TY - JOUR
T1 - Polymyxin dose tunes the evolutionary dynamics of resistance in multidrug-resistant Acinetobacter baumannii
AU - Zhao, Jinxin
AU - Zhu, Yan
AU - Lin, Yu Wei
AU - Yu, Heidi
AU - Wickremasinghe, Hasini
AU - Han, Jiru
AU - Velkov, Tony
AU - McDonald, Michael J.
AU - Li, Jian
N1 - Funding Information:
The authors declare that they have no conflict of interest. This study is supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health ( R01 AI132154 and AI132681 ) and Monash University Platform Access Grant ( PAG21-4032448399 ). J.L. is an Australian National Health and Medical Research Council (NHMRC) Principal Research Fellow. T.V. is an Australian NHMRC Career Development Research Fellow. M.J.M is an Australian Future Fellow supported the Australian Research Council (FT170100441) and the NHMRC (APP1186140). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Allergy and Infectious Diseases or the National Institutes of Health. Part of this work was presented at the 31st European Congress of Clinical Microbiology and Infectious Diseases, 9-12 July 2021.
Publisher Copyright:
© 2022 European Society of Clinical Microbiology and Infectious Diseases
PY - 2022/7
Y1 - 2022/7
N2 - Objectives: Evolutionary principles have informed the design of strategies that slow or prevent antibiotic resistance. However, how antibiotic treatment regimens shape the evolutionary dynamics of resistance mutations remains an open question. Here, we investigate varying concentrations of the last-resort polymyxins on the evolution of resistance in Acinetobacter baumannii. Methods: Polymyxin resistance was measured in 18 multidrug-resistant A. baumannii AB5075 populations treated over 14 days with concentrations of polymyxin B informed by human pharmacokinetics. Time-resolved whole-population sequencing was conducted to track the genetics and population dynamics of susceptible and resistant subpopulations. Results: A critical threshold concentration of polymyxin B (1 mg/L; i.e. 4 × MIC) was identified. Below this threshold concentration, low levels of resistance repeatedly evolved, but no mutations were fixed, and this resistance was reversed upon removal of the antibiotic. This contrasted with evolution at super-MIC levels (≥4 × MIC) of polymyxin B, which drove the evolution of irreversible resistance, with higher levels of antibiotic correlating with greater rates of molecular evolution. Polymyxin-resistant subpopulations carried mutations in a variety of genes, most commonly pmrB, ompA, glmU/glmS, and wecB/wecC, which contributed to membrane remodelling and virulence in A. baumannii. Conclusions: Our results show that the strength of the selective pressure applied by polymyxin tunes the dynamics of genetic variants within the population, leading to different evolutionary outcomes for the degree, cost and reversibility of resistance. Our study highlights the critical role of integrating evolutionary findings into pharmacokinetics/pharmacodynamics to optimise antibiotic use in patients.
AB - Objectives: Evolutionary principles have informed the design of strategies that slow or prevent antibiotic resistance. However, how antibiotic treatment regimens shape the evolutionary dynamics of resistance mutations remains an open question. Here, we investigate varying concentrations of the last-resort polymyxins on the evolution of resistance in Acinetobacter baumannii. Methods: Polymyxin resistance was measured in 18 multidrug-resistant A. baumannii AB5075 populations treated over 14 days with concentrations of polymyxin B informed by human pharmacokinetics. Time-resolved whole-population sequencing was conducted to track the genetics and population dynamics of susceptible and resistant subpopulations. Results: A critical threshold concentration of polymyxin B (1 mg/L; i.e. 4 × MIC) was identified. Below this threshold concentration, low levels of resistance repeatedly evolved, but no mutations were fixed, and this resistance was reversed upon removal of the antibiotic. This contrasted with evolution at super-MIC levels (≥4 × MIC) of polymyxin B, which drove the evolution of irreversible resistance, with higher levels of antibiotic correlating with greater rates of molecular evolution. Polymyxin-resistant subpopulations carried mutations in a variety of genes, most commonly pmrB, ompA, glmU/glmS, and wecB/wecC, which contributed to membrane remodelling and virulence in A. baumannii. Conclusions: Our results show that the strength of the selective pressure applied by polymyxin tunes the dynamics of genetic variants within the population, leading to different evolutionary outcomes for the degree, cost and reversibility of resistance. Our study highlights the critical role of integrating evolutionary findings into pharmacokinetics/pharmacodynamics to optimise antibiotic use in patients.
KW - Acinetobacter baumannii
KW - Antibiotic resistance
KW - Evolutionary dynamics
KW - Polymyxin
KW - Whole-population sequencing
UR - http://www.scopus.com/inward/record.url?scp=85128225982&partnerID=8YFLogxK
U2 - 10.1016/j.cmi.2022.02.043
DO - 10.1016/j.cmi.2022.02.043
M3 - Article
C2 - 35283314
AN - SCOPUS:85128225982
SN - 1198-743X
VL - 28
SP - 1026.e1-1026.e5
JO - Clinical Microbiology and Infection
JF - Clinical Microbiology and Infection
IS - 7
ER -
