title: Polymyxin combinations: pharmacokinetics and pharmacodynamics for rationale use.
abstract: Since their reintroduction into the clinic in the 1980s, the polymyxin antibiotics colistin-administered intravenously as an inactive prodrug, colistin methanesulfonate (CMS)-and polymyxin B have assumed an important role as salvage therapy for otherwise untreatable gram-negative infections. However, the emerging pharmacodynamic and pharmacokinetic data on CMS/colistin and polymyxin B indicate that polymyxin monotherapy is unlikely to generate plasma concentrations that are reliably efficacious. Additionally, regrowth and the emergence of resistance with monotherapy are commonly reported even when concentrations exceed those achieved clinically. Given this situation, polymyxin combination therapy, which is increasingly being used clinically, has been suggested as a possible means of increasing antimicrobial activity and reducing the development of resistance. Although considerable in vitro data support this view, investigations of polymyxin combination therapy in patients have only recently commenced. The currently available clinical data for polymyxin combinations are generally limited to retrospective analyses and small, low-powered, prospective studies using traditional dosage regimens that achieve low plasma concentrations. Considering the potential for rapid development of resistance to polymyxins, well-designed clinical trials that include higher-dose polymyxin regimens are urgently required to provide a more definitive answer regarding the role of polymyxin combination therapy compared with monotherapy. In this article, we provide an overview of key in vitro and clinical investigations examining CMS/colistin and polymyxin B combination therapy.
authors: Laboratory for Antimicrobial Pharmacodynamics, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, SUNY, Buffalo, New York.
authors: Phillip J
authors: PJ
authors: Bergen
authors: Zackery P
authors: ZP
authors: Bulman
authors: Sarith
authors: S
authors: Saju
authors: Juergen B
authors: JB
authors: Bulitta
authors: Cornelia
authors: C
authors: Landersdorfer
authors: Alan
authors: A
authors: Forrest
authors: Jian
authors: J
authors: Li
authors: Roger L
authors: RL
authors: Nation
authors: Brian T
authors: BT
authors: Tsuji
mesh_terms: D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D004359:Drug Therapy, Combination; D016905:Gram-Negative Bacterial Infections / Q000188:drug therapy* / Q000382:microbiology; D006801:Humans; D011113:Polymyxins / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D016896:Treatment Outcome
chemical_list: D000900:Anti-Bacterial Agents; D011113:Polymyxins
keywords: colistin; colistin methanesulfonate; combination; polymyxin B; polymyxins
references: Antimicrob Agents Chemother. 2010 Jun;54(6):2732-4
references: 20368401
references: Clin Infect Dis. 2003 Dec 1;37(11):e154-60
references: 14614688
references: Antimicrob Agents Chemother. 2014;58(3):1757-62
references: 24395223
references: Eur J Clin Microbiol Infect Dis. 2014 Aug;33(8):1311-22
references: 24532009
references: Antimicrob Agents Chemother. 2009 Aug;53(8):3430-6
references: 19433570
references: Antimicrob Agents Chemother. 2003 Mar;47(3):905-9
references: 12604520
references: AMA Arch Intern Med. 1953 Aug;92(2):248-57
references: 13079346
references: Antimicrob Agents Chemother. 2011 Jul;55(7):3284-94
references: 21555763
references: Int J Antimicrob Agents. 2011 Mar;37(3):244-7
references: 21236643
references: Antimicrob Agents Chemother. 2008 Jan;52(1):333-6
references: 17967915
references: Antimicrob Agents Chemother. 2013 Nov;57(11):5394-7
references: 23959321
references: Eur J Clin Microbiol Infect Dis. 2006 Sep;25(9):596-9
references: 16955249
references: Antimicrob Agents Chemother. 2012 Apr;56(4):2108-13
references: 22252816
references: Clin Infect Dis. 2007 Sep 1;45(5):594-8
references: 17682994
references: Diagn Microbiol Infect Dis. 2012 Nov;74(3):213-23
references: 22959816
references: J Antimicrob Chemother. 2014 Sep;69(9):2434-42
references: 24833752
references: Clin Infect Dis. 2013 Aug;57(4):524-31
references: 23697744
references: Antimicrob Agents Chemother. 2012 Oct;56(10):5103-12
references: 22802247
references: Clin Microbiol Infect. 2011 Dec;17(12):1798-803
references: 21595793
references: Int J Antimicrob Agents. 2008 Nov;32(5):450-4
references: 18768302
references: Ann Intern Med. 1970 Jun;72(6):857-68
references: 5448745
references: Clin Ther. 2008 Jan;30(1):143-51
references: 18343250
references: Clin Lab Sci. 2011 Winter;24(1):52-6
references: 21404966
references: Clin Infect Dis. 2012 Jun;54(12):1720-6
references: 22423120
references: Antimicrob Agents Chemother. 2013 Nov;57(11):5258-65
references: 23939888
references: Science. 2009 Sep 11;325(5946):1345-6
references: 19745137
references: Chemotherapy. 2013;59(3):225-31
references: 24356297
references: Epidemiol Infect. 2013 Jun;141(6):1214-22
references: 22954403
references: J Antimicrob Chemother. 2010 Oct;65(10):2231-7
references: 20685752
references: Clin Infect Dis. 2006 Sep 1;43 Suppl 2:S95-9
references: 16894522
references: Diagn Microbiol Infect Dis. 2011 Jun;70(2):246-52
references: 21353436
references: Int J Antimicrob Agents. 2007 Oct;30(4):315-9
references: 17631984
references: Antimicrob Agents Chemother. 2014;58(2):851-8
references: 24277037
references: J Antimicrob Chemother. 2011 May;66(5):1047-51
references: 21393131
references: Antimicrob Agents Chemother. 2011 Dec;55(12):5685-95
references: 21911563
references: Clin Infect Dis. 2012 Oct;55(7):943-50
references: 22752516
references: Antimicrob Agents Chemother. 2010 Dec;54(12):5316-22
references: 20876375
references: J Antimicrob Chemother. 2014 Mar;69(3):857-9
references: 24169582
references: Antimicrob Agents Chemother. 2013 Jun;57(6):2900-1
references: 23571536
references: J Antimicrob Chemother. 2008 Mar;61(3):636-42
references: 18227094
references: Int J Antimicrob Agents. 2007 Dec;30(6):537-40
references: 17851050
references: Clin Infect Dis. 2013 Aug;57(3):349-58
references: 23616495
references: PLoS One. 2012;7(12):e52349
references: 23285002
references: J Infect. 2008 Mar;56(3):185-90
references: 18280570
references: Int J Antimicrob Agents. 2010 Feb;35(2):194-9
references: 20006471
references: Antimicrob Agents Chemother. 2013 Aug;57(8):3738-45
references: 23716052
references: Antimicrob Agents Chemother. 2009 May;53(5):2133-5
references: 19258266
references: Eur J Clin Microbiol Infect Dis. 2010 Mar;29(3):301-5
references: 20063025
references: Diagn Microbiol Infect Dis. 2010 Jun;67(2):191-7
references: 20338710
references: Antimicrob Agents Chemother. 2011 Nov;55(11):5134-42
references: 21876058