Efficacy and pharmacodynamics of simulated human-like treatment with levofloxacin on experimental pneumonia induced with penicillin-resistant pneumococci with various susceptibilities to fluoroquinolones.
Newer fluoroquinolones, such as levofloxacin, have shown an enhanced in vitro and in vivo activity against penicillin-resistant Streptococcus pneumoniae infections. The frequency of S. pneumoniae with reduced susceptibility to quinolones, although currently low, raises the question of the therapeutic efficacy of levofloxacin on infection due to such strains. We used an animal model of penicillin-resistant pneumococcal pneumonia using six strains with various levels of susceptibility to ciprofloxacin and levofloxacin in rabbits to induce pneumonia, and simulated a human-like treatment of 500 mg twice a day for 48 h. Strains' susceptibility profiles for ciprofloxacin and levofloxaxin were (ciprofloxacin/levofloxacin MIC, mg/L; genotype): 0.5/0.5 (Cip0.5), 2/1 (Cip2), 4/1.75 (Cip4), 8/1.75 (parC mutation) (Cip8), 10/2 (parC mutation) (Cip10), 64/16 (parC and gyrA mutations) (Cip64), respectively. All the strains induced a crude pneumonia in all rabbits. Significant bacterial reductions at the end of treatment in lung and spleen were observed for the four former strains (P < 0.05) but not for the latter two. An AUC/MIC ratio of at least 32 identified 95% of an at least bacteriostatic effect (P = 0.038) and 76% of a bactericidal effect (P = 0.09). Mutants were detected in treated animals infected with strains harbouring parC mutations (Cip8 and Cip10) and when the AUC/MIC ratio was between 13 and 31. We conclude that levofloxacin is effective against experimental pneumonia due to pneumococci with MIC < 1.5 mg/L, ineffective on experimental pneumonia due to pneumococci with MIC > or = 2 mg/L, and could be associated with the appearance of mutants when a parC mutation is pre-existing.
Service des Maladies Infectieuses, Microbiologie Médicale et Moléculaire EA562, Hôpital du Bocage, BP 1542, 21034 Dijon Cedex, France.
Delphine
D
Croisier
Pascal
P
Chavanet
Catherine
C
Lequeu
Abderrahmane
A
Ahanou
Anne
A
Nierlich
Catherine
C
Neuwirth
Lionel
L
Piroth
Michel
M
Duong
Marielle
M
Buisson
Henri
H
Portier
D000818:Animals; D000890:Anti-Infective Agents / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D019540:Area Under Curve; D004195:Disease Models, Animal; D005838:Genotype; D006801:Humans; D064704:Levofloxacin; D008168:Lung / Q000382:microbiology; D008297:Male; D008826:Microbial Sensitivity Tests; D009154:Mutation; D015242:Ofloxacin / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D010403:Penicillin Resistance / Q000235:genetics*; D011018:Pneumonia, Pneumococcal / Q000188:drug therapy* / Q000382:microbiology; D011654:Pulmonary Edema / Q000209:etiology; D011817:Rabbits; D013154:Spleen / Q000382:microbiology; D013296:Streptococcus pneumoniae / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development
D000890:Anti-Infective Agents; D064704:Levofloxacin; D015242:Ofloxacin