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Biomedical subjects

F Faurisson

Publications and source records attributed to F Faurisson.

At least 19 recordsLinked to original sources
PubMed2001

Aerosols and anti-infectious agents.

Anti-infectious agents such as pentamidine, antibiotics (mainly colistine and aminoglycosides), and amphotericin B can be administered by aerosol. Apart from pentamidine and Tobi, this route of administration is not officially approved and it constitutes an empirical approach, which has benefited from recent research summarized hereafter. The most fundamental question is related to the potentially deleterious effects of nebulization processes, especially ultrasound, on the anti-infectious properties of the drugs. Colimycin, which was chosen as a reference because its polypeptide structure makes it unstable a priori, proved to be resistant to high frequency ultrasound, which is encouraging for other molecules such as aminoglycosides or betalactamins. The nebulizer characteristics also have to be taken into account. An aerosol can be produced from an amphotericin B suspension and from colistine using both an ultrasonic nebulizer and a jet nebulizer. Differentiating between good and bad nebulizers is not dependent upon the physical process involved to nebulize the drug, but on the intrinsic characteristics of the device and its performance with a known drug. The inhaled mass of an aerosol in the respirable range must be high and dosimetric nebulizers represent significant progress. Finally, administration of anti-infectious aerosols requires a new pharmacological approach to monitor treatment, and urinary assays are promising for this purpose.

Administration, Inhalation↗
PubMed2001

A simple tool for monitoring nebulized amikacin treatments based on a single urine assay.

Aerosolized aminoglycosides have demonstrated their efficacy in the treatment of P. aeruginosa pneumonia in cystic fibrosis (CF) patients. There is wide interpatient variability in the deposited and systemic drug doses that depend on both the nebulization and inhalation conditions and result in a risk of inefficacy or toxicity. We have developed a tool to provide a simple method for individual dose monitoring by estimating the total quantity of amikacin excreted, which corresponds to the dose absorbed systemically. It is based on a single urine assay. Thirty-seven urinary pharmacokinetic time courses in healthy volunteers (groups A and B) or in CF patients (groups C and D) were used. The rules for extrapolating the total dose excreted on the basis of 6-, 8-, 10-, and 12-h urine samples, were determined from group A. The accuracy of these rules was then tested in the other three groups. The total amount excreted was poorly predictable, with a coefficient of variation (CV) of 36 and 30% in the healthy volunteers, and of 48 and 82% in the CF group, whereas the CV of the estimated amount, based on 8- to 12-h samples, was only 10-15% in the healthy volunteers and 4-8% in the CF patients. Collecting a single sample over an 8- to 12-h period requires overnight sampling. The very low circadian variations in renal function, ranging from -2% to +5%, demonstrated the absence of any significant bias resulting from overnight sampling. A single urine assay can therefore be proposed as a simple, noninvasive, low cost, and reliable method for the clinical monitoring of nebulized amikacin in CF patients. Further studies are needed before this method can be extended to aerosol treatments with other aminoglycosides.

Administration, Inhalation↗
PubMed2001

Differential selection of multidrug efflux mutants by trovafloxacin and ciprofloxacin in an experimental model of Pseudomonas aeruginosa acute pneumonia in rats.

The ability of trovafloxacin and ciprofloxacin to select efflux mutants in vivo was studied in a model of acute Pseudomonas aeruginosa pneumonia in rats. Twelve hours after intratracheal inoculation of 10(6) CFU of P. aeruginosa strain PAO1 enmeshed in agar beads, two groups of 12 rats were treated by three intraperitoneal injections of each antibiotic given every 5 h. Dosing regimens were chosen to obtain a comparable area under the concentration-time curve from 0 to infinity/MIC ratio of 27.9 min for trovafloxacin (75 mg/kg of body weight) and of 32.6 min for ciprofloxacin (12.5 mg/kg). Twelve rats were left untreated and served as controls. Rats were sacrificed 12 h after the last injection (34 h after infection) for lung bacteriological studies. Selection of resistant bacteria was determined by plating lung homogenates on Trypticase soy agar plates containing antibiotic. In untreated animals, the frequency of resistant colonies was 10-fold higher than in agar beads. Compared to controls, both treatment regimens resulted in a 2-log reduction of lung bacterial load. The frequency of resistant colonies was 10-fold less with trovafloxacin than with ciprofloxacin at twice the MIC (7.4 x 10(-5) versus 8.4 x 10(-4), respectively) (P < 0.05) and at four times the MIC (6.2 x 10(-4) versus 5.0 x 10(-5), respectively) (P < 0.05). A multidrug resistance phenotype typical of efflux mutants was observed in all 41 randomly tested colonies obtained from treated and untreated rats. In agreement with in vitro results, trovafloxacin and ciprofloxacin preferentially selected MexCD-OprJ and MexEF-OprN overproducers, respectively. These results demonstrate the differential ability of trovafloxacin and ciprofloxacin to select efflux mutants in vivo and highlight the rapid emergence of those mutants, even without treatment.

Acute Disease↗
PubMed2001

Continuous versus intermittent infusion of vancomycin in severe Staphylococcal infections: prospective multicenter randomized study.

A continuous infusion of vancomycin (CIV) may provide an alternative mode of infusion in severe hospital-acquired methicillin-resistant staphylococcal (MRS) infections. A multicenter, prospective, randomized study was designed to compare CIV (targeted plateau drug serum concentrations of 20 to 25 mg/liter) and intermittent infusions of vancomycin (IIV; targeted trough drug serum concentrations of 10 to 15 mg/liter) in 119 critically ill patients with MRS infections (bacteremic infections, 35%; pneumonia, 45%). Microbiological and clinical outcomes, safety, pharmacokinetics, ease of treatment adjustment, and cost were compared. Microbiological and clinical outcomes and safety were similar. CIV patients reached the targeted concentrations faster (36 +/- 31 versus 51 +/- 39 h, P = 0.029) and fewer samples were required for treatment monitoring than with IIV patients (7.7 +/- 2.2 versus 11.8 +/- 3.9 per treatment, P < 0.0001). The variability between patients in both the area under the serum concentration-time curve (AUC(24h)) and the daily dose given over 10 days of treatment was lower with CIV than with IIV (variances, 14,621 versus 53,975 mg(2)/liter(2)/h(2) [P = 0.026] and 414 versus 818 g(2) [P = 0.057], respectively). The 10-day treatment cost per patient was $454 +/- 137 in the IIV group and was 23% lower in the CIV group ($321 +/- 81: P < 0.0001). In summary, for comparable efficacy and tolerance, CIV may be a cost-effective alternative to IIV.

Adult↗
PubMed2001

Urinary excretion reflects lung deposition of aminoglycoside aerosols in cystic fibrosis.

Using nebulization to deliver aminoglycosides may be of benefit in cystic fibrosis (CF) patients colonized by Pseudomonas aeruginosa. However, one problem with this route is the absence of clinical parameters allowing estimation of the mass of drug deposited in the lungs (MDL). The aim of this study was to assess whether aminoglycoside excretion in the urine reflects the MDL. Fourteen studies were performed in seven CF patients. Amikacin was mixed with albumin labelled with 99mTc and nebulized with an ultrasonic nebulizer. The MDL was determined by the mass-balance technique. Urine was collected during the 24 h following inhalation and was assayed for amikacin by fluorescence polarization immunoassay (FPIA). The mean+/-SEM MDL was 14.0+/-2.2% of the nebulizer charge. The mean+/-SEM amount of amikacin excreted in the urine was 20.9+/-4.5 mg and correlated with the MDL (r=0.93; p=0.0001). There was, however, wide intersubject variability in both deposition and excretion in the urine. Monitoring excretion of aminoglycosides in the urine allows noninvasive estimation of the mass of drug deposited in the lung in cystic fibrosis patients, which might be useful to assess the dose-response relationship in groups of patients, but intersubject variability prevents its use for individual follow-up.

Administration, Inhalation↗
PubMed2000

Control of staphylococcal adhesion to polymethylmethacrylate and enhancement of susceptibility to antibiotics by poloxamer 407.

We studied the antiadhesive effect of Poloxamer 407 (P407), together with modifications in the antimicrobial susceptibility of residual adherent staphylococci. Bacterial adherence was markedly inhibited (77% to more than 99.9%) whether polymethylmethacrylate was exposed to P407 before or during the adherence assay. Furthermore, residual adherent staphylococci appeared to be more susceptible to antibiotic activity, suggesting that combination of P407 with antibiotics could be a promising approach to the prevention of infection of foreign material.

Anti-Bacterial Agents↗
PubMed1999

Controlled release of vancomycin from poloxamer 407 gels.

The purpose of this study was to investigate Poloxamer 407 25% (w/w) formulations aimed at prolonging the residence time of vancomycin, a time-dependent antibiotic, in a body site with a high infectious risk. Reversible thermal gelation of the formulations permitted their local injection in liquid form and in situ gelation as they warmed to body temperature. Neither the rheological properties of the Poloxamer matrices nor the antibacterial activity of vancomycin was altered by their combination. In vitro, the dispersed form exhibited prolonged release, with a lower diffusion coefficient of vancomycin compared to the solubilized form (4.7x10(-8) vs 2. 1x10(-7) cm(2) s(-1)131 mg l(-1) for the solubilized form), followed by lower but effective antibacterial levels for at least 8 days. Controlled-release profiles, good preservation of vancomycin activity, good tolerability in rats, and ease of administration suggest that Poloxamer 407 may be useful as a vancomycin delivery vehicle for local prophylaxis of infections, especially in prosthetic surgery.

Animals↗
PubMed1999

Nebulized cyclosporine in the rat: assessment of regional lung and extrapulmonary deposition.

BACKGROUND: Nebulized cyclosporine (CsA) has been shown to limit lung allograft rejection as well as intramuscular (IM) CsA, with limited blood diffusion. The present study determined the pharmacokinetic parameters of nebulized CsA, by the assessment of regional lung deposition and extrapulmonary diffusion of CsA. METHODS: CsA was given either by IM injection (10 mg/kg) or by aerosol (at 10 and 25 mg/kg doses); 70 rats were killed at 25 and 50 min, and at 2, 4, 6, 8, 12, 24, or 48 hr after CsA administration. CsA levels were measured in the whole lung, in central and peripheral parts of the lung, in whole blood, kidney, and heart. The areas under the concentration time curves (AUCs) were determined. RESULTS: In blood, kidney, and heart, CsA levels were significantly higher for IM than for aerosol administrations at 10 and 25 mg/kg doses. In the whole lung, the AUC was greater for the aerosol route at 25 mg/kg doses (588 ng x hr/mg) than for the low-dose (200 ng x hr/mg) or IM administration (200 ng x hr/mg). The central to peripheral index of CsA (ratio of AUC central/peripheral part of the lung) was not significantly different for both aerosol administrations (0.63 and 0.69, respectively) and for the IM route (0.81). CONCLUSIONS: Nebulized CsA allows better pulmonary concentration than IM administration, with equivalent central and peripheral deposition whatever the mode of administration, and results in lower levels in blood, kidney, and heart.

Administration, Intranasal↗
PubMed1999

[Anti-infective aerosols].

Anti-infectious agents such as pentamidine, antibiotics (mainly colistine and aminoglycosides) and amphotericin B can be administered by aerosol. This route of administration is not officially approved and it constitutes an empirical approach which has benefited from recent research which is summarized hereafter. The most fundamental question is related to the potentially deleterious effects of nebulization processes, especially ultrasound, on the anti infectious properties of the drugs. Colimycin, which was chosen as a reference because its polypeptide structure makes it unstable a priori, proved to be resistant to high frequency ultrasound, which is encouraging for other molecules such as aminoglycosides or betalactamins. The nebulizer characteristics have also to be taken into account. An aerosol can be produced from an amphotericin B suspension and from colistine using both an ultrasonic nebulizer and a jet nebulizer. Distinction between good and bad nebulizers does not depend upon the physical process involved to nebulize the drug, but on the intrinsic characteristics of the device and its performance with a known drug. The inhaled mass of an aerosol in the respirable range must be high and dosimetric nebulizers represent a significant progress. Finally, adminnistration of anti infectious aerosols requires a new pharmacological approach to monitor treatment and urinary assays are promising.

Aerosols↗
PubMed1998

[Good clinical practice in nebulization].

A meeting on nebulization held in April 1997 defined good clinical practices. Guidelines that were proposed pertained to the following: pneumatic and ultrasonic nebulizers; delivering circuit, occluded or not, the choice of the tip being done according to the disease to treat and to the drugs to be delivered; various functions, depending on the type of nebulizer; the particle size, as it will indicate which disease may be treated: between 2 and 6 microns for bronchi, between 0.5 et 3 microns for lung, > 5 microns for ear, nose and throat diseases; compatibility between the type of nebulizer and drugs. Ten drugs are currently registered in France. Nebulization has multiple clinical indications, such as asthma, cystic fibrosis, chronic obstructive pulmonary disease, Pneumocystis carinii pneumonia, acute laryngitis, and in infants, acute bronchiolitis. The prescription must be detailed, and the physician should make sure that the medical staff put it into application.

Administration, Inhalation↗
PubMed1998

Effect of a single oral dose of two erythromycin ethylsuccinate formulations on gastric emptying in healthy volunteers: a scintigraphic study.

Macrolides are potential gastrokinetic agents. The purpose of this study was to assess the effect of a single oral dose of two erythromycin formulations on gastric emptying of the solid and liquid phases in twelve healthy volunteers and to seek a correlation between pharmacokinetic parameters and changes in gastric emptying. The gastric emptying times of liquids and solids were measured simultaneously by means of a scintigraphic technique after a single oral administration of amorphous erythromycin ethylsuccinate (500 mg), crystalline erythromycin ethylsuccinate (1000 mg) or a placebo, in a double-blind crossover study in three separate weeks. Blood samples were obtained for erythromycin assay. The two oral formulations induced a similar acceleration of gastric emptying. When compared to the placebo, both erythromycin preparations significantly shortened the gastric transit time of solids and liquids (respectively 30% and 20% on average, p < 0.01). The incidence of gastrointestinal side-effects was similar with the two erythromycin forms and the placebo. No correlation was found between the peak serum erythromycin concentrations and the solid or liquid gastric half-lives. With the amorphous formulation, the area under the plasma time-concentration curves was small and solid and liquid gastric emptying were strongly accelerated, pointing to a direct effect on the gastrointestinal smooth muscle.

Administration, Oral↗
PubMed1996

Efficacy of single-dose ceftriaxone in experimental otitis media induced by penicillin- and cephalosporin-resistant Streptococcus pneumoniae.

We used a gerbil model of otitis media to assess the efficacy of single-dose ceftriaxone against three Streptococcus pneumoniae strains highly resistant to penicillin (MICs, 4 to 8 micrograms/ml) and with various susceptibilities to ceftriaxone (MICs, 0.5, 4, and 8 micrograms/ml). Middle ear infection was induced by bilateral transbullar challenge with 10(7) bacteria per ear. Antibiotic treatment was administered subcutaneously at 2 h postinfection. Infection status was checked 2 days later by counting the bacteria in middle ear and cerebrospinal fluid samples. With the cefriaxone-susceptible strain (MIC, 0.5 microgram/ml), we tested doses of 5 to 100 mg/kg of body weight. With a dose of 50 mg/kg, treatment outcome was equivalent to that with amoxicillin, which was used as a reference (25 mg/kg, two injections); no bacteria were recovered from 82% of the middle ear samples, and the rate of cerebrospinal fluid culture positivity was significantly reduced to 6%, relative to 59% for the untreated controls. Similar efficacy was obtained with a dose of 100 mg/kg against the two ceftriaxone-resistant strains. Pharmacokinetic study indicates that the values of the parameters in plasma after the administration of a dose of 100 mg/kg (peak level of total drug, 268 +/- 33 micrograms/ml; elimination half-life, 0.8 h; area under concentration-time curve, 488 micrograms.h.ml-1) were still suboptimal compared with the values of the parameters measured in pediatric patients after intravenous or intramuscular administration of a dose of 50 mg/kg. Our results indicate the efficacy of ceftriaxone against experimental cephalosporin-resistant pneumococcal otitis and provide a basis for the clinical use of single-dose ceftriaxone against pneumococcal otitis media.

Animals↗
PubMed1996

[Comparative study of the performance and ergonomics of nebulizers in cystic fibrosis].

This study had, as its aim, to test twelve nebulizers (6 jet, 6 ultrasonic) which are used in the treatment of cystic fibrosis. Devices were connected to a respirator in order to mimic the ventilation of a child and of an adult suffering from cystis fibrosis. Three medications: tobramycine, colistine and amiloride were nebulised. The volume of the recommended solution varied between 1.5 and 13 ml according to the manufacturer. During a session of ten minutes the ultrasonic nebulizer delivered an inhaled volume which was significantly greater than the jet (2.72 +/- 0.98 ml vs 1.22 +/- 0.59 ml, p < 0.0001) for the three drugs. Regarding granulometry, the fraction of particles between 0.5 and 5 microns, was higher with ultrasonic than with pneumatic nebulizer for tobramycine (67.1 +/- 10.7 vs 55.5 +/- 11.5%, p < 0.001) and amiloride (66.4 +/- 9.2% vs 58.1 +/- 15%, p < 0.05%). The variation of concentration due to nebulisation were independent of the type of apparatus but influenced by the drug since concentration was increased for tobramycine (+10.5 +/- 18.6%) and amiloride (+13.4 +/- 8/9%). In summary the effective fraction resulting from the inhalable fraction, from granulometry and from changes in concentration was significantly greater for ultrasonic than for jet nebrulizer (17.3 +/- 6.7% vs 9.7 +/- 9.6%, p < 0.001). This study underlines the great variability of the performance of aerosols generators and therefore the need for an accurate evaluation of nebulizer performances in order to prescribe the best nebulizer/drug association in clinical practice.

Administration, Inhalation↗
PubMed1995

Nebulizer performance: AFLM study. Association Française de Lutte contre la Mucoviscidose.

This study was conducted by the AFLM order to determine the performance characteristics of 12 commercially available nebulizers (6 ultrasonic and 6 jet) used in the treatment of cystic fibrosis (CF). The nebulizers were connected to a circuit which simulated the ventilation of a CF child and CF adult, and were tested using three drug solutions: tobramycin (T), colistin (C), and amiloride (A). Nebulizer performance was evaluated according to the volume of drug solution delivered in 10 min during the simulated inspiratory phase (VI), drug granulometry (G%), drug concentration modification in the nebulizer reservoir (delta C), and percentage of efficiently aerosolized drug EA%). The ultrasonic devices delivered a significantly higher VI than the jet nebulizers (p < 0.0001) for all three study drug. Ventilation rate did not influence VI. Regarding granulometry, higher percentages of T and A were found to be contained in droplets ranging from 0.5 to 5.0 micron following ultrasonic nebulization. Drug concentration modifications were independent of the nebulizer used but were influenced by drug type; overconcentrations of T and A were observed (delta C = +10.5 +/- 18.6 and +13.4 +/- 8.9%, respectively). On average, the ultrasonic devices achieved a higher EA% than the jet nebulizers (17.3 +/- 6.7 and 9.7 +/- 9.6%, respectively). This study highlights the significant variability in performance of different nebulizer types and empahsizes the importance of accurately testing nebulizers prior to clinical use so that the most efficacious nebulizer/drug combinations may be prescribed.

Administration, Inhalation↗
PubMed1994

Kinetics and tolerability of intravitreal pefloxacin in rabbits.

In the treatment of patients with bacterial endophthalmitis, the intravitreal administration of antibiotics is suitable for induction therapy since it provides immediate high concentrations in the vitreous humor. Pefloxacin has been shown to have good intraocular penetration when given systemically. In order to extend the potential routes of administration of this agent, we have assessed the kinetics and toxicity of pefloxacin in rabbit phakic eyes following intravitreal instillation. Kinetic parameters were determined for 12 albino and 12 pigmented rabbits after a single injection of 80 micrograms. Pefloxacin was undetectable in the aqueous humor but high concentrations were found in the chorioretina. The vitreal half-life was short (3 h). These results were consistent with posterior elimination via the chorioretina. Pefloxacin concentrations in the iris and chorioretina of pigmented rabbits were two-fold greater than those in albino rabbits, probably because of binding to the pigmentary apparatus. Toxicity studies, including ophthalmological and histopathological investigations, identified a maximum non-toxic dosage of 400 micrograms. Intravitreal pefloxacin may therefore be suitable for induction therapy in patients with endophthalmitis, although further studies in primates are required to confirm the efficacy and tolerability of this route of administration.

Albinism, Ocular↗