A Long Journey from Minimum Inhibitory Concentration Testing to Clinically Predictive Breakpoints: Deterministic and Probabilistic Approaches in Deriving Breakpoints

  title={A Long Journey from Minimum Inhibitory Concentration Testing to Clinically Predictive Breakpoints: Deterministic and Probabilistic Approaches in Deriving Breakpoints},
  author={Axel Dalhoff and Paul G. Ambrose and Johan W. Mouton},
AbstractSince the origin of an "‘International Collaborative Study on Antibiotic Sensitivity Testing’" in 1971, considerable advancement has been made to standardize clinical susceptibility testing procedures of antimicrobial agents. However, a consensus on the methods to be used and interpretive criteria was not reached, so the results of susceptibility testing were discrepant. Recently, the European Committee on Antimicrobial Susceptibility Testing achieved a harmonization of existing methods… 

MASTER: a model to improve and standardize clinical breakpoints for antimicrobial susceptibility testing using forecast probabilities

It is demonstrated that CBPs can be improved and standardized by minimizing methodological categorization error rates and ZMUs may be introduced if an intermediate zone is not appropriate for pharmacokinetic/pharmacodynamic or drug dosing reasons.

Breakpoints for carbapenemase-producing Enterobacteriaceae: is the problem solved?

New Susceptibility Breakpoints for First-Line Antituberculosis Drugs Based on Antimicrobial Pharmacokinetic/Pharmacodynamic Science and Population Pharmacokinetic Variability

  • T. Gumbo
  • Medicine, Biology
    Antimicrobial Agents and Chemotherapy
  • 2010
Current critical concentrations of first-line antituberculosis drugs are overoptimistic and should be set lower with the proposed breakpoints, because the rates of multidrug-resistant tuberculosis could become 4-fold higher than currently assumed.

Declining susceptibilities of gram-negative bacteria to the fluoroquinolones: effects on pharmacokinetics, pharmacodynamics, and clinical outcomes.

  • M. LabrecheC. Frei
  • Medicine, Biology
    American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists
  • 2012
Evidence of rising gram-negative bacterial resistance to fluoroquinolone therapy is reviewed, with a focus on the potential need for revising pharmacokinetic-pharmacodynamic targets in order to maintain acceptable clinical outcomes.

Use of Monte Carlo simulation to determine pharmacodynamic cutoffs of amoxicillin to establish a breakpoint for antimicrobial susceptibility testing in pigs.

Population kinetics and MCS are required to determine robust species-specific interpretive criteria (susceptible, intermediate, and resistant classifications) for antimicrobial susceptibility testing breakpoints (taking into account interanimal variability).

Advanced Phenotypic Antimicrobial Susceptibility Testing Methods

This chapter will address rapid phenotypic susceptibility testing methods, which mean that detection of growth from a pure culture with a defined inoculum is determined more rapidly than can be done with traditional methods.

Multicenter Study of the Relationship between Carbapenem MIC Values and Clinical Outcome of Patients with Acinetobacter Bacteremia

It is revealed that patients with Acinetobacter bacteremia treated with a carbapenem had a more favorable outcome when the carbapENem MICs of their isolates were ≤4 mg/liter than those withMICs of ≥8mg/liter.

En Route towards European Clinical Breakpoints for Veterinary Antimicrobial Susceptibility Testing: A Position Paper Explaining the VetCAST Approach

The procedures and reviews scientific options to solve challenges for the determination of specific CBPs for animal species, drug substances and disease conditions are outlined and expert comments and/or recommendations associated with CBPs are vetted to facilitate their sound implementation in a clinical setting.



Establishing MIC breakpoints and the interpretation of in vitro susceptibility tests.

This paper attempts to summarize the philosophy of the British Society for Antimicrobial Chemotherapy (BSAC) Working Party in its approach to setting breakpoints and to update the activities of the Working Party since it initially published breakpoints, approximately 10 years ago.

Impact of pharmacodynamics on breakpoint selection for susceptibility testing.

  • J. Mouton
  • Medicine
    Infectious disease clinics of North America
  • 2003

Pharmacodynamics in the study of drug resistance and establishing in vitro susceptibility breakpoints: ready for prime time.

Monte Carlo Simulation in the Evaluation of Susceptibility Breakpoints: Predicting the Future: Insights from the Society of Infectious Diseases Pharmacists

Pharmacokinetic‐pharmacodynamic target attainment analyses using Monte Carlo simulation to integrate interpatient variability in drug exposure, drug potency, and in vivo exposure targets predictive of positive therapeutic outcomes are influencing antibacterial susceptibility breakpoints at home and abroad.

Treatment of infections with ESBL-producing organisms: pharmacokinetic and pharmacodynamic considerations.

  • D. AndesW. Craig
  • Biology, Medicine
    Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases
  • 2005
Susceptibility surveillance investigations have demonstrated an increased incidence of ESBL-producing Gram-negative bacilli. Case cohort studies have suggested clinical relevance associated with

History and development of antimicrobial susceptibility testing methodology.

  • P. Wheat
  • Medicine
    The Journal of antimicrobial chemotherapy
  • 2001
The history and development of some methods still in common use for routine AST, e.g. disc diffusion and agar dilution are traced, to increase the speed and reliability of resistance testing, the use of a genotypic approach has been advocated.

Streptococcus pneumoniae in the USA: in vitro susceptibility and pharmacodynamic analysis.

Children 12 years of age were significantly more likely to be infected with a penicillin-resistant pneumococcus than were adolescents or adults, and this finding may explain the lack of clinical response in patients treated with these antibiotics.

The Importance of Pharmacokinetic/Pharmacodynamic Surrogate Markers to Outcome

Pharmacokinetic/pharmacodynamic surrogate relationships have been used to describe the antibacterial activity of various classes of antimicrobial agents and AUIC24 may prove to be an important pharmacokinetic surrogate if both time and concentration are indeed important parameters.

Use of Preclinical Data for Selection of a Phase II/III Dose for Evernimicin and Identification of a Preclinical MIC Breakpoint

It is the thesis of this paper that rational dose-selection decisions can be made on the basis of the pharmacodynamics (PDs) of the test agent predicted by a mathematical model, and drug exposure or the ratio of the area under the concentration-time curve/MIC (AUC/MIC) was found to be the best predictor of microbiological efficacy.