TY - JOUR
T1 - Antimicrobial breakpoints for Gram-negative aerobic bacteria based on pharmacokinetic-pharmacodynamic models with Monte Carlo simulation
AU - Frei, Christopher R.
AU - Wiederhold, Nathan P.
AU - Burgess, David S.
N1 - Funding Information:
This study was made possible by a research grant from the Society of Infectious Diseases Pharmacists. The results were presented in part at the following national meetings: (i) Enterobacteriaceae Working Group, The Committee for Clinical Laboratory Standards in Reston, VA, 26 June 2005; (ii) 43rd Annual Meeting of the Infectious Diseases Society of America in San Francisco, CA, 7 October 2005; (iii) Annual Meeting of the American College of Clinical Pharmacy in San Francisco, CA, 26 October 2005; and (iv) Annual Meeting of the American College of Clinical Pharmacy in St Louis, MO, 29 October 2006. The authors would like to thank Jessica Jimenez, BS-RN Candidate, for her editorial contributions to this manuscript.
Funding Information:
This study was made possible by an investigator development research award to C. R. F. from the Society of Infectious Diseases Pharmacists.
Funding Information:
C. R. F. has received research grants from AstraZeneca, Elan, OrthoMcNeil and Wyeth Pharmaceuticals. D. S. B. has received educational grants, honoraria and research grants and serves as a consultant for AstraZeneca, Elan, OrthoMcNeil and Wyeth Pharmaceuticals. N. P. W. has received research support from Pfizer and Schering-Plough.
PY - 2008/3
Y1 - 2008/3
N2 - Objectives: This study describes a comprehensive programme designed to develop pharmacokinetic-pharmacodynamic (PK-PD) breakpoints for numerous antimicrobial classes against key Gram-negative aerobic bacteria. Methods: A 10 000 subject Monte Carlo simulation was constructed for 13 antimicrobials (21 dosing regimens). Published pharmacokinetic data and protein binding were varied according to log-normal and uniform distributions. MICs were fixed at single values from 0.03 to 64 mg/L. The PK-PD susceptible breakpoint was defined as the MIC at which the probability of target attainment was ≥90%. PK-PD, CLSI and European Committee on Antimicrobial Susceptibility Testing breakpoints were applied to MICs from the 2005 worldwide Meropenem Yearly Susceptibility Test Information Collection database to evaluate the impact of breakpoint discrepancies. Results: PK-PD breakpoints were within one dilution of the CLSI and European breakpoints for all antimicrobials tested - with a few exceptions. When discrepancies were noted, the PK-PD breakpoint was lower than the CLSI breakpoint [ceftriaxone (0.5 versus 8 mg/L), ertapenem (0.25 versus 2 mg/L), ciprofloxacin (0.125 versus 1 mg/L) and levofloxacin (0.25-0.5 versus 2 mg/L)] and higher than the European breakpoint [ceftazidime (4-8 versus 1 mg/L), aztreonam (4-8 versus 1 mg/L), although ciprofloxacin was an exception to this pattern (0.125 versus 0.5-1 mg/L)]. For Enterobacteriaceae, breakpoint discrepancies resulted in modest (≤10%) differences in the percentages susceptible. In contrast, large (>15%) discrepancies were noted for Pseudomonas aeruginosa and Acinetobacter baumannii. Conclusions: Breakpoint agreement exists for imipenem, meropenem and the aminoglycosides. In contrast, discrepancies exist for piperacillin/ tazobactam, cephalosporins, ertapenem, aztreonam and the fluoroquinolones. These discrepancies are most pronounced for P. aeruginosa and A. baumannii.
AB - Objectives: This study describes a comprehensive programme designed to develop pharmacokinetic-pharmacodynamic (PK-PD) breakpoints for numerous antimicrobial classes against key Gram-negative aerobic bacteria. Methods: A 10 000 subject Monte Carlo simulation was constructed for 13 antimicrobials (21 dosing regimens). Published pharmacokinetic data and protein binding were varied according to log-normal and uniform distributions. MICs were fixed at single values from 0.03 to 64 mg/L. The PK-PD susceptible breakpoint was defined as the MIC at which the probability of target attainment was ≥90%. PK-PD, CLSI and European Committee on Antimicrobial Susceptibility Testing breakpoints were applied to MICs from the 2005 worldwide Meropenem Yearly Susceptibility Test Information Collection database to evaluate the impact of breakpoint discrepancies. Results: PK-PD breakpoints were within one dilution of the CLSI and European breakpoints for all antimicrobials tested - with a few exceptions. When discrepancies were noted, the PK-PD breakpoint was lower than the CLSI breakpoint [ceftriaxone (0.5 versus 8 mg/L), ertapenem (0.25 versus 2 mg/L), ciprofloxacin (0.125 versus 1 mg/L) and levofloxacin (0.25-0.5 versus 2 mg/L)] and higher than the European breakpoint [ceftazidime (4-8 versus 1 mg/L), aztreonam (4-8 versus 1 mg/L), although ciprofloxacin was an exception to this pattern (0.125 versus 0.5-1 mg/L)]. For Enterobacteriaceae, breakpoint discrepancies resulted in modest (≤10%) differences in the percentages susceptible. In contrast, large (>15%) discrepancies were noted for Pseudomonas aeruginosa and Acinetobacter baumannii. Conclusions: Breakpoint agreement exists for imipenem, meropenem and the aminoglycosides. In contrast, discrepancies exist for piperacillin/ tazobactam, cephalosporins, ertapenem, aztreonam and the fluoroquinolones. These discrepancies are most pronounced for P. aeruginosa and A. baumannii.
KW - Acinetobacter
KW - Computer modelling
KW - Pseudomonas
KW - Stochastic
KW - β-lactam antibiotics
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U2 - 10.1093/jac/dkm536
DO - 10.1093/jac/dkm536
M3 - Article
C2 - 18252694
AN - SCOPUS:40049093397
SN - 0305-7453
VL - 61
SP - 621
EP - 628
JO - Journal of Antimicrobial Chemotherapy
JF - Journal of Antimicrobial Chemotherapy
IS - 3
ER -