[en] ObjectivesTo examine the evidence on in-vitro synergy of polymyxin-carbapenem combination therapy against Gram-negative bacteria (GNB)MethodsSystematic review and meta-analysis. All studies examining in-vitro interactions of antibiotic combinations consisting of any carbapenem with colistin or polymyxin B against any GNB. A broad search was conducted with no language, date or publication status restrictions. Synergy rates, defined as fractional inhibitory concentration index </=0.5 or >2log colony forming unit reduction, were pooled separately for time-kill, checkerboard, and E-test in a mixed-effects meta-analysis of rates. We examined whether synergy rate depended on testing method, type of antibiotic, bacteria and resistance to carbapenems. Pooled rates with 95% confidence intervals are shown.Results39 published studies and 15 conference proceeding were included, reporting on 246 different tests on 1054 bacterial isolates. In time-kill studies, combination therapy showed synergy rates of 77% (95% CI 64-87) for Acinetobacter baumannii, 44% (95% CI 30-59%) for Klebsiella pneumoniae and 50% (95% CI 30-69%) for Pseudomonas aeruginosa with low antagonism rates for all. Doripenem showed high synergy rates for all three bacteria. For A. baumannii, meropenem was more synergistic than imipenem, whereas for P. aeruginosa the opposite was true. Checkerboard and Etest studies generally reported lower synergy rates than time-kill. Use of combination therapy led to less resistance development in-vitro.ConclusionsThe combination of a carbapenem with a polymyxin against GNB, especially A. baumannii, is supported in-vitro by high synergy rates, with low antagonism and less resistance development. These findings should be examined in clinical studies.
Yahav D, Farbman L, Leibovici L, Paul M. 2012. Colistin: new lessons on an old antibiotic. Clin. Microbiol. Infect. 18:18-29.
Falagas ME, Kasiakou SK, Saravolatz LD. 2005. Colistin: the revival of polymyxins for the management of multidrug-resistant gram-negative bacterial infections. Clin. Infect. Dis. 40:1333-1341.
Paul M, Bishara J, Levcovich A, Chowers M, Goldberg E, Singer P, Lev S, Leon P, Raskin M, Yahav D. 2010. Effectiveness and safety of colistin: prospective comparative cohort study. J. Antimicrob. Chemother. 65: 1019-1027.
Falagas ME, Kasiakou SK. 2006. Toxicity of polymyxins: a systematic review of the evidence from old and recent studies. Crit. Care 10:R27. doi:10.1186/cc3995.
Couet W, Gregoire N, Marchand S, Mimoz O. 2012. Colistin pharmacokinetics: the fog is lifting. Clin. Microbiol. Infect. 18:30-39.
Petrosillo N, Ioannidou E, Falagas ME. 2008. Colistin monotherapy vs. combination therapy: evidence from microbiological, animal and clinical studies. Clin. Microbiol. Infect. 14:816-827.
Peck KR, Kim MJ, Choi JY, Kim HS, Kang CI, Cho YK, Park DW, Lee HJ, Lee MS, Ko KS. 2012. In vitro time-kill studies of antimicrobial agents against blood isolates of imipenem-resistant Acinetobacter baumannii, including colistin- or tigecycline-resistant isolates. J. Med. Microbiol. 61:353-360.
Rodriguez CH, Ambrosio AD, Bajuk M, Spinozzi M, Nastro M, Bombicino K, Radice M, Gutkind G, Vay C, Famiglietti A. 2010. In vitro antimicrobials activity against endemic Acinetobacter baumannii multiresistant clones. J. Infect. Dev. Ctries. 4:164-167.
Tripodi M-F, Durante-Mangoni E, Fortunato R, Utili R, Zarrilli R. 2007. Comparative activities of colistin, rifampicin, imipenem and sulbactam/ ampicillin alone or in combination against epidemic multidrugresistant Acinetobacter baumannii isolates producing OXA-58 carbapenemases. Int. J. Antimicrob. Agents 30:537-540.
Souli M, Rekatsina PD, Chryssouli Z, Galani I, Giamarellou H, Kanellakopoulou K. 2009. Does the activity of the combination of imipenem and colistin in vitro exceed the problem of resistance in metallo-betalactamase- producing Klebsiella pneumoniae isolates? Antimicrob. Agents Chemother. 53:2133-2135.
Khuntayaporn P, Kasemwattanaroj P, Uaviseswong T, Montakantikul P, Chomnawang M 2010. Abstr. 50th Intersci. Conf. Antimicrob. Agents Chemother., abstr E-2054. American Society for Microbiology, Washington, DC.
Tateda K, Ishii Y, Matsumoto T, Yamaguchi K. 2006. Break-point checkerboard plate for screening of appropriate antibiotic combinations against multidrug-resistant Pseudomonas aeruginosa. Scand. J. Infect. Dis. 38:268-272.
Pongpech P, Amornnopparattanakul S, Panapakdee S, Fungwithaya S, Nannha P, Dhiraputra C, Leelarasamee A. 2010. Antibacterial activity of carbapenem-based combinations againts multidrug-resistant Acinetobacter baumannii. J. Med. Assoc. Thai. 93:161-171.
Jernigan MG, Press EG, Nguyen MH, Clancy CJ, Shields RK. 2012. The combination of doripenem and colistin is bactericidal and synergistic against colistin-resistant, carbapenemase-producing Klebsiella pneumoniae. Antimicrob. Agents Chemother. 56:3395-3398.
Rynn C, Wootton M, Bowker KE, Alan Holt H, Reeves DS. 1999. In vitro assessment of colistin's antipseudomonal antimicrobial interactions with other antibiotics. Clin. Microbiol. Infect. 5:32-36.
Milne KEN, Gould IM. 2010. Combination testing of multidrug-resistant cystic fibrosis isolates of Pseudomonas aeruginosa: use of a new parameter, the susceptible breakpoint index. J. Antimicrob. Chemother. 65:82-90.
Poudyal A, Yu H, Davis K, Ku C, Nightingale R, Jacob J, Tsuji B, Bulitta J, Forrest Li J, Nation R 2011. Abstr. 20th Eur. Cong. Clin. Microbiol. Infect. Dis. abstr P-784.
Bergen PJ, Tsuji BT, Bulitta JB, Forrest A, Jacob J, Sidjabat HE, Nation RL, Paterson DL, Li J. 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. 55:5685-5695.
Bergen PJ, Forrest A, Bulitta JB, Tsuji BT, Sidjabat HE, Paterson DL, Li J, Nation RL. 2011. Clinically relevant plasma concentrations of colistin in combination with imipenem enhance pharmacodynamic activity against multidrug-resistant Pseudomonas aeruginosa at multiple inocula. Antimicrob. Agents Chemother. 55:5134-5142.
Deris ZZ, Yu HH, Davis K, Jacob J, Ku CK, Poudyal A, Bergen PJ, Tsuji BT, Bulitta JB, Forrest A, Paterson DL, Velkov T, Li J, Nation RL. 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. 56:5103-5112.
Ly N, Kelchin P, Holden P, Rao G, Forrest A, Bulitta J, Nation R, Li J, Tsuji B 2011. Abstr. 51st. Intersci. Conf. Antimicrob. Agents Chemother., abstr A2-1176. American Society for Microbiology, Washington, DC.
Tan CH, Li J, Nation RL. 2007. Activity of colistin against heteroresistant Acinetobacter baumannii and emergence of resistance in an in vitro pharmacokinetic/ pharmacodynamic model. Antimicrob. Agents Chemother. 51:3413-3415.
Souli M, Galani I, Giamarellou H. 2008. Emergence of extensively drugresistant and pandrug-resistant Gram-negative bacilli in Europe. Euro Surveill. 13:19045.
Paul M, Benuri-Silbiger I, Soares-Weiser K, Leibovici L. 2004. Beta lactam monotherapy versus beta lactam-aminoglycoside combination therapy for sepsis in immunocompetent patients: systematic review and meta-analysis of randomised trials. BMJ 328:668.
Paul M, Soares-Weiser K, Leibovici L. 2003. Beta lactam monotherapy versus beta lactam-aminoglycoside combination therapy for fever with neutropenia: systematic review and meta-analysis. BMJ 326:1111.
Marcus R, Paul M, Elphick H, Leibovici L. 2011. Clinical implications of beta-lactam-aminoglycoside synergism: systematic review of randomised trials. Int. J. Antimicrob. Agents 37:491-503.
Bliziotis IA, Samonis G, Vardakas KZ, Chrysanthopoulou S, Falagas ME. 2005. Effect of aminoglycoside and beta-lactam combination therapy versus beta-lactam monotherapy on the emergence of antimicrobial resistance: a meta-analysis of randomized, controlled trials. Clin. Infect. Dis. 41:149-158.
Chan EL, Zabransky RJ. 1987. Determination of synergy by two methods with eight antimicrobial combinations against tobramycin-susceptible and tobramycin-resistant strains of Pseudomonas. Diagn. Microbiol. Infect. Dis. 6:157-164.
Yoon J, Urban C, Terzian C, Rahal JJ. 2004. In vitro double and triple synergistic activities of polymyxin B, imipenem, and rifampin against multidrug-resistant Acinetobacter baumannii. Antimicrob. Agents Chemother. 48:753-757.
Landman D, Bratu S, Alam M, Quale J. 2005. Citywide emergence of Pseudomonas aeruginosa strains with reduced susceptibility to polymyxin B. J. Antimicrob. Chemother. 55:954-957.
Bratu S, Tolaney P, Karumudi U, Quale J, Mooty M, Nichani S, Landman D. 2005. Carbapenemase-producing Klebsiella pneumoniae in Brooklyn, NY: molecular epidemiology and in vitro activity of polymyxin B and other agents. J. Antimicrob. Chemother. 56:128-132.
Timurkaynak F, Can Azap FOK, Demirbilek M, Arslan H, Karaman SO. 2006. In vitro activities of non-traditional antimicrobials alone or in combination against multidrug-resistant strains of Pseudomonas aeruginosa and Acinetobacter baumannii isolated from intensive care units. Int. J. Antimicrob. Agents 27:224-228.
Wareham DW, Bean DC. 2006. In-vitro activity of polymyxin B in combination with imipenem, rifampicin and azithromycin versus multidrug resistant strains of Acinetobacter baumannii producing OXA-23 carbapenemases. Ann. Clin. Microbiol. Antimicrob. 5:10.
Biancofiore G, Tascini C, Bisa M, Gemignani G, Bindi ML, Leonildi A, Giannotti G, Menichetti F. 2007. Colistin, meropenem and rifampin in a combination therapy for multi-drug-resistant Acinetobacter baumannii multifocal infection. A case report. Minerva Anestesiol. 73:181-185.
Cirioni O, Ghiselli R, Silvestri C, Kamysz W, Orlando F, Mocchegiani F, Matteo FD, Riva A, Lukasiak J, Saba GS, Giacometti VA. 2007. Efficacy of tachyplesin III, colistin, and imipenem against a multiresistant Pseudomonas aeruginosa strain. Antimicrob. Agents Chemother. 51:2005- 2010.
Pankuch GA, Lin G, Seifert H, Appelbaum PC. 2008. Activity of meropenem with and without ciprofloxacin and colistin against Pseudomonas aeruginosa and Acinetobacter baumannii. Antimicrob. Agents Chemother. 52:333-336.
Tascini C, Urbani L, Biancofiore G, Rossolini GM, Leonildi A, Gemignani G, Bindi ML, Mugnaioli C, Filipponi F, Menichetti F. 2008. Colistin in combination with rifampin and imipenem for treating a bla- VIM-1 metallo-beta-lactamase-producing Enterobacter cloacae disseminated infection in a liver transplant patient. Minerva Anestesiol. 74:47-49.
Guzel CB, Gerceker AA. 2008. In vitro activities of various antibiotics, alone and in combination with colistin methanesulfonate, against Pseudomonas aeruginosa strains isolated from cystic fibrosis patients. Chemotherapy 54:147-151.
Guelfi KC, Tognim MCB, Cardoso CL, Carrara-Marrone ACG, Garcia FELB. 2008. In vitro evaluation of the antimicrobial activity of meropenem in combination with polymyxin B and gatifloxacin against Pseudomonas aeruginosa and Acinetobacter baumannii. J. Chemother. 20:180- 185.
Burgess DS, Carden MF, Srisupha-Olarn W, Nathisuwan S. 2008. Abstr. 48th Intersci. Conf. Antimicrob. Agents Chemother., abstr C1-1045. American Society for Microbiology, Washington, DC.
Ullman M, Mitropoulos I, Hovde L, Prince R, Rotschafer J 2008. Abstr. 48th Intersci. Conf. Antimicrob. Agents Chemother., abstr A-1672. American Society for Microbiology, Washington, DC.
Pankey GA, Ashcraft DS. 2009. The detection of synergy between meropenem and polymyxin B against meropenem-resistant Acinetobacter baumannii using Etest and time-kill assay. Diagn. Microbiol. Infect. Dis. 63: 228-232.
Burgess DS, Srisupha-Olarn W, Carden MF 2009. Abstr. 49th Intersci. Conf. Antimicrob. Agents Chemother., abstr E-812. American Society for Microbiology, Washington, DC.
Hilliard J, Fernandez J, Melton J, Foleno B, Wira E, Lynch AS, Flamm RK. 2009. Abstr. 49th Intersci. Conf. Antimicrob. Agents Chemother., abstr B-1327. American Society for Microbiology, Washington, DC.
Elemam A, Rahimian J, Doymaz M. 2010. In vitro evaluation of antibiotic synergy for polymyxin B-resistant carbapenemase-producing Klebsiella pneumoniae. J. Clin. Microbiol. 48:3558-3562.
Lin KH, Chuang YC, Lee SH, Yu WL. 2010. In vitro synergistic antimicrobial effect of imipenem and colistin against an isolate of multidrugresistant Enterobacter cloacae. J. Microbiol. Immunol. Infect. 43:317-322.
Shields RK, Kwak EJ, Potoski BA, Doi Y, Adams-Haduch JM, Silviera FP, Pilewski JM, Crespo M, Pasculle AW, Clancy CJ, Nguyen MH. 2011. High mortality rates among solid organ transplant recipients infected with extensively drug-resistant Acinetobacter baumannii: using in vitro antibiotic combination testing to identify the combination of a carbapenem and colistin as an effective treatment regimen. Diagn. Microbiol. Infect. Dis. 70:246-252.
Sopirala MM, Mangino JE, Gebreyes WA, Biller B, Bannerman T, Balada-Llasat JM, Pancholi P. 2010. Synergy testing by Etest, microdilution checkerboard, and time-kill methods for pan-drug-resistant Acinetobacter baumannii. Antimicrob. Agents Chemother. 54:4678-4683.
Urban C, Mariano N, Rahal JJ. 2010. In vitro double and triple bactericidal activities of doripenem, polymyxin B, and rifampin against multidrug- resistant Acinetobacter baumannii, Pseudomonas aeruginosa, Klebsiella pneumoniae, and Escherichia coli. Antimicrob. Agents Chemother. 54:2732-2734.
Pankuch GA, Seifert H, Appelbaum PC. 2010. Activity of doripenem with and without levofloxacin, amikacin, and colistin against Pseudomonas aeruginosa and Acinetobacter baumannii. Diagn. Microbiol. Infect. Dis. 67:191-197.
Souli M, Rekatsina P, Galani I, Chryssouli Z, Giamarellou H. 2010. Abstr. 20th Eur. Cong. Clin. Microbiol. Infect. Dis., abstr P-1268.
Dorobisz M, Shields RK, Nguyen MH, Doi Y, Clancy CJ, Potoski BA. 2010. Abstr. 50th Intersci. Conf. Antimicrob. Agents Chemother., abstr E-1595. American Society for Microbiology, Washington, DC.
Srisupha-Olarn W, Burgess D. 2010. Abstr. 50th Intersci. Conf. Antimicrob. Agents Chemother., abstr E-1591. American Society for Microbiology, Washington, DC.
Liang W, Liu X-F, Huang J, Zhu D-M, Li J, Zhang J. 2011. Activities of colistin- and minocycline-based combinations against extensive drug resistant Acinetobacter baumannii isolates from intensive care unit patients. BMC Infect. Dis. 11:109. doi:10.1186/1471-2334-11-109.
Pankey GA, Ashcraft DS. 2011. Detection of synergy using the combination of polymyxin B with either meropenem or rifampin against carbapenemase- producing Klebsiella pneumoniae. Diagn. Microbiol. Infect. Dis. 70:561-564.
Sheng W-H, Wang J-T, Li S-Y, Cheng Y-CLA, Chen Y-C, Chang S-C. 2011. Comparative in vitro antimicrobial susceptibilities and synergistic activities of antimicrobial combinations against carbapenem-resistant Acinetobacter species: Acinetobacter baumannii versus Acinetobacter genospecies 3 and 13TU. Diagn. Microbiol. Infect. Dis. 70:380-386.
Santimaleeworagun W, Wongpoowarak P, Chayakul P, Pattharachay- akul S, Tansakul P, Garey KW. 2011. In vitro activity of colistin or sulbactam in combination with fosfomycin or imipenem against clinical isolates of carbapenem-resistant Acinetobacter baumannii producing OXA-23 carbapenemases. Southeast Asian J. Trop. Med. Public Health 42:890.
Lim T-P, Lee W, Tan T-Y, Teo SSJ, Hsu L-Y, Tan T-T, Kwa NS. 2011. Effective antibiotics in combination against extreme drug-resistant Pseudomonas aeruginosa with decreased susceptibility to polymyxin B. PLoS One 6:e28177. doi:10.1371/journal.pone.0028177.
Morosini M, Shan A, García-Castillo M, Tato M, Cantón R 2011. Abstr. 21st Eur. Cong. Clin. Microbiol. Infect. Dis., abstr P-1183.
Teo J, Lim T-P, Lee W, Hsu L-Y, Tan T-Y, Tan TT, Sasikala S, Chia D, Tahir N, Kwa AL. 2011. Abstr. 51st Intersci. Conf. Antimicrob. Agents Chemother., abstr E-726. American Society for Microbiology, Washington, DC.
Principe L, Capone A, Mazzarelli A, D'arezzo S, Bordi E, Di Caro A, Petrosillo N. 2011. Abstr. 51st Intersci. Conf. Antimicrob. Agents Chemother., abstr E-736. American Society for Microbiology, Washington, DC.
Mohamed AF, Karvanen M, Cars O, Friberg LE. 2011. Abstr. 51st Intersci. Conf. Antimicrob. Agents Chemother., abstr A2-1172. American Society for Microbiology, Washington, DC.
Ozseven AG, Cetin ES, Aridogan BC, Ozseven L. 2012. In vitro synergistic activity of carbapenems in combination with other antimicrobial agents against multidrug-resistant Acinetobacter baumannii. Afr. J. Microbiol. Res. 6:2985-2992.
He W, Kaniga K, Lynch AS, Flamm RK, Davies TA. 2012. In vitro Etest synergy of doripenem with amikacin, colistin, and levofloxacin against Pseudomonas aeruginosa with defined carbapenem resistance mechanisms as determined by the Etest method. Diagn. Microbiol. Infect. Dis. 74:417- 419.
Lee GC, Burgess DS. 2013. Polymyxins and doripenem combination against KPC-producing Klebsiella pneumoniae. J. Clin. Med. Res. 5:97- 100.
