Defining antibiotic resistance-towards international harmonization

Figures & data

Table I. Differences in breakpoints between seven breakpoint committees before the harmonization process.

	E. coli versus cefotaxime	E. coli versus gentamicin	%R in EARSS^a
	S≤/R>	S≤/R>
BSAC (United Kingdom)	2/2	1/1	14.3%
CA-SFM (France)	4/32	4/8	1.9%
CRG (Netherlands)	4/8	1/4	3.3%
DIN (Germany)	2/8	1/4	3.3%
NCCLS (CLSI) (USA)	8/32	4/4	3.3%
NWGA (Norway)	1/2	2/4	3.3%
SRGA (Sweden)	0.5/1	2/2	8.1%
EUCAST^b	1/2	2/4	3.3%

^aFrom some countries, MIC values were obtained as part of the activities in the European Resistance Surveillance System (EARSS), organized by EU and run by the Dutch institute RIVM (Bilthoven, the Netherlands). Resistance based on the various gentamicin breakpoints used by countries taking part in EARSS is shown to illustrate the effect on resistance surveillance that different breakpoints may have.

^bEUCAST breakpoints, as a result of the EUCAST process for harmonization of breakpoints (finalized for gentamicin in April 2004 and for cefotaxime March 2006).

Table II. Tools and information defined by EUCAST as necessary for determining breakpoints.

Tool, information	Outcome
Dose	Defined normal (most common) dose and maximum dose for which the breakpoints are valid.
Clinical indication(s)	Clinical indications for which there was reasonable clinical evidence and for which breakpoints are valid.
Target species	Species for which there was reasonable clinical evidence and for which breakpoints are valid.
MIC distributions for target species to define the epidemiological cut-off values (ECOFF).	Epidemiological cut-off value (ECOFF). Defined MIC distributions made available on the EUCAST website and the determination of the ECOFF for species where enough MIC values were obtained. The importance of this is that the final clinical breakpoint should not divide wild-type MIC distributions of important target organisms. This would obviate reproducible susceptibility testing.
Resistance mechanisms in target organisms	When there is obvious correlation between the presence of a defined resistance mechanism (or gene), the breakpoint should separate organisms without and with the resistance mechanism (gene). When the correlation is stronger with the MIC of the organism than with the presence or absence of a resistance mechanism, the breakpoint should be allowed to divide organisms without and with the mechanism (gene).
Pharmacokinetics of the agent; Pharmacodynamics of the agent; Mathematical simulations	PK/PD cut-off value.
Clinical outcome data (when related to MIC)—to determine if the clinical success rates are related to MICs or specific resistance mechanisms	Clinical cut-off value.

Figure 1. EUCAST ciprofloxacin MIC distributions from the EUCAST website (http://mic.eucast.org/Eucast2/SearchController/search.jsp?action=performSearch&BeginIndex=0&Micdif=mic&NumberIndex=50&Antib=47&Specium=-1).

Figure 2. E. coli ciprofloxacin MIC distribution from the EUCAST website, as a result of clicking on ‘E. coli’ in Figure 1 (http://mic.eucast.org/Eucast2/regShow.jsp?Id=1022).

Figure 3. E. coli inhibition zone diameter distribution as a result of changing view from ‘MIC’ to ‘Disk diffusion’ (http://mic.eucast.org/Eucast2/regShow.jsp?Id=26694).

Figure 4. Relationship between E. coli ciprofloxacin MICs and inhibition zone diameters used by EUCAST to determine the correlation between MICs and zone diameters and to determine zone diameter breakpoints. These are available at: http://www.eucast.org/antimicrobial_susceptibility_testing/calibration_and_validation/.