colistina în domeniul infectiilor severe si sepsisului dr dascalescu
TRANSCRIPT
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
Plachouras D et al : 2009 Antimicrob Agents Chemother 53:3430-3436
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 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-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.
Dalfino et al, CID 2012:54 (June)
Infecţii tratate cu colistinăVAP35.7%
10 cazuri
Blood stream
infections64.3%
16 cazuri
Etiology
A. baumannii 47%
P. aeruginosa7%
K. pneumoniae46%
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?
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
Dalfino et al, CID 2012:54 (June)
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?
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
Colistina – profil de siguranţăColistina – profil de siguranţăNefrotoxicitateNefrotoxicitate
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
Dalfino et al, CID 2012:54 (June)
Colistina – profil de siguranţăColistina – profil de siguranţăNefrotoxicitateNefrotoxicitate
• 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
Liang et al, Infectious Diseases 2011
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
Liang et al, Infectious Diseases 2011
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
Contradictie - posologie
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
Contradictie - posologie
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
Plachouras D et al : 2009 Antimicrob Agents Chemother 53:3430-3436
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