1. Treatment of multiresistant gram positive endocarditis Prof. Ermanno Mazza MNX Baku, 2012

8. Gram positive responsible for IE, MDR MRSE (S. epidermidis) MRSE (S. epidermidis) MRSA MRSA VISA VISA Enterococci HLGR ( that means high level genta resistant) Enterococci HLGR ( that means high level genta resistant) VRE (Vanco resistant Enterococci) VRE (Vanco resistant Enterococci) VGS (Streptococci viridanse penicilline resistant) VGS (Streptococci viridanse penicilline resistant) MRSA 30% HLGR 20% VRE 5% VGS 8%

9. VISA For MRSA and MRSE recently appear a reduced susceptibility to Vancomycin (VISA) Vancomycin intermediate SA with For MRSA and MRSE recently appear a reduced susceptibility to Vancomycin (VISA) Vancomycin intermediate SA with will significantly reduce therapeutical effect will significantly reduce therapeutical effect In endocarditis, and bacterimia specially with this bacteria and sensibility is very important to check several times MIC and adapt the therapy to the results In endocarditis, and bacterimia specially with this bacteria and sensibility is very important to check several times MIC and adapt the therapy to the results MIC > 1-1,5

11. VISA mechanism The reduce susceptibility to Vancomycine appears to result from changes in PEPTIDOGLYCAN biosynthesis The reduce susceptibility to Vancomycine appears to result from changes in PEPTIDOGLYCAN biosynthesis VISA strains synthetaze additional quantities of PTGLC that result in irregularly thickened cell wall and with increase number of VISA strains synthetaze additional quantities of PTGLC that result in irregularly thickened cell wall and with increase number of Synthesis of a modified cell-wall precursor “ D-ALA-D- LACTATE” “ D-ALA-D- LACTATE” In PTGLC in the place of D-ALA D-ALA (Antibiotic binding target) that is Vanco place. D-ALA- D-LACTATE reduce the affinity of PTGLC for Glicopeptide (1000 times)

15. Today FDA for IE with MRSA Vanco-( with Genta or Rifam) Vanco-( with Genta or Rifam) Teicoplanin (Targosid) practical, single dose no renal failure problems, very well tolerated, but significant resistances, often high MIC Teicoplanin (Targosid) practical, single dose no renal failure problems, very well tolerated, but significant resistances, often high MIC Daptomicine (Cubicin), alone or in association Daptomicine (Cubicin), alone or in association Dalfopristine-Quinopristine (Synercide) side effects not very well tolerated Dalfopristine-Quinopristine (Synercide) side effects not very well tolerated Linezolide (Zivox) practical also for long time therapy (oral effective like IV) good in renal failure, bacterecidal for Streptococcus, bacteriostatic for Staphilococcus and Enterococcus Linezolide (Zivox) practical also for long time therapy (oral effective like IV) good in renal failure, bacterecidal for Streptococcus, bacteriostatic for Staphilococcus and Enterococcus

16. Tigecicline (Tigacil) the first clinically available drug in a new class of antibiotic called Glycylcyclines. It is similar to the Tetracyclines, derivated of Minocycline. Active for MRSA, MRSE, VISA, VRSA, VRE, Acinetobacter, Klebsiella. Bacteriostatic is not first choice for Endocarditis and Bacteremia, low resistances. Tigecicline (Tigacil) the first clinically available drug in a new class of antibiotic called Glycylcyclines. It is similar to the Tetracyclines, derivated of Minocycline. Active for MRSA, MRSE, VISA, VRSA, VRE, Acinetobacter, Klebsiella. Bacteriostatic is not first choice for Endocarditis and Bacteremia, low resistances. Fusidic Acid (Fucidin) bacteriostatic very effective in MRSA and MRSE and anaerobs( gram+/-), but with good penetration in lungs and blood (IE, septicimia). Fusidic Acid (Fucidin) bacteriostatic very effective in MRSA and MRSE and anaerobs( gram+/-), but with good penetration in lungs and blood (IE, septicimia).

17. Moxifloxacin, last generation of Chinolones, very active against MRSA, VRE with biofilm. Moxifloxacin, last generation of Chinolones, very active against MRSA, VRE with biofilm. Pharmacodinamic of Moxifloxacin versus Vancomicine against biofilm of MRSA and MRSE (Journale of chemiotherapy, 2010) Pharmacodinamic of Moxifloxacin versus Vancomicine against biofilm of MRSA and MRSE (Journale of chemiotherapy, 2010) Ceftobiprole, fifth generation of Cephalosporines, very active in MRSA and MRSE. Ceftobiprole, fifth generation of Cephalosporines, very active in MRSA and MRSE.

19. DAPTOMICIN DAPTOMICIN (Cubicin) a lipopeptide shows fast bactericidal activity against MRSA, MRSE even VISA and VRSE, with very low percent of resistances. DAPTOMICIN (Cubicin) a lipopeptide shows fast bactericidal activity against MRSA, MRSE even VISA and VRSE, with very low percent of resistances. Drug of choice every time, or only IE/ bacterimia from VISA? Drug of choice every time, or only IE/ bacterimia from VISA? Or in patient with an IE where from some reason, for example renal failure, is difficult to use Vanco + Gentamicine Or in patient with an IE where from some reason, for example renal failure, is difficult to use Vanco + Gentamicine

20. MRSA Bacteremia 400 patients, 1991-2005 400 patients, 1991-2005 All patients treated with Vanco All patients treated with Vanco ODDS ratio mortality following MIC ODDS ratio mortality following MIC 1 MIC 1 1 MIC 1 2,8 MIC 1,5 2,8 MIC 1,5 6,3 MIC 2 6,3 MIC 2 Cubicin study (Endocarditis) Cubicin study (Endocarditis) Daptomicine was successful 75% MRSA 71% Enterococci 50% MRSE

21. ICE (International collaboration of IE) 5117 pts from many countries (2000- 2007) with IE 31% of MRSA are VISA (MIC 2-4) with high mortality 50% 5117 pts from many countries (2000- 2007) with IE 31% of MRSA are VISA (MIC 2-4) with high mortality 50% At that time only possibility was to add LINEZOLID in monotherapy or on association with RIFAMPICINE and FUSIDIC ACID At that time only possibility was to add LINEZOLID in monotherapy or on association with RIFAMPICINE and FUSIDIC ACID

22. Association The association of any drug with RIFAMPICINE in IE on prostetic valve, or other intracardiac or intravascular prostetic material is very effective is very effective with a good sterilization of the foreign bodies, more effective that in simple IE

23. Compearing of the activity of different antibiotics versus biofilms A study about Staffilococcical adesivity (mediated by biofilm) to biomedical disposals, and the impact of different antibiotics, showed that, for the adesivity of MRSE to foreign bodies (dacrone filaments) the treatment with Daptomicine was more effective in the eradication of bacteria compare with Vanco and Cefotriaxon A study about Staffilococcical adesivity (mediated by biofilm) to biomedical disposals, and the impact of different antibiotics, showed that, for the adesivity of MRSE to foreign bodies (dacrone filaments) the treatment with Daptomicine was more effective in the eradication of bacteria compare with Vanco and Cefotriaxon

27. MRSA biofilm producer in IE central catheter related After 24 hours of exposition Daptomicine and Tigecicyline are more active against biofilm compare to Linezolid and Vanco After 24 hours of exposition Daptomicine and Tigecicyline are more active against biofilm compare to Linezolid and Vanco After 3 days Daptomicine showed a greater speed in destroying MRSA from biofilm followed by Tigecycline that was faster versus Linezolide, Rifa and Vanco. After 3 days Daptomicine showed a greater speed in destroying MRSA from biofilm followed by Tigecycline that was faster versus Linezolide, Rifa and Vanco.

29. Daptomicine resistance 5% Strong correlation between reduce sensibility to Daptomicine, and Vancomycine resistant in VISA Strong correlation between reduce sensibility to Daptomicine, and Vancomycine resistant in VISA A THIKENING of the bacterial wall like in VISA can contribute to resistance to Daptomicine in S.A. Daptomicine is MW > 1.620, so is difficult penetrate the thikened bacterial wall just like in VISA. In this case increase the daily dose till to have 12 mg/kg monodose for 2 weeks without side effects ( in IE for MRSA 30-40 days) A THIKENING of the bacterial wall like in VISA can contribute to resistance to Daptomicine in S.A. Daptomicine is MW > 1.620, so is difficult penetrate the thikened bacterial wall just like in VISA. In this case increase the daily dose till to have 12 mg/kg monodose for 2 weeks without side effects ( in IE for MRSA 30-40 days) An other way to prevent BR is the association with synergic effect with Genta and Rifampicine very helpful in VISA strains as well An other way to prevent BR is the association with synergic effect with Genta and Rifampicine very helpful in VISA strains as well thikened bacterial wall

30. Previous use of Vanco affect in unfoverable way on the susceptibility to Daptomicine MRSA (aortic prosthesis, infected PM, endocard abscess) MRSA (aortic prosthesis, infected PM, endocard abscess) Before therapy MIC for Vanco (2) MIC for Dapto (1) Before therapy MIC for Vanco (2) MIC for Dapto (1) in the second week of therapy with Vanco MIC Vanco (4) and Dapto (1) with reduced therapeutical effect in the second week of therapy with Vanco MIC Vanco (4) and Dapto (1) with reduced therapeutical effect start therapy with Daptomicine, after 2 weeks of therapy MIC Vanco (8) and Dapto (4) with therapeutic failure probable due to the previous therapy with Vanco start therapy with Daptomicine, after 2 weeks of therapy MIC Vanco (8) and Dapto (4) with therapeutic failure probable due to the previous therapy with Vanco Previous different antibiotic therapy failed or not, don’t affect the activity of daptomicin Previous different antibiotic therapy failed or not, don’t affect the activity of daptomicin

31. Start with a single dose of Rifampicine MIC 0.012  16 Start with a single dose of Rifampicine MIC 0.012  16 Change therapy to Vanco + Imipenem (this for short time only) MIC Vanco 1  8 at the end of the therapy and became resistant Change therapy to Vanco + Imipenem (this for short time only) MIC Vanco 1  8 at the end of the therapy and became resistant The strains not sensible to Vanco show the reduction of sensibility to Dapto of 100 times and MIC 0.01  1 even if this drug was never utilized in therapy The strains not sensible to Vanco show the reduction of sensibility to Dapto of 100 times and MIC 0.01  1 even if this drug was never utilized in therapy Patient with blood culture positive for SA MDR

33. Linezolid and Endocarditis 14 patients surgically treated for left-sided active endocarditis 14 patients surgically treated for left-sided active endocarditis - 10 (85%) NVE, 2(15%)PVE - 10 (85%) NVE, 2(15%)PVE - 11 (85%) with positive blood cultures - 11 (85%) with positive blood cultures - 8 (70%) MRSA - 8 (70%) MRSA - 4 (30%) Penn.R. viridans streptococci. - 4 (30%) Penn.R. viridans streptococci. - 2 (15%) with resected valves positive cultures - 2 (15%) with resected valves positive cultures - Enterococcus MDR (Vanco OK) - Enterococcus MDR (Vanco OK) Switch from Vanco IV to oral Linezolid after 5±4 days from surgery (600mg X 2 ) for 3 weeks Switch from Vanco IV to oral Linezolid after 5±4 days from surgery (600mg X 2 ) for 3 weeks Mean follow-up of 20±7 months Mean follow-up of 20±7 months

34. Clinical follow-up ICU stay 3±3 days ICU stay 3±3 days The total hospital LOS was 10,5±3,4 days The total hospital LOS was 10,5±3,4 days Follow-up in 100% patients Follow-up in 100% patients All blood cultures negative All blood cultures negative No hospital death (30days) No hospital death (30days) 2 late deaths, no cardiac (14,3%) 2 late deaths, no cardiac (14,3%) No cases of recurrent endocarditis No cases of recurrent endocarditis No periprosthetic leakage No periprosthetic leakage

37. VRE therapy Patients with IE by Enterococci Daptomicine was active even in VRE (Vancomycin resisitant Enterococci) in monotherapy at 6 mg/kg/day for 30 days or in association with Gentamycin,Rifampicin, Ampicillin Patients with IE by Enterococci Daptomicine was active even in VRE (Vancomycin resisitant Enterococci) in monotherapy at 6 mg/kg/day for 30 days or in association with Gentamycin,Rifampicin, Ampicillin 1 case of IE by VRE in prosthetic valve with therapeutic failure with Linezolid 1 case of IE by VRE in prosthetic valve with therapeutic failure with Linezolid Succes with Daptomicine + Rifam+Genta thanks to bactericidal action compared to the bacteriostatic of Linezolid that in case of VRE sometime is with high MIC (especially, in prosthetic valve infections) with therapeutic problems. Succes with Daptomicine + Rifam+Genta thanks to bactericidal action compared to the bacteriostatic of Linezolid that in case of VRE sometime is with high MIC (especially, in prosthetic valve infections) with therapeutic problems.

38. VRE- Linezolid First report of Linezolid-resistant Vancomycine resistant Enterococcus F. strain First report of Linezolid-resistant Vancomycine resistant Enterococcus F. strain Journal of Antimicrob.Chem,2004 Linezolid resistant, Vancomycine resistant Enterococcus F. infection in patient without prior exposure to Linezolid Linezolid resistant, Vancomycine resistant Enterococcus F. infection in patient without prior exposure to Linezolid Clinical Infectious desease,2003 Linezolid resistant Enterococci, report of the first isolate in UK Linezolid resistant Enterococci, report of the first isolate in UK Journal of Antimicrob.Chem,2002

40. Enterococcal biofilm

41. Enterococcus biofilm

43. Pulmonary infiltrates in right sided endocarditis Pulmonary infiltrates in right sided endocarditis

44. Vancomycine - Daptomicine In empiric antibiotic therapy in IE Dapto could be the drug of choice for bactericidal activity against MRSA- MRSE -Enterococci when Vanco show MIC >1 In empiric antibiotic therapy in IE Dapto could be the drug of choice for bactericidal activity against MRSA- MRSE -Enterococci when Vanco show MIC >1 The mortality risk related to MIC > 2 is the same to the risk related to an inappropriate therapy The mortality risk related to MIC > 2 is the same to the risk related to an inappropriate therapy Attention because Dapto show stronger bactericidal activity in MRSA-MRSE superior to Vanco in IE Attention because Dapto show stronger bactericidal activity in MRSA-MRSE superior to Vanco in IE in IE (where there is an elevated bacterial charge) Vanco has very slow bactericidal effect, almost bacteriostatic and need higher doses and longer treatment, in continue infusion (keep Vancocynemia of 15-20 mg/dl) in IE (where there is an elevated bacterial charge) Vanco has very slow bactericidal effect, almost bacteriostatic and need higher doses and longer treatment, in continue infusion (keep Vancocynemia of 15-20 mg/dl)

45. About MIC... and Glycopeptides Pulmonary atresia 15 days 3 kg Pulmonary atresia 15 days 3 kg Surgical correction in ECC Surgical correction in ECC ICU – open chest (3 days) ICU – open chest (3 days) Postop:blood cultures positive for MRSA (baby intubated at birth),sensible to glicopeptides Postop:blood cultures positive for MRSA (baby intubated at birth),sensible to glicopeptides Therapy from the begining with Teicoplanin (for preop and postop ARF, creat +++) Therapy from the begining with Teicoplanin (for preop and postop ARF, creat +++) But CRP ++++ PCT without any changing after therapy!!! But CRP ++++ PCT without any changing after therapy!!! We start with Vanco and after 2 days, CRP, PCT and others biochemical parameters start to decrease We start with Vanco and after 2 days, CRP, PCT and others biochemical parameters start to decrease But.... But.... Teico MIC 5 Teico MIC 5 Vanco MIC 0,5 Vanco MIC 0,5..... Unfortunately in delay!!!!..... Unfortunately in delay!!!! E. Mazza 2005