scholarly journals Efficacy of Cethromycin, a New Ketolide, against Streptococcus pneumoniae Susceptible or Resistant to Erythromycin in a Murine Pneumonia Model

2006 ◽  
Vol 50 (9) ◽  
pp. 3033-3038 ◽  
Author(s):  
E. Azoulay-Dupuis ◽  
J. Mohler ◽  
J. P. Bédos ◽  
C. Barau ◽  
B. Fantin
Keyword(s):  
Streptococcus Pneumoniae ◽  
Survival Rates ◽  
Administration Route ◽  
Serum Protein Binding ◽  
In Vitro Activity ◽  
Serotype 1 ◽  
Resistant Strains ◽  
Immunocompetent Mice

ABSTRACT Cethromycin is a ketolide with in vitro activity against macrolide-sensitive and -resistant strains of Streptococcus pneumoniae. We compared its in vivo efficacy to erythromycin in a mouse model of acute pneumonia induced by two virulent clinical strains: a serotype 3 susceptible strain (P-4241) (MICs: erythromycin, 0.03 μg/ml; cethromycin, 0.015 μg/ml) and a serotype 1 strain resistant to erythromycin (P-6254; phenotypically MLSB constitutive) (MICs: erythromycin, 1,024 μg/ml; cethromycin, 0.03 μg/ml). Immunocompetent mice were infected with 105 CFU of each strain. Six treatments given either subcutaneously (s.c.) or per os (p.o.) at 12-h intervals were initiated at 6 or 12 h after infection. Against P-4241, cethromycin given s.c. at 25 or 12.5 mg/kg protected 100% of the animals, with lungs and blood completely cleared of bacteria. Given p.o., cethromycin maintained its efficacy with 100 and 86% survival at 25 and 12.5 mg/kg, respectively. Erythromycin, given s.c. at 50 or 37.5 mg/kg, provided 50 and 38% survival rates, respectively. Against P-6254, cethromycin was effective at 25 mg/kg (100% survival) regardless of the administration route, whereas only 25 and 8% of animals survived after a 75-mg/kg erythromycin treatment given s.c. and p.o., respectively. The serum protein binding levels of cethromycin were 94.8 and 88.5% after doses of 12.5 and 25 mg/kg, respectively. The higher in vivo activity of cethromycin compared to erythromycin could be explained by favorable pharmacokinetic/pharmacodynamic indexes against P-6254 but not against P-4241.

scholarly journals Efficacy of BB-83698, a Novel Peptide Deformylase Inhibitor, in a Mouse Model of Pneumococcal Pneumonia

2004 ◽  
Vol 48 (1) ◽  
pp. 80-85 ◽  
Author(s):  
E. Azoulay-Dupuis ◽  
J. Mohler ◽  
J. P. Bédos
Keyword(s):  
Mouse Model ◽  
Lung Tissue ◽  
Resistant Strain ◽  
Peptide Deformylase ◽  
In Vitro Activity ◽  
Wild Type ◽  
Virulent Strains ◽  
Resistant Strains

ABSTRACT The efficacy of BB-83698, a novel potent peptide deformylase inhibitor, was evaluated in a mouse model of acute pneumonia. The Streptococcus pneumoniae isolates tested included four virulent strains (one penicillin-susceptible wild-type strain, one macrolide-resistant strain, and two quinolone-resistant mutants [a mutant carrying mutations in ParC and GyrA and an efflux mutant] isogenic to the wild type) and two poorly virulent penicillin-resistant strains. Pneumonia was induced by intratracheal inoculation of 105 CFU (virulent strains) into immunocompetent mice or 107 CFU (less virulent strains) into leukopenic mice. Animals received three or six subcutaneous injections of antibiotics at 12- or 24-h intervals, with antibiotic treatment initiated at 3, 6, 12, or 18 h postinfection (p.i.). BB-83698 showed potent in vitro activity against all strains (MICs, 0.06 to 0.25 μg/ml). In the in vivo model, all control animals died within 2 to 5 days of infection. BB-83698 (80 mg/kg of body weight twice daily or 160 mg/kg once daily) protected 70 to 100% of the animals, as measured 10 days p.i., regardless of the preexisting resistance mechanisms. In contrast, the survival rates for animals treated with the comparator antibiotics were 30% for animals treated with erythromycin (100 mg/kg) and infected with the macrolide-resistant strain, 34% for animals treated with amoxicillin (200 mg/kg every 8 h) and infected with the penicillin-resistant strain, and 0 and 78% for animals treated with ciprofloxacin (250 mg/kg) and infected with the ParC and GyrA mutant and the efflux mutant, respectively. At 80 mg/kg, BB-83698 generated a peak concentration in lung tissue of 61.9 μg/ml within 1 h and areas under the concentration-times curves of 57.4 and 229.4 μg · h/ml for plasma and lung tissue, respectively. The emergence of S. pneumoniae isolates with reduced susceptibilities to BB-83698 was not observed following treatment with a suboptimal dosing regimen. In conclusion, the potent in vitro activity of BB-83698 against S. pneumoniae, including resistant strains, translates into good in vivo efficacy in a mouse pneumonia model.

scholarly journals In Vitro Activity of Sanfetrinem and Affinity for the Penicillin-Binding Proteins of Streptococcus pneumoniae

1998 ◽  
Vol 42 (1) ◽  
pp. 173-175 ◽  
Author(s):  
Farid Sifaoui ◽  
Emmanuelle Varon ◽  
Marie-Dominique Kitzis ◽  
Laurent Gutmann
Keyword(s):  
Streptococcus Pneumoniae ◽  
Binding Proteins ◽  
Susceptible Strain ◽  
Vitro Activity ◽  
In Vitro Activity ◽  
Penicillin Binding Proteins ◽  
Resistant Strains

ABSTRACT Against penicillin-susceptible pneumococci, the activity of sanfetrinem was similar to those of penicillin, amoxicillin, cefotaxime, imipenem, and meropenem, while against penicillin-resistant strains, sanfetrinem and the carbapenems exhibited superior activity (MICs at which 90% of strains are inhibited, ≤1 μg/ml). PBP 1a in the penicillin-susceptible strain and PBP 1a and PBP 2b in the more resistant isolates seemed to be the essential penicillin-binding proteins for imipenem and sanfetrinem.

scholarly journals Efficacy of Trovafloxacin against Penicillin-Susceptible and Multiresistant Strains of Streptococcus pneumoniae in a Mouse Pneumonia Model

1998 ◽  
Vol 42 (4) ◽  
pp. 862-867 ◽  
Author(s):  
Jean-Pierre Bédos ◽  
Véronique Rieux ◽  
Jacqueline Bauchet ◽  
Martine Muffat-Joly ◽  
Claude Carbon ◽  
...  
Keyword(s):  
Streptococcus Pneumoniae ◽  
Resistant Strain ◽  
Survival Rates ◽  
Multidrug Resistant ◽  
Pharmacokinetic Parameters ◽  
Beta Lactam ◽  
Time Curve ◽  
Swiss Mice ◽  
Resistant Strains

ABSTRACT The increasing emergence of penicillin-resistant and multidrug-resistant strains of Streptococcus pneumoniaewill create a serious therapeutic problem in coming years. Trovafloxacin is a novel naphthyridone quinolone with promising activity against S. pneumoniae, including penicillin-resistant strains (MIC for 90% of the isolates tested, 0.25 μg/ml). We compared its in vivo efficacy with that of other fluoroquinolones (ciprofloxacin, temafloxacin, and sparfloxacin) and a reference beta-lactam (amoxicillin) in a model of acute experimental pneumonia. Immunocompetent Swiss mice were infected by peroral tracheal delivery of a virulent, penicillin-susceptible strain (MIC, 0.03 μg/ml); leukopenic Swiss mice were infected with three poorly virulent, penicillin-resistant strains (MICs, 4 to 8 μg/ml) and a ciprofloxacin-resistant strain (MIC, 32 μg/ml). Treatments were started 6 h (immunocompetent mice) or 3 h (leukopenic mice) after infection. Doses ranging from 12.5 to 300 mg/kg were given at 12- or 8-h intervals for 3 days. Trovafloxacin (25 mg/kg) was the most effective agent in vivo against penicillin-susceptible and -resistant strains. Corresponding survival rates were 2- to 4-fold higher than with 50-mg/kg sparfloxacin or temafloxacin and 8- to 16-fold higher than with 100-mg/kg ciprofloxacin. The ratios of the area under the concentration-time curve to the MIC in serum and lung tissue were more favorable with trovafloxacin than with the other quinolones. Efficacy in vivo correlated with pharmacokinetic parameters. Trovafloxacin shows potential for the treatment of infections due to penicillin-susceptible and -resistant S. pneumoniae but appears to be ineffective against a ciprofloxacin-resistant strain.

scholarly journals In vitro activity of BAY 12-8039, a novel 8-methoxyquinolone, compared to activities of six fluoroquinolones against Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis.

1997 ◽  
Vol 41 (7) ◽  
pp. 1594-1597 ◽  
Author(s):  
A B Brueggemann ◽  
K C Kugler ◽  
G V Doern
Keyword(s):  
Streptococcus Pneumoniae ◽  
Haemophilus Influenzae ◽  
Moraxella Catarrhalis ◽  
Ambient Air ◽  
Vitro Activity ◽  
In Vitro Activity ◽  
Broth Microdilution ◽  
Agar Dilution ◽  
Resistant Strains

The in vitro activity of a novel 8-methoxyquinolone, BAY 12-8039, against recent clinical isolates of Streptococcus pneumoniae (n = 404), Haemophilus influenzae (n = 330), and Moraxella catarrhalis (n = 250) was evaluated. Activity was compared to those of six other fluoroquinolones: ciprofloxacin, clinafloxacin, levofloxacin, ofloxacin, sparfloxacin and trovafloxacin. BAY 12-8039 and clinafloxacin had the highest levels of activity against S. pneumoniae, both with a MIC at which 90% of the isolates were inhibited (MIC90) of 0.06 microg/ml. Trovafloxacin and sparfloxacin were the next most active agents versus S. pneumoniae (MIC90s = 0.12 microg/ml). No differences in activity against penicillin-susceptible, -intermediate, or -resistant strains of S. pneumoniae were noted for any of the fluoroquinolones tested. MIC90s for the seven fluoroquinolones ranged from 0.008 to 0.06 microg/ml versus H. influenzae and from 0.008 to 0.12 microg/ml for M. catarrhalis. The MICs for two strains of S. pneumoniae and one strain of H. influenzae were noted to be higher than those for the general population of organisms for all of the fluoroquinolones tested. Finally, the activity of BAY 12-8039 versus S. pneumoniae was found to be diminished when MIC determinations were performed with incubation of agar dilution plates or broth microdilution trays in 5 to 7% CO2 versus ambient air.

scholarly journals In Vitro Activities of the New Ketolide Antibiotics HMR 3004 and HMR 3647 against Streptococcus pneumoniae in Germany

1998 ◽  
Vol 42 (6) ◽  
pp. 1509-1511 ◽  
Author(s):  
Ralf René Reinert ◽  
André Bryskier ◽  
Rudolf Lütticken
Keyword(s):  
Streptococcus Pneumoniae ◽  
Vitro Activity ◽  
In Vitro Activity ◽  
Dilution Technique ◽  
Excellent Activity ◽  
Resistance To Penicillin ◽  
Agar Dilution ◽  
Resistant Strains

ABSTRACT The comparative in vitro activity of HMR 3004 and HMR 3647, new ketolide antibiotics, was tested by a standard agar dilution technique against 221 pneumococcal strains, including isolates with intermediate levels of resistance to penicillin and erythromycin-resistant isolates. The ketolides were more active than other macrolides and showed excellent activity against erythromycin-resistant strains. All the strains were inhibited by ≤2 μg of HMR 3004/ml or by ≤0.5 μg of HMR 3647/ml.

scholarly journals Activity of Gemifloxacin against Quinolone-Resistant Streptococcus pneumoniae Strains In Vitro and in a Mouse Pneumonia Model

2005 ◽  
Vol 49 (3) ◽  
pp. 1046-1054 ◽  
Author(s):  
E. Azoulay-Dupuis ◽  
J. P. Bédos ◽  
J. Mohler ◽  
P. Moine ◽  
C. Cherbuliez ◽  
...  
Keyword(s):  
Streptococcus Pneumoniae ◽  
Wild Type Strain ◽  
Acquired Resistance ◽  
Survival Rates ◽  
High Dose ◽  
Single Mutation ◽  
Double Mutation ◽  
Poor Efficacy

ABSTRACT Gemifloxacin is a novel fluoronaphthyridone quinolone with enhanced in vitro activity against Streptococcus pneumoniae. We investigated the activities of gemifloxacin and trovafloxacin, their abilities to select for resistance in vitro and in vivo, and their efficacies in a mouse model of acute pneumonia. Immunocompetent Swiss mice were infected with 105 CFU of a virulent, encapsulated S. pneumoniae strain, P-4241, or its isogenic parC, gyrA, parC gyrA, and efflux mutant derivatives (serotype 3); and leukopenic mice were infected with 107 CFU of two poorly virulent clinical strains (serotype 11A) carrying either a parE mutation or a parC, gyrA, and parE triple mutation. The drugs were administered six times every 12 h, starting at either 3 or 18 h postinfection. In vitro, gemifloxacin was the most potent agent against strains with and without acquired resistance to fluoroquinolones. While control mice died within 6 days, gemifloxacin at doses of 25 and 50 mg/kg of body weight was highly effective (survival rates, 90 to 100%) against the wild-type strain and against mutants harboring a single mutation, corresponding to area under the time-versus-serum concentration curve at 24 h (AUC24)/MIC ratios of 56.5 to 113, and provided a 40% survival rate against a mutant with a double mutation (parC and gyrA). A total AUC24/MIC ratio of 28.5 was associated with poor efficacy and the emergence of resistant mutants. Trovafloxacin was as effective as gemifloxacin against mutants with single mutations but did not provide any protection against the mutant with double mutations, despite treatment with a high dose of 200 mg/kg. Gemifloxacin preferentially selected for parC mutants both in vitro and in vivo.

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