TY - JOUR
T1 - Distinguishing Inducible and Non-Inducible Resistance to Colistin in Pseudomonas aeruginosa by Quantitative and Systems Pharmacology Modeling at Low and Standard Inocula
AU - Bulitta, Jürgen B.
AU - Shin, Eunjeong
AU - Bergen, Phillip J.
AU - Lang, Yinzhi
AU - Forrest, Alan
AU - Tsuji, Brian T.
AU - Moya, Bartolome
AU - Li, Jian
AU - Nation, Roger L.
AU - Landersdorfer, Cornelia B.
N1 - Funding Information:
The assistance of Rebecca E. Imperial for the susceptibility testing and static concentration time kill studies is gratefully acknowledged. This work was supported by the National Institute of Allergy and Infectious Diseases at the National Institutes of Health (Award Numbers R01AI079330 and R01AI111990 ). J.L. is an Australian National Health and Medical Research Council (NHMRC) Principal Research Fellow. 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.
Funding Information:
The assistance of Rebecca E. Imperial for the susceptibility testing and static concentration time kill studies is gratefully acknowledged. This work was supported by the National Institute of Allergy and Infectious Diseases at the National Institutes of Health (Award Numbers R01AI079330 and R01AI111990). J.L. is an Australian National Health and Medical Research Council (NHMRC) Principal Research Fellow. 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.
Publisher Copyright:
© 2023 American Pharmacists Association
PY - 2024/1
Y1 - 2024/1
N2 - Colistin is a polymyxin and peptide antibiotic that can yield rapid bacterial killing, but also leads to resistance emergence. We aimed to develop a novel experimental and Quantitative and Systems Pharmacology approach to distinguish between inducible and non-inducible resistance. Viable count profiles for the total and less susceptible populations of Pseudomonas aeruginosa ATCC 27853 from static and dynamic in vitro infection models were simultaneously modeled. We studied low and normal initial inocula to distinguish between inducible and non-inducible resistance. A novel cutoff filter approach allowed us to describe the eradication and inter-conversion of bacterial populations. At all inocula, 4.84 mg/L of colistin (sulfate) yielded ≥4 log10 killing, followed by >4 log10 regrowth. A pre-existing, less susceptible population was present at standard but not at low inocula. Formation of a non-pre-existing, less susceptible population was most pronounced at intermediate colistin (sulfate) concentrations (0.9 to 5 mg/L). Both less susceptible populations inter-converted with the susceptible population. Simultaneously modeling of the total and less susceptible populations at low and standard inocula enabled us to identify the de novo formation of an inducible, less susceptible population. Inducible resistance at intermediate colistin concentrations highlights the importance of rapidly achieving efficacious polymyxin concentrations by front-loaded dosage regimens.
AB - Colistin is a polymyxin and peptide antibiotic that can yield rapid bacterial killing, but also leads to resistance emergence. We aimed to develop a novel experimental and Quantitative and Systems Pharmacology approach to distinguish between inducible and non-inducible resistance. Viable count profiles for the total and less susceptible populations of Pseudomonas aeruginosa ATCC 27853 from static and dynamic in vitro infection models were simultaneously modeled. We studied low and normal initial inocula to distinguish between inducible and non-inducible resistance. A novel cutoff filter approach allowed us to describe the eradication and inter-conversion of bacterial populations. At all inocula, 4.84 mg/L of colistin (sulfate) yielded ≥4 log10 killing, followed by >4 log10 regrowth. A pre-existing, less susceptible population was present at standard but not at low inocula. Formation of a non-pre-existing, less susceptible population was most pronounced at intermediate colistin (sulfate) concentrations (0.9 to 5 mg/L). Both less susceptible populations inter-converted with the susceptible population. Simultaneously modeling of the total and less susceptible populations at low and standard inocula enabled us to identify the de novo formation of an inducible, less susceptible population. Inducible resistance at intermediate colistin concentrations highlights the importance of rapidly achieving efficacious polymyxin concentrations by front-loaded dosage regimens.
KW - Adaptive resistance
KW - Colistin
KW - Dynamic in vitro infection model
KW - Inducible resistance
KW - Mechanism-based modeling
KW - Pharmacokinetics/pharmacodynamics
KW - Polymyxins
KW - Pseudomonas aeruginosa
KW - S-ADAPT
KW - Static concentration time-kill studies
UR - http://www.scopus.com/inward/record.url?scp=85176598847&partnerID=8YFLogxK
U2 - 10.1016/j.xphs.2023.10.029
DO - 10.1016/j.xphs.2023.10.029
M3 - Article
C2 - 37879409
AN - SCOPUS:85176598847
SN - 0022-3549
VL - 113
SP - 202
EP - 213
JO - Journal of Pharmaceutical Sciences
JF - Journal of Pharmaceutical Sciences
IS - 1
ER -