Dose dependence of emergence of resistance to linezolid in Enterococcus faecalis in vivo.
BACKGROUND
The emergence of resistance to antibiotics in vivo, particularly in commensal, potentially pathogenic bacteria, is a factor that is key to the future of antibiotics. To better document the circumstances favoring the emergence of resistance to linezolid (the first of a new class of antibiotics, the oxazolidinones), we modeled the effect of different regimens of linezolid on Enterococcus faecalis in gnotobiotic mice.


METHODS
We studied the rate of emergence of linezolid-resistant E. faecalis mutants in the digestive tract of gnotobiotic mice monoassociated with linezolid-susceptible E. faecalis and fed with water containing linezolid (0.5, 0.05, or 0.005 g/L). 23S Ribosomal RNA (rRNA) mutations were characterized by sequencing each of the 4 copies of the rRNA genes individually.


RESULTS
Mutants were readily obtained in vivo, but the frequencies, persistence, and type of mutants were all dependent on the linezolid regimen. Mutations conferring resistance, either the G2505A or G2576U mutation, were present in domain V of the 23S rRNA gene of all resistant isolates. Levels of resistance increased with the number of mutated copies of the 23S rRNA gene and with duration of exposure.


CONCLUSIONS
The antibiotic dose appears to be critical in the dynamics and molecular basis of resistance.
Bourgeois-Nicolaos
Nadège
N
Laboratoire de Bacteriologie, Hopital Bichat Claude Bernard, Paris, 75018, France.
Massias
Laurent
L
Couson
Brigitte
B
Butel
Marie-José
MJ
Andremont
Antoine
A
Doucet-Populaire
Florence
F
D000081:Acetamides / Q000494:pharmacology*; D000818:Animals; D000890:Anti-Infective Agents / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D017931:DNA Primers; D004195:Disease Models, Animal; D024881:Drug Resistance, Bacterial / Q000235:genetics; D013293:Enterococcus faecalis / Q000187:drug effects / Q000235:genetics*; D016908:Gram-Positive Bacterial Infections / Q000188:drug therapy*; D000069349:Linezolid; D051379:Mice; D023303:Oxazolidinones / Q000494:pharmacology*; D012329:RNA, Bacterial / Q000235:genetics; D012335:RNA, Ribosomal / Q000235:genetics; D012336:RNA, Ribosomal, 16S / Q000235:genetics; D012341:RNA, Ribosomal, 5S / Q000235:genetics
D000081:Acetamides; D000890:Anti-Infective Agents; D017931:DNA Primers; D023303:Oxazolidinones; D012329:RNA, Bacterial; D012335:RNA, Ribosomal; D012336:RNA, Ribosomal, 16S; D012341:RNA, Ribosomal, 5S; D000069349:Linezolid