Setting and revising antibacterial susceptibility breakpoints

Abstract

Clinical microbiology laboratories need to communicate results of antibacterial susceptibility testing to prescribers. Sophisticated prescribers who are knowledgeable of the pharmacokinetics and pharmacodynamics of antibacterials may desire no more information than the MIC of the drug in question. However, most prescribers require interpretation of antibacterial susceptibility testing results. Breakpoints can assist in determining if an antibacterial is potentially useful in the treatment of a bacterial infection. Breakpoints should be set prior to an antibacterial being used clinically. Breakpoint setting requires integration of knowledge of the wild-type distribution of MICs, assessment of the pharmacokinetics/pharmacodynamics of the antibacterial, and study of the clinical outcome of infections when the antibacterial is used. It is mandatory that breakpoints be reviewed when antibacterial agents have been in clinical use for some time, particularly if mechanisms of bacterial resistance to the drug have been described. In general, greater amounts of information on the pharmacokinetics and pharmacodynamics of an antibacterial are available when breakpoints need to be revised. However, the opportunity to conduct randomized clinical studies of an antibacterial declines after the drug has been released commercially. Well-designed observational clinical studies are therefore necessary in order to provide reliable data to inform those reevaluating breakpoints. Breakpoint-setting organizations may also play a role in developing phenotypic tests for detection of resistance mechanisms, as this information may complement use of the breakpoint in some circumstances.

FIG. 1.

MIC distributions for four organism-antimicrobial pairs. In each case, the wild type appears as the log-normally distributed population at the lower MICs. CO_WT, calculated wild-type cutoff value. (Generated using data from http://217.70.33.99/Eucast2/ and reference .)

FIG. 2.

Relationship between PK/PD parameters and killing of Klebsiella pneumoniae by cefotaxime in the mouse pneumonia model. (Reprinted from reference with permission from Elsevier.)

FIG. 3.

(A) Fractional probability of target attainment (expressed as a percentage) of intravenous levofloxacin at 500 mg daily, based on PK in healthy volunteers. (Generated using data from reference .) (B) Fractional probability of target attainment of intravenous levofloxacin at 750 mg daily, based on PK in a clinical efficacy study, compared to MIC distributions of two major nosocomial pneumonia pathogens. (Reprinted from reference with permission. © 2004 by the Infectious Diseases Society of America. All rights reserved.)

FIG. 4.

“Scattergram” of MICs versus zone diameters. Numbers represent the number of isolates at each MIC/zone diameter pair (e.g., there were 17 isolates whose MICs were ≥256 mg/liter and whose zone diameters were ≤6 mm). (Reprinted from reference with permission of the publisher.)