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Biomedical subjects

J C Pechère

Publications and source records attributed to J C Pechère.

At least 37 records · Page 2Linked to original sources
PubMed1999

Characterization of MexT, the regulator of the MexE-MexF-OprN multidrug efflux system of Pseudomonas aeruginosa.

We investigated the regulation of the MexEF-OprN multidrug efflux system of Pseudomonas aeruginosa, which is overexpressed in nfxC-type mutants and confers resistance to quinolones, chloramphenicol and trimethoprim. Sequencing of the DNA region upstream of the mexEF-oprN operon revealed the presence of an open reading frame (ORF) of 304 amino acids encoding a LysR-type transcriptional activator, termed MexT. By using T7-polymerase, a 34-kDa protein was expressed in Escherichia coli from a plasmid carrying the mexT gene. Expression of a mexE::lacZ fusion was 10-fold higher in nfxC-type mutants than in the wild-type strain; however, transcription of mexT as well as the mexT DNA region was unchanged. Located adjacent to mexT but transcribed in opposite direction, the beginning of an ORF termed qrh (quinone oxidoreductase homologue) was identified. Expression of a qrh::lacZ fusion was also found to be activated by MexT. Further, we present evidence for coregulation at the transcriptional and the posttranscriptional level between the MexEF-OprN efflux system and the OprD porin responsible for cross-resistance of nfxC-type mutants to carbapenem antibiotics.

4-Quinolones↗
PubMed1999

Antibacterial activity of retinaldehyde against Propionibacterium acnes.

BACKGROUND: Retinaldehyde has been shown to exert antibacterial activity in vitro. AIM: This study evaluates the effect of retinaldehyde on Propionibacterium acnes both in vivo and in vitro. METHODS: Microbial minimal inhibitory concentrations (MICs) of retinaldehyde and retinoic acid were determined on reference strains of P. acnes. In vivo activity of daily topical application of 0.05% retinaldehyde on the P. acnes density was evaluated after application in a single-blind randomised study. RESULTS: MICs of retinaldehyde were 4 mg/l for P. acnes No. CIP179 and CIP53119 and 8 mg/l for P. acnes No. CIP53117. In contrast, the MICs of retinoic acid were superior to 128 mg/l for these three strains. In vivo, retinaldehyde-treated areas displayed a significant decrease in counts of viable P. acnes as compared with the untreated areas with a median decrease of 10(2) log P. acnes/cm(2) after 2 weeks of daily application. Vehicle alone had no effect. CONCLUSION: The MIC of retinaldehyde against P. acnes suggests a direct antibacterial activity. Daily topical application of 0.05% retinaldehyde is associated with a clear reduction of the P. acnes density.

Administration, Topical↗
PubMed1998

Bacteriological activity of trovafloxacin, a new quinolone, against respiratory tract pathogens.

The use of established fluoroquinolones, such as ciprofloxacin and ofloxacin, as empirical therapy for the treatment of moderate-to-severe respiratory tract infections is limited by their poor activity against gram-positive and atypical pathogens. Data from in vitro susceptibility studies and in vivo animal protection models suggest that the new fluoroquinolone, trovafloxacin, compared with ciprofloxacin and ofloxacin offers equivalent activity against gram-negative pathogens and improved activity against gram-positive pathogens. In particular, susceptibility data indicate that trovafloxacin is at least 16-fold more potent than either ciprofloxacin or ofloxacin against penicillin-susceptible and penicillin-resistant strains of Streptococcus pneumoniae. Other susceptible pathogens include Streptococcus pyogenes, vancomycin-susceptible Enterococcus faecalis and the atypical respiratory pathogens Legionella pneumophila, Mycoplasma pneumoniae and Chlamydia pneumoniae. In vivo studies involving models of protection against acute systemic infection and pneumococcal pneumonia in mice, and Legionnaires' disease in guinea pigs, indicate that the antibacterial spectrum observed for trovafloxacin in vitro extends to the in vivo setting. Together, these findings suggest that trovafloxacin may offer clinical efficacy against respiratory pathogens superior to that of ciprofloxacin and of ofloxacin, and may find a useful role as empiric therapy in both the community and hospital setting.

Animals↗
PubMed1998

Treatment of vascular graft infection by in situ replacement with cryopreserved aortic allografts: an experimental study.

PURPOSE: The purposes of this study were to prove the efficacy of cryopreserved aortic allografts to treat an established vascular graft infection by in situ replacement in an animal model and to evaluate the role of the antibiotics normally used to decontaminate the allografts. METHODS: Twenty-three dogs underwent infrarenal aortic replacement with a gelatin-sealed knitted polyester graft contaminated in vitro by Staphylococcus epidermidis RP-62. One week later, the 18 surviving animals underwent reoperation for graft removal and were randomized into three groups for in situ replacement: group I (control, n = 6) received a new gelatin-sealed graft; group II (n = 6) received a non-antibiotic-treated cryopreserved allograft; and group III (n = 6) received an antibiotic-treated cryopreserved allograft. Control grafts and allografts were removed 4 weeks after the initial intervention for quantitative bacteriologic analysis and histologic analysis. Bacteriologic results were expressed as colony-forming units per square centimeter of graft material. Qualitative bacteriologic analysis was also obtained from perigraft fluid and tissue. RESULTS: All of the initially implanted grafts and all of the control grafts (group I) were infected at the time of removal. In group II, three out of six allografts were not totally incorporated, whereas in group III incorporation was always complete, with a significantly decreased inflammatory reaction. All of the antibiotic-treated allografts were sterile, whereas three untreated allografts grew bacteria. CONCLUSIONS: In this model, cryopreserved aortic allografts were more resistant to reinfection than synthetic grafts after in situ replacement of an infected prosthetic graft. However, the antibiotic loading of the cryopreserved aortic allograft appears to be essential to obtain optimal therapeutic effects.

Animals↗
PubMed1998

[Antibiotic efflux, a mechanism of multiple resistance in Pseudomonas aeruginosa].

Pseudomonas aeruginosa displays three active efflux systems, made of three components: an inner membrane protein acting as a proton motive pump, a periplasmic linking protein and an outer membrane protein acting as an efflux porin. All three proteins are encoded by genes organised as an operon, with a regulator gene in the vicinity. Efflux systems produce phenotypes of multidrug resistance. The constitutively produced system MexAB-OprM generates intrinsic resistance to most beta-lactams, quinolones, tetracycline, chloramphenicol, trimethoprim and sulfamethoxazole; in addition, genetic derepression causes acquired resistance to the same drugs. The non constitutive MexCD-OprJ and MexEF-OprN can be expressed by mutation, producing then slightly different multidrug resistant phenotypes. Efflux systems are responsible for low level resistance, and seem to promote selection of mutations responsible for higher level resistance. The multidrug resistance associated to active efflux systems should be taken into account in our antibiotic policies, both at the individual and at the institutional level.

Anti-Bacterial Agents↗
PubMed1997

Characterization of MexE-MexF-OprN, a positively regulated multidrug efflux system of Pseudomonas aeruginosa.

Antibiotic-resistant mutants of Pseudomonas aeruginosa were generated using chloramphenicol and ciprofloxacin as selective agents. These mutants displayed a multidrug phenotype and overexpressed an outer membrane protein of 50 kDa, which was shown by Western blot analysis to correspond to OprN. A cosmid clone harbouring the oprN gene was isolated by partial complementation of a mutant deficient in OprM, the outer membrane component of the mexAB-oprM efflux operon. Antibiotic-accumulation studies indicated that OprN was part of an energy-dependent antibiotic-efflux system. Sequencing of a 6180bp fragment from the complementing cosmid revealed the presence of three open reading frames (ORFs), which exhibited amino acid similarity to the components of the mexAB-oprM and mexCD-oprJ efflux operons of P. aeruginosa. The ORFs were designated MexE, MexF and OprN. Mutation of the mexE gene eliminated the multidrug-resistance phenotype in an OprN-overexpressing strain, but did not affect the susceptibility profile of the wild-type strain. Expression of the mexEF-oprN operon was shown to be positively regulated by a protein encoded on a 1.5 kb DNA fragment located upstream of mexE and belonging to the LysR family of transcriptional activators. The presence of a plasmid containing this DNA fragment was sufficient to confer a multidrug phenotype onto the wild-type strain but not onto the mexE mutant. Evidence is provided to show that the mexEF-oprN operon may be involved in the excretion of intermediates for the biosynthesis of pyocyanin, a typical secondary metabolite of P. aeruginosa.

Amino Acid Sequence↗
PubMed1996

Rifampicin loading of vascular grafts.

Antibiotic-bound arterial prostheses may contribute to the management of prosthetic infections. The in-vitro absorption and release of rifampicin was measured in four different polyester arterial prostheses, including unsealed VP 1200, gelatin-sealed Gelsoft, collagen-impregnated Hemashield and gelatin-sealed Unigraft. Gelsoft grafts bound more rifampicin than unsealed VP 1200. Rifampicin concentrations with the gelatin sealed to Gelsoft grafts reached a threshold when the rifampicin concentrations of the soaking solution were 10 mg/mL or more. Rifampicin adsorption plateaued after 15 min of soaking VP 1200, and peaked after 25 min of soaking Gelsoft. pH variations did not significantly influence antibiotic binding. Prosthesis-bound rifampicin concentrations decreased rapidly after soaking, but a significant portion of the antibiotic remained associated with the material after 7 days. Release was slower with Gelsoft than with VP 1200 during the first 3 h, but after 24 h, the amounts of rifampicin released were similar in the two materials. Other experiments were performed in dogs receiving sealed grafts as infrarenal aortic bypass after soaking the material in a 1 mg/mL solution of rifampicin in normal saline. After 3 days of implantation, the amount of rifampicin in explanted grafts was higher in Gelsoft and Hemashield than in Unigraft. This study confirms that rifampicin bonding to prosthetic material occurs and is enhanced by sealed collagen or gelatin.

Absorption↗
PubMed1996

Streptogramins. A unique class of antibiotics.

Streptogramin antibiotics represent a unique class of antibacterials in that each member of the class consists of at least 2 structurally unrelated molecules: group A streptogramins (macrolactones) and group B streptogramins (cyclic hexadepsipeptides). Both group A and group B streptogramins inhibit protein synthesis at the ribosomal level, and they act synergistically against many isolates, their combination generating bactericidal activities and reducing the possibility of emergence of resistant strains. The mechanisms of acquired resistance to group B streptogramins are similar to those induced by erythromycin, but group A streptogramins remain unaffected by target modifications and active efflux. The pharmacokinetic parameters of group A and group B streptogramins in blood are quite similar. In addition, both the A and B groups penetrate and accumulate in macrophages and in the bacterial vegetations of experimental endocarditis. There are important structural and biological differences between the streptogramins and the macrolides. The main differentiating features are the rapid anti-bacterial killing of streptogramins and the rarity of cross-resistance between the 2 groups of antibiotics.

Anti-Bacterial Agents↗
PubMed1996

[Specificities of antibacterial activity of zwitterionic 7-methoxyimino cephems (cephalosporins of fourth generation].

Zwitterionic 7-methoxyimino cephalosporins possess a variable substitution at C3 which contains a quaternary nitrogen. These cephalosporins display low affinities for class I beta-lactamase and rapid penetration through the outer membrane of Gram negative bacilli. Hence, they remain active against some, but not all, ceftazidime-resistant Enterobacteriaceae. Antipseudomonas activities are generally similar to that of ceftazidime except that cefelidin is more active. The new zwitterionic compounds express greater antistaphylococcal potency than does ceftazidime. On the basis of structural and antibacterial characteristics the expression "forth generation" is acceptable to describe the wzitterionic 7-methoxyimino cephalosporins.

Cefepime↗
PubMed1995

Laboratory assessment of antibacterial activity of zwitterionic 7-methoxyimino cephalosporins.

Zwitterionic 7-methoxyimino cephalosporins (cefpirome, cefepime, cefclidin, DQ2556, FK037 and SCE2787) possess a variable substitution at C3 which contains a quarternary nitrogen. These cephalosporins display low affinities for Class I beta-lactamase and rapid penetration through the outer membrane of Gram-negative bacilli, so that an increased number of periplasmic beta-lactam molecules interact with PBP's per unit of time. As a consequence, the new zitterionic compounds remain active against some, but not all, ceftazidime-resistant Enterobacteriaceae producing high levels of Class I beta-lactamase or Bush type 2b beta-lactamases. Antipseudomonas activities are generally similar to that of ceftazidime except that cefclidin is more active. The new zwitterionic compounds, especially cefpirome and FK037, express greater antistaphylococcal potency than does ceftazidime. A variety of animal models including meningitis and endocarditis have confirmed the potential of these compounds in-vivo. On the basis of structural and antibacterial characteristics, the expression 'forth generation' is acceptable to describe the zwitterionic 7-methoxyimino cephalosporins.

Cephalosporins↗
PubMed1995

[Effect of the molecular structure of azithromycin on pharmacokinetics and the antimicrobial activity].

Azithromycin possesses in position 9 of the lactone cycle a nitrogen atom which provides a second site of protonation. Hence, and compared to erythromycin, azithromycin is more stable in the gastric environment, enjoys improved digestive absorption and improved digestive toleration, displays much higher intracellular accumulation responsible for prolonged serum and tissue half-lives, which allows simplified therapeutic schedules. It is also postulated that improved activity against Gram negative isolates such as H. influenzae and B. catarrhalis results from the same structural particularities.

Anti-Bacterial Agents↗
PubMed1994

In vitro stepwise selection of resistance to quinolones, beta-lactams and amikacin in nosocomial gram-negative bacilli.

The ability of six antibiotics to produce resistance by stepwise selection on agar medium was assessed in 24 gram-negative rods. Escherichia coli was the strain least prone to selection of resistance, whereas Pseudomonas aeruginosa frequently developed resistance to all antibiotics. When used alone, ciprofloxacin, pefloxacin, amikacin, ceftazidime and cefpirome were associated with a comparable risk of acquired resistance (in 14 to 17 out of 24 strains); imipenem selected resistant strains in 10/24 isolates (5/18 in non-pseudomonas strains). The number of strains exhibiting cross resistance with structurally unrelated antibiotics was 11 after pefloxacin treatment, eight after exposure to ciprofloxacin, six after ceftazidime, and one after imipenem or cefpirome. The combination of ciprofloxacin with amikacin was less efficient in reducing acquisition of resistance than the combination of ciprofloxacin with a beta-lactam: ciprofloxacin plus cefpirome was especially potent in this respect.

Amikacin↗
PubMed1994

Treatment of vascular graft infection by in situ replacement with a rifampin-bonded gelatin-sealed Dacron graft.

PURPOSE: The purpose of this study was to treat an established prosthetic vascular graft infection by in situ replacement with a rifampin-bonded gelatin-sealed Dacron graft in an animal model. METHODS: The infrarenal aorta of 18 dogs was replaced with a gelatin-sealed graft contaminated in vitro by soaking it in a solution with Staphylococcus epidermidis. One week later, animals were randomized into three groups. In group I (control, (n = 6), the dogs did not undergo repeat operations. The dogs in groups II and III underwent repeat operation. In these animals the infected grafts were removed for bacteriologic analysis and replaced in situ with one of two types of grafts: group II (n = 6) received an untreated, gelatin-sealed graft; group III (n = 6) received a rifampin-bonded, gelatin-sealed graft. Antibiotic bonding was obtained by soaking grafts for 15 minutes in a 60 mg/ml saline solution of rifampin at 37 degrees C. All 18 dogs received no systemic adjunct antibiotic therapy. Control grafts and replacement grafts were removed 4 weeks after the initial implantation for bacteriologic analysis. When harvested, all the grafts were cut into two fragments, and quantitative bacterial cultures were obtained from all the fragments. Results were expressed as colony-forming units (CFU)/cm2 of graft material. RESULTS: All 18 initially implanted grafts and all the untreated replacement grafts were grossly infected at the time of removal, whereas all the rifampin-bonded replacement grafts had normal incorporation. None of the rifampin-bonded grafts grew bacteria, whereas all the initially implanted and all the untreated replacement grafts were infected (p < 0.01). Bacterial counts from the infected fragments were similar in control grafts (2.6 +/- 1.9 x 10(6) CFU/cm2), in initially implanted grafts of groups II (9 +/- 1.1 x 10(5) CFU/cm2) and III (1.3 +/- 1.5 x 10(6) CFU/cm2), and in untreated replacement grafts of group II (1.7 +/- 2.5 x 10(6) CFU/cm2). Blood culture results and culture results of liver, spleen, kidney, and lung specimens at the time of sacrifice were negative. CONCLUSION: This study demonstrates that rifampin-bonded gelatin-sealed Dacron grafts are resistant to infection when used for in situ replacement of an infected graft in the dog.

Animals↗
PubMed1994

Evaluation of the efficacy of prolonged administration of azithromycin in a murine model of chronic toxoplasmosis.

The efficacy of prolonged administration of azithromycin was evaluated in a murine model of lethal chronic toxoplasmosis. Mice were challenged intraperitoneally with cysts of a moderately virulent strain of Toxoplasma gondii, observed for 4 weeks and then allocated to the treatment or control group. All 26 animals given azithromycin 100 mg/kg/day for 100 days were protected compared with 19 of 25 control animals which died (P < 0.001). Nineteen of the 20 mice in the treatment group survived for an additional month while receiving the same azithromycin regimen but viable cysts were identified in the brain tissue of these animals when they were killed. Although there was no significant difference between the groups in terms of the number of cysts in the brain, the administration of azithromycin was associated with a reduction in brain inflammation. The concentrations of azithromycin in the brains of five animals ranged from 0.7 to 2.3 micrograms/g; there was no evidence of accumulation even after 100 doses. Azithromycin merits further evaluation as primary or secondary prophylaxis against toxoplasma encephalitis in individuals at risk of developing this complication.

Animals↗
PubMed1994

Activity of epiroprim (Ro 11-8958), a dihydrofolate reductase inhibitor, alone and in combination with dapsone against Toxoplasma gondii.

We examined the effect of epiroprim (Ro 11-8958), a dihydrofolate reductase inhibitor, alone and in combination with dapsone, against Toxoplasma gondii. In vitro, the anti-T. gondii effects of epiroprim and dapsone were observed at nanogram-per-milliliter levels when a 72-h uracil assay and an infection rate of one parasite per 120 macrophages were used. In combination, these drugs exerted a synergistic effect that, however, was only parasitostatic. In a model of acute infection, mice were infected intraperitoneally with 10(4) parasites of the RH strain of T. gondii and were treated for 14 days by gavage (therapy divided into two daily dosages), starting 24 h after infection. Used alone, dapsone and epiroprim, each at a dose of 50 mg/kg of body weight per day, protected 10 and 0% of the mice, respectively. When these drugs were administered simultaneously, a 100% survival rate was observed. Pyrimethamine-sulfadiazine (4 and 250 mg/kg/day, respectively) protected 100% of the mice. A 3-week therapy of chronically infected mice with either epiroprim (50 mg/kg/day), dapsone (50 mg/kg/day), or pyrimethamine (15 mg/kg/day) reduced the numbers of T. gondii cysts and the inflammation in their brains. A combination of epiroprim and dapsone, both at 50 mg/kg/day, further reduced the number of brain cysts in comparison with the number after the corresponding monotherapies. Epiroprim may have a role in the prophylaxis or therapy of human toxoplasmosis, especially when combined with other drugs active against T. gondii, such as dapsone.

Animals↗