Indian Journal of Critical Care Medicine

Register      Login

SEARCH WITHIN CONTENT

FIND ARTICLE

Volume / Issue

Online First

Archive
Related articles

VOLUME 25 , ISSUE 2 ( February, 2021 ) > List of Articles

SYSTEMATIC REVIEW

Polymyxin Monotherapy vs. Combination Therapy for the Treatment of Multidrug-resistant Infections: A Systematic Review and Meta-analysis

Samir Samal, Shakti B Mishra, Shantanu K Patra, Arun Rath, Abhilash Dash, Biswajit Nayak, Diganta Mohanty

Keywords : Carbapenems, Colistin, Combination therapy, Gram-negative bacilli infections, Monotherapy, Multidrug resistant (MDR), Polymyxin B

Citation Information : Samal S, Mishra SB, Patra SK, Rath A, Dash A, Nayak B, Mohanty D. Polymyxin Monotherapy vs. Combination Therapy for the Treatment of Multidrug-resistant Infections: A Systematic Review and Meta-analysis. Indian J Crit Care Med 2021; 25 (2):199-206.

DOI: 10.5005/jp-journals-10071-23720

License: CC BY-NC 4.0

Published Online: 22-02-2021

Copyright Statement:  Copyright © 2021; Jaypee Brothers Medical Publishers (P) Ltd.


Abstract

Objectives: The objective of this review was to compare the effectiveness of Colistin monotherapy and combination therapy for the treatment of multidrug-resistant gram-negative bacterial infections. Data sources: PubMed, Cochrane Library. Study eligibility, interventions, and exclusions: In this systematic review, we included all retrospective and prospective studies and randomized controlled trials (RCTs) that compared intravenous polymyxin monotherapy and combination therapy with any other antibiotic for treating multidrug-resistant infections. Studies using inhaled polymyxins with 5 or less than 5 patients were excluded. The primary outcome was 30-day all-cause mortality and if not reported at day 30 we extracted and documented the closest time point. Both crude outcome rates and adjusted effect estimates were extracted for mortality. Study appraisal, data extraction and synthesis: Search string used was “(Colistin OR polymyxin) AND (Enterobacteriaceae OR Klebsiella OR Acinetobacter OR Escherichia coli OR Pseudomonas) AND (random OR prospective OR retrospective OR cohort OR observational OR blind).” Thirty-nine studies were included in our analysis; out of which 6 RCTs were included and 9 studies used carbapenem as the adjunctive antibiotic. Each study was screened and reviewed for eligibility independently by two authors and data extrapolated on an Excel sheet. Results: The meta-analysis of polymyxin monotherapy vs. combination therapy in multidrug-resistant infections yielded an odds ratio (OR) of 0.81 (95% confidence interval [CI]: 0.65–1.01) with minimal heterogeneity (I2 = 40%), whereas pooled analysis of this comparison in studies that included carbapenem as combination therapy yielded an OR of 0.64 (CI: 0.40–1.03; I2 = 62%). Likewise, the pooled analysis of the RCTs yielded an OR of 0.82 (95% CI: 0.58–1.16, I2 = 22%). All these showed no statistical significance. However, it was seen that polymyxin combination therapy was more effective in multidrug-resistant infections compared to polymyxin monotherapy. The effectiveness was more glaring when carbapenems were used as the combination drug instead of any other antibiotic and more so in many in vitro studies that used polymyxin combination therapy. Conclusion: Although statistically insignificant, it would be prudent to use polymyxin combination therapy to treat multidrug-resistant gram-negative bacilli (GNB) infection over monotherapy with preference to use carbapenem as the adjunct alongside polymyxins.


PDF Share
  1. Benedict RG, Langlykke AF. Antibiotic activity of Bacillus polymyxa. J Bacteriol 1947;54(1):24.
  2. Hancock RE. Peptide antibiotics. Lancet 1997;349(9049):418–422. DOI: 10.1016/S0140-6736(97)80051-7.
  3. Falagas ME, Rafailidis PI, Matthaiou DK. Resistance to polymyxins: mechanisms, frequency and treatment options. Drug Resist Updat 2010;13(4–5):132–138.DOI: 10.1016/j.drup.2010.05.002.
  4. Li J, Nation RL, Turnidge JD, Milne RW, Coulthard K, Rayner CR, et al. Colistin: the re-emerging antibiotic for multidrug-resistant Gram-negative bacterial infections. Lancet Infect Dis 2006;6(9):589–601. DOI: 10.1016/S1473-3099(06)70580-1.
  5. Brink AJ, Richards GA, Colombo G, Bortolotti F, Colombo P, Jehl F. Multicomponent antibiotic substances produced by fermentation: implications for regulatory authorities, critically ill patients and generics. Int J Antimicrob Agents 2014;43(1):1–6. DOI: 10.1016/j.ijantimicag.2013.06.013.
  6. Gallardo-Godoy A, Muldoon C, Becker B, Elliott AG, Lash LH, Huang JX, et al. Activity and predicted nephrotoxicity of synthetic antibiotics based on polymyxin B. J Med Chem 2016;59(3):1068–1077. DOI: 10.1021/acs.jmedchem.5b01593.
  7. Nation RL, Velkov T, Li J. Colistin and polymyxin B: peas in a pod, or chalk and cheese? Clin Infect Dis 2014;59(1):88–94. DOI: 10.1093/cid/ciu213.
  8. Barnett M, Bushby SR, Wilkinson S. Sodium sulphomethyl derivatives of polymyxins. Br J Pharmacol Chemother 1964;23(3):552–574. DOI: 10.1111/j.1476-5381.1964.tb01610.x.
  9. Li J, Milne RW, Nation RL, Turnidge JD, Coulthard K. Stability of colistin and colistin methanesulfonate in aqueous media and plasma asdetermined by high-performance liquid chromatography. Antimicrob Agents Chemother 2003;47(4):1364–1370. DOI: 10.1128/aac.47.4.1364-1370.2003.
  10. Li J, Milne RW, Nation RL, Turnidge JD, Smeaton TC, Coulthard K. Pharmacokinetics of colistin methanesulphonate and colistin in rats following an intravenous dose of colistin methanesulphonate. J Antimicrob Chemother 2004;53(5):837–840.DOI: 10.1093/jac/dkh167.
  11. Dixon RA, Chopra I. Leakage of periplasmic proteins from Escherichia coli mediated by polymyxin B nonapeptide. Antimicrob Agents Chemother 1986;29(5):781–788. DOI: 10.1128/aac.29.5.781.
  12. Falagas ME, Kasiakou SK. Colistin: the revival of polymyxins for the management of multidrug-resistant Gram-negative bacterial infections. Clin Infect Dis 2005;40(9): DOI: 10.1086/429323.
  13. Li J, Nation RL, Milne RW, Turnidge JD, Coulthard K. Evaluation of colistin as an agent against multi-resistant Gram-negative bacteria. Int J Antimicrob Agents 2005;25(1):11–25.DOI: 10.1016/j.ijantimicag.2004.10.001.
  14. Deris ZZ, Akter J, Sivanesan S, Roberts KD, Thompson PE, Nation RL, et al. A secondary mode of action of polymyxins against Gram-negative bacteria involves the inhibition of NADH-quinone oxidoreductase activity. J Antibiot (Tokyo) 2013;67(2):147–151. DOI: 10.1038/ja.2013.111.
  15. Zusman O, Altunin S, Koppel F, Benattar YD, Gedik H, Paul M. Polymyxin monotherapy or in combination against carbapenem-resistant bacteria: systematic review and meta-analysis. J Antimicrob Chemother 2017;72(1):29–39. DOI: 10.1093/jac/dkw377.
  16. Capone A, Giannella M, Fortini D, Giordano A, Meledandri M, Ballardini M, et al. High rate of colistin resistance among patients with carbapenem-resistant Klebsiella pneumoniae infection accounts for an excess of mortality. Clin Microbiol Infect 2013;19(1):E23–E30. DOI: 10.1111/1469-0691.12070.
  17. Tumbarello M, Viale V, Viscoli C, Trecarichi EM, Tumietto F, Marchese A, et al. Predictors of mortality in bloodstream infections caused by Klebsiella pneumoniae carbapenemase–producing K. pneumoniae: importance of combination therapy. Clin Infect Dis 2012;55(7):943–950. DOI: 10.1093/cid/cis588.
  18. Aydemir H, Akduman D, Piskin N, Comert F, Horuz E, Terzi A, et al. Colistin vs. the combination of colistin and rifampicin for the treatment of carbapenem-resistant Acinetobacter baumannii ventilator-associated pneumonia. Epidemiol Infect 2013;141(6):1214–1222. DOI: 10.1017/S095026881200194X.
  19. Durante-Mangoni E, Signoriello G, Andini R, Mattei A, De Cristoforo M, Murino P, et al. 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 2013;57(3):349–358. DOI: 10.1093/cid/cit253.
  20. Daikos GL, Petrikkos P, Psichogiou M, Kosmidis C, Vryonis E, Skoutelis A, et al. Prospective observational study of the impact of VIM-1 metallo-β-lactamase on the outcome of patients with Kebsiella pneumoniae bloodstream infections. Antimicrob Agents Chemother 2009;53(5):1868–1873. DOI: 10.1128/AAC.00782-08.
  21. Daikos GL, Tsaousi S, Tzouvelekis LS, Anyfantis I, Psichogiou M, Argyropoulou A, et al. Carbapenemase-producing Klebsiella pneumoniae bloodstream infections: lowering mortality by antibiotic combination schemes and the role of carbapenems. Antimicrob Agents Chemother 2014;58(4):2322–2328. DOI: 10.1128/AAC.02166-13.
  22. Falagas ME, Rafailidis PI, Matthaiou DK, Virtzili S, Nikita D, Michalopoulos A. Pandrug-resistant Klebsiella pneumoniae, Pseudomonas aeruginosa and Acinetobacter baumannii infections: characteristics and outcome in a series of 28 patients. Int J Antimicrob Agents 2008;32(5):450–454. DOI: 10.1016/j.ijantimicag.2008.05.016.
  23. Falagas ME, Rafailidis PI, Ioannidou E, Alexiou VG, Matthaiou DK, Karageorgopoulos DE, et al. Colistin therapy for microbiologically documented multidrug-resistant Gram-negative bacterial infections: a retrospective cohort study of 258 patients. Int J Antimicrob Agents 2010;35(2):194–199. DOI: 10.1016/j.ijantimicag.2009.10.005.
  24. Garnacho-Montero J, Amaya-Villar R, Gutiérrez-Pizarraya A, Espejo-Gutiérrez De Tena E, Artero-González ML, Corcia-Palomo Y, et al. Clinical efficacy and safety of the combination of colistin plus vancomycin for the treatment of severe infections caused by carbapenem-resistant Acinetobacter baumannii. Chemotherapy 2014;59(3):225–231. DOI: 10.1159/000356004.
  25. Hernández-Torres A, García-Vázquez E, Gómez J, Canteras M, Ruiz J, Yagüe G. Multidrug and carbapenem-resistant Acinetobacter baumannii infections: factors associated with mortality. Med Clin (Barc) 2012;138(15):650–655. DOI: 10.1016/j.medcli.2011.06.024.
  26. Kontopidou F, Giamarellou H, Katerelos P, Maragos A, Kioumis I, Trikka-Graphakos E, et al. Infections caused by carbapenem-resistant Klebsiella pneumoniae among patients in intensive care units in Greece: a multi-centre study on clinical outcome and therapeutic options. Clin Microbiol Infect [Internet] 2014;20(2):O117–O123. DOI: 10.1111/1469-0691.12341.
  27. López-Cortés LE, Cisneros JM, Fernández-Cuenca F, Bou G, Tomás M, Garnacho-Montero J, et al. Monotherapy versus combination therapy for sepsis due to multidrug-resistant Acinetobacter baumannii: analysis of a multicentre prospective cohort. J Antimicrob Chemother 2014;69(11):3119–3126. DOI: 10.1093/jac/dku233.
  28. Mouloudi E, Protonotariou E, Zagorianou A, Iosifidis E, Karapanagiotou A, Giasnetsova T, et al. Bloodstream infections caused by metallo- β-lactamase/Klebsiella pneumoniae carbapenemase-producing K. pneumoniae among intensive care unit patients in Greece: risk factors for infection and impact of type of resistance on outcomes. Infect Control Hosp Epidemiol 2010;31(12):1250–1256. DOI: 10.1086/657135.
  29. Navarro-San Francisco C, Mora-Rillo M, Romero-Gómez MP, Moreno-Ramos F, Rico-Nieto A, Ruiz-Carrascoso G, et al. Bacteraemia due to OXA-48-carbapenemase-producing Enterobacteriaceae: a major clinical challenge. Clin Microbiol Infect 2013;19(2):E72–E79. DOI: 10.1111/1469-0691.12091.
  30. Özvatan T, Akalin H, Sinirtaş M, Ocakoʇlu G, Yilmaz E, Heper Y, et al. Nosocomial Acinetobacter pneumonia: treatment and prognostic factors in 356 cases. Respirology 2016;21(2):363–369. DOI: 10.1111/resp.12698.
  31. Papadimitriou-Olivgeris M, Marangos M, Christofidou M, Fligou F, Bartzavali C, Panteli ES, et al. Risk factors for infection and predictors of mortality among patients with KPC-producing Klebsiella pneumoniae bloodstream infections in the intensive care unit. Scand J Infect Dis 2014;46(9):642–648. DOI: 10.3109/00365548.2014.923106.
  32. Petrosillo N, Giannella M, Antonelli M, Antonini M, Barsic B, Belanci L, et al. Clinical experience of colistin-glycopeptide combination in critically ill patients infected with gram-negative bacteria. Antimicrob Agents Chemother 2014;58(2):851–858. DOI: 10.1128/AAC.00871-13.
  33. Pintado V, San Miguel LG, Grill F, Mejía B, Cobo J, Fortún J, et al. Intravenous colistin sulphomethate sodium for therapy of infections due to multidrug-resistant gram-negative bacteria. J Infect 2008 Mar;56(3):185–190. DOI: 10.1016/j.jinf.2008.01.003. Epub 2008 Feb 15. PubMed PMID: 18280570.
  34. Samonis G, Korbila IP, Maraki S, Michailidou I, Vardakas KZ, Kofteridis D, et al. Trends of isolation of intrinsically resistant to colistin Enterobacteriaceae and association with colistin use in a tertiary hospital. Eur J Clin Microbiol Infect Dis 2014 Sep;33(9):1505–1510. DOI: 10.1007/s10096-014-2097-8.
  35. Şimsek F, Gedik H, Yildirmak MT, Iris NE, Türkmen A, Ersoy A, et al. Colistin against colistin-only-susceptible Acinetobacter baumannii-related infections: monotherapy or combination therapy? Indian J Med Microbiol 2012;30(4):448–452. DOI: 10.4103/0255-0857.103767.
  36. Souli M, Kontopidou FV, Papadomichelakis E, Galani I, Armaganidis A, Giamarellou H. Clinical experience of serious infections caused by Enterobacteriaceae producing VIM-1 metallo-beta-lactamase in a Greek University Hospital. Clin Infect Dis 2008;46(6):847–854. DOI: 10.1086/528719.
  37. Vardakas KZ, Mavroudis AD, Georgiou M, Falagas ME. Intravenous colistin combination antimicrobial treatment vs. monotherapy: a systematic review and meta-analysis. Int J Antimicrob Agents [Internet] 2018;51(4):535–547. DOI: 10.1016/j.ijantimicag.2017.12.020.
  38. Yilmaz GR, Guven T, Guner R, Tufan ZK, Izdes S, Tasyaran MA, et al. Colistin alone or combined with sulbactam or carbapenem against A. baumannii in ventilator-associated pneumonia. J Infect Dev Ctries 2015;9(5):476–485. DOI: 10.3855/jidc.6195.
  39. Zarkotou O, Pournaras S, Tselioti P, Dragoumanos V, Pitiriga V, Ranellou K, et al. Predictors of mortality in patients with bloodstream infections caused by KPC-producing Klebsiella pneumoniae and impact of appropriate antimicrobial treatment. Clin Microbiol Infect [Internet] 2011;17(12):1798–1803. DOI: 10.1111/j.1469-0691.2011.03514.x.
  40. Batirel A, Balkan II, Karabay O, Agalar C, Akalin S, Alici O, et al. Comparison of colistin-carbapenem, colistin-sulbactam, and colistin plus other antibacterial agents for the treatment of extremely drug-resistant Acinetobacter baumannii bloodstream infections. Eur J Clin Microbiol Infect Dis 2014;33(8):1311–1322. DOI: 10.1007/s10096-014-2070-6.
  41. Makris D, Petinaki E, Tsolaki V, Manoulakas E, Mantzarlis K, Apostolopoulou O, et al. Colistin versus colistin combined with ampicillin-sulbactam for multiresistant Acinetobacter baumannii ventilator-associated pneumonia treatment: an open-label prospective study. Indian J Crit Care Med 2018 Feb;22(2):67–77. DOI: 10.4103/ijccm.IJCCM_302_17. PubMed PMID: 29531445; PubMed Central PMCID PMC5842460.
  42. Paul M, Daikos GL, Durante-Mangoni E, Yahav D, Carmeli Y, Benattar YD, et al. Colistin alone versus colistin plus meropenem for treatment of severe infections caused by carbapenem-resistant Gram-negative bacteria: an open-label, randomised controlled trial. Lancet Infect Dis [Internet]. 2018;18(4):391–400. DOI: 10.1016/S1473-3099(18)30099-9.
  43. Kalin G, Alp E, Akin A, Coskun R, Doganay M. Comparison of colistin and colistin/sulbactam for the treatment of multidrug resistant Acinetobacter baumannii ventilator-associated pneumonia. Infection 2014;42(1):37–42. DOI: 10.1007/s15010-013-0495-y.
  44. Ku K, Pogue JM, Moshos J, Bheemreddy S, Wang Y, Bhargava A, et al. Retrospective evaluation of colistin versus tigecycline for the treatment of Acinetobacter baumannii and/or carbapenem-resistant Enterobacteriaceae infections. Am J Infect Control [Internet] 2012;40(10):983–987. DOI: 10.1016/j.ajic.2011.12.014.
  45. Parchem NL, Bauer KA, Cook CH, Mangino JE, Jones CD, Porter K, 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 2016 Sep;35(9):1433–1439. DOI: 10.1007/s10096-016-2681-1.Epub 2016 May 26. PubMed PMID: 27230510.
  46. Nguyen M, Eschenauer GA, Bryan M, O'Neil K, Furuya EY, Della-Latta P, et al. Carbapenem-resistant Klebsiella pneumoniae bacteremia: factors correlated with clinical and microbiologic outcomes. Diagn Microbiol Infect Dis [Internet] 2010;67(2):180–184. DOI: 10.1016/j.diagmicrobio.2010.02.001.
  47. Crusio R, Rao S, Changawala N, Paul V, Tiu C, Van Ginkel J, et al. Epidemiology and outcome of infections with carbapenem-resistant Gram-negative bacteria treated with polymyxin B-based combination therapy. Scand J Infect Dis 2014;46(1):1–8. DOI: 10.3109/00365548.2013.844350.
  48. Rigatto MH, Vieira FJ, Antochevis LC, Behle TF, Lopes NT, Zavasckic AP. Polymyxin B in combination with antimicrobials lacking in vitro activity versus polymyxin B in monotherapy in critically ill patients with Acinetobacter baumannii or Pseudomonas aeruginosa infections. Antimicrob Agents Chemother 2015;59(10):6575–6580. DOI: 10.1128/AAC.00494-15.
  49. Sirijatuphat R, Thamlikitkul V. Preliminary study of colistin versus colistin plus fosfomycin for treatment of carbapenem-resistant Acinetobacter baumannii infections. Antimicrob Agents Chemother 2014 Sep;58(9):5598–5601. DOI: 10.1128/AAC.02435-13. Epub 2014 Jun 30. PubMed PMID: 24982065; PubMed CentralPMCID: PMC4135862.
  50. Chuang YC, Cheng CY, Sheng WH, Sun HY, Wang JT, Chen YC, et al. Effectiveness of tigecycline-based versus colistin- based therapy for treatment of pneumonia caused by multidrug-resistant Acinetobacter baumannii in a critical setting: a matched cohort analysis. BMC Infect Dis 2014;14(1):1–8. DOI: 10.1186/1471-2334-14-102.
  51. Lim SK, Lee SO, Choi SH, Choi JP, Kim SH, Jeong JY, et al. The outcomes of using colistin for treating multidrug resistant Acinetobacter species bloodstream infections. J Korean Med Sci 2011;26(3):325–331. DOI: 10.3346/jkms.2011.26.3.325.
  52. Porwal R, Gopalakrishnan R, Rajesh NJ, Ramasubramanian V. Carbapenem resistant Gram-negative bacteremia in an Indian intensive care unit: a review of the clinical profile and treatment outcome of 50 patients. Indian J Crit Care Med 2014 Nov;18(11):750–753. DOI: 10.4103/0972-5229.144021. PubMed PMID: 25425843; PubMed Central PMCID: PMC4238093.
  53. Jang HJ, Kim MN, Lee K, Hong SB, Lim CM, Koh Y. The comparative efficacy of colistin monotherapy and combination therapy based on in vitro antimicrobial synergy in ventilator-associated pneumonia caused by multi-drug resistant Acinetobacter baumannii. Tuberc Respir Dis 2009;67(3):212–220. DOI: 10.4046/trd.2009.67.3.212.
  54. Abdelsalam MFA, Abdalla MS, El-Abhar HSED. Prospective, comparative clinical study between high-dose colistin monotherapy and colistin–meropenem combination therapy for treatment of hospital-acquired pneumonia and ventilator-associated pneumonia caused by multidrug-resistant Klebsiella pneumoniae. J Glob Antimicrob Resist [Internet] 2018;15:127–135. DOI: 10.1016/j.jgar.2018.07.003.
PDF Share
PDF Share

© Jaypee Brothers Medical Publishers (P) LTD.