Elucidation of the pharmacokinetic/pharmacodynamic determinants of fosfomycin activity against Pseudomonas aeruginosa using a dynamic in vitro model

Hajira Bilal, Anton Y. Peleg, Michelle P. McIntosh, Ian K. Styles, Elizabeth B. Hirsch, Cornelia B. Landersdorfer, Phillip J. Bergen

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Objectives: To identify the fosfomycin pharmacokinetic (PK)/pharmacodynamic (PD) index (fT > MIC, fAUC/MIC or fCmax/MIC) most closely correlated with activity against Pseudomonas aeruginosa and determine the PK/PD target associated with various extents of bacterial killing and the prevention of emergence of resistance. 

Methods: Dose fractionation was conducted over 24 h in a dynamic one-compartment in vitro PK/PD model utilizing P. aeruginosa ATCC 27853 and two MDR clinical isolates (CR 1005 and CW 7). In total, 35 different dosing regimens were examined across the three strains. Microbiological response was examined by log changes and population analysis profiles. A Hill-type Emax model was fitted to the killing effect data (expressed as the log10 ratio of the area under the cfu/mL curve for treated regimens versus controls). 

Results: Bacterial killing of no more than ~3 log10 cfu/mL was achieved irrespective of regimen. The fAUC/MIC was the PK/PD index most closely correlated with efficacy (R2=0.80). The fAUC/MIC targets required to achieve 1 and 2 log10 reductions in the area under the cfu/mL curve relative to growth control were 489 and 1024, respectively. No regimen was able to suppress the emergence of resistance, and near-complete replacement of susceptible with resistant subpopulations occurred with virtually all regimens. 

Conclusions: Bacterial killing for fosfomycin against P. aeruginosa was most closely associated with the fAUC/MIC. Suppression of fosfomycin-resistant subpopulations could not be achieved even with fosfomycin exposures well above those that can be safely achieved clinically.

Original languageEnglish
Pages (from-to)1570-1578
Number of pages9
JournalJournal of Antimicrobial Chemotherapy
Volume73
Issue number6
DOIs
Publication statusPublished - 1 Jun 2018

Cite this

@article{13a2c122c54a48f58279a53c31d1e8fc,
title = "Elucidation of the pharmacokinetic/pharmacodynamic determinants of fosfomycin activity against Pseudomonas aeruginosa using a dynamic in vitro model",
abstract = "Objectives: To identify the fosfomycin pharmacokinetic (PK)/pharmacodynamic (PD) index (fT > MIC, fAUC/MIC or fCmax/MIC) most closely correlated with activity against Pseudomonas aeruginosa and determine the PK/PD target associated with various extents of bacterial killing and the prevention of emergence of resistance. Methods: Dose fractionation was conducted over 24 h in a dynamic one-compartment in vitro PK/PD model utilizing P. aeruginosa ATCC 27853 and two MDR clinical isolates (CR 1005 and CW 7). In total, 35 different dosing regimens were examined across the three strains. Microbiological response was examined by log changes and population analysis profiles. A Hill-type Emax model was fitted to the killing effect data (expressed as the log10 ratio of the area under the cfu/mL curve for treated regimens versus controls). Results: Bacterial killing of no more than ~3 log10 cfu/mL was achieved irrespective of regimen. The fAUC/MIC was the PK/PD index most closely correlated with efficacy (R2=0.80). The fAUC/MIC targets required to achieve 1 and 2 log10 reductions in the area under the cfu/mL curve relative to growth control were 489 and 1024, respectively. No regimen was able to suppress the emergence of resistance, and near-complete replacement of susceptible with resistant subpopulations occurred with virtually all regimens. Conclusions: Bacterial killing for fosfomycin against P. aeruginosa was most closely associated with the fAUC/MIC. Suppression of fosfomycin-resistant subpopulations could not be achieved even with fosfomycin exposures well above those that can be safely achieved clinically.",
author = "Hajira Bilal and Peleg, {Anton Y.} and McIntosh, {Michelle P.} and Styles, {Ian K.} and Hirsch, {Elizabeth B.} and Landersdorfer, {Cornelia B.} and Bergen, {Phillip J.}",
year = "2018",
month = "6",
day = "1",
doi = "10.1093/jac/dky045",
language = "English",
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pages = "1570--1578",
journal = "Journal of Antimicrobial Chemotherapy",
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Elucidation of the pharmacokinetic/pharmacodynamic determinants of fosfomycin activity against Pseudomonas aeruginosa using a dynamic in vitro model. / Bilal, Hajira; Peleg, Anton Y.; McIntosh, Michelle P.; Styles, Ian K.; Hirsch, Elizabeth B.; Landersdorfer, Cornelia B.; Bergen, Phillip J.

In: Journal of Antimicrobial Chemotherapy, Vol. 73, No. 6, 01.06.2018, p. 1570-1578.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Elucidation of the pharmacokinetic/pharmacodynamic determinants of fosfomycin activity against Pseudomonas aeruginosa using a dynamic in vitro model

AU - Bilal, Hajira

AU - Peleg, Anton Y.

AU - McIntosh, Michelle P.

AU - Styles, Ian K.

AU - Hirsch, Elizabeth B.

AU - Landersdorfer, Cornelia B.

AU - Bergen, Phillip J.

PY - 2018/6/1

Y1 - 2018/6/1

N2 - Objectives: To identify the fosfomycin pharmacokinetic (PK)/pharmacodynamic (PD) index (fT > MIC, fAUC/MIC or fCmax/MIC) most closely correlated with activity against Pseudomonas aeruginosa and determine the PK/PD target associated with various extents of bacterial killing and the prevention of emergence of resistance. Methods: Dose fractionation was conducted over 24 h in a dynamic one-compartment in vitro PK/PD model utilizing P. aeruginosa ATCC 27853 and two MDR clinical isolates (CR 1005 and CW 7). In total, 35 different dosing regimens were examined across the three strains. Microbiological response was examined by log changes and population analysis profiles. A Hill-type Emax model was fitted to the killing effect data (expressed as the log10 ratio of the area under the cfu/mL curve for treated regimens versus controls). Results: Bacterial killing of no more than ~3 log10 cfu/mL was achieved irrespective of regimen. The fAUC/MIC was the PK/PD index most closely correlated with efficacy (R2=0.80). The fAUC/MIC targets required to achieve 1 and 2 log10 reductions in the area under the cfu/mL curve relative to growth control were 489 and 1024, respectively. No regimen was able to suppress the emergence of resistance, and near-complete replacement of susceptible with resistant subpopulations occurred with virtually all regimens. Conclusions: Bacterial killing for fosfomycin against P. aeruginosa was most closely associated with the fAUC/MIC. Suppression of fosfomycin-resistant subpopulations could not be achieved even with fosfomycin exposures well above those that can be safely achieved clinically.

AB - Objectives: To identify the fosfomycin pharmacokinetic (PK)/pharmacodynamic (PD) index (fT > MIC, fAUC/MIC or fCmax/MIC) most closely correlated with activity against Pseudomonas aeruginosa and determine the PK/PD target associated with various extents of bacterial killing and the prevention of emergence of resistance. Methods: Dose fractionation was conducted over 24 h in a dynamic one-compartment in vitro PK/PD model utilizing P. aeruginosa ATCC 27853 and two MDR clinical isolates (CR 1005 and CW 7). In total, 35 different dosing regimens were examined across the three strains. Microbiological response was examined by log changes and population analysis profiles. A Hill-type Emax model was fitted to the killing effect data (expressed as the log10 ratio of the area under the cfu/mL curve for treated regimens versus controls). Results: Bacterial killing of no more than ~3 log10 cfu/mL was achieved irrespective of regimen. The fAUC/MIC was the PK/PD index most closely correlated with efficacy (R2=0.80). The fAUC/MIC targets required to achieve 1 and 2 log10 reductions in the area under the cfu/mL curve relative to growth control were 489 and 1024, respectively. No regimen was able to suppress the emergence of resistance, and near-complete replacement of susceptible with resistant subpopulations occurred with virtually all regimens. Conclusions: Bacterial killing for fosfomycin against P. aeruginosa was most closely associated with the fAUC/MIC. Suppression of fosfomycin-resistant subpopulations could not be achieved even with fosfomycin exposures well above those that can be safely achieved clinically.

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U2 - 10.1093/jac/dky045

DO - 10.1093/jac/dky045

M3 - Article

VL - 73

SP - 1570

EP - 1578

JO - Journal of Antimicrobial Chemotherapy

JF - Journal of Antimicrobial Chemotherapy

SN - 0305-7453

IS - 6

ER -