colistina în 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
Plachouras D et al : 2009 Antimicrob Agents Chemother 53:3430-3436
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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 intra- ventricular/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%
High-Dose, Extended-Interval Colistin administration inCritically Ill Patients: Is This the Right Dosing Strategy?
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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)
High-Dose, Extended-Interval Colistin administration inCritically Ill Patients: Is This the Right Dosing Strategy?
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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 siguranNefrotoxicitate
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)
Colistina profil de siguranNefrotoxicitate
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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
Efectul sinergic al colistinei
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Efectul sinergic al colistinei
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
Confuzie terminologie
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Confuzie terminologie
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
Contradictie - posologie
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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Contradictie - posologie
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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
3 mil UIPerfuzie30 min
3 mil UIPerfuzie30 min
3 mil UIPerfuzie30 min
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
Plachouras D et al : 2009 Antimicrob Agents Chemother 53:3430-3436
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