Locul colistinei n terapia infeciilor 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.
lotti pag.:99-110
R. Imberti, M. Regazzi, and G. A.

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 concentraie si are un efect post-antibiotic modest

Interacioneaz cu lipopolizaharidele membranei externe a germenilor Gram negativi

Dizloc ionii de Ca i Mg inducnd destabilizarea membranei celulare

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 i identificat 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

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 offlabel.

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

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

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

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

Chest 138:1333-1339

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

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.

FINDINGS
1. 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
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
12 MUI loading and 4,5 MUI every 12 h

9 MUI loading and 4,5 MUI every 12 h

3 MUI la 8 ore

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

COLISTIN -Pharmacokinetics in critically ill pacients. CMS 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 doz 0.60 mg/L s.s.: 2.3 mg/L.- la cca 7h
Time after first dose

Colistin

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.

Time after the 4-th dose

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

NEW approach in severe infections

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

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

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)

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.)

0h

12 h

8h

8h

8h

8h

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 31:10581065 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 head trauma meningitis, ventriculitis, abscesses

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 intra- ventricular/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-negative 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 reduce 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 resistance to colistin.

Falagas et al, CID 2005

Locul colistinei n terapia infeciilor cu BGN

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

180 160 155

Localizarea infeciei

Nr infeciei

140 120 100 80 60 40 20 0

33 22 Pneumonii Bacteriemii Infecii abdominale

16 Infecii cateter venos central

32 Altele

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

Colistina n infecii cu Gram negativi MDR

Etiologia infeciilor tratate cu colistin

Etiologia infeciilor tratate cu colistin
Klebsiella 7.0% Enterobacter 0.4% Stenotrophomonas 0.4%

Pseudomonas 26.4%

Acinetobacter 65.9%

Falagas et al, JAA 2009

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

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.

Dalfino et al, CID 2012:54 (June)

High-Dose, Extended-Interval Colistin administration in Critically Ill Patients: Is This the Right Dosing Strategy?
Etiology
P. aeruginosa 7% A. baumannii 47%

K. pneumoniae 46%

Dalfino et al, CID 2012:54 (June)

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

EFICACITATE
Vindecare clinic la 23 de cazuri (82.1%) Clearance bacteriologic 73,9% (17 cazuri cu BSI) dup 3 zile de tratament Clearance bacteriologic 40% (4 cazuri cu VAP) dup 8 zile de tratament Nu au fost raportate cazuri de apariie a rezistenei la colistin

Regimul 9 mil UI doz de ncrcare, 9 mil UI/zi are eficacitate satisfctoare

Dalfino et al, CID 2012:54 (June)

KPC Tsunami

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

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

a agar,

CLSI, b Etest,

c agar, EUCAST

Souli et al, Clinical Inf Disease, 2010

Colistina administrat sistemic infecii pediatrice cu germeni gram negativ multidrog rezisteni
Articole Pubmed, Cochrane, Scopus database 370 copii fr fibroz chistic tratai cu colistin din care: 326 tratament curativ 44 tratament profilactic (intervenii chirurgicale, arsuri)

Deterioare 2,2% Ameliorare 3,7%

Deces 7,4%

70 % din decese au fost atribuite infeciilor

Vindecare 86,7%
Systemic colistin use in children wihout cystic fibrosis: a systematic review of the literature Fagalas et al; Int J Antimicrob Agents: iunie 2009

Colistina administrat sistemic infecii pediatrice cu germeni gram negativ multidrog rezisteni

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

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

Concluzie: colistin este eficace clinic i este o opiune acceptabil din punct de vedere al siguranei
Fagalas et al; Int J Antimicrob Agents: iunie 2009

Colistina parenteral la copii cu infecii severe

oct 2004 nov 2008 7 copii cu infecii grave Acinetobacter, Pseudomonas, Klebsiella multidrogrezistente (snge sau secreii bronice) colistin parenteral: 5 mg/kg/zi (62.500 UI/kg/zi), la 8 ore (doza recomandat 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 sau administrrii de colistin NU a fost raportat nefrotoxicitate sau alt tip de toxicitate

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

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

Colistina profil de siguran

Colistina profil de siguran Nefrotoxicitate

Nefrotoxicitatea incidena ntlnit este de 6 % 14% n unele studii sau de 32% - 55% n alte studii. Plaja larg a incidenei nefrotoxicitii deriv din aplicarea unor criterii diferite de apreciere a insuficienei renale acute: scor RIFLE, Creatinina seric > 2 mg/dl

Factori de risc: Vrsta naintat Preexistena afectrii renale Hipoalbuminemia Utilizarea concomitent a antinflamatoarelor nesteroidiene Utilizarea vancomicinei

Reversibilitatea afectrii renale peste 88% n studiile care au monitorizat pacienii un interval de 1-3 luni

Colistina profil de siguran Nefrotoxicitate

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

Reducerea impuritilor colistimetatului sodic Monitorizarea atent i echilibrarea hidroelectrolitic n seciile de terapie intensiv Evitarea asocierii cu medicamente cu risc nefrotoxic

Colistina profil de siguran Nefrotoxicitate

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

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

Nu exist corelaie statistic ntre variaia creatininei serice i doza zilnic,doza cumulativ sau durata tratamentului cu colistin
Dalfino et al, CID 2012:54 (June)

Ajustarea dozelor de colistin n funcie de clearance-ul de creatinin

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

Colistina Neurotoxicitate

Neurotoxicitatea vertij, slbiciune muscular, parestezii, surditate parial, tulburri vizuale, confuzii, halucinaii, convulsii, ataxie
Paresteziile cel mai frecvent ntlnite, aprox 27% din cazuri

Au intensitate uoar medie i sunt reversibile la ntreruperea tratamentului

Efectul sinergic in antibioticoterapia infectiilor cu BGN MDR

Interaciune sinergic
Log No. Vaiable Organisms

Diminuarea cu cel puin 2 log 10 a nr colonii pentru asocierea de antibiotice, comparativ cu cel mai activ antibiotic din combinaie, la 24 h de incubatie Efect bactericid -scaderea numarului de colonii cu 3 log 10 Combinaii sinergice cu colistina:

8 7 6 5 4 3 2 1 0 2 4 6 8 10 12 14 16 18 20 22 24 Hours Drug A A+B Drug B

Colistin/meropenem Colistin/doripenem Colistin/rifampicin Colistin/minociclin Colistin/tigeciclin

Combinaiile sinergice reprezint soluii terapeutice n infeciile cu germeni multidrogrezisteni

Liang et al, Infectious Diseases 2011

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

Efectul sinergic al al colistinei

Bacteriile Gram negative pompe de eflux ceea ce explica rezistena intrinsec

Efectul sinergic al colistinei

Afectarea membranei externe prin actiunea colistinei favorizeaz accesul 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:

Ps. aeruginosa Carba-R

Monoterapie optiuni *
Colistin Ciprofloxacin Aminoglicozide Aztreonam Ceftazidim Peniciline antipseudom

Posibile asocieri*:
Pen anti-pseudom + AG Ceftazidim + AG Mero / Doripenem + Colistin Mero / Doripenem + Rifa Mero / Doripenem + Tobra Fosfomicina + AG

*Conform antibiogramei

* Pentru care exista date publicate

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 + Rifampicina Pen 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 diferite, colistina 0,125 g/ml
Liang et al, Infectious Diseases 2011

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

Curba time-kill: 2 tulpini Acinetobacter baumanii XDR diferite, colistina 0,25 g/ml
Liang et al, Infectious Diseases 2011

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

0,5x MIC 1xMIC 4xMIC 2xMIC

Evoluia infeciilor cu germeni GN-MDR n funcie de regimul terapeutic administrat in vivo

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

Colistin monoterapie sau colistin+meropenem eficacitate mai mare comparativ 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 i decedai
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

TGC showed a modest but significant inhibitory effect only at Cmax of 18013.33, compared with the GC value of 191 4.4 (P 0.008; 95% confidence interval [CI], 3.3 to 18.1)

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

better antimicrobial activity at all concentrations

Mahableshwar, AAC, 2012

 Multiple evidene referitoare la aciunea superioar a combinaiilor cu colistina cel mai frecvent cu carbapeneme
Avantajele asocierilor de antibiotice
Lrgirea spectrului de activitate Creterea vitezei de bactericidie Evitarea seleciei 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 hidroliz elibereaz moleculele de colistin
Colistin sulfat si colistimetat sodic NU SUNT INTERSCHIMBABILE

Complexitate farmacologie
CMS = 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

Contradictie - posologie
DE CE?
Exprimri diferite ale substanei active
Colistimetat sodic Colistina baz

Uniti de msur diferite ale substanei active

MG MUI

Corespondena dozelor
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
Edherington J Cyst Fibros 2006 Al-Aloul Pediat Pulmonol 2005

Contradictie - posologie
1 mg colistimetat sodic = 12.500 UI = 0.37 mg colistina baz
SUA 2.5 - 5 mg/kg/zi colistina baza 400 - 800 mg/zi colistimetat sodic 5 - 10 mil UI/zi colistimetat sodic

FRANA

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

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

Copii i nou nscui: 150 000 - 225 000 UI/kg/zi, max 12 MUI/zi
Edherington J Cyst Fibros 2006 Al-Aloul Pediat Pulmonol 2005

Colistina : 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?
Factorul de risc pentru apariia rezistenei la colimicin este utilizarea antibioticului
Crit Care, 2008

Emergena tulpinilor rezistente la Acinetobacter care prezint cretere la 24 ore (heterorezisten) Evitarea concentraiilor subterapeutice n prima zi de administrare 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 lupta mpotriva apariiei rezistenei microbiene, n literatura de specialitate se ntlnesc: colistin-meropenem, colistinatigeciclin, colistina imipenem, etc

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 UI Perfuzie 2ore

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

0h

12 h

8h

8h

8h

8h

Calculul dozelor, la pacienii obezi se realizeaz pe greutate ideal i nu actual pentru evitarea riscurilor de supradozare i/sau nefrotoxicitate

Mesaje de luat acasa: NEW approach in severe infections

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

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

ANTIBIOTICE portofoliu complex de antiinfecioase Cefort (ceftriaxona) orale i parenterale Ceftamil (ceftazidima)
Cefuroxima Antibiotice (oral si injectabil) Amoxiplus (amoxicilina + acid clavulanic) oral Ampiplus (ampicilina + sulbactam) Perasin (piperacilina + tazobactam) Colistina Antibiotice Eficef (cefixima)-oral Roclarin (claritromicina) - oral