Ann Lab Med.  2016 Mar;36(2):124-130. 10.3343/alm.2016.36.2.124.

In Vitro Interactions of Antibiotic Combinations of Colistin, Tigecycline, and Doripenem Against Extensively Drug-Resistant and Multidrug-Resistant Acinetobacter baumannii

  • 1Department of Laboratory Medicine, College of Medicine, Chosun University, Gwangju, Korea.
  • 2Research Center for Resistant Cells, College of Medicine, Chosun University, Gwangju, Korea.
  • 3Department of Laboratory Medicine and Research Institute of Bacterial Resistance, Yonsei University College of Medicine, Seoul, Korea.
  • 4Premedical Science, College of Medicine, Chosun University, Gwangju, Korea.


Acinetobacter baumannii infections are difficult to treat owing to the emergence of various antibiotic resistant isolates. Because treatment options are limited for multidrug-resistant (MDR) A. baumannii infection, the discovery of new therapies, including combination therapy, is required. We evaluated the synergistic activity of colistin, doripenem, and tigecycline combinations against extensively drug-resistant (XDR) A. baumannii and MDR A. baumannii.
Time-kill assays were performed for 41 XDR and 28 MDR clinical isolates of A. baumannii by using colistin, doripenem, and tigecycline combinations. Concentrations representative of clinically achievable levels (colistin 2 microg/mL, doripenem 8 microg/mL) and achievable tissue levels (tigecycline 2 microg/mL) for each antibiotic were used in this study.
The colistin-doripenem combination displayed the highest rate of synergy (53.6%) and bactericidal activity (75.4%) in 69 clinical isolates of A. baumannii. Among them, thedoripenem-tigecycline combination showed the lowest rate of synergy (14.5%) and bacteri-cidal activity (24.6%). The doripenem-tigecycline combination showed a higher antagonistic interaction (5.8%) compared with the colistin-tigecycline (1.4%) combination. No antagonism was observed for the colistin-doripenem combination.
The colistin-doripenem combination is supported in vitro by the high rate of synergy and bactericidal activity and lack of antagonistic reaction in XDR and MDR A. baumannii. It seems to be necessary to perform synergy tests to determine the appropri-ate combination therapy considering the antagonistic reaction found in several isolates against the doripenem-tigecycline and colistin-tigecycline combinations. These findings should be further examined in clinical studies.


Extensively drug-resistant; Synergism; Antagonism; Acinetobacter baumannii; Colistin; Doripenem; Tigecycline

MeSH Terms

Acinetobacter Infections/drug therapy/microbiology
Acinetobacter baumannii/*drug effects/genetics/isolation & purification
Anti-Bacterial Agents/*pharmacology/therapeutic use
Bacterial Proteins/genetics
Carbapenems/*pharmacology/therapeutic use
Colistin/*pharmacology/therapeutic use
Drug Resistance, Multiple, Bacterial/*drug effects
Drug Synergism
Drug Therapy, Combination
Microbial Sensitivity Tests
Minocycline/*analogs & derivatives/pharmacology/therapeutic use
Multilocus Sequence Typing
Anti-Bacterial Agents
Bacterial Proteins

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1. Perez F, Hujer AM, Hujer KM, Decker BK, Rather PN, Bonomo RA. Global challenge of multidrug-resistant Acinetobacter baumannii. Antimicrob Agents Chemother. 2007; 51:3471–3484. PMID: 17646423.
2. Appleman MD, Belzberg H, Citron DM, Heseltine PN, Yellin AE, Murray J, et al. In vitro activities of nontraditional antimicrobials against multiresistant Acinetobacter baumannii strains isolated in an intensive care unit outbreak. Antimicrob Agents Chemother. 2000; 44:1035–1040. PMID: 10722508.
3. Sunenshine RH, Wright MO, Maragakis LL, Harris AD, Song X, Hebden J, et al. Multidrug-resistant Acinetobacter infection mortality rate and length of hospitalization. Emerg Infect Dis. 2007; 13:97–103. PMID: 17370521.
4. Fishbain J, Peleg AY. Treatment of Acinetobacter infections. Clin Infect Dis. 2010; 51:79–84. PMID: 20504234.
5. Mera RM, Miller LA, Amrine-Madsen H, Sahm DF. Acinetobacter baumannii 2002-2008: increase of carbapenem-associated multiclass resistance in the United States. Microb Drug Resist. 2010; 16:209–215. PMID: 20707714.
6. Higgins PG, Dammhayn C, Hackel M, Seifert H. Global spread of carbapenem-resistant Acinetobacter baumannii. J Antimicrob Chemother. 2010; 65:233–238. PMID: 19996144.
7. Poirel L, Nordmann P. Carbapenem resistance in Acinetobacter baumannii: mechanisms and epidemiology. Clin Microbiol Infect. 2006; 12:826–836. PMID: 16882287.
8. Maragakis LL, Perl TM. Acinetobacter baumannii: epidemiology, antimicrobial resistance, and treatment options. Clin Infect Dis. 2008; 46:1254–1263. PMID: 18444865.
9. Karageorgopoulos DE, Kelesidis T, Kelesidis I, Falagas ME. Tigecycline for the treatment of multidrug-resistant (including carbapenem-resistant) Acinetobacter infections: a review of the scientific evidence. J Antimicrob Chemother. 2008; 62:45–55. PMID: 18436554.
10. Gordon NC, Wareham DW. Multidrug-resistant Acinetobacter baumannii: mechanisms of virulence and resistance. Int J Antimicrob Agents. 2010; 35:219–226. PMID: 20047818.
11. Peleg AY, Seifert H, Paterson DL. Acinetobacter baumannii: emergence of a successful pathogen. Clin Microbiol Rev. 2008; 21:538–582. PMID: 18625687.
12. Park YK, Jung SI, Park KH, Cheong HS, Peck KR, Song JH, et al. Independent emergence of colistin-resistant Acinetobacter spp. isolates from Korea. Diagn Microbiol Infect Dis. 2009; 64:43–51. PMID: 19362258.
13. Cai Y, Chai D, Wang R, Liang B, Bai N. Colistin resistance of Acinetobacter baumannii: clinical reports, mechanisms and antimicrobial strategies. J Antimicrob Chemother. 2012; 67:1607–1615. PMID: 22441575.
14. Navon-Venezia S, Leavitt A, Carmeli Y. High tigecycline resistance in multidrug-resistant Acinetobacter baumannii. J Antimicrob Chemother. 2007; 59:772–774. PMID: 17353223.
15. Pankuch GA, Seifert H, Appelbaum PC. Activity of doripenem with and without levofloxacin, amikacin, and colistin against Pseudomonas aeruginosa and Acinetobacter baumannii. Diagn Microbiol Infect Dis. 2010; 67:191–197. PMID: 20338710.
16. Dinc G, Demiraslan H, Elmali F, Ahmed SS, Alp E, Doganay M. Antimicrobial efficacy of doripenem and its combinations with sulbactam, amikacin, colistin, tigecycline in experimental sepsis of carbapenem-resistant Acinetobacter baumannii. New Microbiol. 2015; 38:67–73. PMID: 25742149.
17. Principe L, Capone A, Mazzarelli A, D'Arezzo S, Bordi E, Di Caro A, et al. In vitro activity of doripenem in combination with various antimicrobials against multidrug-resistant Acinetobacter baumannii: possible options for the treatment of complicated infection. Microb Drug Resist. 2013; 19:407–414. PMID: 23659601.
18. KARMS. Korean Antimicrobial Resistance Monitoring System. KCDC;2013.
19. Lee MJ, Jang SJ, Li XM, Park G, Kook JK, Kim MJ, et al. Comparison of rpoB gene sequencing, 16S rRNA gene sequencing, gyrB multiplex PCR, and the VITEK2 system for identification of Acinetobacter clinical isolates. Diagn Microbiol Infect Dis. 2014; 78:29–34. PMID: 24157058.
20. Magiorakos AP, Srinivasan A, Carey RB, Carmeli Y, Falagas ME, Giske CG, et al. Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: an international expert proposal for interim standard definitions for acquired resistance. Clin Microbiol Infect. 2012; 18:268–281. PMID: 21793988.
21. Clinical and Laboratory Standards Institute. Performance standards for antimicrobial susceptibility testing, 25th Informational supplement, M100-S25. Wayne, PA: Clinical and Laboratory Standards Institute;2015.
22. Peck KR, Kim MJ, Choi JY, Kim HS, Kang CI, Cho YK, et al. 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. 2012; 61:353–360. PMID: 22016557.
23. Turton JF, Ward ME, Woodford N, Kaufmann ME, Pike R, Livermore DM, et al. The role of ISAba1 in expression of OXA carbapenemase genes in Acinetobacter baumannii. FEMS Microbiol Lett. 2006; 258:72–77. PMID: 16630258.
24. Bartual SG, Seifert H, Hippler C, Luzon MA, Wisplinghoff H, Rodriguez-Valera F. Development of a multilocus sequence typing scheme for characterization of clinical isolates of Acinetobacter baumannii. J Clin Microbiol. 2005; 43:4382–4390. PMID: 16145081.
25. Oleksiuk LM, Nguyen MH, Press EG, Updike CL, O'Hara JA, Doi Y, et al. In vitro responses of Acinetobacter baumannii to two- and three-drug combinations following exposure to colistin and doripenem. Antimicrob Agents Chemother. 2014; 58:1195–1199. PMID: 24247139.
26. Tan TY, Lim TP, Lee WH, Sasikala S, Hsu LY, Kwa AL. In vitro antibiotic synergy in extensively drug-resistant Acinetobacter baumannii: the effect of testing by time-kill, checkerboard, and Etest methods. Antimicrob Agents Chemother. 2011; 55:436–438. PMID: 20956606.
27. Entenza JM, Moreillon P. Tigecycline in combination with other antimicrobials: a review of in vitro, animal and case report studies. Int J Antimicrob Agents. 2009; 34:8.e1–8.e9. PMID: 19162449.
28. Ni W, Cui J, Liang B, Cai Y, Bai N, Cai X, et al. In vitro effects of tigecycline in combination with colistin (polymyxin E) and sulbactam against multidrug-resistant Acinetobacter baumannii. J Antibiot (Tokyo). 2013; 66:705–708. PMID: 23981963.
29. Karaoglan I, Zer Y, Bosnak VK, Mete AO, Namiduru M. In vitro synergistic activity of colistin with tigecycline or β-lactam antibiotic/β-lactamase inhibitor combinations against carbapenem-resistant Acinetobacter baumannii. J Int Med Res. 2013; 41:1830–1837. PMID: 24265334.
30. Principe L, D'Arezzo S, Capone A, Petrosillo N, Visca P. In vitro activity of tigecycline in combination with various antimicrobials against multidrug resistant Acinetobacter baumannii. Ann Clin Microbiol Antimicrob. 2009; 8:18. PMID: 19460166.
31. Shields RK, Kwak EJ, Potoski BA, Doi Y, Adams-Haduch JM, Silviera FP, et al. 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. 2011; 70:246–252. PMID: 21353436.
32. Shields RK, Clancy CJ, Gillis LM, Kwak EJ, Silveira FP, Massih RC, et al. Epidemiology, clinical characteristics and outcomes of extensively drug-resistant Acinetobacter baumannii infections among solid organ transplant recipients. PLoS One. 2012; 7:e52349. PMID: 23285002.
33. Clock SA, Tabibi S, Alba L, Kubin CJ, Whittier S, Saiman L. In vitro activity of doripenem alone and in multi-agent combinations against extensively drug-resistant Acinetobacter baumannii and Klebsiella pneumoniae. Diagn Microbiol Infect Dis. 2013; 76:343–346. PMID: 23601454.
34. O'Hara JA, Ambe LA, Casella LG, Townsend BM, Pelletier MR, Ernst RK, et al. Activities of vancomycin-containing regimens against colistin-resistant Acinetobacter baumannii clinical strains. Antimicrob Agents Chemother. 2013; 57:2103–2108. PMID: 23422916.
35. Dizbay M, Tozlu DK, Cirak MY, Isik Y, Ozdemir K, Arman D. In vitro synergistic activity of tigecycline and colistin against XDR-Acinetobacter baumannii. J Antibiot (Tokyo). 2010; 63:51–53. PMID: 19942947.
36. Ni W, Shao X, Di X, Cui J, Wang R, Liu Y. In vitro synergy of polymyxins with other antibiotics for Acinetobacter baumannii: a systematic review and meta-analysis. Int J Antimicrob Agents. 2015; 45:8–18. PMID: 25465524.
37. Bell A. Antimalarial drug synergism and antagonism: mechanistic and clinical significance. FEMS Microbiol Lett. 2005; 253:171–184. PMID: 16243458.
38. Watine J, Seigneuric B, Charet JC. In vitro quinolone-gentamicin antagonism demonstrated by time-kill and combination experiments with clinical isolates of Enterococcus. J Infect Chemother. 1997; 3:55–57.
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