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Biomedical subjects

J C Pechère

Publications and source records attributed to J C Pechère.

At least 55 records · Page 3Linked to original sources
PubMed1993

Respective role of polymorphonuclear leukocytes and their integrins (CD-11/18) in the local or systemic toxicity of lipopolysaccharide.

The role of neutrophils (PMNs) and leukocyte integrins was investigated in two models of lipopolysaccharide (LPS)-induced toxicity: the systemic lethality assay in D-galactosamine-sensitized mice and the local reaction elicited by intradermal injection of LPS and tumor necrosis factor (TNF) at 24-h intervals. In the local reaction, depletion of PMNs with an anti-PMN monoclonal antibody (mAb) and mAbs against CD-11a (or LFA1) and CD-11b (or CR3) completely prevented the hemorrhagic necrosis. Evaluation of histological sections and myeloperoxidase levels suggested different mechanism of protection because PMNs were abundant in anti-CD-11- and absent in anti-PMN-treated mice. In the systemic assay, depletion of PMNs ensured 100% survival, whereas after administration of anti-CD-11a or b mAb, the percentages of survivors were 6 and 59%, respectively. One hour after LPS injection, the serum TNF-alpha level was higher in PMN-depleted mice than in controls. These studies provide evidence that neutrophils are essential for the expression of local or systemic LPS-induced injury, whereas the requirement for their leukocytic integrins is obvious only in the local reaction.

Animals↗
PubMed1993

Bacterial resistance: new threats, new challenges.

Bacterial resistance remains a major concern. Recently, genetic transfers from saprophytic, non-pathogenic, species to pathogenic S. pneumoniae and N. meningitidis have introduced multiple changes in the penicillin target molecules, leading to rapidly growing penicillin resistance. In enterobacteriaceae, a succession of minute mutations has generated new beta-lactamases with increasingly expanded spectrum, now covering practically all available beta-lactam antibiotics. Resistance emerges in the hospital environment but also, and increasingly, in the community bacteria. Widespread resistance is probably associated with antibiotic use, abuse and misuse but direct causality links are difficult to establish. In some countries as in some hospitals, unusual resistance profiles seem to correspond to unusual antibiotic practices. For meeting the resistance challenge, no simple solutions are available, but combined efforts may help. For improving the situation, the following methods can be proposed. At the world level, a better definition of appropriate antibiotic policies should be sought, together with strong education programmes on the use of antibiotics and the control of cross-infections, plus controls on the strategies used by pharmaceutical companies for promoting antibiotics. At various local levels, accurate guidelines should be adapted to each institution and there should be regularly updated formularies using scientific, and not only economic, criteria; molecular technologies for detecting subtle epidemic variations and emergence of new genes should be developed and regular information on the resistance profiles should be available to all physicians involved in the prevention and therapy of infections.

Bacterial Infections↗
PubMed1993

Two-dimensional polyacrylamide gel electrophoresis isolation and microsequencing of Pseudomonas aeruginosa proteins.

Outer membrane (OM) proteins of beta-lactam-susceptible and -resistant strains of Pseudomonas aeruginosa were analyzed by 2-D polyacrylamide gel electrophoresis. Carrier ampholytes, pH 4-8, and immobilized pH gradient (IPG), pH 3.5-10.0, procedures were used. An acidic-protein spot (pI = 5.2) detected in susceptible but not in an imipenem-resistant strain was sequenced and twenty-five N-terminal amino acids had total homology with the OM protein D, the imipenem-specific porin of P. aeruginosa. A basic-protein spot (pI = 9.0) detected in ceftazidime-resistant, but not in a susceptible strain was sequenced and fourteen N-terminal amino acids had homology with a beta-lactamase encoded by the ampC gene of P. aeruginosa. The IPG procedure allows identification of more than one hundred proteins of the OM fraction from a single gel. Detection of beta-lactamase in OM fractions might reflect a periplasmic contamination, but its anchorage within the OM cannot be ruled out.

Amino Acid Sequence↗
PubMed1993

Quinolones in intracellular infections.

Intracellular parasites are those which spend most of their lives within host cells. The fluoroquinolones demonstrate favourable intracellular pharmacokinetics for the treatment of intracellular infections; these agents diffuse and accumulate in the phagocytes, mainly in the cytosol, and do not associate with cellular organelles. The fluoroquinolones are generally active against Salmonella spp. in vitro, and have been used successfully in the treatment of typhoid fever, Salmonella bacteraemia in patients with AIDS, and chronic enteric carriage. Fluoroquinolone monotherapy has also been found satisfactory in the treatment of tularaemia and Mediterranean spotted fever. Quinolones, alone or in combination with other agents, have also shown promise in animal models of legionellosis and in limited clinical studies. Quinolones, particularly ciprofloxacin and ofloxacin, have notable antimycobacterial activity. Both agents have been used in combination with other antimycobacterial drugs in the treatment of infections caused by Mycobacterium tuberculosis, M. avium-intracellulare complex, rapidly growing mycobacteria and M. leprae, and deserve consideration as part of a multi-drug regimen in otherwise untreatable mycobacterial infections. Clinical data regarding fluoroquinolone monotherapy in brucellosis indicate unacceptable failure rates which preclude the use of these agents in this indication. The quinolones have some efficacy in genital chlamydial infections, but may have limitations in this indication also. In conclusion, as a result of the in vitro activity of the quinolones and their favourable pharmacokinetics, these agents are now an important part of the armamentarium against intracellular infections.

Animals↗
PubMed1993

[Microbiology of nosocomial infections].

The microorganisms causing nosocomial infections belong either to the patient himself (endogenous infections) or to hospital flora. New epidemiological tools, using molecular technologies, have renewed the body of knowledge on this flora. The commonest pathogens producing nosocomial infections include coagulase positive or negative staphylococci, enterococci, enterobacteriaceae, pseudomonas and candida. A recent trend has been shown, indicating the emergence of Gram positive cocci and fungi, when E. coli and Klebsiella tend to decrease. Bacterial resistance to antimicrobials is a growing concern, with the appearance of new resistance mechanisms such as broad-spectrum beta-lactamases in Gram negative rods, vancomycin resistance in several Gram positive species, or multiply resistance in enterococci, staphylococci, pseudomonas or mycobacteria. Some pathogens create new concerns nowadays, such as M. tuberculosis, M. avium intracellulare, Gram positive bacilli (exemplified by Corynebacterium JK), water bacteria, non-albicans Candida and other fungi. Increasing therapeutic challenge underlines the prominent role of infection control programs.

Cross Infection↗
PubMed1992

Fish oil decreases natural resistance of mice to infection with Salmonella typhimurium.

Mortality rate in mice fed fish oil for 4 weeks was remarkably higher after a very low peroral (PO) challenge with Salmonella typhimurium, as compared with those fed diets rich in either corn oil or hydrogenated coconut oil, or a low fat (chow) diet. None of the surviving mice fed the fish oil diet showed bacterial counts in their spleens, unlike 45.4% to 66.6% of surviving mice fed high fat or low fat diets. The spleens of mice fed fish oil presented the highest number of bacteria 7 days after intraperitoneal infection with the same bacterial strain. Thus, the current studies demonstrate that a diet rich in fish oil decreases host resistance to infection.

Adipose Tissue↗
PubMed1992

Dietary supplementation with fish oil enhances in vivo synthesis of tumor necrosis factor.

Studies reported here investigate the influence of dietary fat types on cytokine production in response to endotoxin (LPS) challenge. Tumor necrosis factor (TNF) serum levels were markedly higher (by 10-fold) in mice fed chronically a diet rich in fish oil rather than either a diet rich in corn or coconut oil or a low fat diet. This in vivo hyper-responsiveness in LPS-induced TNF production following fish oil consumption concorded with similar exaggerated in vitro TNF release from macrophages exposed to LPS. These data suggest that high consumption of fish oils, by virtue of their high content of omega-3 polyunsaturated fatty acids, can lead to an exaggerated production of mediators of inflammation with potentially adverse consequences on the outcome and severity of infectious diseases.

Animals↗
PubMed1992

Comparative in-vitro activity of new quinolones against clinical isolates and resistant mutants.

The in-vitro activity of five new fluoroquinolones, WIN 57273, sparfloxacin, fleroxacin, temafloxacin and ciprofloxacin was determined against 543 recent clinical isolates and eight quinolone resistant strains derived by mutation and their five parent strains. WIN 57273 was the most active compound against Gram-positive bacteria, sparfloxacin had a broad spectrum which was similar to that of ciprofloxacin. Ciprofloxacin showed the greatest activity against Gram-negative bacteria. Temafloxacin showing some activity against Gram-positive organisms and Acinetobacter spp. Fleroxacin was the least active compound studied. Compared to wild type parent strains, the mutated strains produced the following results. In Enterobacter cloacae OmpF deficiency increased the MICs of all quinolones by 8-32-fold. In Pseudomonas aeruginosa OmpF deficiency had a limited effect, Omp D2 deficiency combined with an increased lipopolysaccharide content produced greater resistance, i.e. 4-16-fold; mutations in gyrase were associated with variously increased MICs, depending on the strain and compound tested.

4-Quinolones↗
PubMed1992

Development of resistance during ceftazidime and cefepime therapy in a murine peritonitis model.

Resistance emerging after ceftazidime or cefepime therapy was investigated in a peritonitis model. Mice were given a peritoneal challenge (10(8) cfu plus talcum) and treated by either antibiotic (50 mg/kg/dose, which produced similar antibiotic concentrations in peritoneal fluid in both cases). After one or three doses, resistance never developed in Serratia marcescens or Citrobacter freundii infections. After Enterobacter cloacae and Pseudomonas aeruginosa challenge, ceftazidime selected more resistance (21/36 cases) than did cefepime (1/36 cases). In mice challenged with resistant strains selected by ceftazidime therapy, cefepime (six doses) successfully treated 7/18 E. cloacae infections but 0/18 P. aeruginosa infections; ceftazidime was never effective. Neither cefepime nor ceftazidime cured mice infected with the resistant strain selected by cefepime. MICs were poor predictors of further emergence of resistance in mice inoculated with strains classified as susceptible, but antibiotic-containing agar gradients plated with a high inoculum (10(8) cfu) allowed better prediction. In selected clinical situations, cefepime may be preferable because it may be associated with less frequent emergence of resistance.

Animals↗
PubMed1992

In-vitro activity of RP 59500, a semisynthetic streptogramin, against staphylococci and streptococci.

The in-vitro activity of RP 59500, an injectable streptogramin derived from pristinamycin, was determined by agar dilution and compared with that of pristinamycin. Two hundred and sixty-one recent clinical isolates of Gram-positive cocci were tested against both antibiotics. The two compounds displayed similar activities. The MIC90s of RP 59500 ranged from 0.5 to 2 mg/L in 114 strains of Staphylococcus aureus showing various phenotypes of antibiotic resistance (penicillin-susceptible; penicillin-resistant and methicillin-susceptible; methicillin-resistant; erythromycin-resistant, either inducible or constitutive; quinolone-resistant). Similar results were obtained with coagulase-negative staphylococci. RP 59500 was consistently active against streptococci, with MIC90s of 0.25, 0.25 and 0.50 mg/L for Streptococcus pyogenes (n = 20), Streptococcus agalactiae (n = 20) and Streptococcus pneumoniae (n = 20), respectively. Enterococcus faecalis (n = 20) appeared to be notably less susceptible (MIC90, 8 mg/L). In view of this consistent activity against all staphylococci and streptococci tested, including multiply resistant isolates, RP 59500 merits further investigation.

In Vitro Techniques↗
PubMed1992

Transport of pefloxacin across the bacterial cytoplasmic membrane in quinolone-susceptible Staphylococcus aureus.

Binding to phospholipids, uptake by simple diffusion, and an energy-dependent, carrier-mediated efflux are thought to characterize interactions between fluoroquinolones and bacterial cytoplasmic membranes. Here, we have found that an endogenous active efflux is unlikely in quinolone-susceptible Staphylococcus aureus. The protonophore, carbonyl cyanide m-chlorophenylhydrazone (CCCP), increased pefloxacin uptake in different membrane systems under conditions which excluded carrier-mediated transport, i.e., in bacterial cells at 4 degrees C and in protein-free phosphatidylglycerol liposomes. When plotted as a function of outer pH, the CCCP effect, both in S. aureus cells and in phosphatidylglycerol liposomes, correlated with pefloxacin labeling of everted S. aureus membrane vesicles, with all three profiles showing maximal effect at an acidic pH. So the CCCP effect may result not from inhibition of the proton motive force, as previously thought, but rather from acidification of the intramembrane space by the protonophore, leading to enhanced binding of the positive pefloxacin species to the inner leaflet of the bilayer. Moreover, antistaphylococcal potency and uptake profiles of pefloxacin in S. aureus and phosphatidylglycerol liposomes, assayed as a function of outer pH, peaked at a neutral pH. These observations suggest that zwitterionic and positive quinolone species are responsible for diffusion through and binding to the cytoplasmic membrane, respectively.

Anti-Infective Agents↗
PubMed1992

Relative beta-lactamase- and transpeptidase-inhibitory activities of the new quinolone WIN-57273 in Staphylococcus aureus.

The new quinolone WIN-57273 was shown to inhibit Staphylococcus aureus beta-lactamase activity noncompetitively in vitro with an apparent Ki value of 0.5 mM. MICs of penicillin G for a highly quinolone-resistant, beta-lactamase-negative strain in the presence of exogenous beta-lactamase decreased considerably when subinhibitory concentrations of WIN-57273 were added. Furthermore, the attachment transpeptidase reaction, investigated on whole cells of S. aureus, was impeded by WIN-57273 concentrations of greater than or equal to 30 microM. While these interactions suggest a novel mechanism of action for this compound, they are probably not relevant to the overall antibacterial potency of WIN-57273.

Anti-Infective Agents↗
PubMed1991

Newly documented antimicrobial activity of quinolones.

The improved antimicrobial activity of newer fluoroquinolones and novel applications recently found for the drugs already marketed are reviewed. Several new compounds are more active against gram-positive bacteria than the presently marketed fluoroquinolones. WIN 57273, the most potent compound in vitro on a weight basis, is 16 to 128 times more active than ciprofloxacin against various staphylococci, streptococci, Enterococcus spp., Corynebacterium spp., Listeria monocytogenes and Bacillus spp. BMY 40062, PD 117558, PD 127391, sparfloxacin, temafloxacin and tosufloxacin also show enhanced in vitro efficacy against these species. These drugs also possess increased activity against various anaerobes, notably Clostridium perfringens, Clostridium difficile and the Bacteroides fragilis group. Mycobacterium tuberculosis, rapidly growing mycobacteria other than Mycobacterium chelonae, and Mycobacterium leprae are often susceptible to quinolones displaying bactericidal activity which is potentially useful for curing difficult-to-treat mycobacteriosis. In addition, a number of new products, notably those containing a cyclopropyl group, are more active than reference fluoroquinolones against Mycobacterium leprae. Sparfloxacin, BMY 40062 and WIN 57273 compare favorably with older fluoroquinolones in the killing of intracellular Legionella spp., and several of the newer compounds have greater antichlamydial potency. Improved antibacterial activity has also been found against Mycoplasma hominis, Ureaplasma urealyticum, Acinetobacter spp. and Pseudomonas maltophilia. By contrast, the newer quinolones have similar or less activity against Pseudomonas aeruginosa and Enterobacteriaceae. Recently, pefloxacin, ofloxacin and ciprofloxacin were found to be active against protozoa, including Plasmodium spp., Trypanosoma cruzi and Leishmania donovani, but not against Toxoplasma gondii. In the near future, more specific research testing unusual pathogens may lead to the identification of quinolones with more selective activity.

4-Quinolones↗
PubMed1991

The activity of azithromycin in animal models of infection.

High and prolonged tissue levels accompanied by low serum concentrations are a feature of azithromycin, an azalide antibiotic. It has a broad spectrum of activity against gram-positive and gram-negative microorganisms and several intracellular pathogens. A number of animal models of localised infection have been developed which demonstrate that the efficacy of azithromycin correlates with its extravascular pharmacokinetics and not with blood levels. In many instances, because of high tissue bioavailability, azithromycin has better in vivo efficacy than comparative agents, despite a similar or higher minimum inhibitory concentration. Additionally, the extravascular kinetics of azithromycin are associated with bactericidal activity against pathogens such as Staphylococcus aureus, Streptococcus pneumoniae and Escherichia coli. Intracellular pathogens are susceptible to azithromycin and it is believed that the agent penetrates and remains within host cells infected by organisms including Mycobacterium avium, Legionella pneumophila and Borrelia burgdorferi. This paper reviews the in vivo efficacy of azithromycin and standard agents in animal models of infection, especially those involving intracellular pathogens.

Animals↗
PubMed1991

Prevention of vascular graft infection by rifampin bonding to a gelatin-sealed Dacron graft.

This study examines the efficacy of rifampin bonding to a gelatin-sealed knitted Dacron graft to prevent perioperative bacteremic vascular graft infection. Antibiotic bonding was obtained by soaking grafts for 15 minutes in a 1 mg/ml saline solution of rifampin at 37 degrees C. Nineteen dogs had thoracoabdominal aortic bypass: seven (group I) received a rifampin treated graft; six (group II) received an untreated gelatin-coated graft; and six (group III) received an uncoated Dacron graft. Two days later bacteremic challenge was produced by rapid intravenous injection of 5 x 10(5) colony forming units of methicillin resistant Staphylococcus aureus. Grafts were harvested five days after this challenge and cut into 10 fragments, each submitted to bacterial counts. Results were expressed as CFU/cm2 of graft material. In group I, no graft was infected, whereas all grafts in groups II and III were infected (p less than 0.05). Median bacterial counts from the infected fragments (median +/- SD) were similar in groups II (2.5 x 10(5) CFU/cm2) and III (4 x 10(4) CFU/cm2). Blood cultures at time of sacrifice were negative in all dogs in group I and positive in five of six dogs in groups II and III. Cultures of liver, spleen, kidney, and lung specimens were always negative in group I and positive in 22 of 24 specimens in group II and 23 of 24 specimens in group III. Soaking a gelatin-sealed Dacron graft in rifampin solution evidently prevents early bacteremic graft infection and secondary foci of infection in this model.

Animals↗
PubMed1991

Activity of minocycline against Toxoplasma gondii infection in mice.

The chemotherapeutic activity of minocycline, a semi-synthetic tetracycline analogue, was evaluated in a murine model of toxoplasmosis. A lethal acute toxoplasmosis was produced by injecting 10(5) tachyzoites of the RH strain of Toxoplasma gondii into the peritoneal cavities of Swiss-Webster mice. When infected mice were treated once daily for 12 days, starting 2 h after challenge, the survival and cure rates were 100% and 40% respectively after minocycline alone (100 mg/kg per day), 0% and 0% after pyrimethamine alone (8.5 mg/kg per day), and 100% and 50% after combination of the two drugs at the same dosages. Absolute survival and cure with minocycline were observed when mice were treated with two daily doses of 100 mg/kg for 12 days. Mice chronically infected with a low virulent strain of T. gondii (Me49) showed a significant reduction in the number of brain cysts after three weeks of treatment with 50 mg/kg per day of minocycline. Minocycline serum levels after a single oral administration of 50 mg/kg or 100 mg/kg to normal mice, peaked at 1.8 mg/l and 10 mg/l after 1 h, respectively, and showed an extended half-life.

Acute Disease↗