A pharmacodynamic approach to antimicrobial activity in serum and epithelial lining fluid against in vivo-selected Streptococcus pneumoniae mutants and association with clinical failure in pneumonia.
OBJECTIVE
Emergence of resistance may be prevented by killing both the parental infecting strain and subsequent less susceptible step-mutants. The present study analyses eradication and resistance selection in Streptococcus pneumoniae with moxifloxacin, levofloxacin and azithromycin, using a parental serotype 3 clinical strain (strain A) and its correspondent step-mutant derivatives resistant to these antibiotics (B, C, D), which were selected in vivo in a patient with pneumonia.


METHODS
Moxifloxacin, levofloxacin and azithromycin MICs were 1, 2 and 0.5 mg/L for the parental strain; 4, 16 and 4 mg/L for isolate B; and 4, 16 and >128 mg/L for isolates C and D, respectively. A pharmacokinetic computerized device was used to simulate serum and epithelial lining fluid (ELF) concentrations. Initial inoculum was approximately 10(8) cfu/mL. Population analysis profiles were performed using plates with increasing antimicrobial concentrations.


RESULTS
In ELF simulations, moxifloxacin showed a bactericidal pattern against all isolates with a minority (approximately 100 cfu/mL) of the surviving population (isolates B, C and D) growing on plates with moxifloxacin concentrations just above those in ELF. Levofloxacin and azithromycin showed a bactericidal pattern only against isolate A, with the whole population of isolates B, C and D growing on plates with levofloxacin concentrations higher (16-64 mg/L) than those in ELF and in plates with azithromycin concentrations as high as 2048 mg/L (for isolates C and D).


CONCLUSIONS
Antimicrobial activity in pulmonary tissue against possible emerging resistant mutants during pneumonia treatment may prevent failures more than the solely activity against the S. pneumoniae parental infecting strain.
Alou
Luis
L
Microbiology Department, School of Medicine, Universidad Complutense Avda. Complutense s/n, 28040 Madrid, and Microbiology Department, Hospital Donostia, San Sebastián, Spain.
Giménez
María-José
MJ
Sevillano
David
D
Aguilar
Lorenzo
L
Cafini
Fabio
F
Echeverría
Olatz
O
Pérez-Trallero
Emilio
E
Prieto
José
J
D000900:Anti-Bacterial Agents / Q000097:blood / Q000494:pharmacology*; D001372:Aza Compounds / Q000097:blood / Q000494:pharmacology*; D017963:Azithromycin / Q000097:blood / Q000494:pharmacology*; D017714:Community-Acquired Infections / Q000382:microbiology; D024881:Drug Resistance, Bacterial / Q000235:genetics; D024841:Fluoroquinolones; D006801:Humans; D064704:Levofloxacin; D008826:Microbial Sensitivity Tests; D008954:Models, Biological; D000077266:Moxifloxacin; D009154:Mutation; D015242:Ofloxacin / Q000097:blood / Q000494:pharmacology*; D011018:Pneumonia, Pneumococcal / Q000382:microbiology; D011804:Quinolines / Q000097:blood / Q000494:pharmacology*; D015610:Serum Bactericidal Test; D013296:Streptococcus pneumoniae / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification
D000900:Anti-Bacterial Agents; D001372:Aza Compounds; D024841:Fluoroquinolones; D011804:Quinolines; D064704:Levofloxacin; D017963:Azithromycin; D015242:Ofloxacin; D000077266:Moxifloxacin