Biomedical subjects

E Azoulay-Dupuis

Publications and source records attributed to E Azoulay-Dupuis.

At least 37 records · Page 2Linked to original sources

PubMed1994

In vivo efficacy of a broad-spectrum cephalosporin, ceftriaxone, against penicillin-susceptible and -resistant strains of Streptococcus pneumoniae in a mouse pneumonia model.

The increasing emergence of penicillin-resistant (Pr) strains of Streptococcus pneumoniae could pose a therapeutic problem in the next few years. Ceftriaxone (CRO), a broad-spectrum cephalosporin, exhibits a smaller increase in MICs against Pr S. pneumoniae strains than amoxicillin (AMO) (usually referred as to the "gold standard" therapy for pneumococcal infections). Therefore, we compared their respective efficacies in a leukopenic Swiss mouse model of pneumococcal pneumonia. Infection was induced with two serotype 19 strains: a penicillin-susceptible (Ps) strain (MICs of < 0.01 for penicillin, 0.03 for AMO, and 0.03 for CRO) and a Pr strain (MICs of 4 for penicillin, 2 for AMO, and 0.5 for CRO). Untreated mice died within 2 or 3 days. Against the Ps strain, the minimal protective dose (two subcutaneous injections at 12-h intervals for 3 days) for both CRO and AMO was 5 mg/kg of body weight (87% survivors). Ten-fold-increased doses of CRO (50 mg/kg) gave similar protection (75% survivors) against the Pr strain, whereas 20- and 40-fold-increased doses of AMO protected 0 and 34% of the animals, respectively, against the Ps strain. CRO had a marked and prolonged antibacterial effect in the lungs (2.7-log-unit reduction of CFU in 24 h after a single 50-mg/kg injection) against the Pr strain in comparison with AMO. A standard dosage of 50 mg of CRO per kg in mice resulted in peak levels in serum and protein binding comparable to those observed with 1 g given intravenously in humans. This dosage remained effective against a highly Pr S. pneumoniae strain in this model. The microbiological activity and pharmacodynamic and pharmacokinetic properties of CRO (time during which concentrations exceed the MIC for the test pathogen [delta t MIC], > or less than 8 h; and peak/MIC ratio, >90 for free active drug) accounted for its efficacy relative to AMO (50 mg/kg: delta t MIC, <2; peak/MIC ratio, <25) against the highly Pr S. pneumoniae strain used in this study.

Amoxicillin↗

PubMed1993

Correlation between macrolide lung pharmacokinetics and therapeutic efficacy in a mouse model of pneumococcal pneumonia.

The correlation between the pharmacokinetics of erythromycin, roxithromycin, clarithromycin, spiramycin and azithromycin and their efficacy was investigated in two pneumococcal pneumonia models. Female Swiss and C57B1/6 mice were infected with Streptococcus pneumoniae strain P4241 by the intratracheal per oral route. This virulent strain produces acute pneumonia with death within 3-4 days (Swiss mice), or subacute pneumonia with death within 10 days (C57B1/6 mice) in untreated mice and the outcome of the disease is closely related to progressive weight loss. Swiss mice received three doses of each macrolide 50 mg/kg bd beginning 18 h post-infection. C57B1/6 mice received three doses of each macrolide 25 mg/kg, bd (except azithromycin was 12.5 mg/kg bd) beginning 48 h post-infection. Cure rates were evaluated on the basis of body weight variations recorded daily after the end of treatment. Pharmacokinetic parameters were determined in infected and non-infected mice after a single dose of each macrolide 50 mg/kg sc. The pharmacokinetics of azithromycin was also determined in leucopenic Swiss mice. We observed a hierarchy of in-vivo efficacy as follows: azithromycin > spiramycin = clarithromycin > roxithromycin = erythromycin which did not correlate with in-vitro MIC or MBC. The same hierarchy was found in terms of the lung T1/2. Lung T1/2s of macrolides could thus be predictive of their efficacy in respiratory tract infections. A reduced tissue AUC of azithromycin was seen in leucopenic mice suggesting leucocytes may help transport macrolides to sites of infection.

Animals↗

PubMed1992

Individual efficacy of clarithromycin (A-56268) and its major human metabolite 14-hydroxy clarithromycin (A-62671) in experimental pneumococcal pneumonia in the mouse.

In man, clarithromycin (A-56268) is metabolized to a 14-hydroxy derivative (14-OH clarithromycin, A-62671); this metabolite is absent in mice. An experimental mouse model was used to compare the efficacy of clarithromycin versus 14-OH clarithromycin in pneumococcal pneumonia by treatment with either the parent drug or its 14-OH metabolite alone. Four groups of 15 mice were infected intra-tracheally with a virulent strain of Streptococcus pneumoniae serotype 3 (approximately 10(5) cfu/mouse). Treatment was begun 18 h post infection, with clarithromycin or erythromycin 50 mg/kg subcutaneously (sc) bd, 14-OH clarithromycin 25 mg/kg sc bd or antibiotic free saline sc bd for 24 or 48 h. Survival rates ten days after one day of treatment with clarithromycin, 14-OH clarithromycin, erythromycin, or saline were 53%, 60%, 27% and 0% respectively. After two days treatment the rates were 100%, 100%, 53% (P less than 0.01) and 0% respectively. Thirty-six h after two doses, 14-OH clarithromycin demonstrated superior intra-pulmonary killing activity to erythromycin (2.7 +/- 0.4 vs 6.6 +/- 0.8 log10 cfu/mL lung homogenate) (P less than 0.001) and comparable activity to clarithromycin (3.6 +/- 1.3 log10 cfu/mL). These results show that clarithromycin (50 mg/kg sc) and 14-OH clarithromycin (25 mg/kg sc) have similar in vivo efficacy in a mouse model, in which the 14-OH metabolite is not produced from clarithromycin. This suggests that in man, the clinical efficacy of clarithromycin is not impaired by metabolism to 14-OH clarithromycin, which achieves serum concentrations in man of approximately 1 mg/L after multiple doses of clarithromycin 500 mg po.

Animals↗

PubMed1992

In vivo efficacy of a new fluoroquinolone, sparfloxacin, against penicillin-susceptible and -resistant and multiresistant strains of Streptococcus pneumoniae in a mouse model of pneumonia.

The increasing emergence of penicillin-resistant and multiresistant strains of Streptococcus pneumoniae may pose a problem in coming years. We therefore compared sparfloxacin, a new fluoroquinolone with improved potency against streptococci, with amoxicillin, the "gold standard" in this setting, and another fluoroquinolone, ciprofloxacin, in a mouse pneumonia model. Their efficacies against penicillin-susceptible (serotype 3), macrolide-resistant (serotype 1), penicillin-resistant (serotype 23), and multiresistant (serotype 6) S. pneumoniae strains were evaluated. Immunocompetent Swiss mice (serotypes 1 and 3) and leukopenic mice (serotypes 6 and 23) were infected by peroral tracheal delivery of 10(4) to 10(6) CFU. Subcutaneous injections of antibiotics were initiated at 6, 18, 48, or 72 h after infection (six injections at 12-h intervals). In the immunocompetent mice, 100% survival was obtained with sparfloxacin (50 mg/kg) and amoxicillin (5 mg/kg) against both penicillin-susceptible and macrolide-resistant strains; ciprofloxacin gave significantly lower survival rates. Two to four injections of sparfloxacin completely cleared bacteria from lungs and blood; the most rapid eradication was achieved with amoxicillin. Sparfloxacin also fully protected leukopenic mice against penicillin-resistant strains. The dose of amoxicillin (50 mg/kg) required to protect mice and eradicate penicillin-resistant and multiresistant strains was 10 times higher than that effective against penicillin-susceptible strains. The microbiological and pharmacokinetic properties of sparfloxacin (e.g., the time during which concentrations exceed the MIC of the test pathogen) accounted for its efficacy against susceptible and resistant strains of S. pneumoniae in this model.

Animals↗

PubMed1992

Activity and local delivery of azithromycin in a mouse model of Haemophilus influenzae lung infection.

We compared the activities of azithromycin and erythromycin against Haemophilus influenzae in a mouse model of nonparenchymatous lower respiratory tract infection. In vitro and in vivo efficacy data for both drugs were analyzed relative to their pharmacokinetics in lungs and in vivo uptake by phagocytes. Aged C57BL/6 mice (mean age, 15.1 +/- 1.9 months) were infected intratracheally with 10(8) CFU of H. influenzae serotype b. Oral drug administration was initiated 4 h after infection by various dosage regimens. In terms of bacterial killing in the lung, azithromycin was much more active than erythromycin (P less than 0.01). Its in vivo activity was also more durable after a single administration relative to the durability of three doses of erythromycin given at 6-h intervals. The MIC of azithromycin was eightfold lower than that of erythromycin, and better penetration and a longer half-life in lung tissue were achieved after a single oral administration. Phagocytes delivered increased amounts of both drugs to the infected lungs, particularly at the site of infection (bronchoalveolar airspaces), and detectable levels of azithromycin were maintained locally for long periods. The fact that the efficacy of azithromycin coincided with the arrival of large numbers of polymorphonuclear leukocytes within the airspaces suggests that active extracellular concentrations were provided by the release of azithromycin from these cells. This further supports the potential value of once-daily azithromycin regimens for the treatment of lower respiratory tract infections in humans, provided that inhibitory concentrations against common pathogens such as H. influenzae are maintained for adequate periods of time.

Administration, Oral↗

PubMed1992

Kinetic disposition of temafloxacin and ciprofloxacin in a murine model of pneumococcal pneumonia. Relevance for drug efficacy.

The authors studied whether pharmacokinetic parameters could explain differences in the in vivo antipneumococcal activity of temafloxacin and ciprofloxacin in a mouse model of pneumonia. The effects of infection on the disposition and clearance mechanisms of the two drugs were evaluated after a single administration (100 mg/kg s.c.) relative to noninfected controls. Effective drug concentrations and possible drug inactivation at sites of infection were assessed using both microbiological (active drug levels) and high-performance liquid chromatography (total drug levels) procedures and by recording bacterial clearance in blood and lung homogenates. Pulmonary bacterial clearance was correlated more closely to concentrations in serum than to those in lung homogenates, probably because they better reflect interstitial fluid concentrations. Neither the serum and lung concentrations nor the clearance of ciprofloxacin were modified greatly by infection. Ciprofloxacin was not inactivated at sites of infection. Temafloxacin exhibited higher serum concentrations and tissue penetration than ciprofloxacin. The differences between the two drugs in noninfected controls were accentuated, with apparent retention of temafloxacin in infected mice resulting in more persistent activity in lung and serum. The renal failure observed in infected mice did not apparently account for the reduction in the total clearance of temafloxacin, suggesting its probable trapping at sites of infection. The observation that serum (and tissue) concentrations of temafloxacin exceeded the minimal inhibitory concentration of the test organism over the whole dosing interval (12 hr), could account for its efficacy in severe pneumococcal disease.

Animals↗

PubMed1991

Antipneumococcal activity of ciprofloxacin, ofloxacin, and temafloxacin in an experimental mouse pneumonia model at various stages of the disease.

The efficacy of temafloxacin against Streptococcus pneumoniae in an experimental murine pneumonia model was compared with that of ofloxacin and ciprofloxacin. Erythromycin and amoxicillin were used as reference agents. Subcutaneous administration of antibiotics every 12 h for 3 days was initiated at various times after infection. The cumulative survival rates of mice treated with temafloxacin at 50 mg/kg were 100%, 92%, 81%, and 50% with treatment beginning 18, 48, 72, and 96 h after infection, respectively. The activity of temafloxacin at 50 mg/kg was not significantly different from that of erythromycin and amoxicillin but was superior to that of ofloxacin and ciprofloxacin. The maximum cumulative survival rates of mice treated with ofloxacin and ciprofloxacin at 100 mg/kg were 67% and 50%, respectively, with treatment beginning 18 h after infection. Treatment with ofloxacin and ciprofloxacin at 50 mg/kg 18 h after infection did not significantly increase survival rates compared with those of untreated controls.

Amoxicillin↗

PubMed1991

Individual and combined activities of clarithromycin and its 14-hydroxy metabolite in a murine model of Haemophilus influenzae infection.

Clarithromycin is metabolised in man mainly to the 14-hydroxy derivative, which is also biologically active. As this metabolite is not produced in rodents, we used a murine model of Haemophilus influenzae pulmonary infection to compare the in-vivo activity of clarithromycin and 14-hydroxy clarithromycin, alone and in combination, and erythromycin. In terms of bacterial killing, clarithromycin's 14-hydroxy metabolite was much more active than clarithromycin and erythromycin at doses of 100 mg/kg. For the combination tests, low doses of 14-hydroxy clarithromycin (12, 16 and 24 mg/kg) were ineffective alone but potentiated the bactericidal activity of clarithromycin (100 mg/kg) (P less than 0.01-0.001). The in-vivo results can be explained by in-vitro and pharmacokinetic data: the MIC and MBC of 14-hydroxy clarithromycin are half those of clarithromycin and erythromycin, while the combination of clarithromycin and its metabolite was synergistic in terms of bacteriostatic and bactericidal activities. Potentially useful levels of 14-hydroxy clarithromycin were found after oral administration of low doses, with a prolonged half-life compared with that of the parent compound. On the basis of these results it appears that the 14-hydroxy metabolite may have an important role to play in the treatment of bronchopulmonary infections in man due to H. influenzae.

Administration, Cutaneous↗

PubMed1991

Pharmacokinetics of four fluoroquinolones in an animal model of infected lung.

We studied the pharmacokinetic parameters of four fluoroquinolones--ofloxacin, ciprofloxacin, temafloxacin and sparfloxacin--in a mouse model of Streptococcus pneumoniae-infected lung. After a single subcutaneous injection, bioactivities were determined concomitantly in non-infected and infected animals, at a time at which pneumonia was well developed. Fluoroquinolones exhibited generally good activity at the site of infection. Infection did not affect the tissue distribution of either drug. However, the differences observed in non-infected controls (greater AUCs and longer half-lives of temafloxacin and sparfloxacin in lung and serum) were accentuated in infected mice, with probable trapping of temafloxacin and sparfloxacin at the site of infection and more persistent activity in the lung. These data suggest that the anti-pneumococcal activity of temafloxacin, and to a lesser extent sparfloxacin, were greatly favoured by their pharmacokinetic behaviour in the infected lung.

Animals↗

PubMed1991

Comparative activity of fluorinated quinolones in acute and subacute Streptococcus pneumoniae pneumonia models: efficacy of temafloxacin.

We have compared the efficacy of temafloxacin against Streptococcus pneumoniae in experimental murine pneumonia models with that of ofloxacin and ciprofloxacin. Erythromycin and amoxycillin were used as reference agents. Two different strains of mice were used: Swiss mice develop acute pneumonia and die within three to four days, while C57B1/6 mice develop subacute pneumonia and die within eight to ten days. In both cases all animals quickly become bacteraemic. Mice were infected with approximately 10(5) cfu of a virulent S. pneumoniae strain, serotype 3 (P4241), by the intra-tracheal per oral route. In Swiss mice, subcutaneous treatments were initiated early (18 h post-infection) and given every 12 h for 72 h. A 79% cumulative survival rate was obtained in temafloxacin-treated mice (50 mg/kg); a figure not significantly different from those for erythromycin and amoxycillin but far higher than those for ofloxacin and ciprofloxacin (7% survivors). Pulmonary clearance of bacteria was consistent with the survival rates. Complete clearance of bacteria in the lungs and blood was achieved using temafloxacin (50 mg/kg), whereas mice remained bacteraemic even with increased dosages of ofloxacin and ciprofloxacin. In the subacute pneumonia C57B1/6-mice model, the superior efficacy of temafloxacin (compared to ofloxacin and ciprofloxacin) was also seen even when treatment was initiated at late stages of the disease (up to 96 h post-infection). The pharmacokinetics of temafloxacin account for its better efficacy against S. pneumoniae pneumonia relative to the other quinolones.

Acute Disease↗

PubMed1991

Prophylactic and therapeutic activities of azithromycin in a mouse model of pneumococcal pneumonia.

Azithromycin is a new acid-stable 15-membered-ring macrolide that exhibits an extended half-life and excellent tissue distribution, including distribution in the lung. We compared its in vivo activity with that of erythromycin using two models of Streptococcus pneumoniae pneumonia, namely, a model of acute infection in Swiss mice and a model of subacute infection in C57BL/6j mice. Female mice were infected by oral delivery into the trachea of 10(5) CFU of a virulent serotype 3 strain of S. pneumoniae (P 4241). Prophylactic and therapeutic treatments were given orally (p.o.) or subcutaneously (s.c.) by various regimens. In the model of subacute infection, a single dose of azithromycin, 25 mg/kg, given p.o. 7 h before infection protected 92% of the mice, while erythromycin was completely ineffective. In the model of acute infection, a single dose of azithromycin, 50 mg/kg, given s.c. 24 h prior to challenge protected 80% of the mice, whereas only 35% of the mice survived with erythromycin, 50 mg/kg, 1 h before challenge. Therapy, which was studied exclusively in the model of subacute infection, was initiated 48 h postinfection. Two doses of 12.5 mg/kg given p.o. 12 h apart resulted in 80% survival of mice treated with azithromycin versus 7% survival of mice treated with erythromycin. Pulmonary clearance of bacteria was consistent with the survival rates. Two doses (25 mg/kg) of azithromycin given s.c. at 48 and 65 h after infection led to complete clearance of bacteria from the lungs and blood, whereas erythromycin-treated mice remained bacteremic. The pharmacokinetics of azithromycin account for its superior efficacy against S. pneumoniae pneumonia relative to the efficacy of erythromycin.

Animals↗

PubMed1988

Protective effect of beta-naphthoflavone against NO2 toxicity in mice with genetically inducible lung cytochrome P450.

The effects of the cytochrome P450 inducer beta-naphthoflavone (BNF) on NO2 toxicity were studied in two strains of mice. In one strain (C57B1/6J), cytochrome P450 could be induced by the aromatic hydrocarbon, while in the other strain (DBA/2J) cytochrome P450 was not inducible by this compound. Mice were treated with BNF before and during 4 days of exposure to 20 ppm NO2. The body growth of NO2-exposed mice improved only in BNF-treated C57B1/6J mice. In this strain, BNF reduced both pulmonary edema (as measured by wet and dry lung weights or as assessed by histological studies) and lung peroxidation (as measured by malondialdehyde). This protective effect of BNF on NO2 toxicity in C57B1/6J mice was associated with an increase in the components of the cytochrome P450 system (cytochrome P450 and cytochrome b5), whereas the activities of pulmonary antioxidant enzymes (superoxide dismutase, glutathione peroxidase, and glutathione reductase) were not significantly increased. These data suggest that the induction of the cytochrome P450 system may be important in promoting NO2 tolerance in those strains of mice in which the cytochrome P450 system is genetically inducible.

Animals↗

PubMed1988

Genetic differences in response to pulmonary cytochrome P-450 inducers and oxygen toxicity.

The effects of cytochrome P-450 inducers on O2 toxicity were studied in mice. We first examined three cytochrome P-450 inducers, which differ by their specific tissue affinity: phenobarbital sodium (PB), essentially active in the liver, and 3-methylcholanthrene (3-MC) and beta-naphthoflavone (BNF), which are also active in the lung. Both BNF and 3-MC increased the survival rate and significantly decreased pulmonary edema (pulmonary water and wet-to-dry weight ratio) in C57BL/6J mice exposed to hyperoxia (O2 greater than or equal to 95%), whereas PB had no protective effect. In the second part of this study, we compared the action of BNF in two strains of mice. In one (C57BL/6J), cytochrome P-450 can be induced by aromatic hydrocarbons, whereas in the other (DBA/2J) cytochrome P-450 is not inducible by these compounds. Protection against O2 toxicity was assessed in terms of lethality and pulmonary edema and of lung lipid peroxidation (assessed by measuring malondialdehyde). BNF only protected against O2 toxicity in the inducible strain. This protective effect of BNF on O2 toxicity in C57BL/6J mice was associated mainly with a large increase in the components of the cytochrome P-450 system (cytochrome P-450 and cytochrome b5) in the lung. The activity of pulmonary superoxide dismutase was also slightly increased, but the enhancement was not statistically significant. In contrast, in DBA/2J mice neither the components of the cytochrome P-450 system nor the activity of superoxide dismutase showed any increase.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1987

In vivo nitrogen dioxide exposure depresses spleen cell in vitro mitogenic responses: effects of sulfur compounds.

The in vivo mitogenic responses to lipopolysaccharide or concanavalin A by spleen cells of mice exposed to 20 ppm nitrogen dioxide (NO2) for 96 hr, were evaluated. [3H]Thymidine incorporation after addition of either mitogen, was significantly lower in spleen cells from acutely NO2-exposed mice (NO2 SC) than from control mice, although cell viability was not affected. T- and B-cell mitogenic responses were inhibited to the same extent by NO2 exposure. NO2 SC responses were protected by the thiol compounds 2-mercaptoethanol, L-cysteine, and selenomethionine. No restoration of mitogenic response was observed after treatment with reduced glutathione. Mechanisms accounting for this in vivo NO2 immune toxicity, are discussed in terms of oxidative injury.

Animals↗

PubMed1987

Evidence for humoral immunodepression in NO2-exposed mice: influence of food restriction and stress.

The effects of food restriction or 20 ppm NO2 exposure on humoral immunity were investigated in normal and adrenalectomized C57Bl/6 mice. The thymic and splenic weights of sham-operated mice were similarly diminished after 4 days of NO2 exposure or 4 days of food depletion. The responses of corresponding adrenalectomized mice were less depressed. Undernutrition induced lymphoid organ involution and corticosteroids were partly involved. Plaque-forming cells (PFC) per spleen and per 10(6) cells were markedly depressed after 4 days of NO2 exposure, but less so after food deprivation. The same significant suppression of PFC was observed in adrenalectomized groups. Depression of humoral immunity was independent of stress-induced endogenous steroids. Moreover, NO2 had a specific effect on humoral immunodepression, food restriction being an associated factor.

Animals↗

PubMed1986

Impaired acquired resistance of mice to Klebsiella pneumoniae infection induced by acute NO2 exposure.

The natural resistance of nonimmunized C57Bl/6 mice to an intraperitoneal Klebsiella pneumoniae challenge was not significantly affected by prior continuous exposure to 20 ppm NO2 for 4 days. In contrast, the acquired resistance of mice immunized just before and infected just after NO2 exposure was seriously impaired. This could not be explained by the loss of appetite (about 30%) observed in NO2 treated mice, for neither the natural nor acquired resistance of control air exposed mice given approximately 70% ad libitum food and water were significantly modified.

Animals↗

PubMed1985

Humoral immunodepression following acute NO2 exposure in normal and adrenalectomized mice.

The effects following 20 ppm NO2 exposure on humoral immunity were investigated in C57Bl/6 mice after 48, 72, and 96 h exposure. Both spleen plaque-forming cell (PFC) responses and serum hemagglutinins (HA) using sheep red blood cells (SRBC) as antigen were studied. Splenic and thymic weight and cellularity decreased on acute exposure to NO2. PFC were markedly depressed after 48 h exposure and continued to decrease as exposure time was lengthened. HA titers were also depressed. The same significant suppression of PFC and HA titers was observed in adrenalectomized mice after 96 h NO2 exposure. The depression of humoral immunity in NO2-exposed mice was independent of stress-induced endogenous steroids.

Adrenal Glands↗

PubMed1984

Lung alterations in guinea-pigs infected with influenza virus.

Guinea-pigs were infected intranasally with influenza A Hong Kong 68 (H3N2) virus. Infective particles were re-isolated from lung homogenates up to 3 days after inoculation and indicated local replication. The subsequent lung inflammatory stages were studied by light microscopy, scanning and transmission electron microscopy (TEM). Lung alterations appeared after 24 h and intensified up to 7 days after virus inoculation, progressively decreasing until 3 weeks thereafter. The damage was reversible and complete restoration of structure was obtained within 5 weeks. The lesions commenced with the infiltration of bronchiolar and alveolar walls by polymorphonuclear cells, histiocytes and macrophages. A purulent exudate was seen to occupy the bronchiolar lumen. Cilia disappeared from tracheal and bronchiolar epithelia. Tracheal epithelium desquamated in some animals. TEM examination showed deterioration in type I pneumocytes, an increase in type II pneumocytes and concomitant damage to alveolar capillaries. Alveolar oedema and fibrinous deposits were seen. The pleura presented slight modifications. These results show that infection of guinea-pigs with influenza virus is a useful model for the study of lung pathology associated with a non-lethal respiratory viral infection.

Animals↗