18/03/2014 How to use colistin? Joost Wauters, UZ Leuven BAPCOC National Study Day 22 03 2014 Scope/limits • Colistin in ICU • No data presented on: – Cystic fibrosis – Children Colistin on ICU • Dose-outcome • Nephrotoxicity • Clinical use: – Colistin for VAP – Colistin for sepsis – Combination therapy • Emerging resistance 1 18/03/2014 • • • • • • 76 pt (79% ICU), retrospective (2005-2010) APACHE II ?? 45% catheter-related, 25% abdominal, 20% respiratory Coli >= 72h, dosing decided by clinician Microbiological success = eradication blood cultures d7 therapy Microbiological failure = persistence blood cultures d7 or death by d7 (7% no BC) • No difference in baseline characteristics • Combination therapy: 70% in both groups (p=0,79) Vicari, CID 2013 Outcome-dose CMS (MIU) Microbiological success day 7 (n=52, 68%) Microbiological failure day 7 (n=24, 32%) p 7 (4-8,5) 3,5 (2,5-4,5) 0,01 • Survival day 7 (?? %): 6 vs 3,5 MIU CMS (p=0,007) • No correlation dose – 28d survival • AKI day 7 (36%): 8,5 vs 4 MIU CMS (p=0,007) • Tigecycline 31% vs 54% in failure group (p=0,051) Vicari, CID 2013 • • • • • 258 pt (86% ICU), retrospective (2000-2007) APACHE II 17 (2-39), hospital-mortality: 35% 60% pneumonie (infection/colonization??), 13% bacteremia Coli >= 72h, dosing decided by clinician Combination therapy (86%): – 14% coli mono – 63% coli/mero – 23% coli/other Falagas, Int J Antimicrob Agents 2010 2 18/03/2014 Outcome-dose • Clinical cure: – Coli (mono/+mero): 83% – Coli+other: 61-75% • Hospital mortality: – – – – 3 MIU CMS/day: 39% 6 MIU CMS/day: 28% 9 MIU CMS/day: 22% Multivariate: daily colistin dose OR 1,22 (1,05-1,42), p=0,009 Falagas, Int J Antimicrob Agents 2010 Colistin on ICU • Dose-outcome • Nephrotoxicity • Clinical use: – Colistin for VAP – Colistin for sepsis – Combination therapy • Emerging resistance Mechanism nefrotoxicity • Charge/hydrophobicity Activation caspase pathway Mitochondrial morfology/m Apoptosis tubular cells • Time/concentration dependent • Develop new-generation polymyxins 3 18/03/2014 Nephrotoxicity • Old studies: AKI up to 50% • Newer studies: 10-30% AKI • Disparity between old/new studies: – – – – More purified colistin Use of CMS instead of colistin More adequate dose adjustment Improvement ICU care • Newest studies use RIFLE criteria: – very sensitive higher incidences AKI N AKI (RIFLE) Pogue, CID 2011 126 43% Hartzell, CID 2009 66 45% Sorli, BMC Inf 2013 102 26-49% • Dose dependent • Time dependent • Partially reversible Adverse effects of colistin Neurotoxicity • Rate: 0-7%, reversible • Dose dependent, in the first few days of therapy • Dizziness, weakness, facial and peripheral paresthesia, vertigo, confusion, ataxia-neuromuscular blockade, acute respiratory failure and apnea CMS: 3*3 MIU/d Creat 1,2 mg/dL Coli: 8,1 mg/L CMS onmeetbaar hoog Miscellaneous • Hypersensitivity reactions (rash, urticaria, itching): 2% of patients • pseudomembranous colitis Falagas, CCM 2006 Spaepen, J Infection 2011 4 18/03/2014 Colistin on ICU • Dose-outcome • Nephrotoxicity • Clinical use: – Colistin for VAP – Colistin for sepsis – Combination therapy • Emerging resistance Colistin: clinical use – Directed therapy: • Coli + carbapenem (tigecycline?) • VAP (ventilator-associated pneumonia) • HAP (hospital acquired pneumonia) • Bacteremia • Urinary/abdominal – Empiric therapy: • Surveillance cultures • Endemic region/local microbiological flora • combination Petrosillo, CMI 2008 Nation, Curr Opin Inf Dis 2009 Colistin on ICU • Dose-outcome • Nephrotoxicity • Clinical use: – Colistin for VAP – Colistin for sepsis – Combination therapy • Emerging resistance 5 18/03/2014 – – – – – 6 controlled studies (coli vs. comparator) 359 patients, APACHE II 18 Clinical response: OR 1,14 (0,74-1,77), p=0,56 Hospital mortality: OR 0,92 (0,50-1,67), p=0,78 Nefrotoxicity: no difference Florescu, CID 2012 Colistin aerosol for VAP – inhaled colistin versus placebo on top of iv antibiotics • Rattanaupawan 2010 (RCT): – No difference clinical outcome – bacteriological outcome: colistin 61% (n=51) vs. placebo 38% (n=49), p=0.03 – No difference in nefrotoxicity: 26% vs. 22% (p=0.82) – iv colistin versus iv colistin + inhaled colistin: • Korbila 2010 (retrospective): – Clinical cure: 61% (n=43) iv colistin vs. 80% (n=78) iv + aerosol colistin (p=0.025) – No effect mortality • Kofteridis 2010 (retrospective): n=43/43 – No difference clinical cure, mortality, bacteriological eradication • Doshi 2013 (retrospective): n=51/44 – No difference clinical cure, mortality, bacteriological eradicationPetrosillo, CMI 2008 Nation, Curr Opin Inf Dis 2009 6 18/03/2014 Colistin: aerosol Kofteridis, CID 2010 Colistin aerosol for VAP – Remarks: • • • • • Colistin aerosol without iv: better for nephrotoxicity Lung penetration: plugging, atelectasis, hepatisation??? Variety of nebulizers applied Cost devices: +++ Interference with functioning mechanical ventilator => Conclusion: • Evidence still debated, no recommendation for additional benefit • RCT = urgent !! Petrosillo, CMI 2008 Nation, Curr Opin Inf Dis 2009 Colistin on ICU • Dose-outcome • Nephrotoxicity • Clinical use: – Colistin for VAP – Colistin for sepsis – Combination therapy • Emerging resistance 7 18/03/2014 Colistin for sepsis • Meta-analysis clinical studies – Covering systemic colistin/polymyxin B vs. comparator/s – Patients with sepsis – Outcome = mortality • Regardless of type of infection, bacteria, dosing • Published in the last decade Paul, Prato 2013 Description of studies I Study Location Betrosian 2008 Greece Durakovic 2010 Croatia Garnacho‐Montero 2003 Spain Gounden 2009 South Africa Hachem 2007 US, Texas Infection Bacteria VAP Acinetobacter P. aeruginosa infections / P. aeruginosa hematology VAP A. baumannii Kallel 2007 Tunisia ICU infections A. baumannii P. aeruginosa infections/ P. aeruginosa cancer VAP A. baumanii or P. aeruginosa Ku 2012 US, Detroit any nosocomial Kvitko 2011 Brazil P. aeruginosa bacteremia P. aeruginosa Acinetobacter, Klebsiella Oliveira 2008 Brazil any nosocomial Paul 2010 Israel any nosocomial Acinetobacter Acinetobacter, Klebsiella Reina 2005 Argentina ICU infections Rigatto 2013 Brazil VAP or VAT Rios 2007 Argentina VAP A. baumanii or P. aeruginosa A. baumanii or P. aeruginosa A. baumanii or P. aeruginosa Betrosian 2008 Greece VAP Acinetobacter Description of studies II Study Coli/polymyx Dose Combi Comparator Betrosian 2008 Colistin 9 MU No Ampicillin/ sulbactam Durakovic 2010 Colistin 9 MU Yes Beta‐lactams Garnacho‐Monte 2003 Colistin Gounden 2009 Colistin 2.5–5.0 mg/kg ? Imipenem 4 MU Tobramycin ? Hachem 2007 Colistin 5 mg/kg Yes Antipseudomonal Kallel 2007 Colistin 6 MU ? Imipenem Ku 2012 Colistin NR ? Tigecycline Kvitko 2011 Polymyx 141+‐54 mg ? Antipseudomonals Oliveira 2008 C or Polymyx NR ? Paul 2010 Colistin 6 MU ? Reina 2005 Colistin 5 mg/kg No ampicillin/sulb Imipenem, meropenem or ampicillin/ sulbactam Any Rigatto 2013 Polymyx med 150 mg ? Beta‐lactams Rios 2007 Colistin 5 mg/kg ? Imipenem or meropenem Betrosian 2008 Colistin 9 MU No Ampicillin/ sulbactam 8 18/03/2014 IV colistin vs. comparator antibiotics for sepsis all-cause mortality OR 1.90 (95% CI 1.53-2.33) Paul, Prato 2013 Colistin probably somewhat less effective than betalactams and more toxic Colistin on ICU • Dose-outcome • Nephrotoxicity • Clinical use: – Colistin for VAP – Colistin for sepsis – Combination therapy • Emerging resistance 9 18/03/2014 • 39 publications, 1054 bacterial isolates (A. baumanii, Ps. Aeruginosa, K. pneumoniae) • Synergy rates: 44-77%, no antagonism • Clinical translation? – Beta-lactam + aminoglycoside in gram-: • in vitro synergy • no evidence of survival benefit or less resistance AAC online, 2013 CPE: combination therapy for BSI Study Organism Combi Therapy Mono Therapy Mortality Combi vs mono Qureshi, AAC 2012, n=34 KPC Klebsiella BSI single center retrospective Carbapenem + coli of tige (44%) Carbapenem or coli or tige (56%) 13% vs 58% (p=0,01)* Tumbarello, CID 2012, n=125 KPC Klebsiella BSI multicenter (3) retrospective Carbapenem + coli + tige (of 2 vd 3) (63%) Carbapenem or coli or tige (37%) 34% vs 54% (p=0,02)* Zarkotou, CMI 2011, n=35 KPC Klebsiella BSI single center retrospective Carbapenem + coli + tige + genta (57%) Carbapenem or coli or tige or genta (43%) 0% vs 47% (p=0,001)* Tam, JAC 2010, n=55 multiple foci review 15 studies 28-day 30-day Hospital mortality (7d) 71-75% vs 14-40% Clinical success rate *confirmed in multivariate analysis 47% colistin 10 18/03/2014 Colistin probably somewhat less effective than betalactams and more toxic Prevent carbapenemresistant infection Dosing/ schedule Improve efficacy Compare colistin and safety profile with of colistin aminoglycoside Combination therapy Prevention of nephrotoxicity Combinatie therapie • Data studies: – in vitro synergism – mortality↓ in patients with BSI • Treat subpopulations (not cultured) • Prevent development resistence • Prevent nefrotoxicity: high dose for normal clearance/ARC The Future in Prato: RCTs Colistin efficacy • Colistin vs. carbapenem/ conventional treatment – 2 trials Colistin combination therapy • Colistin - imipenem/ meropenem (2 trials, AIDA, NIH) • Colistin - fosfomycin (1 trial) • Colistin –rifampin (2 trials) Inhalation colistin • IV vs. nebulized+IV colistin for VAP/ HAP (2 trials) Prevention of nephrotoxicity • Colistin - ascorbic acid (1 trial) 11 18/03/2014 Colistin on ICU • Dose-outcome • Nephrotoxicity • Clinical use: – Colistin for VAP – Colistin for sepsis – Combination therapy • Emerging resistance Resistance to polymyxins • Acquired resistance – Mutations on prmA/prmB with modifications of lipid A (=component LPS) – Mutations on lpxA, lpxC and lpxI with complete loss of lipid A (A. baumannii) • Heteroresistance (resistance manifested by a fraction of a microbial population that is considered susceptible) seems a frequent event • Colistin monotherapy in-vitro <=24h • Difference with in vivo: immune system, … MIC and susceptibility categorization results to 15 antimicrobials of 13 CPE isolates Ctr Nr Org Bacterial species Carbapenem. enzyme TMO C03 Uri K. pneumoniae OXA-48 C10 Uri K. pneumoniae OXA-48 C10 Uri K. pneumoniae OXA-48 C12 Res p K. oxytoca KPC C12 Pus K. pneumoniae NDM C12 Res p K. pneumoniae KPC C13 Res p E. coli OXA-48 768 >64 2 C15 Uri K. pneumoniae OXA-48 1024 >64 16 C17 Scre K. pneumoniae OXA-48 >1024 >64 >64 C17 Res p K. pneumoniae OXA-48 >1024 2 C17 Scre K. pneumoniae OXA-48 >1024 C19 Uri K. pneumoniae KPC C23 Pus K. pneumoniae KPC susceptible intermediat CTX CAZ FEP PTZ >1024 4 512 >64 ≤0,5 2 >128 16 16 >128 1024 >64 16 16 128 16 32 >64 32 48 >64 >64 48 >64 >64 MER AZT GEN AMI TOB CIB TIG COL 2 1 ≤0,5 ≤1 ≤4 ≤1 ≤0,25 0,25 0,5 0,5 0,5 31 ≤1 ≤4 8 >2 0,5 1 0,5 ≤0,25 32 ≤1 ≤4 8 >2 0,25 1 >128 4 8 >64 2 16 >8 >2 1 0,5 >64 >128 4 2 >64 >8 ≤4 8 >2 0,5 >8 32 >128 2 2 >64 >8 >32 >8 >2 1 0,5 4 128 4 8 8 >8 ≤4 4 0,5 ≤0,12 0,5 32 >128 2 0,5 32 >8 ≤4 >8 >2 0,5 2 >64 >128 4 16 >64 >8 ≤4 >8 >2 2 1 ≤0,5 ≤0,5 128 1 2 ≤0,5 ≤1 ≤4 ≤1 ≤0,25 2 1 >64 32 >64 >128 8 16 64 >8 ≤4 >8 >2 0,5 0,5 64 >64 >64 >64 >128 >32 >32 >64 8 16 >8 ≤0,25 0,5 1 1024 >64 >64 >64 >128 32 >32 >64 4 32 >8 >2 0,5 0,5 resistant IMI Glupczynski, AAC 2012 12 18/03/2014 Antibiotic susceptibilities for New Delhi metallo-β‐lactamase 1 positive Enterobacteriaceae UK (n = 37) MIC50/MIC90 Meropenem Pip-tazo Cefotaxime Cefepime Ciprofloxacin Amikacin Tigecycline Colistin Chennai (n = 44) % susc. MIC50/MIC90 3 0 0 0 8 0 64 89* 32/32 >64/>64 >256/>256 >64/>64 >8/>8 >64/>64 4/8 1/32 32/32 >64/>64 >256/>256 >64/>64 >8/>8 >64/>64 1/4 0.5/8 Haryana (n = 26) % susc. MIC50/MIC9 3 0 0 0 8 0 56 94** >32/>32 >64/>64 >256/>256 >64/>64 >8/>8 >64/>64 1/2 1/2 0 % susc. 3 0 0 0 8 0 67 100 *M. morganii, Providencia spp., Enterobacter spp., Klebsiella spp. **2x Proteus spp., 1x K. pneumoniae Kumarasamy, Lancet Inf 2010 Antimicrobial sensitivities of 536 multi-drug-resistant Gramnegative bacilli isolated from patients treated on surgical wards in Greece All (N=536) P. aeruginosa (N= 118) A. baumannii (N = 115) K. pneumoniae (N=50) E. coli (N=161) Pip-tazobactam 37,1 19,5 6,1 66 64 ceftazidime 39,6 28,8 6,1 66 64,6 cefepime 40,7 28 3,5 72 68,3 meropenem 56,9 32,2 18,3 92 84,5 tobramycin 50,4 55,9 12,2 72 67,7 amikacin 55,8 55,1 20,9 76 74,2 ciprofloxacin 35,1 18,6 0,9 72 56,5 colistin 82,5 94,1 93,9 74 68,9 Maraki, Surg Inf 2012 De Smet, NEJM 2009 13 18/03/2014 • 1246 respiratory samples, 1840 rectal swabs • Acquisition colistin-resistant GNB – respiratory tract • 1/1000 patient-days (very low) • No difference SDD, SOD, standard care (SC) – Gastro-intestinal tract: • 3.3/1000 patient-days • Conversion rates to colistin-resistance in colistin-sensible GNB carriage: – Respiratory tract: 1-4/1000 patient-days, no difference SDD-SC – Gastro-intestinal tract: 3-16/1000 patient-days (!!if tobra-resistance) Conclusions • Dosing regimen: – Loading/maintainance dose: 9MIU – Higher dose => better outcome • Directed therapy VAP/HAP/sepsis • Combination therapy: colistin + carbapenem • Emerging resistance 14
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