Concentration-Dependent Enrichment of Linezolid-Resistant Staphylococcus aureus in an in vitro Dynamic Model
Abstract
To establish the relationships between the enrichment of resistant Staphylococcus aureus mutants and the ratio of daily area under the concentration - time curve (AUC24) to the MIC of linezolid, a mixed inoculum of linezolid-susceptible and -resistant cells of three strains of S.aureus was exposed to twice daily linezolid in an in vitro dynamic model. Simulated pharmacokinetic profiles mimicked five-day treatments with linezolid dosing over a 32-fold range of the AUC24/MIC ratio. Population analysis of linezol-id-exposed staphylococci was performed daily over 120 h after the start of the treatments. Minor if any enrichment of mutants resistant to 2Х, 4Х and 8XMIC of antibiotic was observed at the lowest and the highest AUC24/MIC ratios in contrast to pronounced enrichment of resistant mutants at the intermediate AUC24/MICs. An integral parameter AUBCM, the area under the time course of resistance mutants, was shown to be a more appropriate endpoint to establish AUC24/MIC relationships with resistance than postexposure number of mutants (NM).
About the Authors
K. N. Alieva
Gause Research Institute of New Antibiotics
Russian Federation
Russian Federation
E. N. Strukova
Gause Research Institute of New Antibiotics
Russian Federation
Russian Federation
M. V. Golikova
Gause Research Institute of New Antibiotics
Russian Federation
Russian Federation
Yu. A. Portnoy
Gause Research Institute of New Antibiotics
Russian Federation
Russian Federation
A. A. Firsov
Gause Research Institute of New Antibiotics
Russian Federation
Russian Federation
References
1. Firsov A.A., Vostrov S.N., Lubenko I.Y, Drlica K., Portnoy Y.A., Zinner S.H. In vitro pharmacodynamic evaluation of the mutant selection window hypothesis using four fluoroquinolones against Staphylococcus aureus. Antimicrob Agents Chemother 2003; 47: 1604-1613.
2. Firsov A.A., Vostrov S.N., Lubenko I.Y., Arzamastsev A.P., Portnoy Y.A., Zinner S.H. ABT492 and levofloxacin: comparison of their pharmacodynamics and their abilities to prevent selection of resistant Staphylococcus aureus in an in vitro dynamic model. J Antimicrob Chemother 2004; 54: 178-186.
3. Firsov A.A., Smirnova M. V., Strukova E.N., Vostrov S.N., Portnoy Y.A., Zinner S.H.Enrichment of resistant Staphylococcus aureus at ciprofloxacin concentrations simulated within the mutant selection window: bolus versus continuous infusion. Int J Antimicrob Agents 2008, 32: 488-493.
4. MacGowan A.P., Rogers C.A., Holt H.A., Bowker K.E. Activities of moxifloxacin against, and emergence of resistance in, Streptococcus pneumoniae and Pseudomonas aeruginosa in an in vitro pharmacokinetic model. Antimicrob Agents Chemother 2003, 47: 1088-1095.
5. Zinner S.H., Lubenko I.Y., Gilbert D., Simmons K., Zhao X., Drlica K. et al. Emergence of resistant Streptococcus pneumoniae in an in vitro dynamic model that simulates moxifloxacin concentrations inside and outside the mutant selection window: related changes in susceptibility, resistance frequency and bacterial killing. J Antimicrob Chemother 2003; 52: 616-622.
6. Oonishi Y., Mitsuyama О., Yamaguchi K. Effect of GrlA mutation on the development quinolone resistance in Staphylococcus aureus in an in vitro pharmacokinetic model. J Antimicrob Chemother 2007; 60: 1030-1037.
7. Tam V.H., Louie A., Deziel M.R., Liu W., Leary R., Drusano G.L. The relationship between quinolone exposures and resistance amplification is characterized by an inverted U: a new paradigm for optimizing pharmacodynamics to counterselect resistance. Antimicrob Agents Chemother 2007;51: 744-747.
8. Liang B., Bai N., Cai Y., Wang R., Drlica K., Zhao X. Mutant prevention concentration-based pharmacokinetic/pharmacodynamic indices as dosing targets for suppressing the enrichment of levofloxacin-resistant subpopulations of Staphylococcus aureus. Antimicrob Agents Chemother 2011; 55: 2409-24012.
9. Gebru E., Choi M-J., Lee S-J., Damte D., Park S.C. Mutant-prevention concentration and mechanism of resistance in clinical isolates and enrofloxacin/ marbofloxacin-selected mutants of Escherichia coli of canine origin. J Med Microbiol 2011; 60: 1512-1522.
10. Firsov A.A., Strukova E.N., Shlykova D.S., Portnoy Y.A., Kozyreva V.K., Edelstein M. V. et al. Bacterial resistance studies using in vitro dynamic models: the predictive power of the mutant prevention and minimum inhibitory antibiotic concentrations. Antimicrob Agents Chemother 2013; 57: 4956-4962.
11. Firsov A.A., Portnoy Y.A., Strukova E.N., Shlykova D.S., Zinner S.H. Predicting bacterial resistance using the time inside the mutant selection window: possibilities and limitations. Int J Antimicrob Agents 2014; 44: 301-305.
12. Firsov A.A., Strukova E.N., Portnoy Y.A., Shlykova D.S., Zinner S.H. Bacterial antibiotic resistance studies using in vitro dynamic models: population analysis vs. susceptibility testing as endpoints of mutant enrichment. Int J Antimicrob Agents 2015, 46: 313-318.
13. Firsov A.A., Smirnova M.V., Lubenko I.Y., Vostrov S.N., Portnoy Y.A., Zinner S.H. Testing the mutant selection window hypothesis with Staphylococcus aureus exposed to daptomycin and vancomycin in an in vitro dynamic model. J Antimicrob Chemother. 2006; 58: 1185-1192.
14. Smirnova M.V., Vostrov S.N., Strukova E.N., Dovzhenko S.A., Kobrin M.B., Portnoy Y.A. et al. The impact of duration of antibiotic exposure on bacterial resistance predictions using in vitro dynamic models. J Antimicrob Chemother 2009; 64: 815-820.
15. Blondeau J.M., Zhao X., Hansen G., Drlica K. Mutant prevention concentrations of fluoroquinolones for clinical isolates of Streptococcus pneumoniae. Antimicrob Agents Chemother 2001; 45: 433-438.
16. Blondeau J.M., Hansen G., Metzler K., Hedlin P. The role of PK/PD parameters to avoid selection and increase of resistance: mutant prevention concentration. J Chemother 2004; 16: 1-19.
17. Miller K., Dunsmore C.J., Fishwick C.W., Chopra I. Linezolid and tiamulin cross-resistance in Staphylococcus aureus mediated by point mutations in the peptidyl transferase center. Antimicrob Agents Chemother 2008; 52: 1737-1742.
18. Clark C., Kosowska-Shick K., McGhee P., Dewasse B., Beachel L., Appelbaum P.C. Resistance selection studies comparing the activity of razupenem (PTZ601) to vancomycin and linezolid against eight methicillin -resistant and two methicillin-susceptible Staphylococcus aureus strains. Antimicrob Agents Chemother 2009; 53: 3118-3121.
19. Locke J.B., Hilgers M., Shaw K.J. Novel ribosomal mutations in Staphylococcus aureus strains identified through selection with the oxazo-lidinones linezolid and torezolid (TR-700). Antimicrob Agents Chemother 2009; 53: 5265-5274.
20. Smirnova M.V., Strukova E.N., Portnoy Y.A., Dovzhenko S.A., Kobrin M.B., Zinner S.H. et al. The antistaphylococcal pharmacodynamics of linezolid alone and in combination with doxycycline in an in vitro dynamic model. J Chemother 2011; 23: 140-144.
21. Firsov A.A., Golikova M.V., Strukova E.N., Portnoy Y.A., Romanov A.V., Edelstein M.V. et al. In vitro resistance studies with bacteria that exhibit low mutation frequencies: prediction of «antimutant» linezolid concentrations using a mixed inoculum containing both susceptible and resistant Staphylococcus aureus. Antimicrob Agents Chemother 2015; 59: 1014-1019.
22. CLSI. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically. Approved Standard. Eighth Edition. CLSI document M-07-08, Clinical and Laboratory Standards Institute; 2009.
23. Moellering R.C. Jr. A novel antimicrobial agent joins the battle against resistant bacteria. Ann Intern Med 1999; 130: 155-1557.
24. Firsov A.A., Shevchenko A.A., Vostrov S.N., Zinner S.H. Inter- and intra-quinolone predictors of antimicrobial effect in an in vitro dynamic model: new insight into a widely used concept. Antimicrob Agents Chemother 1998; 42: 659-665.
25. Голикова М.В., Струкова Е.Н., Портной Ю.А., Фирсов А.А. Прогнозирование антибиотикорезистентности бактерий методами фармако-кинетико-фармакодинамического моделирования: альтернативные подходы к анализу экспериментальных данных. Клин микробиол антимикроб химиотер 2015; 60: 12-16.
26. Strukova E.N., Portnoy Y.A., Zinner S.H., Firsov A.A. Predictors of bacterial resistance using in vitro dynamic models: area under the concentrationtime curve related to either the minimum inhibitory or mutant prevention antibiotic concentration. J Antimicrob Chemother 2016; 71: 678-684
Review
For citations:
Alieva K.N., Strukova E.N., Golikova M.V., Portnoy Yu.A., Firsov A.A. Concentration-Dependent Enrichment of Linezolid-Resistant Staphylococcus aureus in an in vitro Dynamic Model. Antibiot Khimioter = Antibiotics and Chemotherapy. 2016;61(9-10):28-32. (In Russ.)
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