive heart failure (n = 19), large arterial emboli (n = 8), and focal abscesses (n = 7). Five strains were penicillin-resistant. Twenty (66.7%) patients underwent valve replacement, 12 of them during the first month. The overall mortality rate was 24.1%. According to a multivariate analysis, the risk factors independently associated with dying were age > or = 65 yr and septic shock, while cardiac surgery was protective (p < 0.01). In conclusion, PE is usually fulminant and causes severe valve damage and embolic complications; its short-term prognosis might be improved by early valve replacement.

Adult↗
PubMed2000

Activity of LY333328 combined with gentamicin in vitro and in rabbit experimental endocarditis due to vancomycin-susceptible or -resistant Enterococcus faecalis.

We investigated the activity of LY333328 alone and combined with gentamicin, both in vitro and in a rabbit model of experimental endocarditis, against the susceptible strain Enterococcus faecalis JH2-2 and its two glycopeptide-resistant transconjugants, BM4316 (VanA) and BM4275 (VanB). MICs of LY333328 and gentamicin were 2 and 16 microgram/ml, respectively, for the three strains. In vitro, LY333328 alone was bactericidal at 24 h against JH2-2 at a concentration of 2 microgram/ml and against BM4316 and BM4275 at a concentration of 30 microgram/ml. The combination of LY333328 and gentamicin (4 microgram/ml) was synergistic and bactericidal after 24 h of incubation against the three strains at LY333328 concentrations of 2 microgram/ml for JH2-2 and 8 microgram/ml for BM4275 and BM4316. The combination of LY333328 and gentamicin was the only regimen demonstrating in vitro bactericidal activity against BM4316. In vivo, intravenous treatment with LY333328 alone, providing peak and trough serum levels of 83.3 +/- 1.3 and 3.8 +/- 0.2 microgram/ml, respectively, was inactive against BM4316 and BM4275 and selected mutants resistant to LY333328 in half of the rabbits infected with the VanA-type strain (MICs, 8 to 20 microgram/ml). However, the LY333328-gentamicin combination was active against the three strains and prevented the emergence of mutants resistant to both components of the combination. We conclude that the LY333328-gentamicin combination might be of interest for the treatment of enterococcal infections, particularly against VanA-type strains.

Animals↗
PubMed2000

Bactericidal activity of gentamicin against Enterococcus faecalis in vitro and in vivo.

The activity of gentamicin at various concentrations against two strains of Enterococcus faecalis was investigated in vitro and in a rabbit model of aortic endocarditis. In vitro, gentamicin at 0.5 to 4 times the MIC failed to reduce the number of bacteria at 24 h. Rabbit or human serum dramatically increased gentamicin activity, leading to a >/=3-log(10) CFU/ml decrease in bacterial counts when the drug concentration exceeded the MIC. Susceptibility testing in the presence of serum was predictive of in vivo activity, since gentamicin alone significantly reduced the number of surviving bacteria in the vegetations if the peak-to-MIC ratio was greater than 1. However, gentamicin selected resistant mutants in rabbits. The intrinsic activity of gentamicin should be taken into account in evaluation of combinations of gentamicin and cell wall-active agents against enterococci.

Animals↗
PubMed1999

Activity and diffusion of LY333328 in experimental endocarditis due to vancomycin-resistant Enterococcus faecalis.

The activity of LY333328 against Enterococcus faecalis JH2-2, which is susceptible to glycopeptides, and against its transconjugants E. faecalis BM4281 and BM4316, with VanB and VanA phenotypes, respectively, was investigated. LY333328 was active in vitro against the three strains, for which MICs were 2 microg/ml on agar and 0.25 microg/ml in broth. LY333328 was bactericidal in broth against E. faecalis JH2-2 and BM4281 at a concentration of 8 microg/ml and against BM4316 at a concentration of 30 microg/ml. The protein binding of LY333328 to rabbit serum was >99%, and the bactericidal activity of LY333328 in broth was reduced when it was tested in the presence of 90% rabbit serum. Autoradiographic studies performed in rabbits with enterococcal endocarditis showed that 14[C]LY333328 was distributed heterogeneously throughout cardiac vegetations. In rabbits with aortic endocarditis, a regimen of 20 mg of LY333328 per kg of body weight administered intramuscularly twice a day for 5 days after a loading dose of 40 mg/kg was active against the three strains in vivo (P < 0.01), whereas vancomycin was not active against the VanB-type strain and teicoplanin was not active against the VanA-type strain. We conclude that the activity of LY333328 is not significantly modified by acquired resistance to glycopeptides in E. faecalis either in vitro or in experimental endocarditis.

Animals↗
PubMed1999

Two-step acquisition of resistance to the teicoplanin-gentamicin combination by VanB-type Enterococcus faecalis in vitro and in experimental endocarditis.

The activity of vancomycin and teicoplanin combined with gentamicin was investigated in vitro against strains of Enterococcus faecalis resistant to vancomycin and susceptible to teicoplanin (VanB type) and against mutants that had acquired resistance to teicoplanin by three different mechanisms. In vitro, gentamicin selected mutants with two- to sixfold increases in the level of resistance to this antibiotic at frequencies of 10(-6) to 10(-7). Teicoplanin selected teicoplanin-resistant mutants at similar frequencies. Both mutations were required to abolish the activity of the gentamicin-teicoplanin combination. As expected, simultaneous acquisition of the two types of mutations was not observed. In therapy with gentamicin or teicoplanin alone, each selected mutants in three of seven rabbits with aortic endocarditis due to VanB-type E. faecalis BM4275. The vancomycin-gentamicin combination selected mutants that were resistant to gentamicin and to the combination. In contrast, the teicoplanin-gentamicin regimen prevented the emergence of mutants resistant to one or both components of the combination. These results suggest that two mutations are also required to suppress the in vivo activity of the teicoplanin-gentamicin combination.

Animals↗