Treatment of Treatment of multiresistant multiresistant gram positive gram positive endocarditisendocarditis

Prof. Ermanno MazzaProf. Ermanno Mazza

MNXMNX

Baku, 2012Baku, 2012

Gram positive responsible Gram positive responsible for IE, MDRfor IE, MDR

MRSEMRSE (S. epidermidis) (S. epidermidis) MRSAMRSA VISAVISA EnterococciEnterococci HLGRHLGR ( that means high level ( that means high level

genta resistant)genta resistant) VRE VRE (Vanco resistant Enterococci)(Vanco resistant Enterococci) VGSVGS (Streptococci viridanse penicilline (Streptococci viridanse penicilline

resistant)resistant)MRSA MRSA 30%30% HLGR HLGR 20%20% VRE VRE 5%5% VGS VGS 8%8%

VISAVISA

For For MRSAMRSA and and MRSEMRSE recently appear a recently appear a reduced susceptibility to Vancomycinreduced susceptibility to Vancomycin ((VISAVISA) ) Vancomycin intermediate SAVancomycin intermediate SA with with

will significantly will significantly reduce reduce therapeutical effecttherapeutical effect

In In endocarditisendocarditis, and , and bacterimiabacterimia specially specially with this bacteria and sensibility is very with this bacteria and sensibility is very important to important to check several timescheck several times MICMIC and and adapt adapt the therapy to the results the therapy to the results

MIC > 1-1,5MIC > 1-1,5

VISA mechanism VISA mechanism The reduce susceptibility to Vancomycine appears to The reduce susceptibility to Vancomycine appears to

result from result from changeschanges in in PEPTIDOGLYCANPEPTIDOGLYCAN biosynthesisbiosynthesis

VISAVISA strains synthetaze additional quantities of strains synthetaze additional quantities of PTGLC PTGLC that result in that result in irregularly thickened cell wallirregularly thickened cell wall and with and with increase number of increase number of

Synthesis of a Synthesis of a modified cell-wall precursormodified cell-wall precursor “ “ D-ALA-D- LACTATE”D-ALA-D- LACTATE”

In In PTGLCPTGLC in the place of in the place of D-ALA D-ALAD-ALA D-ALA (Antibiotic (Antibiotic binding target)binding target) that is that is Vanco placeVanco place..

D-ALA- D-LACTATED-ALA- D-LACTATE reduce the affinity of reduce the affinity of PTGLCPTGLC for for Glicopeptide (1000 times)Glicopeptide (1000 times)

Today FDA for IE with Today FDA for IE with MRSAMRSA

Vanco-Vanco-( with Genta or Rifam)( with Genta or Rifam) TeicoplaninTeicoplanin ( (TargosidTargosid) practical, single dose no ) practical, single dose no

renal failure problems, very well tolerated, but renal failure problems, very well tolerated, but significant resistances, often high MIC significant resistances, often high MIC

DaptomicineDaptomicine (Cubicin)(Cubicin), alone or in association, alone or in association Dalfopristine-QuinopristineDalfopristine-Quinopristine ((SynercideSynercide)) side side

effects not very well tolerated effects not very well tolerated Linezolide Linezolide ((ZivoxZivox) practical also for long time ) practical also for long time

therapy (oral effective like IV) good in renal therapy (oral effective like IV) good in renal failure, failure, bacterecidalbacterecidal for Streptococcus, for Streptococcus, bacteriostaticbacteriostatic for Staphilococcus and for Staphilococcus and EnterococcusEnterococcus

TigeciclineTigecicline ((TigacilTigacil)) the first clinically the first clinically available drug in a new class of available drug in a new class of antibiotic called antibiotic called GlycylcyclinesGlycylcyclines. It is . It is similar to the Tetracyclines, derivated similar to the Tetracyclines, derivated of Minocycline. Active for of Minocycline. Active for MRSA, MRSA, MRSE, VISA, VRSA, VREMRSE, VISA, VRSA, VRE, , Acinetobacter, KlebsiellaAcinetobacter, Klebsiella. . BacteriostaticBacteriostatic is not first choice for is not first choice for Endocarditis and Bacteremia, low Endocarditis and Bacteremia, low resistances.resistances.

Fusidic AcidFusidic Acid ((FucidinFucidin)) bacteriostatic bacteriostatic very effective in MRSA and MRSE and very effective in MRSA and MRSE and anaerobs( gram+/-), but with anaerobs( gram+/-), but with good good penetrationpenetration in in lungs and blood (IE, lungs and blood (IE, septicimia).septicimia).

MoxifloxacinMoxifloxacin, last generation of , last generation of Chinolones, very active against Chinolones, very active against MRSA, VRE with biofilm.MRSA, VRE with biofilm.

Pharmacodinamic of Moxifloxacin Pharmacodinamic of Moxifloxacin versus Vancomicine against versus Vancomicine against biofilm of MRSA and MRSE biofilm of MRSA and MRSE (Journale of chemiotherapy, 2010)(Journale of chemiotherapy, 2010)

CeftobiproleCeftobiprole, fifth generation of , fifth generation of Cephalosporines, very active in Cephalosporines, very active in MRSA and MRSE.MRSA and MRSE.

DAPTOMICINDAPTOMICIN

DAPTOMICIN DAPTOMICIN (Cubicin)(Cubicin) a lipopeptide a lipopeptide shows fast shows fast bactericidal activitybactericidal activity against against MRSA, MRSEMRSA, MRSE even even VISA VISA andand VRSE VRSE,, with with very low percent of resistances. very low percent of resistances.

Drug of choice every time, or only Drug of choice every time, or only IE/ IE/ bacterimiabacterimia from from VISAVISA??

Or in patient with an Or in patient with an IEIE where from where from some reason, for example renal failure, some reason, for example renal failure, is difficult to use is difficult to use Vanco + GentamicineVanco + Gentamicine

MRSA BacteremiaMRSA Bacteremia 400 patients, 1991-2005 400 patients, 1991-2005 All patients treated with All patients treated with VancoVanco ODDS ratio mortality following ODDS ratio mortality following MICMIC 11 MIC MIC 1 1

2,82,8 MIC MIC 1,51,5 6,36,3 MIC MIC 22

Cubicin study Cubicin study (Endocarditis)(Endocarditis)

Daptomicine was successful Daptomicine was successful 75%75% MRSA MRSA71%71% Enterococci Enterococci50%50% MRSE MRSE

ICEICE (International (International collaboration of IE)collaboration of IE)

5117 pts from many countries (2000-5117 pts from many countries (2000-2007) with 2007) with IE 31% of MRSA are VISA IE 31% of MRSA are VISA (MIC 2-4)(MIC 2-4) with with high mortalityhigh mortality 50% 50%

At that time only possibility was to At that time only possibility was to add add LINEZOLIDLINEZOLID in monotherapy or on in monotherapy or on association with association with RIFAMPICINERIFAMPICINE and and FUSIDIC ACIDFUSIDIC ACID

AssociationAssociation

The association of any drug with The association of any drug with RIFAMPICINE RIFAMPICINE in in IEIE on on prostetic valveprostetic valve, , or other intracardiac or intravascular or other intracardiac or intravascular prostetic materialprostetic material

is very effectiveis very effective

with a good sterilization of the foreign with a good sterilization of the foreign bodies, more effective that in simple bodies, more effective that in simple IE IE

Compearing of the activity Compearing of the activity of different antibiotics of different antibiotics

versus biofilmsversus biofilms A study about A study about Staffilococcical Staffilococcical

adesivityadesivity (mediated by (mediated by biofilmbiofilm) to ) to biomedical disposals, and the impact biomedical disposals, and the impact of different antibiotics, showed that, of different antibiotics, showed that, for the for the adesivity of MRSE to foreign adesivity of MRSE to foreign bodiesbodies (dacrone filaments) the (dacrone filaments) the treatment with treatment with DaptomicineDaptomicine was more was more effective in the eradication of bacteria effective in the eradication of bacteria compare with compare with VancoVanco and and CefotriaxonCefotriaxon

MRSA MRSA biofilmbiofilm producer in producer in IEIE central catheter related central catheter related

After After 24 hours24 hours of exposition of exposition Daptomicine Daptomicine and and TigecicylineTigecicyline are more are more active against active against biofilm biofilm compare to compare to Linezolid Linezolid and and VancoVanco

After After 3 days3 days DaptomicineDaptomicine showed a showed a greater speed in destroying greater speed in destroying MRSAMRSA from from biofilmbiofilm followed by followed by TigecyclineTigecycline that was that was faster versus faster versus Linezolide, RifaLinezolide, Rifa and and Vanco.Vanco.

Daptomicine resistance Daptomicine resistance 5%5%

Strong Strong correlationcorrelation between reduce sensibility to between reduce sensibility to Daptomicine, Daptomicine, andand Vancomycine Vancomycine resistant resistant in in VISAVISA

A A THIKENING THIKENING of the bacterial wall like of the bacterial wall like in VISAin VISA can contribute to can contribute to resistance to Daptomicineresistance to Daptomicine in in S.A.S.A. Daptomicine is Daptomicine is MW > 1.620MW > 1.620, so is difficult , so is difficult penetrate the penetrate the thikened bacterial wallthikened bacterial wall just like in just like in VISAVISA. In this case increase the daily dose till to . In this case increase the daily dose till to have have 12 mg/kg12 mg/kg monodose for 2 weeks without monodose for 2 weeks without side effects ( side effects ( in IE for MRSA 30-40 days)in IE for MRSA 30-40 days)

An other way to prevent BR is the An other way to prevent BR is the associationassociation with with synergicsynergic effect with effect with Genta and RifampicineGenta and Rifampicine very helpful in VISA strains as wellvery helpful in VISA strains as well

thikened bacterial wallthikened bacterial wall

Previous use of Vanco affect Previous use of Vanco affect in unfoverable way on the in unfoverable way on the

susceptibility to susceptibility to DaptomicineDaptomicine MRSA (aortic prosthesis, infected PM, endocard MRSA (aortic prosthesis, infected PM, endocard

abscess)abscess)

Before therapy Before therapy MICMIC for Vanco for Vanco (2)(2) MICMIC for Dapto for Dapto (1)(1)

in the second week of in the second week of therapy with Vancotherapy with Vanco MICMIC Vanco Vanco (4)(4) and Dapto and Dapto (1)(1) with reduced therapeutical with reduced therapeutical effecteffect

start therapy with start therapy with DaptomicineDaptomicine,, after 2 weeks of after 2 weeks of therapy therapy MICMIC Vanco Vanco (8)(8) and Dapto and Dapto (4)(4) with with therapeutic failuretherapeutic failure probable due to the probable due to the previousprevious therapy with therapy with VancoVanco

Previous Previous different antibiotic therapydifferent antibiotic therapy failed or not, failed or not, don’tdon’t affect the activity of affect the activity of daptomicindaptomicin

Start with a single dose of Start with a single dose of RifampicineRifampicine MIC MIC 0.0120.01216 16

Change therapy to Change therapy to Vanco + ImipenemVanco + Imipenem (this (this for short time only) for short time only) MIC Vanco 1 MIC Vanco 1 8 8 at the at the end of the therapy and end of the therapy and became resistantbecame resistant

The strains The strains not sensible to Vanconot sensible to Vanco show the show the reductionreduction of sensibility to of sensibility to Dapto of 100Dapto of 100 timestimes and and MIC 0.01 MIC 0.01 1 1 even if this drug even if this drug was never utilized in therapywas never utilized in therapy

Patient with Patient with blood culture blood culture positivepositive for for SA MDRSA MDR

Linezolid and Linezolid and Endocarditis Endocarditis

14 patients14 patients surgically treated for surgically treated for left-sided left-sided active endocarditisactive endocarditis - - 1010 (85%) (85%) NVENVE, 2(15%), 2(15%)PVEPVE - - 1111 (85%) with positive blood cultures (85%) with positive blood cultures

- - 88 (70%) (70%) MRSAMRSA - - 44 (30%) (30%) Penn.R. viridans Penn.R. viridans

streptococci.streptococci. - - 22 (15%) with resected valves positive (15%) with resected valves positive culturescultures

- - Enterococcus MDR (Vanco OK)Enterococcus MDR (Vanco OK) Switch from Switch from Vanco IVVanco IV to to oral Linezolidoral Linezolid after after

5±45±4 days from surgery (600mg X 2 ) for days from surgery (600mg X 2 ) for 3 3 weeksweeks

Mean follow-up of 20±7 monthsMean follow-up of 20±7 months

Clinical follow-upClinical follow-up

ICU stay 3±3 daysICU stay 3±3 days The total hospital LOS was 10,5±3,4 The total hospital LOS was 10,5±3,4

daysdays Follow-up in 100% patientsFollow-up in 100% patients All blood cultures negativeAll 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 endocarditisNo cases of recurrent endocarditis No periprosthetic leakageNo periprosthetic leakage

VRE therapyVRE therapy Patients with Patients with IE by EnterococciIE by Enterococci Daptomicine Daptomicine was was

active even in active even in VREVRE (Vancomycin resisitant (Vancomycin resisitant Enterococci) Enterococci) in monotherapyin monotherapy at 6 mg/kg/day for 30 at 6 mg/kg/day for 30 days days or in associationor in association with with Gentamycin,Rifampicin, Gentamycin,Rifampicin, AmpicillinAmpicillin

1 case of 1 case of IE by VRE in prosthetic valveIE by VRE in prosthetic valve with with therapeutic failure with therapeutic failure with LinezolidLinezolid

Succes with Succes with Daptomicine + Rifam+GentaDaptomicine + Rifam+Genta thanks to thanks to bactericidal bactericidal action compared to the action compared to the bacteriostaticbacteriostatic of of Linezolid Linezolid that in case of that in case of VREVRE sometime is with sometime is with high MIChigh MIC (especially, in (especially, in prosthetic valveprosthetic valve infections) infections) with therapeutic problems.with therapeutic problems.

VRE- LinezolidVRE- Linezolid First report of First report of Linezolid-resistantLinezolid-resistant

Vancomycine resistant Enterococcus F. Vancomycine resistant Enterococcus F. strainstrain

Journal of Antimicrob.Chem,2004Journal of Antimicrob.Chem,2004

Linezolid resistantLinezolid resistant, Vancomycine , Vancomycine resistant Enterococcus F. infection in resistant Enterococcus F. infection in patient without prior exposure to patient without prior exposure to LinezolidLinezolid

Clinical Infectious desease,2003Clinical Infectious desease,2003

Linezolid resistantLinezolid resistant Enterococci, report of the Enterococci, report of the first isolate in UK first isolate in UK

Journal of Antimicrob.Chem,2002Journal of Antimicrob.Chem,2002

Enterococcal Enterococcal biofilmbiofilm

Enterococcus biofilmEnterococcus biofilm

Pulmonary Pulmonary

infiltrates in right infiltrates in right sided endocarditis sided endocarditis

Vancomycine - Vancomycine - Daptomicine Daptomicine

In empiric antibiotic therapy in In empiric antibiotic therapy in IEIE DaptoDapto could be the could be the drug of choice for bactericidal activity against drug of choice for bactericidal activity against MRSA-MRSA-MRSE -Enterococci MRSE -Enterococci when when VancoVanco show show MIC >1MIC >1

The mortality risk related to MIC > 2 is the same to The mortality risk related to MIC > 2 is the same to the risk related to an inappropriate therapythe risk related to an inappropriate therapy

Attention because Attention because DaptoDapto show show stronger bactericidal stronger bactericidal activity in MRSA-MRSEactivity in MRSA-MRSE superior to superior to VancoVanco in in IEIE

in in IEIE (where there is an (where there is an elevated bacterial chargeelevated bacterial charge) ) VancoVanco has very has very slowslow bactericidalbactericidal effect, effect, almost almost bacteriostaticbacteriostatic and need and need higher doses and longer higher doses and longer treatmenttreatment, in continue infusion, in continue infusion (keep Vancocynemia (keep Vancocynemia of 15-20 mg/dl)of 15-20 mg/dl)

About MIC... and About MIC... and GlycopeptidesGlycopeptides

Pulmonary atresia 15 days 3 kgPulmonary atresia 15 days 3 kg Surgical correction in ECCSurgical correction in ECC ICU – open chest (3 days)ICU – open chest (3 days) Postop:blood cultures positive for MRSA (baby Postop:blood cultures positive for MRSA (baby

intubated at birth),sensible to glicopeptidesintubated at birth),sensible to glicopeptides Therapy from the begining with Therapy from the begining with Teicoplanin Teicoplanin (for (for

preop and postop ARF, creat +++)preop and postop ARF, creat +++) But But CRP ++++ PCTCRP ++++ PCT without any changing after without any changing after

therapy!!!therapy!!! We start with We start with VancoVanco and after 2 days, and after 2 days, CRP, PCTCRP, PCT

and others biochemical parameters start to and others biochemical parameters start to decreasedecrease

But ....But .... Teico Teico MIC 5MIC 5

VancoVanco MIC 0,5MIC 0,5

..... Unfortunately in delay!!!!..... Unfortunately in delay!!!!

E. Mazza 2005