Abstract
Currently, in vitro synergy with colistin has not translated into improved clinical outcomes. This study aimed to compare colistin combination therapy to colistin monotherapy in critically ill patients with multi-drug resistant gram-negative (MDR-GN) pneumonia. This was a retrospective analysis of critically ill adult patients receiving intravenous colistin for MDR-GN pneumonia comparing colistin combination therapy to colistin monotherapy with a primary endpoint of clinical cure. Combination therapy was defined by administration of another antibiotic to which the MDR-GN pathogen was reported as susceptible or intermediate. Ninety patients were included for evaluation (41 combination therapy and 49 monotherapy). Baseline characteristics were similar between groups. No difference in clinical cure was observed between combination therapy and monotherapy in univariate analysis, nor when adjusted for APACHE II score and time to appropriate antibiotic therapy (57.1 vs. 63.4 %, adjusted OR 1.15, p = 0.78). Microbiological cure was significantly higher for combination therapy (87 vs. 35.5 %, p < 0.001). Colistin combination therapy was associated with a significant improvement in microbiological cure, without improvement in clinical cure. Based on the in vitro synergy and improvement in microbiological clearance, colistin combination therapy should be prescribed for MDR-GN pneumonia. Further research is warranted to determine if in vitro synergy with colistin translates into improved clinical outcomes.
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Dellit TH, Owens RC, McGowan JE Jr, Gerding DN, Weinstein RA, Burke JP et al (2007) Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America guidelines for developing an institutional program to enhance antimicrobial stewardship. Clin Infect Dis 44(2):159–177
Lu Q, Girardi C, Zhang M, Bouhemad B, Louchahi K, Petitjean O et al (2010) Nebulized and intravenous colistin in experimental pneumonia caused by Pseudomonas aeruginosa. Intensive Care Med 36(7):1147–1155
Li J, Rayner CR, Nation RL, Owen RJ, Spelman D, Tan KE et al (2006) Heteroresistance to colistin in multidrug-resistant Acinetobacter baumannii. Antimicrob Agents Chemother 50(9):2946–2950
Molina J, Cordero E, Pachon J (2009) New information about the polymyxin/colistin class of antibiotics. Expert Opin Pharmacother 10(17):2811–2828
Falagas ME, Kasiakou SK, Tsiodras S, Michalopoulos A (2006) The use of intravenous and aerosolized polymyxins for the treatment of infections in critically ill patients: a review of the recent literature. Clin Med Res 4(2):138–146
Bergen PJ, Bulman ZP, Saju S, Bulitta JB, Landersdorfer C, Forrest A et al (2015) Polymyxin combinations: pharmacokinetics and pharmacodynamics for rationale use. Pharmacotherapy 35(1):34–42
Bergen PJ, Tsuji BT, Bulitta JB, Forrest A, Jacob J, Sidjabat HE et al (2011) Synergistic killing of multidrug-resistant Pseudomonas aeruginosa at multiple inocula by colistin combined with doripenem in an in vitro pharmacokinetic/pharmacodynamic model. Antimicrob Agents Chemother 55(12):5685–5695
Deris ZZ, Yu HH, Davis K, Soon RL, Jacob J, Ku CK et al (2012) The combination of colistin and doripenem is synergistic against Klebsiella pneumoniae at multiple inocula and suppresses colistin resistance in an in vitro pharmacokinetic/pharmacodynamic model. Antimicrob Agents Chemother 56(10):5103–5112
Dizbay M, Tozlu DK, Cirak MY, Isik Y, Ozdemir K, Arman D (2010) In vitro synergistic activity of tigecycline and colistin against XDR-Acinetobacter baumannii. J Antibiot (Tokyo) 63(2):51–53
Petrosillo N, Ioannidou E, Falagas ME (2008) Colistin monotherapy vs. combination therapy: evidence from microbiological, animal and clinical studies. Clin Microbiol Infect 14(9):816–827
Tan TY, Ng LS, Tan E, Huang G (2007) In vitro effect of minocycline and colistin combinations on imipenem-resistant Acinetobacter baumannii clinical isolates. J Antimicrob Chemother 60(2):421–423
Charlson ME, Pompei P, Ales KL, MacKenzie CR (1987) A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis 40(5):373–383
Knaus WA, Draper EA, Wagner DP, Zimmerman JE (1985) APACHE II: a severity of disease classification system. Crit Care Med 13(10):818–829
Magiorakos AP, Srinivasan A, Carey RB, Carmeli Y, Falagas ME, Giske CG et al (2012) Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: an international expert proposal for interim standard definitions for acquired resistance. Clin Microbiol Infect 18(3):268–281
Doshi NM, Cook CH, Mount KL, Stawicki SP, Frazee EN, Personett HA et al (2013) Adjunctive aerosolized colistin for multi-drug resistant gram-negative pneumonia in the critically ill: a retrospective study. BMC Anesthesiol 13(1):45
Kalin G, Alp E, Coskun R, Demiraslan H, Gundogan K, Doganay M (2012) Use of high-dose IV and aerosolized colistin for the treatment of multidrug-resistant Acinetobacter baumannii ventilator-associated pneumonia: do we really need this treatment? J Infect Chemother 18(6):872–877
Kofteridis DP, Alexopoulou C, Valachis A, Maraki S, Dimopoulou D, Georgopoulos D et al (2010) Aerosolized plus intravenous colistin versus intravenous colistin alone for the treatment of ventilator-associated pneumonia: a matched case-control study. Clin Infect Dis 51(11):1238–1244
Michalopoulos A, Fotakis D, Virtzili S, Vletsas C, Raftopoulou S, Mastora Z et al (2008) Aerosolized colistin as adjunctive treatment of ventilator-associated pneumonia due to multidrug-resistant Gram-negative bacteria: a prospective study. Respir Med 102(3):407–412
Korbila IP, Michalopoulos A, Rafailidis PI, Nikita D, Samonis G, Falagas ME (2010) Inhaled colistin as adjunctive therapy to intravenous colistin for the treatment of microbiologically documented ventilator-associated pneumonia: a comparative cohort study. Clin Microbiol Infect 16(8):1230–1236
Garnacho-Montero J, Amaya-Villar R, Gutierrez-Pizarraya A, Espejo-Gutierrez de Tena E, Artero-Gonzalez ML, Corcia-Palomo Y et al (2013) Clinical efficacy and safety of the combination of colistin plus vancomycin for the treatment of severe infections caused by carbapenem-resistant Acinetobacter baumannii. Chemotherapy 59(3):225–231
Petrosillo N, Giannella M, Antonelli M, Antonini M, Barsic B, Belancic L et al (2014) Clinical experience of colistin-glycopeptide combination in critically ill patients infected with Gram-negative bacteria. Antimicrob Agents Chemother 58(2):851–858
Durante-Mangoni E, Signoriello G, Andini R, Mattei A, De Cristoforo M, Murino P et al (2013) Colistin and rifampicin compared with colistin alone for the treatment of serious infections due to extensively drug-resistant Acinetobacter baumannii: a multicenter, randomized clinical trial. Clin Infect Dis 57(3):349–358
Aydemir H, Akduman D, Piskin N, Comert F, Horuz E, Terzi A et al (2013) Colistin vs. the combination of colistin and rifampicin for the treatment of carbapenem-resistant Acinetobacter baumannii ventilator-associated pneumonia. Epidemiol Infect 141(6):1214–1222
Sirijatuphat R, Thamlikitkul V (2014) Preliminary study of colistin versus colistin plus fosfomycin for treatment of carbapenem-resistant Acinetobacter baumannii infections. Antimicrob Agents Chemother 58(9):5598–5601
Pogue JM, Kaye KS (2013) Is there really no benefit to combination therapy with colistin? Expert Rev Anti-Infect Ther 11(9):881–884
Vicari G, Bauer SR, Neuner EA, Lam SW (2013) Association between colistin dose and microbiologic outcomes in patients with multidrug-resistant gram-negative bacteremia. Clin Infect Dis 56(3):398–404
Cheng A, Chuang YC, Sun HY, Sheng WH, Yang CJ, Liao CH et al (2015) Excess mortality associated with colistin-tigecycline compared with colistin-carbapenem combination therapy for extensively drug-resistant acinetobacter baumannii bacteremia: a multicenter prospective observational study. Crit Care Med 43(6):1194–1204
Giamarellou H, Poulakou G (2011) Pharmacokinetic and pharmacodynamic evaluation of tigecycline. Expert Opin Drug Metab Toxicol 7(11):1459–1470
Ramirez J, Dartois N, Gandjini H, Yan JL, Korth-Bradley J, McGovern PC (2013) Randomized phase 2 trial to evaluate the clinical efficacy of two high-dosage tigecycline regimens versus imipenem-cilastatin for treatment of hospital-acquired pneumonia. Antimicrob Agents Chemother 57(4):1756–1762
Kumar A, Roberts D, Wood KE, Light B, Parrillo JE, Sharma S et al (2006) Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med 34(6):1589–1596
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Parchem, N.L., Bauer, K.A., Cook, C.H. et al. Colistin combination therapy improves microbiologic cure in critically ill patients with multi-drug resistant gram-negative pneumonia. Eur J Clin Microbiol Infect Dis 35, 1433–1439 (2016). https://doi.org/10.1007/s10096-016-2681-1
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DOI: https://doi.org/10.1007/s10096-016-2681-1