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V Joly

Publications and source records attributed to V Joly.

At least 19 recordsLinked to original sources
PubMed1992

[Choice and monitoring of the treatment of systemic mycoses. Value and limitations of in vitro tests].

Systemic fungal infections are an important cause of morbidity and mortality among immunocompromised patients. New antifungal agents, such as triazoles, are now available, and the place of in vitro tests has to be discussed. It has been shown that interlaboratory reproducibility of in vitro susceptibility tests against fungi was low, due to the lack of standardization. Recently, the NCCLS defined conditions permitting a good interlaboratory reproducibility. However, the predictive value of in vitro susceptibility tests on the therapeutic outcome remain to be demonstrated, and is now under investigation. At the present time, susceptibility testing can be useful: in patients treated by amphotericin B for a severe fungal infection and who do not improve under therapy; to detect resistance to 5-fluorocytosine; to compare the sensitivity to triazoles before and after treatment, in case of therapeutic failure. Serum levels monitoring is useful to prevent the toxicity due to 5-fluorocytosine and to control the digestive absorption of triazoles, especially the lipophilic compound itraconazole.

Acquired Immunodeficiency Syndrome↗
PubMed1992

Inhibiting cholesterol synthesis reduces the binding and toxicity of amphotericin B against rabbit renal tubular cells in primary culture.

Renal tubular cells are a target of amphotericin B (AmB) toxicity, but the mechanisms involved in the tubular cell-AmB interactions are unknown. Ketoconazole was selected to lower the cholesterol content of rabbit renal tubular cells in primary culture. The consequences of cholesterol depletion on AmB nephrotoxicity was investigated in vitro as the inhibition of Na(+)-dependent phosphate uptake. After 1 h of exposure, AmB decreased phosphate uptake (49%, 77%, and 82% inhibition with 5, 10, and 20 microM of AmB, respectively). Pretreatment of cells with ketoconazole (10 microM for 24 h) reduced by 50% (P less than .01) the phosphate uptake inhibition induced by AmB, decreased cellular cholesterol synthesis (greater than 80% inhibition), and decreased AmB binding to cell membrane by 50%, as measured by the fluorescence extinction of a probe bound to tubular cell membrane. Incubation with exogenous exchangeable cholesterol again increased AmB binding to plasma membrane and restored AmB toxicity. These results demonstrate that the first step of AmB renal tubular toxicity is mediated by cellular cholesterol content and is parallel to the binding of AmB to cell membrane.

Amphotericin B↗
PubMed1992

Activity of MS-8209, a nonester amphotericin B derivative, in treatment of experimental systemic mycoses.

The in vitro and in vivo toxicities and activities of MS-8209, a new hydrosoluble amphotericin B (deoxycholate-amphotericin B [D-AmB]; Fungizone) derivative, were studied. In vitro, MS-8209 was less toxic than AmB against renal tubular cells in primary culture and less active against Candida albicans and Cryptococcus neoformans. However, at 10-fold the AmB concentration, MS-8209 in vitro antifungal activity paralleled that of AmB. Fifty-percent lethal doses of MS-8209 and D-AmB in OF1 noninfected mice were 26 and 2.3 mg/kg, respectively. Therapeutic efficacy of MS-8209 was assessed in murine candidiasis, cryptococcosis, and aspergillosis. In each model of infection, we determined the maximum tolerated dosages of MS-8209 and D-AmB, i.e., the dosage inducing less than 15% mortality due to toxicity; the efficacies of MS-8209 and D-AmB at their respective maximum tolerated dosages were compared. In candidiasis, MS-8209 (15 mg/kg) significantly increased the survival time compared with D-AmB (0.5 mg/kg). Both compounds were equally effective at reducing CFU counts in the kidney. MS-8209 was the most effective agent for increasing the survival time in cryptococcal meningoencephalitis and for reducing CFU counts in spleen, brain, and lung during both cryptococcal pneumonia and meningoencephalitis. In aspergillosis, MS-8209 and D-AmB similarly prolonged the survival of treated mice compared with controls. These results show that when MS-8209 and D-AmB were used at the maximum tolerated dosage, MS-8209 was as effective as or more effective than D-AmB for the treatment of systemic mycoses. These findings warrant further experiments to study the pharmacokinetic properties and toxicity of MS-8209 under conditions of chronic administration.

Amphotericin B↗
PubMed1992

Influence of phospholipid/amphotericin B ratio and phospholipid type on in vitro renal cell toxicities and fungicidal activities of lipid-associated amphotericin B formulations.

We studied the influence of the lipid/amphotericin B (AMB) ratio and the phospholipid type on the in vitro renal cell toxicity and antifungal efficacy of lipid-associated AMB (L-AMB). L-AMB was prepared at one of two different lipid/AMB ratios (1 and 40) by incubating AMB with empty small unilamellar vesicles, made from one of three different phospholipids: dipalmitoyl-, dimirystoyl-, and distearoylphosphatidylcholine (DPPC, DMPC, and DSPC, respectively). Renal cell toxicity, investigated through an assessment of the Na-dependent uptake of phosphate by proximal tubular cells, and fungicidal effect against Candida albicans were studied after 1 h of treatment at 37 degrees C. The amount of unbound AMB present in each L-AMB formulation was studied by use of circular dichroism. At a lipid/AMB ratio of 40, the three lipidic formulations were not toxic for renal cells but were less effective against C. albicans than AMB; however, DSPC-AMB, which contained 50% unbound AMB, was more effective against C. albicans than DPCC-AMB or DMPC-AMB, containing 0 and 13% unbound AMB, respectively. At a lipid/AMB ratio of 1, the antifungal effects of L-AMB and AMB were similar, whatever the phospholipid used, but only DMPC-AMB remained highly protective against AMB renal cell toxicity, despite the presence of the same amount of unbound AMB (50%) in DMPC-AMB and DPPC-AMB. We conclude that the in vitro activities and renal cell toxicities of different L-AMB formulations are influenced by the phospholipid type and the lipid/AMB ratio. The optimal ratio depends on the phospholipid itself. At a lipid/AMB ratio of 40, the antifungal activity depends mainly on the amount of unbound AMB in the formulation. At a lipid/AMB ratio of 1, the renal cell toxicity also depends on the fluidity of the phospholipid.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed1992

Tissue distribution and antifungal effect of liposomal itraconazole in experimental cryptococcosis and pulmonary aspergillosis.

We studied the tissue distribution and in vivo antifungal effect of itraconazole, incorporated into pure dipalmitoylphosphatidylcholine (DPPC) multilamellar liposomes and administered intravenously. Eighty percent of the itraconazole was associated with DPPC. Drug levels in lung, brain, and liver, obtained after intravenous administration of tritiated itraconazole, were higher when the drug was administered intravenously as liposomal than when it was dissolved in cyclodextrin. Administration of the liposomal formulation also led to higher and sustained levels of intact itraconazole in serum. Efficacy was assessed in DBA/2 mice infected intravenously with 3 x 10(6) Cryptococcus neoformans, an inoculum responsible for early fatal pneumonia, or 3 x 10(5) C. neoformans, leading to delayed meningitis. In pneumonia, 20 mg/kg of liposomal itraconazole was more effective on survival than the same dose given intravenously in cyclodextrin or twice the dose administered orally dissolved in polyethylene glycol 200. In meningitis, liposomal itraconazole was also more efficient than the drug dissolved in cyclodextrin. These results were confirmed by colony counts in the brain and lung of infected mice. In immunosuppressed OF1 mice infected after inhalation of Aspergillus fumigatus spores, liposomal itraconazole (20 mg/kg x 3) was the only effective treatment. We conclude that intravenous liposomal delivery of itraconazole enhances both concentrations in infected tissues and the in vivo efficacy of the drug. Such passive targeting of antifungal agents other than amphotericin B might be helpful in the treatment of severe systemic mycoses, especially in the case of lung or brain involvement.

Animals↗
PubMed1991

Endotoxin-tobramycin additive toxicity on renal proximal tubular cells in culture.

Aminoglycoside-induced renal damage is enhanced in animals with Escherichia coli pyelonephritis. Bacterial endotoxin is liberated during antibiotic therapy. The toxic effect of endotoxin and tobramycin, alone or in combination, was investigated in primary cultures of rabbit proximal tubular cells grown to confluence in serum-free medium. Sodium-dependent uptakes of Pi and alpha-methylglucopyranoside (MGP) and enzymatic activities (lactate dehydrogenase [LDH] released as a marker of cell necrosis and gamma-glutamyltransferase [GGT] and N-acetyl-beta-D-glucosaminidase [NAG] present in the homogenate as markers of brush border membrane and lysosome integrity) were measured. Cells were exposed to (i) endotoxin (20 mg/liter), tobramycin (1 mM), or endotoxin plus tobramycin for 48 h, or (ii) endotoxin (100 mg/liter), tobramycin (4 mM), or endotoxin plus tobramycin for 72 h. Endotoxin alone did not alter Pi uptake, but tobramycin inhibited Pi uptake through a decrease in Vmax. The effect was not enhanced by the combination of endotoxin and tobramycin. Endotoxin and tobramycin alone exerted no significant effect upon MGP uptake, but strong inhibition of the Vmax was observed after exposure to a combination of endotoxin plus tobramycin, without alteration of the Km. Endotoxin decreased residual GGT activity in the cell homogenate. Tobramycin increased LDH release in the medium and NAG activity in the homogenate. Endotoxin plus tobramycin resulted in an additive effect upon LDH and NAG activities. In conclusion, by disturbing apical membrane integrity, endotoxin increased tobramycin toxicity in vitro in the absence of serum hormonal mediator.

Acetylglucosaminidase↗
PubMed1991

Limited protection by small unilamellar liposomes against the renal tubular toxicity induced by repeated amphotericin B infusions in rats.

Amphotericin B (AMB), either alone or incorporated into small unilamellar vesicles of pure dipalmitoylphosphatidyl choline (DPPC SUV-AMB), was administered intravenously to male Sprague-Dawley rats once daily for 5 days. Either 1.5 or 3.5 mg of AMB or DPPC SUV-AMB per kg was given, since these concentrations corresponded, respectively, to the lowest nephrotoxic dose and the sublethal dose of AMB in our model. Tubular functions were evaluated daily, and AMB concentrations in plasma, urine, and tissues were measured by high-performance liquid chromatography. AMB at both doses induced tubular toxicity, hyposthenuria being the earliest symptom. DPPC SUV-AMB at 1.5 mg/kg/day was atoxic, but the tubular alterations induced by 3.5 mg of DPPC SUV-AMB per kg were similar to those observed with 3.5 mg of AMB per kg, except that the ability to concentrate urine was partly restored 72 h after the last infusion. Incorporating AMB into DPPC SUV did not influence the pharmacokinetics of the drug. Using this lipidic AMB formulation, we thus observed a beneficial effect toward limiting the renal tubular toxicity of repeated low doses of AMB but, unexpectedly, not that of high doses. These results indicate that tubular renal functions and electrolyte serum values should be closely monitored in patients treated with AMB liposomal formulations, especially high-dose regimens.

Acetylglucosamine↗
PubMed1991

Use of a reamplification protocol improves sensitivity of detection of Mycobacterium tuberculosis in clinical samples by amplification of DNA.

We have compared the sensitivity and specificity of quantitative mycobacterial culture against results obtained by using the polymerase chain reaction for the detection of DNA from organisms of the Mycobacterium tuberculosis complex in 82 clinical specimens from patients suspected of having tuberculosis. Two amplification protocols were used, a standard amplification protocol, which amplifies a segment of the gene coding for the 65-kDa antigen, and a protocol in which the initial amplification products are reamplified with a second set of nested oligonucleotide primers. Although the standard amplification protocol gave positive results for 18 of 18 samples which grew greater than 100 CFU/ml and gave positive results in 4 of 35 specimens from patients with tuberculosis which were negative by culture, only 1 of 6 samples which grew less than 100 CFU/ml was positive. This lack of sensitivity could not be explained by the presence of inhibitors of Taq polymerase present in the original samples. In contrast, the reamplification protocol gave positive results for 24 of 24 samples which were positive by culture as well as for 13 of 35 samples from patients with tuberculosis which were negative by culture (overall sensitivity, 63%, P less than 0.02, compared with the standard amplification protocol and routine culture). Two of 23 samples from patients not diagnosed as having tuberculosis gave positive results when the standard amplification protocol was used, but no additional false-positive results were seen with the reamplification protocol (overall specificity, 91%). We conclude that the use of a reamplification protocol improves the sensitivity of detection of mycobacterial DNA in clinical samples without sacrificing specificity. The sensitivity of this approach appears to be superior to that of standard culture techniques.

Base Sequence↗
PubMed1990

Interactions of free and liposomal amphotericin B with renal proximal tubular cells in primary culture.

We studied in vitro the renal toxicity of amphotericin B (AMB) and liposomal AMB using primary cultures of rabbit proximal tubular cells grown to confluence in serum-free medium. Toxicity was assessed by changes 1) in the Na(+)-dependent uptakes of P1 and alpha-methylglucopyranoside (MGP), characteristic functions of proximal tubular cells; 2) K+ release into the supernatant, dependent upon membrane permeability; and 3) lactic dehydrogenase release as a marker for cellular death. Cells were exposed for 1 hr to AMB, alone or intercalated in small unilamellar vesicles prepared with one of the following phospholipids: dipalmitoylphosphatidyl choline, distearoylphosphatidyl choline or dimyristoylphosphatidyl choline. Although AMB concentrations of 20 microM or less did not increase lactic dehydrogenase release, P1 and MGP uptakes were significantly reduced (50% inhibition) by 2.5 and 5 microM AMB, respectively. AMB toxicity was dose-dependent, up to 20 microM. Analysis of P1 and MGP uptake kinetics, after treatment of the cells with 10 microM AMB, showed that inhibition occurred through a decrease in Vmax (66 and 57% inhibition for P1 and MGP, respectively) without affecting Km value. K+ release appeared for 2.5 microM AMB and increased with higher concentrations. Alteration of Na(+)-dependent uptakes by AMB, which parallels K+ release, may result from an alteration of the sodium gradient. Na(+)-dependent uptakes and K+ release were unaffected by liposomal AMB, even at the highest concentration tested (80 microM). The protective effect of liposomes was the same regardless of the phospholipid used.(ABSTRACT TRUNCATED AT 250 WORDS)

Amphotericin B↗
PubMed1989

[Liposomes].

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Anti-Bacterial Agents↗
PubMed1989

Incorporation of amphotericin B (AMB) into liposomes alters AMB-induced acute nephrotoxicity in rabbits.

To investigate the protective effect of liposomes on acute amphotericin B (AMB) renal toxicity, we compared in rabbits the acute toxicity of 4 mg/kg of free-AMB and 4 or 10 mg/kg of liposomal AMB (L-AMB) during 90 min after antibiotic infusion. Free-AMB exhibited immediate nephrotoxicity with a 44% decrease of the glomerular filtration rate and alteration of tubular cell membrane permeability expressed as increases in urinary pH (6.5 vs. 4.7), potassium fractional excretion (95% vs. 30%) and sodium fractional excretion (26% vs. 4%). Urinary excretion of the lysosomal enzyme N-acetylglucosaminidase was unchanged by free-AMB. Incorporation of AMB into liposomes prevented the toxic effects of free-AMB on glomerular filtration and tubular cells membrane, but significantly increased N-acetylglucosaminidase urinary excretion (380 and 180% in animals receiving 4 and 10 mg/kg of L-AMB, respectively). Absolute AMB urinary excretion during the experiment was unchanged by liposomes and was always less than 1% of the total dose administered. Liposomes alone exhibited no toxicity. These results suggest that liposomes could increase the interaction between AMB and lysosomes leading to an additional mechanism of cellular injury. They admonish close monitoring of renal function and enzymuria in clinical situations in which L-AMB is being used.

Amphotericin B↗
PubMed1988

[Effect of an immunomodulator, RU 41740, on experimental infections].

RU 41740 is an immunomodulator of organic origin acting on cells of the immune system (B cells, T cells, phagocytic cells) and on mediators IL1-CSF). Its mode of action has been explored by means of experimental infections. The types of defence involved differ according to whether the experimental infection is caused by an extracellular or intracellular micro-organism. Candida albicans and Saccharomyces cerevisiae were used to produce fungal infections, while bacterial infections were obtained with Staph. aureus, E. coli, Strep. pneumoniae and other organisms. The influenza virus was used to produce a viral infection. In these experimental models, RU 41740 increased the survival time of the infected animals and reduced bacterial, fungal and viral proliferation. These effects were observed even in immunocompromised mice. These in vitro and in vivo studies have demonstrated that RU 41740 is effective whatever the type of body defence involved.

Adjuvants, Immunologic↗
PubMed1988

The pharmacokinetics and extravascular diffusion of teicoplanin in rabbits and comparative efficacy with vancomycin in an experimental endocarditis model.

The serum protein binding, extravascular diffusion and urinary excretion of teicoplanin were studied in rabbits. Extravascular diffusion was studied after a 20 min iv infusion, and after one or five im injections (7.5 mg/kg), and was compared with the results obtained after im administration of vancomycin (7.5 and 15 mg/kg). In an experimental model of Staphylococcus aureus endocarditis, the efficacy of both antibiotics was also investigated. We observed teicoplanin serum protein binding of 87 +/- 4%. The serum concentrations of teicoplanin showed a three-phase exponential decline: T1/2 alpha, 0.11 +/- 0.01 h; T1/2 beta, 1.4 +/- 0.4 h; T1/2 gamma, 8.3 +/- 2.2 h. Teicoplanin appeared to be slightly secreted by renal tubules. The extravascular diffusion and the therapeutic efficacy of both drugs were studied with intervals between two injections based on the same multiple of beta half-life. Teicoplanin, like vancomycin, appeared slowly in extravascular fluid and the diffusibility of both drugs was similar. Peak extravascular concentrations of teicoplanin after 5 im injections were greater when the compound was administered every 16 h, rather than every 24 h and, for this drug, iv administration induced higher peak extravascular concentrations (P less than 0.01) than im injection. In the experimental model of S. aureus endocarditis, vancomycin 9 mg/kg/12 h and teicoplanin 4.5 mg/kg/16 h were similarly active and more effective than teicoplanin 4.5 mg/kg/24 h.

Animals↗
PubMed1988

Enhancement of the therapeutic effect of cephalosporins in experimental endocarditis by altering their pharmacokinetics with diclofenac.

We studied the effect of a nonsteroidal anti-inflammatory drug, diclofenac, in rabbits on the kinetics of three cephalosporins: cefotiam, cefmenoxime and ceftriaxone, and compared the antibacterial effect of these antibiotics, given alone or with diclofenac, in experimental endocarditis. Diclofenac significantly increased (P less than .05) the area under the curve in tissue-cage fluid of ceftriaxone and cefotiam-treated animals, and the terminal half-life of ceftriaxone in their sera (3.45 +/- 0.4 vs. 2.8 +/- 0.5 hr). Diclofenac reduced urinary excretion of cefotiam only. Cefmenoxime pharmacokinetics remained unchanged by diclofenac. The alteration of ceftriaxone kinetics appeared to be due to nonrenal mechanisms and could suggest reduction of biliary excretion. In Escherichia coli endocarditis, diclofenac enhanced the concentration (P less than .05) of cefotiam (23 +/- 16 vs. 8.9 +/- 5 micrograms/g) and ceftriaxone (13.2 +/- 3 vs. 8.5 +/- 4 micrograms/g) in infected vegetations, but not that of cefmenoxime. The antibacterial effect of ceftriaxone increased with diclofenac (5.5 +/- 1 vs. 7.2 +/- 1 log10 colony forming unit/g of vegetation). In vitro, neither protein binding to rabbit serum proteins nor intrinsic activity on the E. coli strain of each antibiotic was modified by diclofenac. These results suggest that anti-inflammatory drugs could increase antibiotic efficacy by altering their pharmacokinetics. The renal and nonrenal site of interaction may be involved for drugs belonging to the same class. Results obtained in tissue-cage fluid were predictive of the interference at the infected site.

Animals↗
PubMed1987

Value of antibiotic levels in serum and cardiac vegetations for predicting antibacterial effect of ceftriaxone in experimental Escherichia coli endocarditis.

In a rabbit model of Escherichia coli endocarditis, we studied the penetration into infected vegetations and the antibacterial effect of ceftriaxone. Ceftriaxone was given at different dosages, alone or with an interfering agent, diclofenac, a nonsteroidal anti-inflammatory drug, to determine the predictive value of the antibiotic levels in serum or infected vegetations on the antibacterial efficacy. Diclofenac increased the serum terminal half-life of ceftriaxone and increased its extravascular diffusion in tissue cage fluid, as well as in infected vegetations, allowing us to obtain various antibiotic concentrations in the infected site. Two hours after the fourth injection, around the time of peak level in serum, we observed a linear relationship between (i) serum and local antibiotic levels in vegetations, (ii) local antibiotic levels in a range of 142 to 600 X MBC and bacterial titer (log10 CFU/g) in vegetations, and (iii) serum antibiotic levels in a range of 800 to 1,400X MBC and bacterial titer in vegetations. In vivo, antibacterial effect was obtained only with high antibiotic levels in vegetations (greater than or equal to 220X MBC). This was confirmed by incubating vegetations sampled from infected animals in rabbit serum containing ceftriaxone (ex vivo experiment). Given once daily at a therapeutic dosage (30 mg/kg) for 4 days, ceftriaxone exhibited good efficacy (log10 CFU/g of vegetation = 2.41 +/- 2.7 versus 7.41 +/- 0.92 in control animals) and prevented regrowth of bacteria until 24 h after the last injection. We concluded that (i) provided the dose is sufficient, a long-acting cephalosporin can prove effective in severe gram-negative infections even when given infrequently, and (ii) serum antibiotic levels around the peak value, reflecting high effective local levels, could predict the therapeutic efficacy and represent a simple test to monitor the clinical course of a severe infectious process.

Animals↗
PubMed1987

Comparative efficacy of cefotiam, cefmenoxime, and ceftriaxone in experimental endocarditis and correlation with pharmacokinetics and in vitro efficacy.

To determine the influence of in vitro activity, pharmacokinetic properties, and therapeutic regimen on the antibacterial effect in vivo, we compared three cephalosporins, cefotiam, cefmenoxime, and ceftriaxone, in a rabbit model of experimental Escherichia coli endocarditis after 4 days of treatment. The MBCs of cefotiam, cefmenoxime, and ceftriaxone for the E. coli strain were 0.5, 0.125, and 0.06 microgram/ml, respectively. Killing curves at 10 times the MBC were similar for the three cephalosporins. In serum, the elimination half-life of ceftriaxone was twice as much as the elimination half-life of cefotiam or cefmenoxime (2.8 +/- 0.45 versus 1.4 +/- 0.25 or 1.3 +/- 0.4 h, respectively). Ceftriaxone was much more effective than cefotiam. The bacterial titer in the vegetations (log10 CFU per gram of vegetation) was 7.56 +/- 1 with cefotiam and 2.41 +/- 2.6 with ceftriaxone, as their concentrations were 18 and 466 times higher, respectively, than their MBCs. Although ceftriaxone and cefmenoxime exhibited a similar rate of killing and percentage of protein binding, ceftriaxone was more effective than cefmenoxime at the same regimen of 15 mg/kg twice a day (3.08 +/- 1.1 versus 4.82 +/- 3.2 log10 CFU/g of vegetation). When antibiotic was given as a single daily injection of 30 mg/kg, the antibacterial effect persisted for ceftriaxone, but not for cefmenoxime. The longer elimination half-life and the higher local concentration/MBC ratio of ceftriaxone explained these results. The bacterial titer measured 24 h after the fourth injection of 30 mg of ceftriaxone per kg confirmed that this regimen prevented regrowth of bacteria. These results suggest that the local antibiotic level/MBC ratio roughly correlated with the antibacterial effect and could represent an adequate basis to explain the differences observed between the drugs in vivo. They also demonstrate that, provided that the dose is sufficient, a long-acting broad-spectrum cephalosporin may be effective in severe gram-negative infections, even when given at relatively long dosing intervals, in contrast with a rapidly cleared drug with the same intrinsic activity.

Animals↗