Colistina în domeniul infectiilor severe si sepsisului

8/13/2019 Colistina n domeniul infectiilor severe si sepsisului

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Locul colistinei n terapiainfeciilor cu BGN


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The last few years have been characterized by the

emergence of certain Gram- negative bacteria, especiallyAcinetobacter baumannii, Pseudomonas aeruginosa andKlebsiella pneumoniae,which are resistant to almost allcurrently available antibiotics, except colistin.

R. Imberti, M. Regazzi, and G. A.

lotti pag.:99-110


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Ce este colistina?Un antibiotic complex

Peptid ciclic policationic amfipatic

Colistina(cunoscuta ca sipolymyxina E) este un amesteccomplex de polimixine, 2 dintre ele fiind cele mai

importante : colistina A(polimixina E1) si colistina B(polimixina E2)

Colistina este bactericida, efect dependent deconcentraie si are un efect post-antibiotic modest

Interacioneaz cu lipopolizaharidele membraneiexternea germenilor Gram negativi

Dizloc ionii de Ca i Mg inducnd destabilizareamembranei celulare


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Scurt istorie a colistinei Descoperit n 1947 n categoria polimixinelor A-E, introdusa in 1959

Doar polimixina B i polimixina E (colistin)sunt de uz uman

Izolat n Japonia, n 1949, produs de Bacillus polymyxa var. colistinus iidentificat ca polimixina E

Difer de polimixina B printr-un singur aminoacid (D-Phe inlocuit cu D-Leu)

Exist sub forma a 2 componente (E1 i E2, denumite i colistina A i B) difer prin lungimea lanului de acizi grai

Incepe sa fie abandonata in anii 1970 dupa introducerea

aminoglicozidelor

Anii 1980 se renun la utilizarea colistinei din cauza reaciilor adverse

2003 2005 reluarea utilizrii colistinei, reevaluarea toxicitii, reaciile

adverse fiind mai reduse


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COLISTIN

3 pharmaceutical forms of colistin exist:

- colistin methanesulfonate (CMS, colistimethate or colistin sulphomethate)- colistin base- colistin sulfate

Colistin is generally administered systemically (parenterally) as CMS.

CMS (which is inactive)is converted to colistin (active form) both in vitroandin vivoby hydrolysis of methane sulphonate radicals.

In many countries:- CMS isapproved for intramuscular (i.m.) use only- intravenous (i.v.), nebulized and intraventricular use of the drug is off-label.


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CMS should not be confused with colistin base :

1mg colistin base (CBA) = 2.4mg of CMS.

1mg CBA = 30,000 -33,333 IU of CMS

(150 mg CBA is equivalent to approximately 5 million units CMS)

1,000,000 IU of CMS = 80 mg CMS= 29.6 mg colistin base

the vial concentration of CMS is often reported in IUand not in mg : source of potential confusion.


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Pharmacokinetics and Pharmacodynamics

In the past, colistin concentrations in biological fluids and tissues wereevaluated by microbiological assayswhich did not discriminate betweenCMS and colistin.

Moreover, during the incubation period of the microbiological assay, CMS isconverted to colistin,resulting in measured concentrations of CMS andcolistin that do not reliably reflect their concentration in fluids andtissues.

NEW : liquid chromatographyand mass spectrometry enable CMS andcolistin to be measured separately and quantified accurately, wereintroduced only a few years ago ( 2002-2010)


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Pharmacokinetics and Pharmacodynamics

in the last decade, the pharmacokinetics of colistin (the active

form) and CMShave been studied in animals and critically illpatients

CMS undergoes tubular secretion and renal clearance

Colistinhas a very extensive tubular reabsorption and itsclearance is mainly via non-renal pathways

The very high concentration of colistinin urine after systemic CMSadministration is very likely due to conversion of CMS within theurinary tract


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Pharmacokinetics

Colistin after i.v. administration of CMS critically ill patients with MDR Gram -inf.

Imberti et al. : 2 million IU CMS (174 mg) i.v. every 8 h- the C max,ss was 2.21 1.08 mcg/ml- MIC of colistin is 2 mcg/ml- the Cmax,ss/MIC ratio 1.1 0.5- AUC0-24/MIC ratio was 17.39.3

Imberti R, Cusato M, Villani P et al : 2010, Chest

138:1333-1339

Markou : 2.8 million IU CMS (approx. 244 mg):- the Cmax,ss of colistin was 2.93 1.24 mcg/ml and the apparent half-life 7.41.7h.

Markou N et al.: 2008 Clin Ther 30:143-151

Plachouras: CMS 3 million IU (approx. 240 mg) every 8 h.- the predicted Cmax plasma were 0.60 mcg/ml and 2.3 mcg/ml for the first dose and

at SS- very low plasma colistin concentrations for 2-3 days before reaching steady state,

suggesting the need for a loading dose.

- a large proportion of patients had plasma conc. < the MIC breakpoint of 2 mcg/ml.Plachouras D et al : 2009 Antimicrob Agents Chemother

53:3430-3436


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Pharmacokinetics

in these studies:

- 2to 3 hours after CMS administration, plasma colistinconcentrations were below the MIC breakpoint of 2 mcg/ml in mostpatients

Imberti R, Cusato M, Villani P et al : 2010,

Chest 138:1333-1339


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Pharmacokinetics

- in 2011 Garonzik etal.investigated the PK of CMS and colistin in 105 critically ill

pts. with a large range of renal function (creatinine clearance 3-169 ml/min/1.72m2) some pts. on CRRT.

FINDINGS1. with decreasing renal functiona larger fraction of CMS was converted to

colistin, whereas the clearance of formed colistin decreased.

2. developed equations suggesting :- the loading dose- maintenance dose

in order to achieve a given colistin average concentration at steady state(Css,avg)during the dosing interval.


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CONCLUSIONS

1. Our current data suggest that because of the inability to achieve adequateplasma concentrations of colistin with CMS monotherapy :

CMS/colistin might best be used as part of a highly active combination,especially when treating an infection caused by an organism with an MIC of>0.5 mg/literin a patient with creatinine clearance of >70 ml/min/1.73 m2.

2. The loading and maintenance dosing suggestions reported herein should beregarded as interim; they will be refined as we complete recruitment to atotal of 238 critically ill patients and also model the pharmacodynamic andtoxicodynamic endpoints.


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Pharmacokinetics

Population Pharmacokinetic Analysis of Colistin Methanesulfonate and Colistin after Intravenous Administration in CriticallyIll Patients with Infections Caused by Gram-Negative Bacteria

Plachouras D et al : 2009 Antimicrob Agents Chemother 53:3430-3436

CMS 3 millions IU every 8 h

Mathematic model:

Loading dose: 9 million UI and then 4,5 million UI every 12 h Loading dose:12 million UI and then 4,5 million UI every 12 h

3 MUI la 8 ore

12 MUI loading and 4,5 MUIevery 12 h

9 MUI loading and 4,5 MUIevery 12 h


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COLISTIN -Pharmacokinetics in critically ill pacients.

Colistimetat (CMS):240 mg (3 x 106U ) la 8 hCMS T1/2~ 2.3 h,

Colistin:T1/2~ 14.4 h

Cmax la prima doz 0.60 mg/Ls.s.: 2.3 mg/L.- la cca 7h

Colistin displayed a half-life that wassignificantly long in relation to thedosing interval.

In consequence: plasma colistinconcentrations are insufficient beforesteady state and the administration of aloading dose would benefit critically ill

pts.

CMS Colistin

Timeafter first dose

Timeafter the 4-thdosePlachouras D et al : 2009 Antimicrob Agents Chemother 53:3430-3436


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NEW approach in severe infections

The optimal results of this regimen are influenced by :

o increasing Colistine half-time to 14,4 hours

o avoiding under-therapeutic concentrations during Day 1

Loading dose : 9 mil UI and then3 mil UI every 8 h



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S

Bergen 2008, JAC


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Pharmacokineticsand Administration in critically ill

Loading dose : 9 million UI(2 hours perfusion)

3 millionUI after 12 hours

Maintenamce : 3 millionevery 8 hours

9 mil UI( 2 hrs.

perfusion)

0 h 12 h 8 h 8 h 8 h 8 h

3 mil UI(30 min.

perf.)

3 mil UI(30 min.

perf.)

3 mil UI(30 min.

perf.)

3 mil UI(30 min.

perf.)

3 mil UI(30 min.

perf.)

I t COLISTIN i P i d


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IntravenousCOLISTIN in Pneumonia andVAP

clinical studies :CMS is effective in serious MDR Gram infections(prospective and retrospective)

Conclusions for CMS

1. No differences in mortality or clinical cure rates when compared(susceptible strains) with others atb.

2. high-dose CMS ( blood stream infection and VAP)resulted in clinical curein 82.1 % of cases

3. effective and safe in children and neonates

Reina R et al: 2005 Intensive Care Med 31:10581065Kallel H et al : 2007 Intensive Care Med 33:1162-1167Michalopoulos AS, Falagas ME : 2005 Clin Microbiol Infect 11:115-121Dalfino L et al : 2012 Clin Infect Dis 54:1720-1726Iosifidis E et al : 2010 Eur J Pediatr 169:867-874Celebi S : 2010 Pediatr Int 52:410-414

Jajoo M et al : 2011 Pediatr Infect Dis J 30:218-221


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Dose Regimen for Intravenous CMS

CMS should not be confused with colistin base 1mg colistin base (CBA) = 2.4mg of CMS.

1mg CBA = 30.000 -33.333 IU of CMS 1,000,000 IU of CMS = 80 mg CMS

the vial concentration of CMS is often reported in IU and not in mg : source ofpotential confusion.

The optimal dosage regimen is not known

a possible CMSdose could be 3-3.5 mg/kg/8 h.( 37.500 43.750 ui/kg/8 h )7.8 million ui 9 million ui / day

R. Imberti, M. Regazzi, and G. A. lotti : Annual Update in IC and EM 2013 :pag.:99-110

a loading dose might be beneficial in order to reduce the time to steady stateconcentration

although Colistin is mainly cleared by non-renal mechanisms, since CMSaccumulates in pts. with renal impairment : dose must be adjusted

Garonzik formulas ?


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Nebulized COLISTIN

a fraction of CMS is absorbed and is then partially converted into colistin within thesystemic circulation

another fraction of CMS dose is converted into colistin within the lungs and is then partiallyabsorbed within the systemic circulation

small clinical trials in VAP and NP ( 120-150 pts)

- CMS + nebulized CMS versus i.v. CMS alone: clinical cure 79.5% vs.60.5%(p = 0.025).

Korbila IP, Falagas ME : 2010 Clin Microbiol Infect 16:1230-1236

- Carbapenems + CMS + nebulized CMS sv. ATB alone: No effect on clinical cureRattanaumpawan P et al: 2010 J Antimicrob Chemother 65:2645-2649

- used doses : 1 million IU/8 h (80 mg/8 h)

- it is probably better to administer higher doses of nebulized CMS- the optimal dose is not known- monotherapy nebulized CMS is inappropriate inpneumonia is associated with

bacteremia.Athanassa ZE et al: 2012 Intensive Care Med 38:1779-1786


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Combination Therapy

In vitro :- colistin acts synergistically with other antibiotics- most frequently combined : rifampicin and carbapenems.

- all studies: synergy with rifampicin against P. Aer.andA. baumannii

In vivo :- a few clinical studies have investigated CMS in combination therapy.- in critically ill patients are scant, great variability, low number pts.- all are retrospective !

a recent study performed in 258 patients (A. baumannii, P. aeruginosa and K.pneumoniae)combination therapy was not superior to colistin alone!

Falagas ME et al: 2010 J Antimicrob Agents 35:194-199

in contrast, another study ( 125 patients KPC -producing K. pneumoniae ) :combination of colistin, tigecycline, and meropenem = lower mortality !

Tumbarello M et al: 2012 Clin Infect Dis 55:943-950

Since i.v. CMS monotherapy results in suboptimal plasma concentrations ofcolistin even at high doses and may lead to the emergence of resistance,

it is of paramount importance to investigate combination therapy !


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COLISTIN in Central Nervous System Infections

neurosurgical procedures otorhinological procedures meningitis, ventriculitis, abscesses

head trauma

CSM and colistin hardly cross the or blood-brain barrier in animals or humans,even if the meninges are inflamed

CMS must, therefore, be administered into the cerebral ventricles or via the

intrathecal route

Guidelines IDSA suggest that the intraventricular dosage of colistin ( CMS) should be10 mg , but the dosages of intraventricular/intrathecal CMS reported in theliterature range between 1.6-40 mg, as a single dose or in divided doses

A recent study intraventricular CMS was administered at doses of> 5.2 mg/day, themeasured CSF concentrations of colistin were continuously > than MIC of 2 mcg/ml

Imberti R . 2012 Antimicrob Agents Chemother 56:1416-1421

Intraventricular administration of CMS is effective and safe in the treatment of CNSinfections caused by MDR Gram-negative bacteria susceptible only to colistin.


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Toxicity

Nephrotoxicity :

the most common and threatening adverse reaction extremely variable rate : 0 - 53% due to studies non-uniformity the risk is correlated to : - the total CMS dose

- the duration of CMS therapy

Dose adjustment according to renal function, daily serum creatinine

monitoring and careful management of volemia can help to reduce the riskof nephrotoxicity.

Neurotoxiciy after systemic or intraventricular/intrathecal administration

manifestations : seizures, aseptic meningitis, hypotonia, neuromuscularblockade with respiratory paralysis, and cauda equina

is rare, not a major issue in critically ill pts. (might be underestimated insedated and MV pts.)


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Minimum Inhibitory Concentrations and Resistance

Different susceptibility breakpoints have been introduced by variousorganizations.

These breakpoints have been obtained with colistin sulfate, the active drug,whereas CMS should not be used for susceptibility testing.

According to the European Committee on Antimicrobial Susceptibility Testing(EUCAST) and the US Clinical and Laboratory Standards Institution (CLSI) thesusceptibility breakpoint :

- A. baumanniiand K. pneumoniaeis 2 mcg/ml- P. aeruginosa is 2 mcg/ml according to the CLSI and 4 mcg/ml according to the

EUCAST.However, strains of P. aeruginosaandA. baumanniiwith a MIC< 1mcg/ml have

been reported in several published clinical studies.

Resistance to colistin:

- is not very common and from 2006 to 2009 remained stable because : colistin-resistant bacteria present downregulation of several proteins andinduces phenotype instability

- is likely due to the increasing use of CMS and colistin heteroresistance tocolistin (defined as the presence of colistin-resistant subpopulations in anisolate that is susceptible based upon MIC).

- Combination therapy might reduce the risk of the emergence of resistance tocolistin.


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Falagas et al, CID 2005


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Locul colistinei n terapiainfeciilor cu BGN


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Colistina n infecii cu Gram negativi MDR

Studiu retrospectiv, 2000-2007, 258 pacieni

Administrare colistina cel puin 72 ore Infecii cu Gram negativi MDR documentate bacteriologic

Localizarea infeciei

N

rinfeciei

Falagas et al, JAA 2009, Colistin therapy for microbilogically documented multidrug rezistant Gram-negative bacterial infections.

155

3322 16

32

0

20

40

60

80

100

120

140

160

180

Pneumonii Bacteriemii Infecii

abdominale

Infecii cateter

venos central

Altele


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Etiologia infeciilor tratate cu colistin

Etiologia infeciilor tratate cu colistin

Acinetobacter

65.9%

Pseudomonas

26.4%

Klebsiella

7.0%

Enterobacter

0.4% Stenotrophomonas

0.4%

Falagas et al, JAA 2009

Colistina n infecii cu Gram negativi MDR


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High-Dose, Extended-Interval Colistin administration inCritically Ill Patients: Is This the Right Dosing Strategy?

Dalfino et al, CID 2012:54 (June)

Prospective study in ICU

28 severe sepsis or septic shock pts.

BGN : minimal answer to ATB or answering only to COLISTIN

DOSES: loading dose 9 mil UI , then 4,5 mil UI every 12 hrs.


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Dalfino et al, CID 2012:54 (June)

Etiology

A. baumannii

47%

P. aeruginosa

7%

K. pneumoniae

46%



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EFICACITATE

Vindecare clinic la 23 de cazuri (82.1%)

Clearance bacteriologic 73,9% (17 cazuri cu BSI) dup 3 zile detratament

Clearance bacteriologic 40% (4 cazuri cu VAP) dup 8 zile detratament

Nu au fost raportate cazuri de apariie a rezistenei la colistin

Regimul 9 mil UI doz de ncrcare, 9 mil UI/ziare eficacitate satisfctoare

Dalfino et al, CID 2012:54(June)



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KPC Tsunami

P fil d tibilit t Kl b i ll i


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Profil de susceptibilitate - Klebsiella pneumoniaeproductoare de carbapenemaze-2 (KPC-2)

Souli et al, Clinical Inf Disease, 2010

a agar, CLSI, b Etest, c agar, EUCAST

50 pacieni (34 TI, 16 non TI), Grecia

Alturi de KPC-2 s-au regsit: TEM-1 like, SHV-11, SHV-12, CTX-M-15, LEN-19

Mortalitate secundar: 22,2% in seciile de TI, 33,3% n seciile non TI


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Colistina administrat sistemic infecii pediatricecu germeni gram negativ multidrog rezisteni

Articole Pubmed, Cochrane, Scopus database 370 copii fr fibroz chistic tratai cucolistin din care:

326 tratament curativ 44 tratament profilactic (intervenii chirurgicale, arsuri)

Ameliorare

3,7%

Deterioare

2,2% Deces

7,4%

Vindecare

86,7%

70 % din deceseau fost atribuiteinfeciilor

Systemic colistin use in children wihout cystic fibrosis: a systematic review of the literatureFagalas et al; Int J Antimicrob Agents: iunie 2009


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44 tratament profilactic (intervenii chirurgicale, arsuri)- nu au survenit infecii- 20,5 % deces secundar comorbiditilor

Nefrotoxicitate- 2,8 % (10/355 copii) modificarea parametrilor renali

Fagalas et al; Int J Antimicrob Agents: iunie 2009

Concluzie: colistin este eficace clinic i este o opiune acceptabil din punct

de vedere al siguranei

Colistina administrat sistemic infecii pediatricecu germeni gram negativ multidrog rezisteni


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Colistina parenteral la copii cu infecii severe

oct 2004 nov 2008 7 copii cu infecii grave

Acinetobacter, Pseudomonas, Klebsiella multidrogrezistente (snge sausecreii bronice)

colistin parenteral: 5 mg/kg/zi (62.500 UI/kg/zi), la 8 ore (dozarecomandat la copii 50.000 75.000 UI/kg/zi)

Evoluie:

5 copii s-au vindecat

2 copii au decedat , decesul nu a fost secundar infeciei sauadministrrii de colistin

NU a fost raportat nefrotoxicitate sau alt tip de toxicitate

Dei numarul de copii raportat este mic, colistina are un rol esenial ntratamentul infeciilor grave la copii

Falagas et al, The Pediatric Infectious Disease Journal, Februarie 2009


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Colistina profil de siguran

C li ti fil d i


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Nefrotoxicitateaincidena ntlnit este de 6 % 14% n unele studii saude 32% - 55% n alte studii.

Plaja larg a incidenei nefrotoxicitii deriv din aplicarea unorcriterii diferite de apreciere a insuficienei renale acute: scorRIFLE, Creatinina seric > 2 mg/dl

Factori de risc:

Vrsta naintat

Preexistena afectrii renale

HipoalbuminemiaUtilizarea concomitent a antinflamatoarelor nesteroidiene

Utilizarea vancomicinei

Reversibilitatea afectrii renale peste 88% n studiile care aumonitorizat acien ii un interval de 1-3 luni

Colistina profil de siguranNefrotoxicitate

C li ti fil d ig


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Riscul de nefrotoxicitate este mai redus dect cel raportat nlitaratura anilor 70 80 prin:

Reducerea impuritilor colistimetatului sodic

Monitorizarea atent i echilibrarea hidroelectrolitic nseciile de terapie intensiv

Evitarea asocierii cu medicamente cu risc nefrotoxic


Colistina profil de siguran


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NEFROTOXICITATE Lipsa modificrilor renale la 82,1% (23 cazuri)

Afectare renal acut 17,9% (5 cazuri, unul cu afectarepreexistent) continuarea terapiei cu ajustarea dozei

Nu exist corelaie statistic ntre variaiacreatininei serice i doza zilnic,doza cumulativ

sau durata tratamentului cu colistinDalfino et al, CID 2012:54(June)



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posologia: 75.000 150.000 UI/kg/zi, fr a depi 12 MUI/zi.

Agence franaise de scurit sanitaire des produits de sant

www.affsaps.fr

Ajustarea dozelor de colistin n funcie declearance-ul de creatinin

Colistina Neurotoxicitate


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Neurotoxicitatea vertij, slbiciune muscular,parestezii, surditate parial, tulburri vizuale,confuzii, halucinaii, convulsii, ataxie

Paresteziilecel mai frecvent ntlnite, aprox

27% din cazuri

Au intensitate uoar medie i sunt reversibile

la ntreruperea tratamentului

Colistina Neurotoxicitate


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Efectu l sinergic in

an t ibio t ico terap ia infect i i lor cu

BGN MDR


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Interaciune sinergic

Combinaii sinergice cu colistina:Colistin/meropenemColistin/doripenemColistin/rifampicinColistin/minociclin

Colistin/tigeciclin

Combinaiile sinergice reprezintsoluii terapeutice n infeciile cu germenimultidrogrezisteni

0

1

2

3

4

5

6

7

8

2 4 6 8 10 12 14 16 18 20 22 24

Hours

L

ogNo.VaiableOrganism

s

Drug A A+B Drug B

Liang et al, Infectious Diseases 2011

Diminuarea cu cel puin 2 log 10 a nrcolonii pentru asocierea de antibiotice,comparativ cu cel mai activ antibiotic dincombinaie, la 24 h de incubatie

Efect bactericid -scaderea numarului decolonii cu 3 log 10


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Efectul sinergic al colistinei

Bacilii Gram-negativi membran intern i membran extern

inta AB se regsete la nivelul membranei interne sau intracelular

Cele mai multe AB trebuie s traverseze membrana extern pentru a

ajunge la molecula inta, aceasta putnd fi o etap limitatoare


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Efectul sinergic al al colistinei

Bacteriile Gram negative pompe de eflux ceea ce explicarezistena intrinsec



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Afectarea membranei externe prin actiunea colistinei favorizeazaccesul altor antibiotice ctre inta lor de aciune

Acest aspect se aplic chiar dac bacteria este rezistent, din cauza

impermeabilitii membranei externe sau fenomenului de eflux

Ghid Sanford 2012:


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Ghid Sanford, 2012:Ps. aeruginosa Carba-R

Monoterapieoptiuni *

Colistin

CiprofloxacinAminoglicozide

Aztreonam

Ceftazidim

Peniciline antipseudom

*Conform antibiogramei

Posibile asocieri*:

Pen anti-pseudom + AG

Ceftazidim + AGMero / Doripenem + Colistin

Mero / Doripenem + Rifa

Mero / Doripenem + Tobra

Fosfomicina + AG

* Pentru care exista date publicate


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Ghid Sanford, 2012:A baumanii MDR (R la IMP, Cef3, Pen anti-P, AG, FQ)

Monoterapie - optiuni

Colistin

Ampi - sulbactam

* Conform ATB-grama

Posibile asoccieri*:

FQ + AG

Imipenem + AG

Imipenem + RifampicinaPen antipseudom. + AG

Ceftazidim + AG

Rifampicina + Colistin

Meropenem + Sulbactam

Colistin + Imipenem / Mero + Rifa

* Pentru care exista date publicate

Curba time-kill: 2 tulpini Acinetobacter baumanii XDR


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Curba time kill : 2 tulpini Acinetobacter baumanii XDRdiferite, colistina 0,125 g/ml

Liang et al, Infectious Diseases2011

Combinaiile colistinei cu meropenem, rifampicin,minociclin suntsinergice in vitro mpotriva Acinetobacter Baumanii XDR

Curba time-kill: 2 tulpini Acinetobacter baumanii XDR


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Cu ba t e ll : tulpdiferite, colistina 0,25 g/ml

Combinaiile colistinei cu meropenem, rifampicin,minociclin suntsinergice in vitro mpotriva Acinetobacter Baumanii XDR

Liang et al, Infectious Diseases2011


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0,5xMIC

1xMIC

2xMIC4xMIC

Evoluia infeciilor cu germeni GN-MDR n funcie de regimul


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terapeutic administrat in vivo

*Alte medicamente: aminoglicozide, imipenem, cefalosporine, aztreonam, ciprofloxacin

Colistin monoterapie sau colistin+meropenemeficacitate mai marecomparativ cu alte combinaii

Doza medie de colistina/zi este un factor independent pentru mortalitate exist o diferen de 800.000 UI ntre doza medie zilnic la supravieuitori idecedai

Falagas et al, JAA 2009, Colistin therapy for microbilogically documented multidrug rezistant Gram-negative bacterial infections.

Bactericidal Activity of Multiple Combinations of


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Bactericidal Activity of Multiple Combinations ofColistin against NDM-1-Producing Enterobacteriaceae

Mahableshwar, AAC, 2012

TGC showed a modest but significant inhibitoryeffect only at Cmax of 18013.33, compared with the GC

value of191 4.4 (P 0.008; 95% confidence interval [CI], 3.3 to

18.1)

better antimicrobial

activityat all concentrations

better antimicrobial

activityat all concentrations

Evaluare Time-kill a sinergieiTigacil +Colistin asupra a 8tulpini de enterobacteriaceeNDM1 secretoare.

Studiul a aratat o indiferenta aasocierii tigacil/colistin, sauchiar efect antagonic laconcentratii mici de tigacil.

NDM 1 = New Delhi Metallo-betalactamase 1


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Multiple evidene referitoare la aciuneasuperioara combinaiilor cu colistina cel maifrecvent cu carbapeneme

Avantajele asocierilor de antibioticeLrgirea spectrului de activitate

Creterea vitezei de bactericidieEvitarea seleciei de tulpini rezistente


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3 C pentru COLISTIN

Confuzie terminologie

Complexitate farmacologie

Contradictie - posologie



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Exista 2 forme de colistin in practica medicala

Colistin sulfatde uz topic (cutanat, digestiv)

Colistimetat sodic sau CMS(sodium colistinmethanesulphonate) utilizat parenteral;colistimetat sodic care prin hidroliz elibereazmoleculele de colistin

Colistin sulfat si colistimetat sodic NU SUNT INTERSCHIMBABILE

Complexitate farmacologie


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Complexitate farmacologieCMS = colistimetat

CMS in mediu apos este hidrolizat in colistin si derivati metansulfonati

CMS este prodrog, substanta activa fiind colistinul eliberat prin hidroliza

Colistin se elimina prin mecanisme non renale (este reabsorbit inproportie importanta prin reabsorbtie tubulara)

CMS se elimina prin secretie tubulara

C t di ti l i


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Edherington J Cyst Fibros 2006 Al-Aloul Pediat Pulmonol 2005


80 mg colistimetat sodic = 1.000.000 UI = 29.6 mg colistina baz

1 mg colistimetat sodic = 12.500 UI = 0.37 mg colistina baz

ATENIE la:

calculul dozelor de administrare

analiza studiilor din literatur

DE CE?Exprimri diferiteale substaneiactiveColistimetat sodicColistina baz

Uniti de msurdiferite ale substaneiactive

MGMUI

Corespondena dozelor


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SUA2.5 - 5 mg/kg/zi colistina baza

400 - 800 mg/zi colistimetat sodic

5 - 10 mil UI/zi colistimetat sodic

Edherington J Cyst Fibros 2006 Al-Aloul Pediat Pulmonol 2005

p g

1 mg colistimetat sodic = 12.500 UI = 0.37 mg colistina baz

FRANA

Aduli i adolesceni: 75 000 - 150 000UI/kg/zi,max 12 MUI/zi

(420 840 mg colistimetat sodic/zi, max 960 mg)

Copii i nou nscui: 150 000 - 225 000UI/kg/zi,max 12 MUI/zi

Colistina :


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Restaurarea sensibilitii la carbapeneme

7 sue P. aeruginosa multi-rezistente (CMI >16 g/ml)

Pre-expunere la colistin 4 24 g/ml pentru 30 minute

6 din 7 sue i-au recptat sensibilitatea la carbapeneme

Prin aciunea asupra peretelui celular

Ullman, Poster ICAAC, 2009

Rezisten la colimicin?


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Rezisten la colimicin?

Factorul de risc pentru apariia rezistenei la colimicin este

utilizarea antibioticului Crit Care, 2008

Emergena tulpinilor rezistente la Acinetobacter care prezintcretere la 24 ore (heterorezisten)

Evitarea concentraiilor subterapeuticen prima zi deadministrare prin utilizarea unei doze de ncarcare 9 mil UI,urmat de 3 mil UI la 8 ore

Plachouras D ett Al, AAC 2009

Asocieri multiple cu efect sinergic - abordare eficace n luptampotriva apariiei rezistenei microbiene, n literatura despecialitate se ntlnesc: colistin-meropenem, colistina-tigeciclin, colistina imipenem, etc

Administrare Profiluri de pacieni (1)


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Administrare. Profiluri de pacieni (1)

Mod de administrare Doz de ncrcare 9 milioane UI, n perfuzie 2 ore

Ulterior 3 milioane UI la 12 ore

Doza de meninere 3 mil la 8 ore

9 mil UIPerfuzie

2ore

0 h 12 h 8 h 8 h 8 h 8 h

3 mil UIPerfuzie30 min





Calculul dozelor, la pacienii obezi se realizeazpe greutate ideali nu

actual pentru evitarea riscurilor de supradozare i/sau nefrotoxicitate

Mesaje de luat acasa:


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NEW approach in severe infections

The optimal results of this regimen are influenced by :

o increasing Colistine half-time to 14,4 hours

o avoiding under-therapeutic concentrations during Day 1

Loading dose : 9 mil UI and then3 mil UI every 8 h



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Colistina în domeniul infectiilor severe si sepsisului

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