by author How to effectively report laboratory findings to clinicians (Breakpoints and Interpretation)

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1 How to effectively report laboratory findings to clinicians (Breakpoints and Interpretation) A Vatopoulos National School of Public Health & Central Public Health Laboratory KEELPNO

2 Antibiotic Activity Microbiological (in vitro). Clinical (in vivo). 1 December 2011 Basic definitions 2 Antibiotic Resistance Microbiological (in vitro). Clinical (in vivo).

3 3 IN VITRO

4 Ιn vitro activity Minimum Inhibition concentration (MIC) MIC: Minimum Inhibition Concentration of the antibiotic that inhibits in vitro bacterial growth 4

5 The in vitro activity of an antibiotic is expressed in vitro as distributions of MICs or zone diameters If the population is homogeneous the distribution is normal Wild Type Population: A bacterial population without resistance 1 December 2011 Ιn vitro activity 5

6 5/4/2008 EUCAST Wild Type distributions 6

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12 Defining wild type population 12

13 Bacterial Resistance Emergence of a mechanism of resistance in a bacterial population (clone). Decrease activity (in vitro) Increase MIC in this population. Distortion of the normal distribution of MIC Emergence of subpopulation (-s) 13

14 Microbiological definition of resistance Emergence of resistance mechanism Emergence of a subpopulation with elevated MIC. 1 December

15 % December 2011 Penicillin G Etest (mcg/ml) S. Pneumoniae Distribution of ΜΙCs WT population Resistant subpopulation > < % Erythromycin < > Etest (mcg/ml) WT population Resistant subpopulation

16 % Resistance to CIP 1 December 2011 Histogram of zone diameters around ciprofloxacin disks, E. coli Greece Resistant subpopulation Zone diameter (mm) >4

17 Some times mechanisms are not phenotypically apparent. There is no change in MIC 17

18 Microbiological resistance Result of a genetic event emergence of a mechanism. Relevance in Epidemiology. Early detection and understanding. Clinical relevance? 18

19 19 In vivo

20 Clinical Criterion: 1 December 2011 Clinical activity Will the patient be cured? Pharmacological criterion: Will serum levels be higher than MIC; Pharmacokinetic / Pharmacodynamic predictors (PK/PD). 20

21 Pharmacokinetic / Pharmacodynamic predictors (PK/PD). Time > MIC AUC /MIC (24h) Cmax/MIC 1 December

22 Pharmacokinetic / Pharmacodynamic predictors (PK/PD). IN VITRO studies Concentration depended killing Time depended killing Post antibiotic effect Delayed regrowth Rapid regrowth 22

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24 24 Turnidge & Paterson 2007

25 Clinical Resistance Clinical outcome. Clinical studies. Pharmacological criteria: PK/PD parameters. 25

26 Defining Resistance Clinical criterion: Will patient be cured? Pharmacological criterion: Are serum (infection cite) levels enough to kill the organisms? Microbiological criterion: Is there a resistance mechanism? 26

27 Detecting Antibiotic Resistance As a properly to the organism. The presence of the resistance mechanism will be detected Resistance <=> mechanism. «biological» resistance. 27 As a property associated with the patient. In vivo resistance is detected resistance <=> clinical failure «clinical» resistance

28 BREAKPOINT: The point on the antibiogramme that will discriminate resistant from sensitive strains 28

29 Microbiological. Discriminates bacteria with mechanisms. Based on MIC destributions BREAKPOINT. 29 Clinical. Discriminates the clinical resistant strains. The breakpoint is based on criteria. PK/PD Clinical studies

30 Microbiological Discriminate wild type population Has (mainly) epidemiological value Early detection of mechanisms BREAKPOINT. 30 Clinical Detects clinical resistance Has clinical value

31 Microbiological: Is a physical quantity Defined by MIC distributions 1 December 2011 BREAKPOINT. 31 Clinical : Is defined by the clinical outcome Can depend on: dosage. Rute of administration Is defined by committees CLSI EUCAST

32 5/4/ S. pyogenes. Clinical Breakpoints Βiological BP Clinical ΒΡ ΕΘνική Σχολή Δημόσιας Υγείας, Εργαστήριο Μικροβιολογίας

33 % Resistance to CIP 1 December 2011 Histogram of zone diameters around ciprofloxacin disks, E. coli Greece Clinical ΒΡ Zone diameter (mm) Βiological BP >4

34 New Mechanism of Resistance do Emerge. ESBL VRE MRSA Carbapenemases

35 New mechanism Increase in MIC Clinical issues Epidemiological issues

36 A main issue: How important is the monitoring of a mechanism in Epidemiology & Public Health?; How important is for clinical practice the presence of a mechanism How the presence of a mechanism will amend Breakpoints; 36

37 Important issues : To predict clinical effectiveness ; Is measurement of MIC enough; Is it important to detect the mechanism ; Will and how the emergence of a mechanism will influence Breakpoints; 37

38 Clinical studies 1 December Answers: Microbiological studies Pharmacological studies Purpose: How clinical resistance will be detected

39 VIM negative VIM positive 1 December 2011 Zone diameter distribution

40 KPC (+) Automatic Instruments

41 Distribution of Meropenem MICs for 372 Consecutive Kp Bloodstream Isolates 1 December 2011 G. Daikos unpublished

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44 K. pneumoniae with MICS 0.5μg/ml Negative MBL (PCR, E-test-Imp/Imp+EDTA). K. pneumoniae with MICs 1μg/ml or zone dieameter Imp <19mm should be tested for ΜΒLs. 1 December 2011 D. Petropoulou, K. Tzanetou, G. Ganteris, V. Syriopoulou, G. Daikos, E. Malamou-Lada. Evaluation of Imipenem/Imipenem+EDTA disc method for detection of metallo-b-lactamase producing K. pneumoniae isolated from blood cultures. Microbial Drug Resistance, Spring;12(1):39-43

45 What is the clinical breakpoint? Must we seek the mechanism? Can we afford not to use carbapenems in a era of broad resistance? 1 December 2011

46 Bulic CC et al Antimicrob Agents Chemother 2010; 54: December 2011 ft>mic 100% ft>mic 75%

47 In Vivo Killing Kinetics of VIM and Non-VIM- Producing K. pneumoniae in the Thighs of Neutropenic Mice Treated with Imipenem 1 December 2011 VIM-negative MIC=0.125 μg/ml VIM-positive MIC=2 μg/ml Daikos GL et al Clin Microbiol Infect 2007; 13:

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51 MIC (μg/ml) 1 December 2011 Outcome of Patients with CPKP Infections Treated with a Carbapenem According to MICs No. of failures/ No. of patients Failure rate (%) 1 5/ / / / >8 6/8 75 Data compiled from 15 studies published in English literature

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53 To conclude The determination of (clinical) susceptibility is a dynamic process that depends on: The emergence of (new) mechanisms The development of (new) scientific data. 53

54 How to effectively report laboratory 1 December 2011 findings to clinicians? Use (EUCAST) clinical breakpoints Report phase value MIC <4 mg/l Report presence of mechanism mainly for Epidemiology