Abstract
PK/PD (pharmacokinetic/pharmacodynamic) relationships with the emergence of bacterial resistance are a basis for designing “anti-mutant” antibiotic dosing regimens, i.e., regimens that are expected to prevent or restrict the enrichment of resistant mutant subpopulations. In vitro dynamic models provide a way to study the enrichment of resistant mutants while simulating human antibiotic pharmacokinetics. A key observation made using these models is that a bell-shaped curve is observed when the recovery of resistant mutants is plotted against AUC/MIC, an integrated measure of drug exposure. This observation strongly supports the window hypothesis, which predicts the selective enrichment of resistant mutants when antimicrobial concentrations fall between the MIC of the bulk population and the mutant prevention concentration (MPC). In most cases examined, doses used clinically place drug concentrations inside the window where mutant enrichment is observed. Reports that contradict the mutant selection window hypothesis are addressed, and flaws in the arguments are pointed out. When considering the time that antimicrobial concentrations are inside the window as a predictor of mutant enrichment, it is important to consider the position of drug concentrations inside the window, since they affect mutant subpopulation size. Plots of mutant enrichment against “time in the window” display a distinct hysteresis loop that explains previous failures to show that “time in the window” is predictive of mutant enrichment. Dynamic models are also suited for optimizing combination therapies. Overall, bacterial resistance studies with in vitro dynamic models provide a way to identify dosing conditions that are likely to severely restrict the emergence of new resistance, a feature that should be especially useful in the development of new compounds.
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References
Linder KE, Nicolau DP, Nailor MD. Predicting and preventing antimicrobial resistance utilizing pharmacodynamics: part I gram positive bacteria. Expert Opin Drug Metabol Toxicol. 2016;12:267–80.
Abdelraouf K, Linder KE, Nailor MD, Nicolau DP. Predicting and preventing antimicrobial resistance utilizing pharmacodynamics: part II gram-negative bacteria. Expert Opin Drug Metabol Toxicol, 2017; doi: https://doi.org/10.1080/17425255.2017.1329417.
Zhao X, Drlica K. Restricting the selection of antibiotic-resistant mutants: a general strategy derived from fluoroquinolone studies. Clin Infect Dis. 2001;33:147–56.
Blondeau JM, Zhao X, Hansen G, Drlica K. Mutant prevention concentrations of fluoroquinolones for clinical isolates of Streptococcus pneumoniae. Antimicrob Agents Chemother. 2001;45:433–8.
Firsov AA, Zinner SH. Lubenko IY. In: Nightingale CH, Ambrose PG, Drusano GL, Murakawa T, editors. vitro dynamic models as tools to predict antibiotic pharmacodynamics, Antimicrobial pharmacodynamics in theory and clinical practice. 2nd ed. New York: Informa Healthcare USA, Inc.; 2007. p. 45–78.
Lacy MK, Lu W, Xu X, Tessier PR, Nicolau DP, Quintiliani R, Nightingale CH. Pharmacodynamic comparisons of levofloxacin, ciprofloxacin, and ampicillin against Streptococcus pneumoniae in an in vitro model of infection. Antimicrob Agents Chemother. 1999;43:672–7.
Aeschlimann JR, Kaatz GW, Rybak MJ. The effects of NorA inhibition on the activities of levofloxacin, ciprofloxacin and norfloxacin against two genetically related strains of Staphylococcus aureus in an in-vitro infection model. J Antimicrob Chemother. 1999;44:343–9.
Peterson ML, Hovde LB, Wright DH, Hoang AD, Raddatz JK, Boysen PJ, Rotschafer JC. Fluoroquinolone resistance in Bacteroides fragilis following sparfloxacin exposure. Antimicrob Agents Chemother. 1999;43:2251–5.
Madaras-Kelly KJ, Demasters TA. In vitro characterization of fluoroquinolone concentration/MIC antimicrobial activity and resistance while simulating clinical pharmacokinetics of levofloxacin, ofloxacin, or ciprofloxacin against Streptococcus pneumoniae. Diagn Microbiol Infect Dis. 2000;37:253–60.
Coyle EA, Kaatz GW, Rybak MJ. Activities of newer fluoroquinolones against ciprofloxacin-resistant Streptococcus pneumoniae. Antimicrob Agents Chemother. 2001;45:1654–9.
Zhanel GG, Walters M, Laing N, Hoban DJ. In vitro pharmacodynamic modelling simulating free serum concentrations of fluoroquinolones against multidrug-resistant Streptococcus pneumoniae. J Antimicrob Chemother. 2001;47:435–40.
Thorburn CE, Edwards DI. The effect of pharmacokinetics on the bactericidal activity of ciprofloxacin and sparfloxacin against Streptococcus pneumoniae and the emergence of resistance. J Antimicrob Chemother. 2001;48:15–22.
Ross GH, Wright DH, Hovde LB, Peterson ML, Rotschafer JC. Fluoroquinolone resistance in anaerobic bacteria following exposure to levofloxacin, trovafloxacin, and sparfloxacin in an in vitro pharmacodynamic model. Antimicrob Agents Chemother. 2001;45:2136–40.
Klepser ME, Ernst EJ, Petzold CR, Rhomberg P, Doern GV. Comparative bactericidal activities of ciprofloxacin, clinafloxacin, grepafloxacin, levofloxacin, moxifloxacin, and trovafloxacin against Streptococcus pneumoniae in a dynamic in vitro model. Antimicrob Agents Chemother. 2001;45:673–8.
Peterson ML, Hovde LB, Wright DH, Brown GH, Hoang AD, Rotschafer JC. Pharmacodynamics of trovafloxacin and levofloxacin against Bacteroides fragilis in an in vitro pharmacodynamic model. Antimicrob Agents Chemother. 2002;46:203–10.
Wright DH, Gunderson SM, Hovde LB, Ross GH, Ibrahim AS, Rotschafer JC. Comparative pharmacodynamics of three newer fluoroquinolones versus six strains of staphylococci in an in vitro model under aerobic and anaerobic conditions. Antimicrob Agents Chemother. 2002;46:1561–3.
Firsov AA, Vostrov SN, Lubenko IY, Drlica K, Portnoy YA, Zinner SH. In vitro pharmacodynamic evaluation of the mutant selection window hypothesis using four fluoroquinolones against Staphylococcus aureus. Antimicrob Agents Chemother. 2003;47:1604–13.
Firsov AA, Vostrov SN, Lubenko IY, Arzamastsev AP, Portnoy YA, Zinner SH. ABT492 and levofloxacin: comparison of their pharmacodynamics and their abilities to prevent the selection of resistant Staphylococcus aureus in an in vitro dynamic model. J Antimicrob Chemother. 2004;54:178–86.
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;55:2409–12.
Tam VH, Louie A, Deziel MR, Liu W, Leary R, Drusano GL. The relationship between quinolone exposures and resistance amplification is characterized by an inverted U: a new paradigm for optimizing pharmacodynamics to counter select resistance. Antimicrob Agents Chemother. 2007;51:744–7.
MacGowan AP, Rogers CA, Holt HA, Bowker KE. Activities of moxifloxacin against, and emergence of resistance in, Streptococcus pneumoniae and Pseudomonas aeruginosa in an in vitro pharmacokinetic model. Antimicrob Agents Chemother. 2003;47:1088–95.
Zinner SH, Lubenko IY, Gilbert D, Simmons K, Zhao X, Drlica K, Firsov AA. 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;52:616–22.
Gebru E, Choi M-J, Lee S-J, Damte D, Park SC. 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;60:1512–22.
Firsov AA, Strukova EN, Shlykova DS, Portnoy YA, Kozyreva VK, Edelstein MV, Dovzhenko SA, Kobrin MB, Zinner SH. Bacterial resistance studies using in vitro dynamic models: the predictive power of the mutant prevention and minimum inhibitory antibiotic concentrations. Antimicrob Agents Chemother. 2013;57:4956–62.
Firsov AA, Portnoy YA, Strukova EN, Shlykova DS, Zinner SH. Predicting bacterial resistance using the time inside the mutant selection window: possibilities and limitations. Int J Antimicrob Agents. 2014;44:301–5.
Firsov AA, Portnoy YA, Strukova EN, Shlykova DS, Zinner SH. Bacterial antibiotic resistance studies using in vitro dynamic models: population analysis vs. susceptibility testing as endpoints of mutant enrichment. Int J Antimicrob Agents. 2015;46:313–8.
Strukova EN, Portnoy YA, Romanov AV, Edelstein MV, Zinner SH Firsov AA. Searching for the optimal predictor of ciprofloxacin resistance in Klebsiella pneumoniae by using in vitro dynamic models. Antimicrob Agents Chemother. 2016;60:1208–15.
Strukova EN, Portnoy YA, Zinner SH, Firsov AA. Predictors of bacterial resistance using in vitro dynamic models: area under the concentration-time curve related to either the minimum inhibitory or mutant prevention antibiotic concentration. J Antimicrob Chemother. 2016;71:678–84.
Firsov AA, Smirnova MV, Strukova EN, Vostrov SN, Portnoy YA, Zinner SH. Enrichment of resistant Staphylococcus aureus at ciprofloxacin concentrations simulated within the mutant selection window: bolus versus continuous infusion. Int J Antimicrob Agents. 2008;32:488–93.
Golikova MV, Strukova EN, Portnoy YA, Firsov AA. PK/PD modeling as a tool to predict bacterial resistance to antibiotics: alternative analyses of the experimental data. Antibiot Chimiother. 2015;60:11–6. rus
Firsov AA, Smirnova MV, Lubenko IY, Vostrov SN, Portnoy YA, Zinner SH. Testing the mutant selection window hypothesis with Staphylococcus aureus exposed to daptomycin and vancomycin in an in vitro dynamic model. J Antimicrob Chemother. 2006;58:1185–92.
Smirnova MV, Vostrov SN, Strukova EN, Dovzhenko SA, Kobrin MB, Portnoy YA, Zinner SH, Firsov AA. The impact of duration of antibiotic exposure on bacterial resistance predictions using in vitro dynamic models. J Antimicrob Chemother. 2009;64:815–20.
VanScoy BD, McCauley J, Ellis-Grosse EJ, Okusanya OO, Bhavnani SM, Forrest A, Ambrose PG. Exploration of the pharmacokinetic-pharmacodynamic relationships for fosfomycin efficacy using an in vitro infection model. Antimicrob Agents Chemother. 2015;59:7170–7.
Firsov AA, Alieva KN, Strukova EN, Golikova MV, Portnoy YA, Dovzhenko SA, Kobrin MB, Romanov AV, Edelstein MV, Zinner SH. Testing the mutant selection window hypothesis with Staphylococcus aureus exposed to linezolid in an in vitro dynamic model. J Antimicrob Chemother. 2017;72:3100–7.
Firsov AA, Golikova MV, Strukova EN, Portnoy YA, Romanov AV, Edelstein MV, Zinner SH. In vitro resistance studies with bacteria that exhibit low mutation frequencies: the prediction of “antimutant” linezolid concentrations using a mixed inoculum containing both susceptible and resistant Staphylococcus aureus. Antimicrob Agents Chemother. 2015;59:1014–9.
Drlica K, Zhao X. Mutant selection window hypothesis updated. Clin Infect Dis. 2007;44:681–68.
Zhao X, Drlica K. A unified anti-mutant dosing strategy. J Antimicrob Chemother. 2008;62:434–6.
Blondeau JM. New concepts in antimicrobial susceptibility testing: the mutant prevention concentration and mutant selection window approach. Vet Dermatol. 2009;20:383–96.
Allen GP, Kaatz GW, Rybak MJ. In vitro activities of mutant prevention concentration-targeted concentrations of fluoroquinolones against Staphylococcus aureus in a pharmacodynamic model. Int J Antimicrob Agents. 2004;24:150–60.
Olofsson SK, Marcusson LL, Lindgren PK, Hughes D, Cars O. Selection of ciprofloxacin resistance in Escherichia coli in an in vitro kinetic model: relation between drug exposure and mutant prevention concentration. J Antimicrob Chemother. 2006;57:1116–21.
Firsov AA, Vostrov SN, Lubenko IY, Zinner SH, Portnoy YA. Concentration-dependent changes in the susceptibility and killing of Staphylococcus aureus in an in vitro dynamic model that simulates normal and impaired gatifloxacin elimination. Int J Antimicrob Agents. 2004;23:60–6.
Campion JJ, McNamara PJ, Evans ME. Evolution of ciprofloxacin-resistant Staphylococcus aureus in in vitro pharmacokinetic environments. Antimicrob Agents Chemother. 2004;48:4733–44.
Gumbo T, Louie A, Liu W, Brown D, Ambrose PG, Bhavnani SM, Drusano GL. Isoniazid bactericidal activity and resistance emergence: integrating pharmacodynamics and pharmacogenomics to predict efficacy in different ethnic populations. Antimicrob Agents Chemother. 2007;51:2329–36.
Homma T, Hori T, Sugimori G, Yamano Y. Pharmacodynamic assessment based on mutant prevention concentrations of fluoroquinolones to prevent the emergence of resistant mutants of Streptococcus pneumoniae. Antimicrob Agents Chemother. 2007;51:3810–5.
Zinner SH, Gilbert D, Greer K, Portnoy YA, Firsov AA. Сoncentration-resistance relationships with Pseudomonas aeruginosa exposed to doripenem and ciprofloxacin in an in vitro model. J Antimicrob Chemother. 2013;68:881–7.
Firsov AA, Lubenko IY, Smirnova MV, Strukova EN, Zinner SH. Enrichment of fluoroquinolone-resistant Staphylococcus aureus: oscillating ciprofloxacin concentrations simulated at the upper and lower portions of the mutant selection window. Antimicrob Agents Chemother. 2008;52:1924–8.
Alieva KN, Strukova EN, Golikova MV, Portnoy YA, Zinner SH, Firsov AA. Time inside the mutant selection window as a predictor of staphylococcal resistance to linezolid. J Antibiot. 2017; (in press).
Li X, Wang L, Zhang XJ, Yang Y, Gong WT, Xu B, Zhu YQ, Liu W. Evaluation of meropenem regimens suppressing emergence of resistance in Acinetobacter baumannii with human simulated exposure in an in vitro intravenous-infusion hollow-fiber infection model. Antimicrob Agents Chemother. 2014;58:6773–81.
Firsov AA, Lubenko IY, Vostrov SN, Portnoy YA, Zinner SH. Antistaphylococcal effect related to the area under the curve/MIC ratio in an in vitro dynamic model: predicted breakpoints versus clinically achievable values for seven fluoroquinolones. Antimicrob Agents Chemother. 2005;49:2642–7.
Strukova EN, Portnoy YA, Zinner SH, Firsov AA. Species differences in ciprofloxacin resistance among gram-negative bacteria: can “anti-mutant” ratios of the area under the concentration–time curve to the MIC be achieved clinically?. J Chemother. 2017; doi:https://doi.org/10.1080/1120009X.2017.1335980.
Drlica K. The mutant selection window and antimicrobial resistance. J Antimicrob Chemother. 2003;52:11–7.
Firsov AA, Vostrov SN, Lubenko IY, Portnoy YA, Zinner SH. Prevention of the selection of resistant Staphylococcus aureus by moxifloxacin plus doxycycline in an in vitro dynamic model: an additive effect of the combination. Int J Antimicrob Agents. 2004;23:451–6.
Zinner SH, Gilbert D, Lubenko IY, Greer K, Firsov AA. Selection of linezolid-resistant Enterococcus faecium in an in vitro dynamic model: protective effect of doxycycline. J Antimicrob Chemother. 2008;61:629–6357.
Deris ZZ, Yu HH, Davis K, Soon RL, Jacob J, Ku CK, Poudyal A, Bergen PJ, Tsuji BT, Bulitta JB, Forrest A, Paterson DL, Velkov T, Li J, Nation RL. The combination of colistin and doripenem is synergistic against Klebsiella pneumoniae at multiple inocula and suppresses colistin resistance in an in vitro pharmacokinetic/pharmacodynamic model. Antimicrob Agents Chemother. 2012;56:5103–12.
Albur MS, Noel A, Bowker K, MacGowan A. The combination of colistin and fosfomycin is synergistic against NDM-1-producing Enterobacteriaceae in in vitro pharmacokinetic/pharmacodynamic model experiments. Int J Antimicrob Agents. 2015;46:560–7.
Liu X, Zhao M, Chen Y, Bian X, Li Y, Shi J, Zhang J. Synergistic killing by meropenem and colistin combination of carbapenem-resistant Acinetobacter baumannii isolates from Chinese patients in an in vitro pharmacokinetic/pharmacodynamic model. Int J Antimicrob Agents. 2016;48:559–63.
Cai X, Yang Z, Dai J, Chen K, Liu H, Ni W, Wei C, Cui J. Pharmacodynamics of tigecycline alone and in combination with colistin against clinical isolates of multidrug-resistant Acinetobacter baumannii in an in vitro pharmacodynamic model. Int J Antimicrob Agents. 2017;49:609–16.
Yim J, Smith JR, Singh NB, Rice S, Stamper K, Garcia de la Maria C, Bayer AS, Mishra NN, Miró JM, Tran TT, Arias CA, Sullam P, Rybak MJ. Evaluation of daptomycin combinations with cephalosporins or gentamicin against Streptococcus mitis group strains in an in vitro model of simulated endocardial vegetations (SEVs). J Antimicrob Chemother. 2017;72:2290–6.
Drusano GL, Neely M, Van Guilder M, Schumitzky A, Brown D, Fikes S, Peloquin C, Louie A. Analysis of combination drug therapy to develop regimens with shortened duration of treatment for tuberculosis. PLoS One. 2014;9:1–10.
Firsov AA, Golikova MV, Strukova EN, Portnoy YA, Dovzhenko SA, Kobrin MB, Zinner SH. Pharmacokinetically based prediction of the effects of antibiotic combinations on resistant Staphylococcus aureus mutants: in vitro model studies with linezolid and rifampicin. J Chemother. 2017;29:220–6.
Zhanel GG, Mayer M, Laing N, Adam HJ. Mutant prevention concentrations of levofloxacin alone and in combination with azithromycin, ceftazidime, colistin (polymyxin E), meropenem, piperacillin-tazobactam, and tobramycin against Pseudomonas aeruginosa. Antimicrob Agents Chemother. 2006;50:2228–30.
Cai Y, Yang J, Kan Q, Nie X, Wang R, Liang B, Bai N. Mutant prevention concentration of colistin alone and in combination with levofloxacin or tobramycin against multidrug-resistant Acinetobacter baumannii. Int J Antimicrob Agents. 2012;40:477–8.
Liu LG, Zhu YL, Hu LF, Cheng J, Ye Y, Li JB. Comparative study of the mutant prevention concentrations of vancomycin alone and in combination with levofloxacin, rifampicin and fosfomycin against methicillin-resistant Staphylococcus epidermidis. J Antibiot. 2013;66:709–12.
Wei W, Yang H, Hu L, Ye Y, Li J. Activity of levofloxacin in combination with colistin against Acinetobacter baumannii: in vitro and in a Galleria mellonella model. J Microbiol Immunol Infect. 2015; doi: https://doi.org/10.1016/j.jmii.2015.10.010.
Wu J, Jiang TT, Su JR, Li L. Antimicrobial activity of linezolid combined with minocycline against vancomycin-resistant Enterococci. Chin Med J. 2013;126:2670–5.
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Firsov, A.A., Portnoy, Y.A., Zinner, S.H. (2018). PK/PD-Based Prediction of “Anti-Mutant” Antibiotic Exposures Using In Vitro Dynamic Models. In: Fong, I., Shlaes, D., Drlica, K. (eds) Antimicrobial Resistance in the 21st Century. Emerging Infectious Diseases of the 21st Century. Springer, Cham. https://doi.org/10.1007/978-3-319-78538-7_21
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