Journal of Microbiology

, Volume 55, Issue 11, pp 837–849 | Cite as

Antibiotic resistance of pathogenic Acinetobacter species and emerging combination therapy

  • Bora Shin
  • Woojun Park


The increasing antibiotic resistance of Acinetobacter species in both natural and hospital environments has become a serious problem worldwide in recent decades. Because of both intrinsic and acquired antimicrobial resistance (AMR) against last-resort antibiotics such as carbapenems, novel therapeutics are urgently required to treat Acinetobacter-associated infectious diseases. Among the many pathogenic Acinetobacter species, A. baumannii has been reported to be resistant to all classes of antibiotics and contains many AMR genes, such as blaADC (Acinetobacter-derived cephalosporinase). The AMR of pathogenic Acinetobacter species is the result of several different mechanisms, including active efflux pumps, mutations in antibiotic targets, antibiotic modification, and low antibiotic membrane permeability. To overcome the limitations of existing drugs, combination theraphy that can increase the activity of antibiotics should be considered in the treatment of Acinetobacter infections. Understanding the molecular mechanisms behind Acinetobacter AMR resistance will provide vital information for drug development and therapeutic strategies using combination treatment. Here, we summarize the classic mechanisms of Acinetobacter AMR, along with newly-discovered genetic AMR factors and currently available antimicrobial adjuvants that can enhance drug efficacy in the treatment of A. baumannii infections.


Acinetobacter multidrug resistance biofilm membrane permeability natural compounds adjuvants 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Aleksic, V., Mimica-Dukic, N., Simin, N., Nedeljkovic, N.S., and Knezevic, P. 2014. Synergistic effect of Myrtus communis L. essential oils and conventional antibiotics against multi-drug resistant Acinetobacter baumannii wound isolates. Phytomedicine 21, 1666–1674.PubMedCrossRefGoogle Scholar
  2. Anwar, M., Ejaz, H., Zafar, A., and Hamid, H. 2016. Phenotypic detection of metallo-beta-lactamases in carbapenem resistant Acinetobacter baumannii isolated from pediatric patients in Pakistan. J. Pathog. 2016, 8603964.PubMedPubMedCentralCrossRefGoogle Scholar
  3. Atasoy, A.R., Ciftci, I.H., and Petek, M. 2015. Modifying enzymes related aminoglycoside: analyses of resistant Acinetobacter isolates. Int. J. Clin. Exp. Med. 8, 2874–2880.PubMedPubMedCentralGoogle Scholar
  4. Aydemir, H., Akduman, D., Piskin, N., Comert, F., Horuz, E., Terzi, A., Kokturk, F., Ornek, T., and Celebi, G. 2013. Colistin vs. the combination of colistin and rifampicin for the treatment of carbapenem-resistant Acinetobacter baumannii ventilator-associated pneumonia. Epidemiol. Infect. 141, 1214–1222.PubMedCrossRefGoogle Scholar
  5. Azizi, O., Shakibaie, M.R., Badmasti, F., Modarresi, F., Ramazanzadeh, R., Mansouri, S., and Shahcheraghi, F. 2016. Class 1 integrons in non-clonal multidrug-resistant Acinetobacter baumannii from Iran, description of the new blaIMP-55 allele in In1243. J. Med. Microbiol. 65, 928–936.PubMedCrossRefGoogle Scholar
  6. Bae, S., Kim, M.C., Park, S.J., Kim, H.S., Sung, H., Kim, M.N., Kim, S.H., Lee, S.O., Choi, S.H., Woo, J.H., et al. 2016. In vitro synergistic activity of antimicrobial agents in combination against clinical isolates of colistin-resistant Acinetobacter baumannii. Antimicrob. Agents Chemother. 60, 6774–6779.PubMedPubMedCentralCrossRefGoogle Scholar
  7. Bajpai, T., Pandey, M., Varma, M., and Bhatambare, G.S. 2017. Prevalence of TEM, SHV, and CTX-M Beta-Lactamase genes in the urinary isolates of a tertiary care hospital. Avicenna. J. Med. 7, 12–16.PubMedPubMedCentralCrossRefGoogle Scholar
  8. Batirel, A., Balkan, Ii, Karabay, O., Agalar, C., Akalin, S., Alici, O., Alp, E., Altay, F.A., Altin, N., Arslan, F., et al. 2014. 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. 33, 1311–1322.PubMedCrossRefGoogle Scholar
  9. Beceiro, A., Tomás, M., and Bou, G. 2013. Antimicrobial resistance and virulence: a successful or deleterious association in the bacterial world? Clin. Microbiol. Rev. 26, 185–230.PubMedPubMedCentralCrossRefGoogle Scholar
  10. Benjamin, A. and Sebastian, G.B. 2014. OXA β-lactamases. Clin. Microbiol. Rev. 27, 241–263.CrossRefGoogle Scholar
  11. Blair, J.M., Webber, M.A., Baylay, A.J., Ogbolu, D.O., and Piddock, L.J. 2015. Molecular mechanisms of antibiotic resistance. Nat. Rev. Microbiol. 13, 42–51.PubMedCrossRefGoogle Scholar
  12. Boluki, E., Kazemian, H., Peeridogaheh, H., Alikhani, M.Y., Shahabi, S., Beytollahi, L., and Ghorbanzadeh, R. 2017. Antimicrobial activity of photodynamic therapy in combination with colistin against a pan-drug resistant Acinetobacter baumannii isolated from burn patient. Photodiagnosis Photodyn. Ther. 18, 1–5.PubMedCrossRefGoogle Scholar
  13. Boo, T.W. and Crowley, B. 2009. Detection of blaOXA-58 and blaOXA-23-like genes in carbapenem-susceptible Acinetobacter clinical isolates: should we be concerned? J. Med. Microbiol. 58, 839–841.PubMedCrossRefGoogle Scholar
  14. Bowers, D.R., Cao, H., Zhou, J., Ledesma, K.R., Sun, D., Lomovskaya, O., and Tam, V.H. 2015. Assessment of minocycline and polymyxin B combination against Acinetobacter baumannii. Antimicrob. Agents Chemother. 59, 2720–2725.PubMedPubMedCentralCrossRefGoogle Scholar
  15. Briers, Y., Walmagh, M., Van Puyenbroeck, V., Cornelissen, A., Cenens, W., Aertsen, A., Oliveira, H., Azeredo, J., Verween, G., Pirnay, J.P., et al. 2014. Engineered endolysin-based “Artilysins” to combat multidrug-resistant Gram-negative pathogens. MBio 5, E01379–14.CrossRefGoogle Scholar
  16. Cabrera, C., Artacho, R., and Gimenez, R. 2006. Beneficial effects of green tea—a review. J. Am. Coll. Nutr. 25, 79–99.PubMedCrossRefGoogle Scholar
  17. Cai, X., Yang, Z., Dai, J., Chen, K., Zhang, L., Ni, W., Wei, C., and Cui, J. 2017. Pharmacodynamics of tigecycline alone and in combination with colistin against clinical isolates of multidrug-resistant Acinetobacter baumannii in an in vitro pharmacodynamic model. Int. J. Antimicrob. Agents 49, 609–616.PubMedCrossRefGoogle Scholar
  18. Chaib, F., Allali, H., Bennaceur, M., and Flamini, G. 2017. Chemical composition and antimicrobial activity of essential oils from the aerial parts of Asteriscus graveolens (FORSSK.) LESS. and Pulicaria incisa (LAM.) DC.: Two asteraceae herbs growing wild in the hoggar. Chem. Biodivers. 14, e1700092.CrossRefGoogle Scholar
  19. Chatterjee, S., Datta, S., Roy, S., Ramanan, L., Saha, A., and Viswanathan, R. 2016. Carbapenem resistance in Acinetobacter baumannii and other Acinetobacter spp. causing neonatal sepsis: focus on NDM-1 and its linkage to ISAba125. Front. Microbiol. 7, 1126.PubMedPubMedCentralCrossRefGoogle Scholar
  20. Chau, S.L., Chu, Y.W., and Houang, E.T. 2004. Novel resistance nodulation-cell division efflux system AdeDE in Acinetobacter genomic DNA group 3. Antimicrob. Agents Chemother. 48, 4054–4055.PubMedPubMedCentralCrossRefGoogle Scholar
  21. Chin, C.Y., Gregg, K.A., Napier, B.A., Ernst, R.K., and Weiss, D.S. 2015. A PmrB-regulated deacetylase required for lipid a modification and polymyxin resistance in Acinetobacter baumannii. Antimicrob. Agents Chemother. 59, 7911–7914.PubMedPubMedCentralCrossRefGoogle Scholar
  22. Choi, A.H., Slamti, L., Avci, F.Y., Pier, G.B., and Maira-Litrán, T. 2009. The pgaABCD locus of Acinetobacter baumannii encodes the production of poly-beta-1-6-N-acetylglucosamine, which is critical for biofilm formation. J. Bacteriol. 191, 5953–5963.PubMedPubMedCentralCrossRefGoogle Scholar
  23. Chu, Y.W., Chau, S.L., and Houang, E.T. 2006. Presence of active efflux systems AdeABC, AdeDE and AdeXYZ in different Acinetobacter genomic DNA groups. J. Med. Microbiol. 55, 477–478.PubMedCrossRefGoogle Scholar
  24. Chu, H., Zhao, L., Wang, M., Liu, Y., Gui, T., and Zhang, J. 2013. Sulbactam-based therapy for Acinetobacter baumannii infection: a systematic review and meta-analysis. Braz. J. Infect. Dis. 17, 389–394.PubMedCrossRefGoogle Scholar
  25. Chusri, S., Na-Phatthalung, P., Siriyong, T., Paosen, S., and Voravuthikunchai, S.P. 2014a. Holarrhena antidysenterica as a resistance modifying agent against Acinetobacter baumannii: Its effects on bacterial outer membrane permeability and efflux pumps. Microbiol. Res. 169, 417–424.PubMedCrossRefGoogle Scholar
  26. Chusri, S., Siriyong, T., Na-Phatthalung, P., and Voravuthikunchai, S.P. 2014b. Synergistic effects of ethnomedicinal plants of Apocynaceae family and antibiotics against clinical isolates of Acinetobacter baumannii. Asian Pac. J. Trop. Med. 7, 456–461.PubMedCrossRefGoogle Scholar
  27. Coyne, S., Courvalin, P., and Périchon, B. 2011. Efflux-mediated antibiotic resistance in Acinetobacter spp. Antimicrob. Agents Chemother. 55, 947–953.CrossRefGoogle Scholar
  28. Coyne, S., Rosenfeld, N., Lambert, T., Courvalin, P., and Périchon, B. 2010. Overexpression of resistance-nodulation-cell division pump AdeFGH confers multidrug resistance in Acinetobacter baumannii. Antimicrob. Agents Chemother. 54, 4389–4393.PubMedPubMedCentralCrossRefGoogle Scholar
  29. Dai, T., Huang, Y.Y., Sharma, S.K., Hashmi, J.T., Kurup, D.B., and Hamblin, M.R. 2010. Topical antimicrobials for burn wound infections. Recent Pat. Antiinfect. Drug Discov. 5, 124–151.PubMedPubMedCentralCrossRefGoogle Scholar
  30. Damier-Piolle, L., Magnet, S., Brémont, S., Lambert, T., and Courvalin, P. 2008. AdeIJK, a resistance-nodulation-cell division pump effluxing multiple antibiotics in Acinetobacter baumannii. Antimicrob. Agents Chemother. 52, 557–562.PubMedCrossRefGoogle Scholar
  31. Dinc, G., Demiraslan, H., Elmali, F., Ahmed, S.S., Alp, E., and Doganay, M. 2015. Antimicrobial efficacy of doripenem and its combinations with sulbactam, amikacin, colistin, tigecycline in experimental sepsis of carbapenem-resistant Acinetobacter baumannii. New Microbiol. 38, 67–73.PubMedGoogle Scholar
  32. Dinc, G., Demiraslan, H., Elmali, F., Ahmed, S.S., Metan, G., Alp, E., and Doganay, M. 2013. Efficacy of sulbactam and its combination with imipenem, colistin and tigecycline in an experimental model of carbapenem-resistant Acinetobacter baumannii sepsis. Chemotherapy 59, 325–329.PubMedCrossRefGoogle Scholar
  33. Djeribi, R., Bouchloukh, W., Jouenne, T., and Menaa, B. 2012. Characterization of bacterial biofilms formed on urinary catheters. Am. J. Infect. Control. 40, 854–859.PubMedCrossRefGoogle Scholar
  34. Doi, Y., Wachino, J., Yamane, K., Shibata, N., Yagi, T., Shibayama, K., Kato, H., and Arakawa, Y. 2004. Spread of novel aminoglycoside resistance gene aac(6′)-Iad among Acinetobacter clinical isolates in Japan. Antimicrob. Agents Chemother. 48, 2075–2080.PubMedPubMedCentralCrossRefGoogle Scholar
  35. Duarte, A., Ferreira, S., Silva, F., and Domingues, F.C. 2012. Synergistic activity of coriander oil and conventional antibiotics against Acinetobacter baumannii. Phytomedicine 19, 236–238.PubMedCrossRefGoogle Scholar
  36. Durante-Mangoni, E., Signoriello, G., Andini, R., Mattei, A., De Cristoforo, M., Murino, P., Bassetti, M., Malacarne, P., Petrosillo, N., Galdieri, N., 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, 349–358.PubMedCrossRefGoogle Scholar
  37. Dwyer, D.J., Kohanski, M.A., and Collins, J.J. 2009. Role of reactive oxygen species in antibiotic action and resistance. Curr. Opin. Microbiol. 12, 482–489.PubMedPubMedCentralCrossRefGoogle Scholar
  38. Falagas, M.E., Rafailidis, P.I., Ioannidou, E., Alexiou, V.G., Matthaiou, D.K., Karageorgopoulos, D.E., Kapaskelis, A., Nikita, D., and Michalopoulos, A. 2010. Colistin therapy for microbiologically documented multidrug-resistant Gram-negative bacterial infections: a retrospective cohort study of 258 patients. Int. J. Antimicrob. Agents 35, 194–199.PubMedCrossRefGoogle Scholar
  39. Fan, B., Guan, J., Wang, X., and Cong, Y. 2016. Activity of colistin in combination with meropenem, tigecycline, fosfomycin, fusidic acid, rifampin or sulbactam against extensively drug-resistant Acinetobacter baumannii in a murine thigh-infection model. PLoS One 11, e0157757.Google Scholar
  40. Farajnia, S., Azhari, F., Alikhani, M.Y., Hosseini, M.K., Peymani, A., and Sohrabi, N. 2013. Prevalence of PER and VEB type extended spectrum betalactamases among multidrug resistant Acinetobacter baumannii isolates in North-West of Iran. Iran J. Basic Med. Sci. 16, 751–755.PubMedPubMedCentralGoogle Scholar
  41. Fournier, P.E., Vallenet, D., Barbe, V., Audic, S., Ogata, H., Poirel, L., Richet, H., Robert, C., Mangenot, S., Abergel, C., et al. 2006. Comparative genomics of multidrug resistance in Acinetobacter baumannii. PLoS Genet. 2, e7.CrossRefGoogle Scholar
  42. Gales, A.C., Jones, R.N., and Sader, H.S. 2006. Global assessment of the antimicrobial activity of polymyxin B against 54 731 clinical isolates of Gram-negative bacilli: report from the SENTRY antimicrobial surveillance programme (2001-2004). Clin. Microbiol. Infect. 12, 315–321.PubMedCrossRefGoogle Scholar
  43. Gaze, W.H., Abdouslam, N., Hawkey, P.M., and Wellington, E.M.H. 2005. Incidence of class 1 integrons in a quaternary ammonium compound-polluted environment. Antimicrob. Agents Chemother. 49, 1802–1807.PubMedPubMedCentralCrossRefGoogle Scholar
  44. Geisinger, E. and Isberg, R.R. 2015. Antibiotic modulation of capsular exopolysaccharide and virulence in Acinetobacter baumannii. PLoS Pathog. 11, e1004691.CrossRefGoogle Scholar
  45. Ghasemi, F. and Jalal, R. 2016. Antimicrobial action of zinc oxide nanoparticles in combination with ciprofloxacin and ceftazidime against multidrug-resistant Acinetobacter baumannii. J. Glob. Antimicrob. Resist. 6, 118–122.PubMedCrossRefGoogle Scholar
  46. Ghosh, S., Patil, S., Ahire, M., Kitture, R., Kale, S., Pardesi, K., Cameotra, S.S., Bellare, J., Dhavale, D.D., Jabgunde, A., et al. 2012. Synthesis of silver nanoparticles using Dioscorea bulbifera tuber extract and evaluation of its synergistic potential in combination with antimicrobial agents. Int. J. Nanomedicine 7, 483–496.PubMedPubMedCentralGoogle Scholar
  47. Gopal, R., Kim, Y.G., Lee, J.H., Lee, S.K., Chae, J.D., Son, B.K., Seo, C.H., and Park, Y. 2014. Synergistic effects and antibiofilm properties of chimeric peptides against multidrug-resistant Acinetobacter baumannii strains. Antimicrob. Agents Chemother. 58, 1622–1629.PubMedPubMedCentralCrossRefGoogle Scholar
  48. Gordon, N.C., Png, K., and Wareham, D.W. 2010. Potent synergy and sustained bactericidal activity of a vancomycin-colistin combination versus multidrug-resistant strains of Acinetobacter baumannii. Antimicrob. Agents Chemother. 54, 5316–5322.PubMedPubMedCentralCrossRefGoogle Scholar
  49. Guclu, E., Genc, H., Zengin, M., and Karabay, O. 2014. Antibacterial activity of Lythrum salicaria against multidrug-resistant Acinetobacter baumannii and Pseudomonas aeruginosa. Annu. Res. Rev. Biol. 4, 1099–1105.CrossRefGoogle Scholar
  50. Hagihara, M., Housman, S.T., Nicolau, D.P., and Kuti, J.L. 2014. In vitro pharmacodynamics of polymyxin B and tigecycline alone and in combination against carbapenem-resistant Acinetobacter baumannii. Antimicrob. Agents Chemother. 58, 874–879.PubMedPubMedCentralCrossRefGoogle Scholar
  51. Hassan, K.A., Liu, Q., Henderson, P.J., and Paulsen, I.T. 2015. Homologs of the Acinetobacter baumannii AceI transporter represent a new family of bacterial multidrug efflux systems. MBio 6, E01982–14.CrossRefGoogle Scholar
  52. He, S., He, H., Chen, Y., Chen, Y., Wang, W., and Yu, D. 2015. In vitro and in vivo analysis of antimicrobial agents alone and in combination against multi-drug resistant Acinetobacter baumannii. Front. Microbiol. 6, 507.PubMedPubMedCentralGoogle Scholar
  53. Heo, A., Jang, H.J., Sung, J.S., and Park, W. 2014. Global transcriptome and physiological responses of Acinetobacter oleivorans DR1 exposed to distinct classes of antibiotics. PLoS One 9, e110215.CrossRefGoogle Scholar
  54. Higgins, P.G., Dammhayn, C., Hackel, M., and Seifert, H. 2010. Global spread of carbapenem-resistant Acinetobacter baumannii. J. Antimicrob. Chemother. 65, 233–238.PubMedCrossRefGoogle Scholar
  55. Hood, M.I., Jacobs, A.C., Sayood, K., Dunman, P.M., and Skaar, E.P. 2010. Acinetobacter baumannii increases tolerance to antibiotics in response to monovalent cations. Antimicrob. Agents Chemother. 54, 1029–1041.PubMedCrossRefGoogle Scholar
  56. Hornsey, M., Phee, L., Stubbings, W., and Wareham, D.W. 2013. In vitro activity of the novel monosulfactam BAL30072 alone and in combination with meropenem versus a diverse collection of important Gram-negative pathogens. Int. J. Antimicrob. Agents 42, 343–346.PubMedCrossRefGoogle Scholar
  57. Hornsey, M. and Wareham, D.W. 2011. in vivo efficacy of glycopeptide-colistin combination therapies in a Galleria mellonella model of Acinetobacter baumannii infection. Antimicrob. Agents Chemother. 55, 3534–3537.PubMedPubMedCentralCrossRefGoogle Scholar
  58. Huang, L., Dai, T., Xuan, Y., Tegos, G.P., and Hamblin, M.R. 2011. Synergistic combination of chitosan acetate with nanoparticle silver as a topical antimicrobial: efficacy against bacterial burn infections. Antimicrob. Agents Chemother. 55, 3432–3438.PubMedPubMedCentralCrossRefGoogle Scholar
  59. Jacobs, A.C., Sayood, K., Olmsted, S.B., Blanchard, C.E., Hinrichs, S., Russell, D., and Dunman, P.M. 2012. Characterization of the Acinetobacter baumannii growth phase-dependent and serum responsive transcriptomes. FEMS Immunol. Med. Microbiol. 64, 403–412.PubMedCrossRefGoogle Scholar
  60. Jang, I.A., Kim, J., and Park, W. 2016. Endogenous hydrogen peroxide increases biofilm formation by inducing exopolysaccharide production in Acinetobacter oleivorans DR1. Sci. Rep. 6, 21121.PubMedPubMedCentralCrossRefGoogle Scholar
  61. Jiang, X., Yu, T., Jiang, X., Zhang, W., Zhang, L., and Ma, J. 2014. Emergence of plasmid-mediated quinolone resistance genes in clinical isolates of Acinetobacter baumannii and Pseudomonas aeruginosa in Henan, China. Diagn. Microbiol. Infect. Dis. 79, 381–383.PubMedCrossRefGoogle Scholar
  62. Jung, J. and Park, W. 2015. Acinetobacter species as model microorganisms in environmental microbiology: current state and perspectives. Appl. Microbiol. Biotechnol. 99, 2533–2548.PubMedCrossRefGoogle Scholar
  63. Karah, N., Dwibedi, C.K., Sjostrom, K., Edquist, P., Johansson, A., Wai, S.N., and Uhlin, B.E. 2016. Novel aminoglycoside resistance transposons and transposon-derived circular forms detected in carbapenem-resistant Acinetobacter baumannii clinical isolates. Antimicrob. Agents Chemother. 60, 1801–1818.PubMedPubMedCentralCrossRefGoogle Scholar
  64. Karthikeyan, K., Thirunarayan, M.A., and Krishnan, P. 2010. Coexistence of blaOXA-23 with blaNDM-1 and armA in clinical isolates of Acinetobacter baumannii from India. J. Antimicrob. Chemother. 65, 2253–2254.PubMedCrossRefGoogle Scholar
  65. Kim, J., Noh, J., and Park, W. 2013. Insight into norfloxacin resistance of Acinetobacter oleivorans DR1: target gene mutation, persister, and RNA-Seq analyses. J. Microbiol. Biotechnol. 23, 1293–1303.PubMedCrossRefGoogle Scholar
  66. Knezevic, P., Aleksic, V., Simin, N., Svircev, E., Petrovic, A., and Mimica-Dukic, N. 2016. Antimicrobial activity of Eucalyptus camaldulensis essential oils and their interactions with conventional antimicrobial agents against multi-drug resistant Acinetobacter baumannii. J. Ethnopharmacol. 178, 125–136.PubMedCrossRefGoogle Scholar
  67. Lee, S., Razqan, G.S., and Kwon, D.H. 2017. Antibacterial activity of epigallocatechin-3-gallate (EGCG) and its synergism with betalactam antibiotics sensitizing carbapenem-associated multidrug resistant clinical isolates of Acinetobacter baumannii. Phytomedicine 24, 49–55.PubMedCrossRefGoogle Scholar
  68. Lee, Y.T., Tsao, S.M., and Hsueh, P.R. 2013. Clinical outcomes of tigecycline alone or in combination with other antimicrobial agents for the treatment of patients with healthcare-associated multidrug-resistant Acinetobacter baumannii infections. Eur. J. Clin. Microbiol. Infect. Dis. 32, 1211–1220.PubMedCrossRefGoogle Scholar
  69. Lenhard, J.R., Thamlikitkul, V., Silveira, F.P., Garonzik, S.M., Tao, X., Forrest, A., Soo Shin, B., Kaye, K.S., Bulitta, J.B., Nation, R.L., et al. 2017. Polymyxin-resistant, carbapenem-resistant Acinetobacter baumannii is eradicated by a triple combination of agents that lack individual activity. J. Antimicrob. Chemother. 72, 1415–1420.PubMedCrossRefGoogle Scholar
  70. Li, S., Wu, C., Zhao, X., Jiang, H., Yan, H., and Wang, X. 2013. Synergistic antibacterial activity of new isomeric carborane derivatives through combination with nanoscaled titania. J. Biomed. Nanotechnol. 9, 393–402.PubMedCrossRefGoogle Scholar
  71. Li, J., Yang, X., Chen, L., Duan, X., and Jiang, Z. 2017. In vitro activity of various antibiotics in combination with tigecycline against Acinetobacter baumannii: A systematic review and meta-analysis. Microb. Drug. Resist. DOI: 10.1089/mdr.2016.0279.Google Scholar
  72. Liang, W., Liu, X.F., Huang, J., Zhu, D.M., Li, J., and 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.PubMedPubMedCentralCrossRefGoogle Scholar
  73. Liao, Y.T., Kuo, S.C., Chiang, M.H., Lee, Y.T., Sung, W.C., Chen, Y.H., Chen, T.L., and Fung, C.P. 2015. Acinetobacter baumannii extracellular OXA-58 is primarily and selectively released via outer membrane vesicles after Sec-dependent periplasmic translocation. Antimicrob. Agents Chemother. 59, 7346–7354.PubMedPubMedCentralCrossRefGoogle Scholar
  74. Lim, T.P., Tan, T.Y., Lee, W., Sasikala, S., Tan, T.T., Hsu, L.Y., and Kwa, A.L. 2011. In-vitro activity of polymyxin B, rifampicin, tigecycline alone and in combination against carbapenem-resistant Acinetobacter baumannii in Singapore. PLoS One 6, e18485.CrossRefGoogle Scholar
  75. Lin, M.F., Lin, Y.Y., and Lan, C.Y. 2017. Contribution of EmrAB efflux pumps to colistin resistance in Acinetobacter baumannii. J. Microbiol. 55, 130–136.PubMedCrossRefGoogle Scholar
  76. Lutsar, I., Telling, K., and Metsvaht, T. 2014. Treatment option for sepsis in children in the era of antibiotic resistance. Expert Rev. Anti. Infect. Ther. 12, 1237–1252.PubMedCrossRefGoogle Scholar
  77. Maifiah, M.H., Creek, D.J., Nation, R.L., Forrest, A., Tsuji, B.T., Velkov, T., and Li, J. 2017. Untargeted metabolomics analysis reveals key pathways responsible for the synergistic killing of colistin and doripenem combination against Acinetobacter baumannii. Sci. Rep. 7, 45527.PubMedPubMedCentralCrossRefGoogle Scholar
  78. Malone, L. and Kwon, D.H. 2013. Carbapenem-associated multidrug-resistant Acinetobacter baumannii are sensitised by aztreonam in combination with polyamines. Int. J. Antimicrob. Agents 41, 70–74.PubMedCrossRefGoogle Scholar
  79. Muller, G.L., Tuttobene, M., Altilio, M., Martinez Amezaga, M., Nguyen, M., Cribb, P., Cybulski, L.E., Ramírez, M.S., Altabe, S., and Mussi, M.A. 2017. Light modulates metabolic pathways and other novel physiological traits in the human pathogen Acinetobacter baumannii. J. Bacteriol. 199, E00011–17.CrossRefGoogle Scholar
  80. Mussi, M.A., Relling, V.M., Limansky, A.S., and Viale, A.M. 2007. CarO, an Acinetobacter baumannii outer membrane protein involved in carbapenem resistance, is essential for L-ornithine uptake. FEBS Lett. 581, 5573–5578.PubMedCrossRefGoogle Scholar
  81. Naas, T., Cuzon, G., Bogaerts, P., Glupczynski, Y., and Nordmann, P. 2011. Evaluation of a DNA microarray (Check-MDR CT102) for rapid detection of TEM, SHV, and CTX-M extended-spectrum β-lactamases and of KPC, OXA-48, VIM, IMP, and NDM-1 carbapenemases. J. Clin. Microbiol. 49, 1608–1613.PubMedPubMedCentralCrossRefGoogle Scholar
  82. Nait Chabane, Y., Marti, S., Rihouey, C., Alexandre, S., Hardouin, J., Lesouhaitier, O., Vila, J., Kaplan, J.B., Jouenne, T., and Dé, E. 2014. Characterisation of pellicles formed by Acinetobacter baumannii at the air-liquid interface. PLoS One 9, e111660.CrossRefGoogle Scholar
  83. Nemec, A., Krizova, L., Maixnerova, M., Van Der Reijden, T.J., Deschaght, P., Passet, V., Vaneechoutte, M., Brisse, S., and Dijkshoorn, L. 2011. Genotypic and phenotypic characterization of the Acinetobacter calcoaceticus-Acinetobacter baumannii complex with the proposal of Acinetobacter pittii sp. nov. (formerly Acinetobacter genomic species 3) and Acinetobacter nosocomialis sp. nov. (formerly Acinetobacter genomic species 13TU). Res. Microbiol. 162, 393–404.PubMedCrossRefGoogle Scholar
  84. Nepka, M., Perivolioti, E., Kraniotaki, E., Politi, L., Tsakris, A., and Pournaras, S. 2016. In vitro bactericidal activity of trimethoprimsulfamethoxazole alone and in combination with colistin against carbapenem-resistant Acinetobacter baumannii clinical isolates. Antimicrob. Agents Chemother. 60, 6903–6906.PubMedPubMedCentralCrossRefGoogle Scholar
  85. Nikaido, H. 2003. Molecular basis of bacterial outer membrane permeability revisited. Microbiol. Mol. Biol. Rev. 67, 593–656.PubMedPubMedCentralCrossRefGoogle Scholar
  86. Nikaido, H. 2009. Multidrug resistance in bacteria. Annu. Rev. Biochem. 78, 119–146.PubMedPubMedCentralCrossRefGoogle Scholar
  87. Obara, M. and Nakae, T. 1991. Mechanisms of resistance to betalactam antibiotics in Acinetobacter calcoaceticus. J. Antimicrob. Chemother. 28, 791–800.PubMedCrossRefGoogle Scholar
  88. Pachon-Ibanez, M.E., Docobo-Perez, F., Lopez-Rojas, R., Dominguez-Herrera, J., Jimenez-Mejias, M.E., Garcia-Curiel, A., Pichardo, C., Jiménez, L., and Pachón, J. 2010. Efficacy of rifampin and its combinations with imipenem, sulbactam, and colistin in experimental models of infection caused by imipenem-resistant Acinetobacter baumannii. Antimicrob. Agents Chemother. 54, 1165–1172.PubMedPubMedCentralCrossRefGoogle Scholar
  89. Pagano, M., Martins, A.F., and Barth, A.L. 2016. Mobile genetic elements related to carbapenem resistance in Acinetobacter baumannii. Braz. J. Microbiol. 47, 785–792.PubMedPubMedCentralCrossRefGoogle Scholar
  90. Pankuch, G.A., Seifert, H., and Appelbaum, P.C. 2010. Activity of doripenem with and without levofloxacin, amikacin, and colistin against Pseudomonas aeruginosa and Acinetobacter baumannii. Diagn. Microbiol. Infect. Dis. 67, 191–197.PubMedCrossRefGoogle Scholar
  91. Petrosillo, N., Giannella, M., Antonelli, M., Antonini, M., Barsic, B., Belancic, L., Inkaya, A.C., De Pascale, G., Grilli, E., Tumbarello, M., et al. 2014. Clinical experience of colistin-glycopeptide combination in critically ill patients infected with Gram-negative bacteria. Antimicrob. Agents Chemother. 58, 851–858.PubMedPubMedCentralCrossRefGoogle Scholar
  92. Poirel, L., Bonnin, R.A., and Nordmann, P. 2011. Genetic basis of antibiotic resistance in pathogenic Acinetobacter species. IUBMB Life 63, 1061–1067.PubMedCrossRefGoogle Scholar
  93. Post, V., White, P.A., and Hall, R.M. 2010. Evolution of AbaR-type genomic resistance islands in multiply antibiotic-resistant Acinetobacter baumannii. J. Antimicrob. Chemother. 65, 1162–1170.PubMedCrossRefGoogle Scholar
  94. Rafii, F., Sutherland, J.B., and Cerniglia, C.E. 2008. Effects of treatment with antimicrobial agents on the human colonic microflora. Ther. Clin. Risk Manag. 4, 1343–1358.PubMedPubMedCentralCrossRefGoogle Scholar
  95. Rajamohan, G., Srinivasan, V.B., and Gebreyes, W.A. 2010. Molecular and functional characterization of a novel efflux pump, AmvA, mediating antimicrobial and disinfectant resistance in Acinetobacter baumannii. J. Antimicrob. Chemother. 65, 1919–1925.PubMedCrossRefGoogle Scholar
  96. Ramírez, M.S., Traglia, G.M., Pérez, J.F., Müller, G.L., Martínez, M.F., Golic, A.E., and Mussi, M.A. 2015. White and blue light induce reduction in susceptibility to minocycline and tigecycline in Acinetobacter spp. and other bacteria of clinical importance. J. Med. Microbiol. 64, 525–537.PubMedCrossRefGoogle Scholar
  97. Ribera, A., Roca, I., Ruiz, J., Gibert, I., and Vila, J. 2003. Partial characterization of a transposon containing the tet(A) determinant in a clinical isolate of Acinetobacter baumannii. J. Antimicrob. Chemother. 52, 477–480.PubMedCrossRefGoogle Scholar
  98. Roca, I., Espinal, P., Vila-Farrés, X., and Vila, J. 2012. The Acinetobacter baumannii oxymoron: commensal hospital dweller turned pan-drug-resistant menace. Front. Microbiol. 3, 148.PubMedPubMedCentralCrossRefGoogle Scholar
  99. Roca, I., Marti, S., Espinal, P., Martínez, P., Gibert, I., and Vila, J. 2009. CraA, a major facilitator superfamily efflux pump associated with chloramphenicol resistance in Acinetobacter baumannii. Antimicrob. Agents Chemother. 53, 4013–4014.PubMedPubMedCentralCrossRefGoogle Scholar
  100. Rodríguez, C.H., Nastro, M., Vay, C., and Famiglietti, A. 2015. In vitro activity of minocycline alone or in combination in multidrug-resistant Acinetobacter baumannii isolates. J. Med. Microbiol. 64, 1196–1200.PubMedCrossRefGoogle Scholar
  101. Rodríguez-Martínez, J.M., Nordmann, P., Ronco, E., and Poirel, L. 2010. Extended-spectrum cephalosporinase in Acinetobacter baumannii. Antimicrob. Agents Chemother. 54, 3484–3488.PubMedPubMedCentralCrossRefGoogle Scholar
  102. Rosato, A., Piarulli, M., Corbo, F., Muraglia, M., Carone, A., Vitali, M.E., and Vitali, C. 2010. In vitro synergistic antibacterial action of certain combinations of gentamicin and essential oils. Curr. Med. Chem. 17, 3289–3295.PubMedCrossRefGoogle Scholar
  103. Scandorieiro, S., De Camargo, L.C., Lancheros, C.A., Yamada-Ogatta, S.F., Nakamura, C.V., De Oliveira, A.G., Andrade, C.G., Duran, N., Nakazato, G., and Kobayashi, R.K. 2016. Synergistic and additive effect of oregano essential oil and biological silver nanoparticles against multidrug-resistant bacterial strains. Front. Microbiol. 7, 760.PubMedPubMedCentralCrossRefGoogle Scholar
  104. Schwarz, S., Kehrenberg, C., Doublet, B., and Cloeckaert, A. 2004. Molecular basis of bacterial resistance to chloramphenicol and florfenicol. FEMS Microbiol. Rev. 28, 519–542.PubMedCrossRefGoogle Scholar
  105. Shen, G.H., Wang, J.L., Wen, F.S., Chang, K.M., Kuo, C.F., Lin, C.H., and Luo, H.R., Hung, C.H. 2012. Isolation and characterization of φkm18p, a novel lytic phage with therapeutic potential against extensively drug resistant Acinetobacter baumannii. PLoS One 7, e46537.CrossRefGoogle Scholar
  106. Shields, R.K., Clancy, C.J., Gillis, L.M., Kwak, E.J., Silveira, F.P., Massih, R.C., and Eschenauer, G.A., Potoski, B.A., Nguyen, M.H. 2012. Epidemiology, clinical characteristics and outcomes of extensively drug-resistant Acinetobacter baumannii infections among solid organ transplant recipients. PLoS One 7, e52349.CrossRefGoogle Scholar
  107. Shields, R.K., Kwak, E.J., Potoski, B.A., Doi, Y., Adams-Haduch, J.M., Silviera, F.P., Toyoda, Y., Pilewski, J.M., Crespo, M., Pasculle, A.W., et al. 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.PubMedCrossRefGoogle Scholar
  108. Shin, B. and Park, W. 2015. Synergistic effect of oleanolic acid on aminoglycoside antibiotics against Acinetobacter baumannii. PLoS One 10, e0137751.Google Scholar
  109. Srinivasan, V.B., Rajamohan, G., and Gebreyes, W.A. 2009. Role of AbeS, a novel efflux pump of the SMR family of transporters, in resistance to antimicrobial agents in Acinetobacter baumannii. Antimicrob. Agents Chemother. 53, 5312–5316.PubMedPubMedCentralCrossRefGoogle Scholar
  110. Stogios, P.J., Kuhn, M.L., Evdokimova, E., Law, M., Courvalin, P., and Savchenko, A. 2017. Structural and biochemical characterization of Acinetobacter spp. aminoglycoside acetyltransferases highlights functional and evolutionary variation among antibiotic resistance enzymes. ACS Infect. Dis. 3, 132–143.PubMedCrossRefGoogle Scholar
  111. Su, X.Z., Chen, J., Mizushima, T., Kuroda, T., and Tsuchiya, T. 2005. AbeM, an H+-coupled Acinetobacter baumannii multidrug efflux pump belonging to the MATE family of transporters. Antimicrob. Agents Chemother. 49, 4362–4364.PubMedPubMedCentralCrossRefGoogle Scholar
  112. Sugawara, E. and Nikaido, H. 2012. OmpA is the principal nonspecific slow porin of Acinetobacter baumannii. J. Bacteriol. 194, 4089–4096.PubMedPubMedCentralCrossRefGoogle Scholar
  113. Sun, Y., Wang, L., Li, J., Zhao, C., Zhao, J., Liu, M., Wang, S., Lu, C., Shang, G., Jia, Y., et al. 2014. Synergistic efficacy of meropenem and rifampicin in a murine model of sepsis caused by multidrug-resistant Acinetobacter baumannii. Eur. J. Pharmacol. 729, 116–122.PubMedCrossRefGoogle Scholar
  114. Tangden, T., Karvanen, M., Friberg, L.E., Odenholt, I., and Cars, O. 2017. Assessment of early combination effects of colistin and meropenem against Pseudomonas aeruginosa and Acinetobacter baumannii in dynamic time-kill experiments. Infect. Dis. (Lond.) 49, 521–527.CrossRefGoogle Scholar
  115. Temocin, F., Erdinc, F.S., Tulek, N., Demirelli, M., Ertem, G., Kinikli, S., and Koksal, E. 2015. Synergistic effects of sulbactam in multidrug-resistant Acinetobacter baumannii. Braz. J. Microbiol. 46, 1119–1124.PubMedPubMedCentralCrossRefGoogle Scholar
  116. Thummeepak, R., Kitti, T., Kunthalert, D., and Sitthisak, S. 2016. Enhanced Antibacterial Activity of Acinetobacter baumannii bacteriophage OABP-01 endolysin (LysABP-01) in combination with colistin. Front. Microbiol. 7, 1402.PubMedPubMedCentralCrossRefGoogle Scholar
  117. Tian, G.B., Adams-Haduch, J.M., Taracila, M., Bonomo, R.A., Wang, H.N., and Doi, Y. 2011. Extended-spectrum AmpC cephalosporinase in Acinetobacter baumannii: ADC-56 confers resistance to cefepime. Antimicrob. Agents Chemother. 55, 4922–4925.PubMedPubMedCentralCrossRefGoogle Scholar
  118. Timurkaynak, F., Can, F., Azap, O.K., Demirbilek, M., Arslan, H., and Karaman, S.O. 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.PubMedCrossRefGoogle Scholar
  119. Tiwari, V., Roy, R., and Tiwari, M. 2015. Antimicrobial active herbal compounds against Acinetobacter baumannii and other pathogens. Front. Microbiol. 6, 618.PubMedPubMedCentralCrossRefGoogle Scholar
  120. Tomaras, A.P., Dorsey, C.W., Edelmann, R.E., and Actis, L.A. 2003. Attachment to and biofilm formation on abiotic surfaces by Acinetobacter baumannii: involvement of a novel chaperone-usher pili assembly system. Microbiology 149, 3473–3484.PubMedCrossRefGoogle Scholar
  121. Tran, J.H. and Jacoby, G.A. 2002. Mechanism of plasmid-mediated quinolone resistance. Proc. Natl. Acad. Sci. USA 99, 5638–5642.PubMedPubMedCentralCrossRefGoogle Scholar
  122. Tsai, T., Chien, H.F., Wang, T.H., Huang, C.T., Ker, Y.B., and Chen, C.T. 2011. Chitosan augments photodynamic inactivation of Gram-positive and Gram-negative bacteria. Antimicrob. Agents Chemother. 55, 1883–1890.PubMedPubMedCentralCrossRefGoogle Scholar
  123. Urban, C., Mariano, N., and Rahal, J.J. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  124. Urban, C., Mariano, N., Rahal, J.J., Tay, E., Ponio, C., Koprivnjak, T., and Weiss, J. 2001. Polymyxin B-resistant Acinetobacter baumannii clinical isolate susceptible to recombinant BPI and cecropin P1. Antimicrob. Agents Chemother. 45, 994–995.PubMedPubMedCentralCrossRefGoogle Scholar
  125. Valcourt, C., Saulnier, P., Umerska, A., Zanelli, M.P., Montagu, A., Rossines, E., and Joly Guillou, M.L. 2016. Synergistic interactions between doxycycline and terpenic components of essential oils encapsulated within lipid nanocapsules against Gram negative bacteria. Int. J. Pharm. 498, 23–31.PubMedCrossRefGoogle Scholar
  126. Vila, J., Ruiz, J., Goñi, P., and Jimenez de Anta, T. 1997. Quinoloneresistance mutations in the topoisomerase IV parC gene of Acinetobacter baumannii. J. Antimicrob. Chemother. 39, 757–762.PubMedCrossRefGoogle Scholar
  127. Wan, G., Ruan, L., Yin, Y., Yang, T., Ge, M., and Cheng, X. 2016. Effects of silver nanoparticles in combination with antibiotics on the resistant bacteria Acinetobacter baumannii. Int. J. Nanomedicine 11, 3789–3800.PubMedPubMedCentralCrossRefGoogle Scholar
  128. Weber, B.S., Kinsella, R.L., Harding, C.M., and Feldman, M.F. 2017. The secrets of Acinetobacter secretion. Trends Microbiol. 25, 532–545.PubMedCrossRefGoogle Scholar
  129. Wei, W.J. and Yang, H.F. 2017. Synergy against extensively drugresistant Acinetobacter baumannii in vitro by two old antibiotics: colistin and chloramphenicol. Int. J. Antimicrob. Agents 49, 321–326.PubMedCrossRefGoogle Scholar
  130. Wong, D., Nielsen, T.B., Bonomo, R.A., Pantapalangkoor, P., Luna, B., and Spellberg, B. 2017. Clinical and pathophysiological overview of Acinetobacter infections: a century of challenges. Clin. Microbiol. Rev. 30, 409–447.PubMedGoogle Scholar
  131. Wu, X., Chavez, J.D., Schweppe, D.K., Zheng, C., Weisbrod, C.R., Eng, J.K., Murali, A., Lee, S.A., Ramage, E., Gallagher, L.A., et al. 2016. in vivo protein interaction network analysis reveals porinlocalized antibiotic inactivation in Acinetobacter baumannii strain AB5075. Nat. Commun. 7, 13414.PubMedPubMedCentralCrossRefGoogle Scholar
  132. Yang, Y.S., Lee, Y., Tseng, K.C., Huang, W.C., Chuang, M.F., Kuo, S.C., Lauderdale, T.L., and Chen, T.L. 2016. in vivo and in vitro efficacy of minocycline-based combination therapy for minocycline-resistant acinetobacter baumannii. Antimicrob. Agents Chemother. 60, 4047–4054.PubMedPubMedCentralCrossRefGoogle Scholar
  133. Yilmaz, G.R., Guven, T., Guner, R., Kocak Tufan, Z., Izdes, S., Tasyaran, M.A., and Acikgoz, Z.C. 2015. Colistin alone or combined with sulbactam or carbapenem against A. baumannii in ventilatorassociated pneumonia. J. Infect. Dev. Ctries. 9, 476–485.PubMedCrossRefGoogle Scholar
  134. Yoon, E.J., Balloy, V., Fiette, L., Chignard, M., Courvalin, P., and Grillot-Courvalin, C. 2016. Contribution of the Ade resistancenodulation-cell division-type efflux pumps to fitness and pathogenesis of Acinetobacter baumannii. MBio 7, E00697–16.CrossRefGoogle Scholar
  135. Yoon, E.J., Courvalin, P., and Grillot-Courvalin, C. 2013. RND-type efflux pumps in multidrug-resistant clinical isolates of Acinetobacter baumannii: Major role for AdeABC overexpression and AdeRS mutations. Antimicrob. Agents Chemother. 57, 2989–2995.PubMedPubMedCentralCrossRefGoogle Scholar
  136. Yu, Y.S., Zhou, H., Yang, Q., Chen, Y.G., and Li, L.J. 2007. Widespread occurrence of aminoglycoside resistance due to ArmA methylase in imipenem-resistant Acinetobacter baumannii isolates in China. J. Antimicrob. Chemother. 60, 454–455.PubMedCrossRefGoogle Scholar
  137. Yun, S.H., Choi, C.W., Kwon, S.O., Park, G.W., Cho, K., Kwon, K.H., Kim, J.Y., Yoo, J.S., Lee, J.C., Choi, J.S., et al. 2011. Quantitative proteomic analysis of cell wall and plasma membrane fractions from multidrug-resistant Acinetobacter baumannii. J. Proteome Res. 10, 459–469.PubMedCrossRefGoogle Scholar
  138. Zhang, Y., Chen, F., Sun, E., Ma, R., Qu, C., and Ma, L. 2013. In vitro antibacterial activity of combinations of fosfomycin, minocycline and polymyxin B on pan-drug-resistant Acinetobacter baumannii. Exp. Ther. Med. 5, 1737–1739.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© The Microbiological Society of Korea and Springer-Verlag GmbH Germany 2017

Authors and Affiliations

  1. 1.Laboratory of Molecular Environmental Microbiology, Department of Environmental Science and Ecological EngineeringKorea UniversitySeoulRepublic of Korea

Personalised recommendations