In what circunstances is the MIC really needed? Dr JR Zahar Infection Control Unit CHU d Angers Université d Angers

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1 In what circunstances is the MIC really needed? Dr JR Zahar Infection Control Unit CHU d Angers Université d Angers 1

2 Plan PK/PD parameters that we should reach Correlation between MIC and cure or failure MRSA GNB What about «alternatives» treatment for ESBL Conclusion 2

3 Some considerations: Our objectives To cure the patient To avoid resistance What do we know? Antibiotic time dependent Antibiotic concentration dependent Could we predict efficacy? We have some parameters It depend of concentration at the site of infection 3

4 Parameters that predict efficacy (ex) ATB/specie T>MIC for bactericidal activity Third G CSP/enterobactericeae 70% Third G CSP/S aureus 40% Third G CSP/ S pneumoniae 40% Amoxicillin/ S pneumoniae 50% Third G CP: thrid generation cephalosporin 4 Craig et al, Diagn Microbiol Inf Dis 1995

5 There are some problems due to severe infections Different molecules= different diffusion Different site of infection = different diffusion Parameters of efficacy are different? GNB infection? T > 8 MIC = 100% Substantial change in drug PK/PD encountered Most importantly, the majority of efficacy data, establishing standard antibiotic doses are derived from studies in healthy volunteers or ward patients 5

6 Is there any relation between MIC and cure? 6

7 Aminoglycosides 236 patients with Gram-negative bacterial infection treated with aminoglycosides (gentamicin, tobramycin or amikacin) Maximum Cmax / MIC Ratio Moore, JID 1987 Moore et al, J Inf Dis

8 Percentage of patients cured (%) 100 Fluoroquinolones Pneumonia in seriouly ill patients Clinically Microbiologically >500 AUC/MIC at 24 hours Forrest et al, AAC

9 9 Dulhunty et al, Clin Inf Dis 2013

10 What are the problems related with the spread of resistance More patients infected with resistant strains Alhashash et al, Emerg Inf Dis 2013 More sensitive strains with decreased susceptibility Robert et al, JAC 2006 More alternative antibiotics proposed (with limited data!) Rodriguez-Bano et al, Clin Inf Dis 20 10

11 11 Robert et al, JAC 2006

12 Prospective study, including 414 MRSA bacteremia Groups studied: Vancomycin with strains 1mg/l Vancomycin with strains 1,5 mg/l Vancomycin with strains 2 mg/l Inapropriate treatment 12 Soriano et al, Clin Inf Dis 2008

13 Initial response based on target trough achievement Final response based on target trough achievement 13 Hidayat et al, Ann Int Med 2006

14 Pharmacodynamics of Vancomycin and Other Antimicrobials in Patients with Staphylococcus aureus Lower Respiratory Tract Infections Moise-Broder PA et al., Clin Pharmacokinet

15 Pharmacodynamics of Vancomycin and Other Antimicrobials in Patients with Staphylococcus aureus Lower Respiratory Tract Infections Moise-Broder PA et al., Clin Pharmacokinet 2004 MIC = 1 mg/l MIC = 2 mg/l Probability of achieving AUC/MIC (with trough concentration) 10 mg/l 15 mg/l 10 mg/l 15 mg/l 40% 60% 0% 0% 15

16 16 Van Hal et al, Clin Inf Dis 2012

17 17 Chang et al, JAC 2012

18 Retrospective cohort study, including 118 vancomycin treated patients with 59 daptomycin treated patients (all with vancomycin MIC >1mg/l) 18 Moore et al, Clin inf Dis 2012

19 19 Murray et al, Clin Inf Dis 2013

20 Retrospective study including 312 GNB Groups studied:» Low MIC < 0.25 mg/l» Intermediate 0.5 mg/l» High 1-2 mg/l 20 Defifie et al, AAC 2009

21 Higher risk of failure in case of Salmonella infection with high fluoroquinolones MICs In Enterobacteriacea infection, higher all cause mortality for patients infected with high MICs In non fermentative GNB more frequent failure and higher risk of mortality with high MICs 21 Falagas et al, AAC 2012

22 Rodriguez-Bano et al, Clin Inf Dis, Jan 2012,

23 Failure and MIC - ESBL 23 Craig et al, Clin Microb Inf 2005

24 Treatment with PIP/TAZ of ESBL-coli bacteremia (n=39) 24 Retamar et al AAC 2013

25 Paterson et al, JCM

26 26 Lee et al, Clin Inf Dis 2013

27 27 Lee et al, Clin Inf Dis 2013

28 28 Esterly et al, AAC 2013

29 ESBL-new breakpoints S< MIC mg/l R> Cefoxitine Cefotaxime Cefepime Piperacilline - Tazobactam Tigecycline

30 ESBL -Beware of diameters For cefoxitin CMI 59 (83%) of Klebsiella sp are sensitive (according to diameter) 55 (77%) of Klebsiella sp are sensitive (according to E- test) Diamètre 30

31 ESBL -Beware of diameters For Pipera-tazobactam 65 (91%) of Klebsiella sp are sensitive (according to diameter) CMI 64 (90%) of Klebsiella sp are sensitive (according to E- test) Diamètre 31

32 ESBL -Beware of diameters E. coli K. pneumoniae E. clocae Nb of isolates with a diameter 21 (mm) 133/144 (92,4%) 74/111 (66,7%) 21/48 (43,7%) Nb of isolates with MIC 8 mg/l 128/133 (96,2%) 51/74 (68,9%) 9/21 (42,8%) MIC 50 % (mg/l) MIC min (mg/l) 0,5 0,19 0,125 MIC max (mg/l) Data for Piperacillin Tazobactam 32

33 The antibiogramm gives you Diameters!!!, correlated with MIC A range of susceptibility The diameters may not correspond to the real susceptibility A sensitive strains could be more or less sensitive The reference test is the E-Test 33

34 In what circunstances is the MIC really needed? The new indications Decrease susceptibility but isolates still Sensitive New antibiotics with a higher PK/PD activity (ie Daptomycin) Use old antibiotics (or alternatives) with a high risk of failure (ie ESBL-Cephalosporins or KPC and Carbapenems) 34

35 In what circunstances is the MIC really needed? Site of infection (non drainable) Specific clincal situation (ie, Septic shock and hemodiafiltration) CAUSE OF FAILURE Bacteria with number of resistance mechanisms Wrong antibiotic/ wrong dosage according to MIC 35

36 Cause of failure! Antibiotics-Site of infection Using heavy molecules (Colsitin-Glycopetides) Non drainable infections (VAP) I ask for test antimicrobial susceptibility AND Infectious focus difficult to reach PLASMATIC DOSAGE Cerebral abcess Endocarditis Difficult to treat bacteria/ resistance mechanisms Carbapenemases MDR-Pseudomonas aeruginosa 36