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. 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 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. 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. produsă de Bacillus polymyxa var. reacţiile adverse fiind mai reduse . reevaluarea toxicităţii. 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. introdusa in 1959 Doar polimixina B şi polimixina E (colistină) sunt de uz uman Izolată în Japonia. în 1949. ) use only . colistimethate or colistin sulphomethate) .).colistin methanesulfonate (CMS. .m.colistin sulfate Colistin is generally administered systemically (parenterally) as CMS.COLISTIN 3 pharmaceutical forms of colistin exist: .colistin base .v.CMS is approved for intramuscular (i.intravenous (i. CMS (which is inactive) is converted to colistin (active form) both in vitro and in vivo by hydrolysis of methane sulphonate radicals. nebulized and intraventricular use of the drug is offlabel. In many countries: . CMS should not be confused with colistin base : 1 mg colistin base (CBA) = 2. 1mg CBA = 30.333 IU of CMS (150 mg CBA is equivalent to approximately 5 million units CMS) 1.000.4 mg of CMS.000 IU of CMS = 80 mg CMS= 29.000 -33.6 mg colistin base the vial concentration of CMS is often reported in IU and not in mg : source of potential confusion. . were introduced only a few years ago ( 2002-2010) . during the incubation period of the microbiological assay. NEW : liquid chromatography and mass spectrometry enable CMS and colistin to be measured separately and quantified accurately. colistin concentrations in biological fluids and tissues were evaluated by microbiological assays which did not discriminate between CMS and colistin.Pharmacokinetics and Pharmacodynamics In the past. Moreover. resulting in measured concentrations of CMS and colistin that do not reliably reflect their concentration in fluids and tissues. CMS is converted to colistin. 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 and Pharmacodynamics in the last decade. the C max. 240 mg) every 8 h.very low plasma colistin concentrations for 2-3 days before reaching steady state.4±1.Pharmacokinetics Colistin after i.08 mcg/ml .v.1 ±0. Markou N et al.ss of colistin was 2. Chest Markou : 2.93 ± 1. < the MIC breakpoint of 2 mcg/ml. .v.3 mcg/ml for the first dose and at SS .60 mcg/ml and 2. administration of CMS critically ill patients with MDR Gram inf.: 2008 Clin Ther 30:143-151 · Plachouras: CMS 3 million IU (approx. . 53:3430-3436 Plachouras D et al : 2009 Antimicrob Agents Chemother .ss was 2. 244 mg): .3 138:1333-1339 Imberti R. Imberti et al.a large proportion of patients had plasma conc. Cusato M. every 8 h .the predicted Cmax plasma were 0.21 ± 1.ss/MIC ratio 1. Villani P et al : 2010.24 mcg/ml and the apparent half-life 7.MIC of colistin is 2 mcg/ml .the Cmax.8 million IU CMS (approx. : 2 million IU CMS (174 mg) i.7h.5 .AUC0-24/MIC ratio was 17.3±9. suggesting the need for a loading dose.the Cmax. plasma colistin concentrations were below the MIC breakpoint of 2 mcg/ml in most patients Chest 138:1333-1339 Imberti R. . Villani P et al : 2010.2 to 3 hours after CMS administration.Pharmacokinetics in these studies: . Cusato M. Pharmacokinetics - in 2011 Garonzik etal.the loading dose .maintenance dose in order to achieve a given colistin average concentration at steady state (Css. whereas the clearance of formed colistin decreased.72 m2) some pts. with a large range of renal function (creatinine clearance 3-169 ml/min/1. investigated the PK of CMS and colistin in 105 critically ill pts.avg) during the dosing interval. developed equations suggesting : . with decreasing renal function a larger fraction of CMS was converted to colistin. 2. . FINDINGS 1. on CRRT. CONCLUSIONS 1.73 m2. 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. they will be refined as we complete recruitment to a total of 238 critically ill patients and also model the pharmacodynamic and toxicodynamic endpoints. 2. The loading and maintenance dosing suggestions reported herein should be regarded as interim. . 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. 5 million UI every 12 h 12 MUI loading and 4.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 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 . .3 h.s. CMS Colistimetat (CMS): •240 mg (3 x 106 U ) la 8 h •CMS T1/2 ~ 2.60 mg/L •s.COLISTIN -Pharmacokinetics in critically ill pacients.: 2.3 mg/L.4 h •Cmax la prima doză 0. Time– after the 4-th dose Plachouras D et al : 2009 Antimicrob Agents Chemother 53:3430-3436 . In consequence: plasma colistin concentrations are insufficient before steady state and the administration of a loading dose would benefit critically ill pts. Colistin: •T1/2 ~ 14.la cca 7h Time– after first dose Colistin Colistin displayed a half-life that was significantly long in relation to the dosing interval. 4 hours o avoiding under-therapeutic concentrations during Day 1 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. JAC .S Bergen 2008. perf. perf.) 0h 12 h 8h 8h 8h 8h . perf. perf.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.) 3 mil UI (30 min. perfusion) 3 mil UI (30 min.) 3 mil UI (30 min. perf.) 3 mil UI (30 min.) 3 mil UI (30 min. 2. 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.1 % of cases 3. high-dose CMS ( blood stream infection and VAP) resulted in clinical cure in 82. 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 . No differences in mortality or clinical cure rates when compared (susceptible strains) with others atb.Intravenous COLISTIN in Pneumonia and VAP clinical studies : CMS is effective in serious MDR Gram – infections (prospective and retrospective) Conclusions for CMS 1. :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. Regazzi. since CMS accumulates in pts.500 – 43. The optimal dosage regimen is not known a possible CMS dose could be 3-3.000 -33. Imberti.5 mg/kg/8 h.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.4 mg of CMS.8 million ui – 9 million ui / day R.000.( 37. 1mg CBA = 30. lotti : Annual Update in IC and EM 2013 :pag. and G. M.Dose Regimen for Intravenous CMS CMS should not be confused with colistin base 1 mg colistin base (CBA) = 2.750 ui/kg/8 h ) 7. A. with renal impairment : dose must be adjusted Garonzik formulas ? .333 IU of CMS 1. used doses : 1 million IU/8 h (80 mg/8 h) . ATB alone: No effect on clinical cure Rattanaumpawan P et al: 2010 J Antimicrob Chemother 65:2645-2649 .5% vs.CMS + nebulized CMS versus i.monotherapy nebulized CMS is inappropriate in pneumonia is associated with bacteremia.025).it is probably better to administer higher doses of nebulized CMS .v.5% (p = 0.60. Korbila IP.Carbapenems + CMS + nebulized CMS sv. CMS alone: clinical cure 79.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) . Falagas ME : 2010 Clin Microbiol Infect 16:1230-1236 . Athanassa ZE et al: 2012 Intensive Care Med 38:1779-1786 .the optimal dose is not known . and meropenem = lower mortality ! Tumbarello M et al: 2012 Clin Infect Dis 55:943-950 Since i.most frequently combined : rifampicin and carbapenems. pneumoniae ) : combination of colistin. P. baumannii In vivo : . . 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 ! . low number pts.a few clinical studies have investigated CMS in combination therapy.v. another study ( 125 patients KPC -producing K.colistin acts synergistically with other antibiotics . baumannii.in critically ill patients are scant.Combination Therapy In vitro : . aeruginosa and K.all studies: synergy with rifampicin against P.and A. pneumoniae) combination therapy was not superior to colistin alone! Falagas ME et al: 2010 J Antimicrob Agents 35:194-199 in contrast. great variability. Aer. tigecycline. . .all are retrospective ! a recent study performed in 258 patients (A. 6-40 mg. as a single dose or in divided doses A recent study intraventricular CMS was administered at doses of> 5. therefore. but the dosages of intra. ventriculitis.ventricular/intrathecal CMS reported in the literature range between 1. 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. . 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 .2 mg/day. abscesses CSM and colistin hardly cross the or blood-brain barrier in animals or humans.COLISTIN in Central Nervous System Infections neurosurgical procedures otorhinological procedures head trauma meningitis. the measured CSF concentrations of colistin were continuously > than MIC of 2 mcg/ml Imberti R . even if the meninges are inflamed CMS must. not a major issue in critically ill pts. Neurotoxiciy after systemic or intraventricular/intrathecal administration manifestations : seizures. and cauda equina is rare. daily serum creatinine monitoring and careful management of volemia can help to reduce the risk of nephrotoxicity.the total CMS dose .the duration of CMS therapy Dose adjustment according to renal function.53% due to studies non-uniformity the risk is correlated to : .Toxicity Nephrotoxicity : the most common and threatening adverse reaction extremely variable rate : 0 . neuromuscular blockade with respiratory paralysis. hypotonia.) . aseptic meningitis. (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 în terapia infecţiilor cu BGN Colistina în infecţii cu Gram negativi MDR Studiu retrospectiv. JAA 2009. Colistin therapy for microbilogically documented multidrug rezistant Gram-negative bacterial infections. . 2000-2007. 258 pacienţi Administrare colistina cel puţin 72 ore Infecţii cu Gram negativi MDR documentate bacteriologic 180 160 155 Localizarea infecției Nr infecției 140 120 100 80 60 40 20 0 33 22 Pneumonii Bacteriemii Infecții abdominale 16 Infecții cateter venos central 32 Altele Falagas et al. 4% Pseudomonas 26.4% Acinetobacter 65.4% Stenotrophomonas 0.9% Falagas et al.Colistina în infecţii cu Gram negativi MDR Etiologia infecţiilor tratate cu colistină Etiologia infecţiilor tratate cu colistină Klebsiella 7.0% Enterobacter 0. JAA 2009 . 5 mil UI every 12 hrs. CID 2012:54 (June) . 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. then 4.High-Dose. BGN : minimal answer to ATB or answering only to COLISTIN DOSES: loading dose 9 mil UI . Dalfino et al. baumannii 47% K. pneumoniae 46% Dalfino et al.High-Dose. aeruginosa 7% A. Extended-Interval Colistin administration in Critically Ill Patients: Is This the Right Dosing Strategy? Etiology P. CID 2012:54 (June) . CID 2012:54 (June) . 9 mil UI/zi are eficacitate satisfăcătoare Dalfino et al.1%) Clearance bacteriologic 73. Extended-Interval Colistin administration in Critically Ill Patients: Is This the Right Dosing Strategy? EFICACITATE Vindecare clinică la 23 de cazuri (82.9% (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.High-Dose. KPC “Tsunami” . c – agar. SHV-11. CLSI. EUCAST Souli et al. Clinical Inf Disease. b – Etest. SHV-12.Profil de susceptibilitate . 16 non TI). CTX-M-15. LEN-19 • Mortalitate secundară: 22. Grecia • Alături de KPC-2 s-au regăsit: TEM-1 like.Klebsiella pneumoniae producătoare de carbapenemaze-2 (KPC-2) • 50 pacienţi (34 TI.2% in secţiile de TI. 33.3% în secţiile non TI a – agar. 2010 . 7% Deces 7.Colistina administrată sistemic –infecţii pediatrice cu germeni gram negativ multidrog rezistenţi Articole Pubmed.2% Ameliorare 3. Int J Antimicrob Agents: iunie 2009 . arsuri) Deterioare 2. Cochrane.7% Systemic colistin use in children wihout cystic fibrosis: a systematic review of the literature Fagalas et al. Scopus database – 370 copii fără fibroză chistică trataţi cu colistin din care: 326 tratament curativ 44 tratament profilactic (intervenţii chirurgicale.4% 70 % din decese au fost atribuite infecţiilor Vindecare 86. 20. arsuri) .Colistina administrată sistemic –infecţii pediatrice cu germeni gram negativ multidrog rezistenţi 44 tratament profilactic (intervenţii chirurgicale.2.nu au survenit infecţii .5 % deces secundar comorbidităţilor Nefrotoxicitate .8 % (10/355 copii) modificarea parametrilor renali Concluzie: colistin este eficace clinic şi este o opţiune acceptabilă din punct de vedere al siguranţei Fagalas et al. Int J Antimicrob Agents: iunie 2009 . Pseudomonas.000 – 75.Colistina parenteral la copii cu infecţii severe oct 2004 – nov 2008 – 7 copii cu infecţii grave Acinetobacter.000 UI/kg/zi) Evoluţie: 5 copii s-au vindecat 2 copii au decedat . Februarie 2009 . The Pediatric Infectious Disease Journal. Klebsiella multidrogrezistente (sânge sau secreţii bronşice) colistin parenteral: 5 mg/kg/zi (62. la 8 ore (doza recomandată la copii 50. 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.500 UI/kg/zi). colistina are un rol esenţial în tratamentul infecţiilor grave la copii Falagas et al. Colistina – profil de siguranţă . Creatinina serică > 2 mg/dl Factori de risc: Vârsta înaintată Preexistenţa afectării renale Hipoalbuminemia Utilizarea concomitentă a antinflamatoarelor nesteroidiene Utilizarea vancomicinei Reversibilitatea afectării renale peste 88% în studiile care au monitorizat pacienţii un interval de 1-3 luni .55% în alte studii. Plaja largă a incidenţei nefrotoxicităţii derivă din aplicarea unor criterii diferite de apreciere a insuficienţei renale acute: scor RIFLE.Colistina – profil de siguranţă Nefrotoxicitate • Nefrotoxicitatea – incidenţa întâlnită este de 6 % – 14% în unele studii sau de 32% . Colistina – profil de siguranţă Nefrotoxicitate Riscul de nefrotoxicitate este mai redus decât cel raportat în litaratura anilor ’70 – ’80 prin: Reducerea impurităţilor colistimetatului sodic Monitorizarea atentă şi echilibrarea hidroelectrolitică în secţiile de terapie intensivă Evitarea asocierii cu medicamente cu risc nefrotoxic . CID 2012:54 (June) .Colistina – profil de siguranţă Nefrotoxicitate NEFROTOXICITATE Lipsa modificărilor renale la 82. unul cu afectare preexistentă) – continuarea terapiei cu ajustarea dozei Nu există corelaţie statistică între variaţia creatininei serice şi doza zilnică.1% (23 cazuri) Afectare renală acută 17.9% (5 cazuri.doza cumulativă sau durata tratamentului cu colistină Dalfino et al. 000 UI/kg/zi.affsaps.fr .000 – 150. fără a depăşi 12 MUI/zi. Agence française de sécurité sanitaire des produits de santé www.Ajustarea dozelor de colistină în funcţie de clearance-ul de creatinină • posologia: 75. tulburări vizuale. slăbiciune musculară. parestezii. halucinaţii.Colistina – Neurotoxicitate • Neurotoxicitatea – vertij. surditate parţială. ataxie Paresteziile – cel mai frecvent întâlnite. convulsii. confuzii. aprox 27% din cazuri • Au intensitate uşoară – medie şi sunt reversibile la întreruperea tratamentului . Efectul sinergic in antibioticoterapia infectiilor cu BGN MDR . Vaiable Organisms • Diminuarea cu cel puţin 2 log 10 a nr colonii pentru asocierea de antibiotice. Infectious Diseases 2011 .Interacţiune sinergică Log No. comparativ cu cel mai activ antibiotic din combinaţie. la 24 h de incubatie •Efect bactericid -scaderea numarului de colonii cu ≥ 3 log 10 Combinaţii 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 Colistină/meropenem Colistină/doripenem Colistină/rifampicină Colistină/minociclină Colistină/tigeciclină Combinaţiile sinergice reprezintă soluţii terapeutice în infecţiile cu germeni multidrogrezistenţi Liang et al. 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 . 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. FQ) Monoterapie .sulbactam * Conform ATB-grama Posibile asoccieri*: FQ + AG Imipenem + AG Imipenem + Rifampicina Pen antipseudom. Pen anti-P. + AG Ceftazidim + AG Rifampicina + Colistin Meropenem + Sulbactam Colistin + Imipenem / Mero + Rifa * Pentru care exista date publicate . Cef3.optiuni Colistin Ampi .Ghid Sanford. AG. 125 µg/ml Liang et al.Curba “time-kill”: 2 tulpini Acinetobacter baumanii XDR diferite. colistina 0. Infectious Diseases 2011 Combinaţiile colistinei cu meropenem. rifampicină.minociclină sunt sinergice in vitro împotriva Acinetobacter Baumanii XDR . colistina 0.Curba “time-kill”: 2 tulpini Acinetobacter baumanii XDR diferite.minociclină sunt sinergice in vitro împotriva Acinetobacter Baumanii XDR . Infectious Diseases 2011 Combinaţiile colistinei cu meropenem. rifampicină.25 µg/ml Liang et al. 5x MIC 1xMIC 4xMIC 2xMIC .0. Evoluţia infecţiilor cu germeni GN-MDR în funcţie de regimul terapeutic administrat – in vivo *Alte medicamente: aminoglicozide. 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. Colistin therapy for microbilogically documented multidrug rezistant Gram-negative bacterial infections. cefalosporine.000 UI între doza medie zilnică la supravieţuitori şi decedaţi Falagas et al. JAA 2009. . aztreonam. imipenem. Studiul a aratat o indiferenta a asocierii tigacil/colistin. 95% confidence interval [CI]. 2012 .3 to 18.Bactericidal Activity of Multiple Combinations of Colistin against NDM-1-Producing Enterobacteriaceae TGC showed a modest but significant inhibitory effect only at Cmax of 18013.1) Evaluare Time-kill a sinergiei Tigacil +Colistin asupra a 8 tulpini de enterobacteriacee NDM1 secretoare. 3. compared with the GC value of 191 4. AAC.4 (P 0. sau chiar efect antagonic la concentratii mici de tigacil.33.008. NDM 1 = New Delhi Metallo-betalactamase 1 better antimicrobial activity at all concentrations Mahableshwar. Multiple evidenţe referitoare la acţiunea superioară a combinaţiilor cu colistina – cel mai frecvent cu carbapeneme Avantajele asocierilor de antibiotice Lărgirea spectrului de activitate Creșterea vitezei de bactericidie Evitarea selecției de tulpini rezistente . posologie .3 “C” pentru COLISTIN Confuzie – terminologie Complexitate – farmacologie Contradictie . colistimetat sodic care prin hidroliză eliberează moleculele de colistină Colistin sulfat si colistimetat sodic NU SUNT INTERSCHIMBABILE .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. 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 .Complexitate – farmacologie CMS = colistimetat CMS – in mediu apos este hidrolizat in colistin si derivati metansulfonati CMS este prodrog. 6 mg colistina bază 1 mg colistimetat sodic = 12.37 mg colistina bază ATENŢIE la: calculul dozelor de administrare analiza studiilor din literatură Edherington J Cyst Fibros 2006 Al-Aloul Pediat Pulmonol 2005 .Contradictie .000 UI = 29.posologie • DE CE? Exprimări diferite ale substanţei active Colistimetat sodic Colistina bază Unităţi de măsură diferite ale substanţei active MG MUI • Corespondenţa dozelor 80 mg colistimetat sodic = 1.000.500 UI = 0. . 225 000 UI/kg/zi. max 12 MUI/zi (420 – 840 mg colistimetat sodic/zi.500 UI = 0.5 .37 mg colistina bază SUA 2.10 mil UI/zi colistimetat sodic FRANŢA Adulţi şi adolescenţi: 75 000 .150 000 UI/kg/zi.800 mg/zi colistimetat sodic 5 . max 12 MUI/zi Edherington J Cyst Fibros 2006 Al-Aloul Pediat Pulmonol 2005 .5 mg/kg/zi colistina baza 400 . max 960 mg) Copii şi nou născuţi: 150 000 .posologie 1 mg colistimetat sodic = 12.Contradictie . Poster ICAAC.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. 2009 . în literatura de specialitate se întâlnesc: colistină-meropenem. AAC 2009 Asocieri multiple cu efect sinergic . etc . colistinatigeciclină. colistina – imipenem. urmat de 3 mil UI la 8 ore Plachouras D ett Al. 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.Rezistenţă la colimicină? Factorul de risc pentru apariţia rezistenţei la colimicină este utilizarea antibioticului Crit Care.abordare eficace în lupta împotriva apariţiei rezistenţei microbiene. în perfuzie 2 ore Ulterior 3 milioane UI la 12 ore Doza de menţinere 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 pacienţii obezi se realizează pe greutate ideală şi nu actuală pentru evitarea riscurilor de supradozare şi/sau nefrotoxicitate . Profiluri de pacienţi (1) Mod de administrare Doză de încărcare 9 milioane UI.Administrare. 4 hours o avoiding under-therapeutic concentrations during Day 1 Plachouras D et al : 2009 Antimicrob Agents Chemother 53:3430-3436 .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. oral .ANTIBIOTICE – portofoliu complex de antiinfecţioase Cefort® (ceftriaxona) orale şi 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) .
Report "Colistina în domeniul infectiilor severe si sepsisului "