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Fluoroquinolones 비감수성 Streptococcus pneumoniae에서 Topoisomerase 돌연변이 및 Efflux Pump의 역할
남우진 외 중앙대학교 의과대학 의과학연구소 2010 中央醫大誌 Vol.35 No.3/4
Rapid spread of pneumococcal clones resistant to β-lactam and macrolide antibiotics has increased the use of selected fluoroquinolones for the treatment of pneumococcal infections. Fluoroquinolones resistance in pneumococci is known to be associated with mutations in the quinolone resistance-determining regions (QRDRs) of topoisomerase IV and/or DNA gyrase genes and with active efflux of agents from the cell. This study assessed topoisomerase mutation and role of efflux pump in fluoroquinolones non-susceptible S. pneumoniae. A total of 625 strains were isolated from 1997 to 2002 at Asan Medical Center. Minimum inhibitory concentrations of fluoroquinolones were determined by the agar dilution method. Randomly selected 52 isolates with levofloxacin MIC <= 2 ㎍/ml and all three with levofloxacin MIC >= 4 ㎍/ml were analyzed for QRDRs mutation of the parC and gyrA genes by PCR and sequencing. In addition, efflux pump was tested by comparing fluoroquinolones MICs in the presence and absence of reserpine (20 ㎍/ml). Among 625 isolates, only three strains (2=MIC 8 ㎍/ml; 1=MIC 4 ㎍/ml) were non-susceptible to levofloxacin. Both of two strains with MIC 8 ㎍/ml had mutations in the QRDRs of parC (Lys137Asn, Ser79Phe) and gyrA (Ser83Phe). Although a strain with MIC 4 ㎍/ml had no amino acid change in parC, it had double amino acid change in gyrA (Asp82Tyr, Ser83Phe) that was not reported in previous study. Among susceptible isolates, 13 of 17 (76%) strains with MIC 2 ㎍/ml had amino acid change in parC (Lys137Asn, Ser79Phe, Asp83Asn, Asp83Gly), however, only three of 17 (18%) had mutations in gyrA (Ser83Phe). Eleven (73%) strains with MIC 1 ㎍/ml, four (27%) strains with MIC 0.5 ㎍/ml had amino acid change in parC (Lys137Asn) and no amino acid change detected in gyrA. In levofloxacin non-susceptible isolates, efflux of ciprofloxacin was found in all strains and levofloxacin susceptible strains had efflux of ciprofloxacin in only 15 strains (29%). In conclusion, increased MIC to a panel of fluoroquinolones was associated with accumulation of target enzyme mutation in those strains with a reserpine-sensitive efflux pump mechanism. Because the role of efflux pump differs among the various fluoroquinolones, efflux pump should be considered at the the use of fluoroquinolones for pneumococcal infection.
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