colistina în domeniul infectiilor severe si sepsisului dr dascalescu

Locul colistinei în terapia infecţiilor cu BGN

The last few years have been characterized by the emergence of certain Gram- negative bacteria, especially Acinetobacter baumannii, Pseudomonas aeruginosa and Klebsiella pneumoniae, which are resistant to almost all currently available antibiotics, except colistin.

R. Imberti, M. Regazzi, and G. A. lotti pag.:99-110

Ce este colistina?Un antibiotic complex Peptid ciclic policationic amfipatic

Colistina (cunoscuta ca si polymyxina E) este un amestec complex de polimixine, 2 dintre ele fiind cele mai importante : colistina A (polimixina E1) si colistina B (polimixina E2)

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

Interacţionează cu lipopolizaharidele membranei externe a germenilor Gram negativi

Dizlocă ionii de Ca şi Mg inducând destabilizarea membranei celulare

Scurtă istorie a colistinei Descoperită în 1947 în categoria polimixinelor A-E, introdusa in 1959

Doar polimixina B şi polimixina E (colistină) sunt de uz uman

Izolată în Japonia, în 1949, produsă de Bacillus polymyxa var. colistinusBacillus polymyxa var. colistinus şi identificată ca polimixina E

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

Există sub forma a 2 componente (E1 şi E2, denumite şi colistina A şi B) – diferă prin lungimea lanţului de acizi graşi

Incepe sa fie abandonata in anii 1970 dupa introducerea aminoglicozidelor

Anii 1980 – se renunţă la utilizarea colistinei din cauza reacţiilor adverse

2003 – 2005 – reluarea utilizării colistinei, reevaluarea toxicităţii, reacţiile adverse fiind mai reduse

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 vitro and in vivo by hydrolysis of methane sulphonate radicals.

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

is off-label.

CMS should not be confused with colistin base :

1 mg colistin base (CBA) = 2.4 mg 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 IU and not in mg : source of potential confusion.

Pharmacokinetics and Pharmacodynamics

In the past, colistin concentrations in biological fluids and tissues were evaluated by microbiological assays which did not discriminate between CMS and colistin.

Moreover, during the incubation period of the microbiological assay, CMS is converted to colistin, resulting in measured concentrations of CMS and colistin that do not reliably reflect their concentration in fluids and tissues.

NEW : liquid chromatography and mass spectrometry enable CMS and colistin to be measured separately and quantified accurately, were introduced only a few years ago ( 2002-2010)

Pharmacokinetics and Pharmacodynamics in the last decade, the pharmacokinetics of colistin (the

active form) and CMS have been studied in animals and critically ill patients

CMS undergoes tubular secretion and renal clearance

Colistin has a very extensive tubular reabsorption and its clearance is mainly via non-renal pathways

The very high concentration of colistin in urine after systemic CMS administration is very likely due to conversion of CMS within the urinary tract

PharmacokineticsColistin 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 17.3±9.3 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

7.4±1.7h. 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

Pharmacokinetics

in these studies:

- 2 to 3 hours after CMS administration, plasma colistin concentrations were below the MIC breakpoint of 2 mcg/ml in most patients

Imberti R, Cusato M, Villani P et al : 2010, Chest 138:1333-1339

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/1.72 m2) some pts. on CRRT.

FINDINGS1. with decreasing renal function a 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.

CONCLUSIONS

1. Our current data suggest that because of the inability to achieve adequate plasma 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/liter in a patient with creatinine clearance of >70 ml/min/1.73 m2.

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

Pharmacokinetics

Population Pharmacokinetic Analysis of Colistin Methanesulfonate and Colistin after Intravenous Administration in Critically Ill 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 MUI every 12 h

9 MUI loading and 4,5 MUI every 12 h

COLISTIN -Pharmacokinetics in critically ill pacients.

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

Colistin: •T1/2 ~ 14.4 h•Cmax la prima doză 0.60 mg/L•s.s.: 2.3 mg/L.- la cca 7h

Colistin displayed a half-life that was significantly long in relation to the dosing interval.

In consequence: plasma colistin concentrations are insufficient before steady state and the administration of a loading dose would benefit critically ill pts.

CMSColisti

n

Time– after first dose

Time– after the 4-th dosePlachouras D et al : 2009 Antimicrob Agents Chemother 53:3430-3436

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 :Loading dose : 9 mil UI 9 mil UI and thenand then 3 mil UI 3 mil UI every 8 hevery 8 h


S

Bergen 2008, JAC

Pharmacokinetics and Administration in critically ill

Loading dose : 9 million UI (2 hours perfusion) 3 million UI after 12 hours Maintenamce : 3 million every 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.)

Intravenous COLISTIN in Pneumonia and VAP

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 cure in 82.1 % of cases

3. effective and safe in children and neonates

Reina R et al: 2005 Intensive Care Med 31:1058—1065 Kallel H et al : 2007 Intensive Care Med 33:1162-1167 Michalopoulos AS, Falagas ME : 2005 Clin Microbiol Infect

11:115-121 Dalfino L et al : 2012 Clin Infect Dis 54:1720-1726 Iosifidis E et al : 2010 Eur J Pediatr 169:867-874 Celebi S : 2010 Pediatr Int 52:410-414 Jajoo M et al : 2011 Pediatr Infect Dis J 30:218-221

Dose Regimen for Intravenous CMS

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

The optimal dosage regimen is not known

a possible CMS dose 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

state concentration

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

Garonzik formulas ?

Nebulized COLISTIN

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

another fraction of CMS dose is converted into colistin within the lungs and is then partially absorbed 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 cure

Rattanaumpawan 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 in pneumonia is

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

Combination Therapy

In vitro : - colistin acts synergistically with other antibiotics - most frequently combined : rifampicin and carbapenems. - all studies: synergy with rifampicin against P. Aer.and A.

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 of colistin even at high doses and may lead to the emergence of resistance,

it is of paramount importance to investigate combination therapy !

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 be 10 mg , but the dosages of intraventricular/intrathecal CMS reported in the literature 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, the measured 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 CNS infections caused by MDR Gram-neg ative bacteria susceptible only to colistin.

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 re duce the risk of nephrotoxicity.

Neurotoxiciy after systemic or intraventricular/intrathecal administration

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

is rare, not a major issue in critically ill pts. (might be

underestimated in sedated and MV pts.)

Minimum Inhibitory Concentrations and Resistance

Different susceptibility breakpoints have been introduced by various organizations.

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) the susceptibility breakpoint :

- A. baumannii and K. pneumoniae is 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. aeruginosa and A. baumannii with 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

and induces phenotype instability

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

- Combination therapy might reduce the risk of the emergence of resis tance to colistin.

Falagas et al, CID 2005

Locul colistinei în terapia infecţiilor cu BGN

Colistina în infecţii cu Gram Colistina în infecţii cu Gram negativi MDRnegativi MDR Studiu retrospectiv, 2000-2007, 258 pacienţi Administrare colistina cel puţin 72 ore Infecţii cu Gram negativi MDR documentate bacteriologic

Localizarea infecției

Nr

infe

cție

i

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

Etiologia infecţiilor tratate cu colistină

Etiologia infecţiilor tratate cu colistină

Acinetobacter65.9%

Pseudomonas26.4%

Klebsiella7.0%

Enterobacter 0.4% Stenotrophomonas

0.4%

Falagas et al, JAA 2009

Colistina în infecţii cu Gram Colistina în infecţii cu Gram negativi MDRnegativi MDR

High-Dose, Extended-Interval ColistinHigh-Dose, Extended-Interval Colistin aadministration in dministration in Critically Ill Patients: Is ThisCritically Ill Patients: Is This t the Right Dosing he Right Dosing Strategy?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.


Infecţii tratate cu colistinăVAP35.7%

10 cazuri

Blood stream

infections64.3%

16 cazuri

Etiology

A. baumannii 47%

P. aeruginosa7%

K. pneumoniae46%


EFICACITATE Vindecare clinică la 23 de cazuri (82.1%) Clearance bacteriologic 73,9% (17 cazuri cu BSI) după 3 zile

de tratament Clearance bacteriologic 40% (4 cazuri cu VAP) după 8 zile de

tratament Nu au fost raportate cazuri de apariţie a rezistenţei la

colistină

Regimul 9 mil UI doză de încărcare, 9 mil UI/zi are eficacitate satisfăcătoare



KPC “Tsunami”

Profil de susceptibilitate - Klebsiella pneumoniae producătoare de carbapenemaze-2 (KPC-2)

Souli et al, Clinical Inf Disease, 2010

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

• 50 pacienţi (34 TI, 16 non TI), Grecia• Alături de KPC-2 s-au regăsit: TEM-1 like, SHV-11, SHV-12, CTX-M-15,

LEN-19• Mortalitate secundară: 22,2% in secţiile de TI, 33,3% în secţiile non TI

Colistina administrată sistemic –infecţii pediatrice cu germeni gram negativ multidrog rezistenţiArticole Pubmed, Cochrane, Scopus database – 370 copii fără fibroză

chistică trataţi cu colistin din care:

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

Ameliorare3,7%

Deterioare2,2% Deces

7,4%

Vindecare86,7%

70 % din decese au fost atribuite infecţiilor

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

44 tratament profilactic (intervenţii chirurgicale, arsuri)- nu au survenit infecţii- 20,5 % deces secundar comorbidităţilor

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

Fagalas et al; Int J Antimicrob Agents: iunie 2009

Concluzie: colistin este eficace clinic şi este o opţiune acceptabilă din punct de vedere al siguranţei

Colistina administrată sistemic –infecţii pediatrice cu germeni gram negativ multidrog rezistenţi

Colistina parenteral la copii cu infecţii severe

oct 2004 – nov 2008 – 7 copii cu infecţii grave

Acinetobacter, Pseudomonas, Klebsiella multidrogrezistente (sânge sau secreţii bronşice)

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

Evoluţie:5 copii s-au vindecat2 copii au decedat , decesul nu a fost secundar

infecţiei sau administrării de colistin

NU a fost raportată nefrotoxicitate sau alt tip de toxicitate

Deşi numarul de copii raportat este mic, colistina are un rol esenţial în tratamentul infecţiilor grave la copii

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

Colistina – profil de siguranţă

• Nefrotoxicitatea – incidenţa întâlnită este de 6 % – 14% în unele studii sau de 32% - 55% în alte studii. Plaja largă a incidenţei nefrotoxicităţii derivă din

aplicarea unor criterii diferite de apreciere a insuficienţei renale acute: scor RIFLE, Creatinina serică > 2 mg/dl

Factori de risc:Vârsta înaintatăPreexistenţa afectării renaleHipoalbuminemiaUtilizarea concomitentă a antinflamatoarelor

nesteroidieneUtilizarea vancomicinei

Reversibilitatea afectării renale peste 88% în studiile care au monitorizat pacienţii un interval de 1-3 luni

Colistina – profil de siguranţăColistina – profil de siguranţăNefrotoxicitateNefrotoxicitate

Riscul de nefrotoxicitate este mai redus decât cel raportat în litaratura anilor ’70 – ’80 prin:

Reducerea impurităţilor colistimetatului sodicMonitorizarea atentă şi echilibrarea

hidroelectrolitică în secţiile de terapie intensivăEvitarea asocierii cu medicamente cu risc

nefrotoxic


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

Afectare renală acută 17,9% (5 cazuri, unul cu afectare preexistentă) – continuarea terapiei cu ajustarea dozei

Nu există corelaţie statistică între variaţia creatininei serice şi doza zilnică,doza

cumulativă sau durata tratamentului cu colistină



• posologia: 75.000 – 150.000 UI/kg/zi, fără a depăşi 12 MUI/zi.

Agence française de sécurité sanitaire des produits de santé

www.affsaps.fr

Ajustarea dozelor de colistină în Ajustarea dozelor de colistină în funcţie de clearance-ul de creatininăfuncţie de clearance-ul de creatinină

• Neurotoxicitatea – vertij, slăbiciune musculară, parestezii, surditate parţială, tulburări vizuale, confuzii, halucinaţii, convulsii, ataxie

Paresteziile – cel mai frecvent întâlnite, aprox 27% din cazuri

• Au intensitate uşoară – medie şi sunt reversibile la întreruperea tratamentului

Colistina – NeurotoxicitateColistina – Neurotoxicitate

Efectul sinergic in antibioticoterapia infectiilor cu BGN MDR

Interacţiune sinergică

Combinaţii sinergice cu colistina:Colistină/meropenemColistină/doripenemColistină/rifampicinăColistină/minociclinăColistină/tigeciclină

Combinaţiile sinergice reprezintă soluţii terapeutice în infecţiile cu germeni multidrogrezistenţi

0

1

2

3

4

5

6

7

8

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

Hours

Log

No.

Vai

able

Org

anism

s

Drug A A+B Drug B

Liang et al, Infectious Diseases 2011

• Diminuarea cu cel puţin 2 log 10 a nr colonii pentru asocierea de antibiotice, comparativ cu cel mai activ antibiotic din combinaţie, la 24 h de incubatie

•Efect bactericid -scaderea numarului de colonii cu ≥ 3 log 10

Efectul sinergic al colistinei –

• Bacilii Gram-negativi – membrană internă şi membrană externă

• Ţinta AB se regăseşte la nivelul membranei interne sau intracelular

• Cele mai multe AB trebuie să traverseze membrana externă pentru a ajunge la molecula ţinta, aceasta putând fi o etapă limitatoare

Efectul sinergic al al colistinei –

•Bacteriile Gram negative – pompe de eflux ceea ce explica rezistenţa intrinsecă

Efectul sinergic al colistinei –

•Afectarea membranei externe prin actiunea colistinei favorizează accesul altor antibiotice către ţinta lor de acţiune

• Acest aspect se aplică chiar dacă bacteria este rezistentă, din cauza impermeabilităţii membranei externe sau fenomenului de

eflux

Ghid Sanford, 2012:Ps. aeruginosa Carba-R

Monoterapie – optiuni *ColistinCiprofloxacinAminoglicozideAztreonamCeftazidimPeniciline antipseudom

*Conform antibiogramei

Posibile asocieri*:Pen anti-pseudom + AGCeftazidim + AGMero / Doripenem + ColistinMero / Doripenem + RifaMero / Doripenem + TobraFosfomicina + AG

* Pentru care exista date publicate

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

Monoterapie - optiuni ColistinAmpi - sulbactam

* Conform ATB-grama

Posibile asoccieri*:FQ + AGImipenem + AGImipenem + RifampicinaPen antipseudom. + AGCeftazidim + AGRifampicina + ColistinMeropenem + SulbactamColistin + Imipenem / Mero + Rifa

* Pentru care exista date publicate

Curba “time-kill”: 2 tulpini Acinetobacter baumanii XDRdiferite, colistina 0,125 µg/ml


Combinaţiile colistinei cu meropenem, rifampicină,minociclină sunt sinergice in vitro împotriva Acinetobacter Baumanii XDR

Curba “time-kill”: 2 tulpini Acinetobacter baumanii XDR

diferite, colistina 0,25 µg/ml

Combinaţiile colistinei cu meropenem, rifampicină,minociclină sunt sinergice in vitro împotriva Acinetobacter Baumanii XDR


0,5xMIC

1xMIC

2xMIC4xMIC

Evoluţia infecţiilor cu germeni GN-MDR în funcţie de regimul terapeutic administrat – in vivo

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

Colistină monoterapie sau colistină+meropenem – eficacitate mai mare comparativ cu alte combinaţii

Doza medie de colistina/zi este un factor independent pentru mortalitate – există o diferenţă de 800.000 UI între doza medie zilnică la supravieţuitori şi decedaţi

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

Bactericidal Activity of Multiple Combinations of Colistin 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 activity

at all concentrations

better antimicrobial activity

at all concentrations

Evaluare Time-kill a sinergiei Tigacil +Colistin asupra a 8 tulpini de enterobacteriacee NDM1 secretoare.

Studiul a aratat o indiferenta a asocierii tigacil/colistin, sau chiar efect antagonic la concentratii mici de tigacil. NDM 1 = New Delhi Metallo-betalactamase 1

Multiple evidenţe referitoare la acţiunea superioară a combinaţiilor cu colistina – cel mai frecvent cu carbapeneme

Avantajele asocierilor de antibioticeLărgirea spectrului de activitateCreșterea vitezei de bactericidieEvitarea selecției de tulpini rezistente

3 “C” pentru COLISTIN

Confuzie – terminologie

Complexitate – farmacologie

Contradictie - posologie

Confuzie – terminologie

Exista 2 forme de colistin in practica medicala

Colistin sulfat – de uz topic (cutanat, digestiv)

Colistimetat sodic sau CMS (sodium colistin methanesulphonate) – utilizat parenteral; colistimetat sodic care prin hidroliză eliberează moleculele de colistină

Colistin sulfat si colistimetat sodic NU SUNT INTERSCHIMBABILE

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 in proportie importanta prin reabsorbtie tubulara)

• CMS se elimina prin secretie tubulara

Edherington J Cyst Fibros 2006 Al-Aloul Pediat Pulmonol 2005


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

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

ATENŢIE la:calculul dozelor de administrareanaliza studiilor din literatură

• DE CE? Exprimări diferite ale substanţei activeColistimetat sodicColistina bază

Unităţi de măsură diferite ale substanţei active

MG MUI

• Corespondenţa dozelor

SUA 2.5 - 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


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

FRANŢA

Adulţi şi adolescenţi: 75 000 - 150 000 UI/kg/zi,

max 12 MUI/zi (420 – 840 mg colistimetat sodic/zi, max 960 mg)

Copii şi nou născuţi: 150 000 - 225 000

UI/kg/zi, max 12 MUI/zi

Colistina :Restaurarea sensibilităţii la carbapeneme

7 suşe P. aeruginosa multi-rezistente (CMI >16 µg/ml)

Pre-expunere la colistină 4 – 24 µg/ml pentru 30 minute

6 din 7 suşe şi-au recăpătat sensibilitatea la carbapeneme

Prin acţiunea asupra peretelui celular

Ullman, Poster ICAAC, 2009

Rezistenţă la colimicină?

Factorul de risc pentru apariţia rezistenţei la colimicină este utilizarea antibioticului

Crit Care, 2008

Emergenţa tulpinilor rezistente la Acinetobacter care prezintă creştere la 24 ore (heterorezistenţă)

Evitarea concentraţiilor subterapeutice în prima zi de administrare prin utilizarea unei doze de încarcare 9 mil UI, urmat de 3 mil UI la 8 ore

Plachouras D ett Al, AAC 2009

Asocieri multiple cu efect sinergic - abordare eficace în lupta împotriva apariţiei rezistenţei microbiene, în literatura de specialitate se întâlnesc: colistină-meropenem, colistina-tigeciclină, colistina – imipenem, etc

Administrare. Profiluri de pacienţi (1)

Mod de administrare Doză de încărcare 9 milioane UI, în perfuzie 2 ore Ulterior 3 milioane UI la 12 ore Doza de menţinere 3 mil la 8 ore

9 mil UI

Perfuzie 2ore

0 h

12 h 8 h 8 h 8 h 8 h

3 mil UI

Perfuzie

30 min

3 mil UI

Perfuzie

30 min

3 mil UI

Perfuzie

30 min

3 mil UI

Perfuzie

30 min

3 mil UI

Perfuzie

30 min

Calculul dozelor, la pacienţii obezi se realizează pe greutate ideală şi nu actuală pentru evitarea riscurilor de supradozare şi/sau

nefrotoxicitate

Mesaje de luat acasa: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 :Loading dose : 9 mil UI 9 mil UI and thenand then 3 mil UI 3 mil UI every 8 hevery 8 h


ANTIBIOTICE – portofoliu complex de antiinfecţioase orale şi parenterale

Cefort® (ceftriaxona)Ceftamil ® (ceftazidima)Cefuroxima Antibiotice (oral si injectabil)Amoxiplus ® (amoxicilina + acid clavulanic) –oral si injectabilAmpiplus ® (ampicilina + sulbactam)Perasin ® (piperacilina + tazobactam)Colistina AntibioticeEficef ®(cefixima)-oralRoclarin ® (claritromicina) - oral

colistina în domeniul infectiilor severe si sepsisului dr dascalescu

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