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Drugs

, Volume 74, Issue 12, pp 1315–1333 | Cite as

Treatment Options for Carbapenem-Resistant and Extensively Drug-Resistant Acinetobacter baumannii Infections

  • J. Alexander Viehman
  • M. Hong Nguyen
  • Yohei DoiEmail author
Therapy in Practice

Abstract

Acinetobacter baumannii is a leading cause of healthcare-associated infections worldwide. Because of various intrinsic and acquired mechanisms of resistance, most β-lactam agents are not effective against many strains, and carbapenems have played an important role in therapy. Recent trends show many infections are caused by carbapenem-resistant or even extensively drug-resistant (XDR) strains, for which effective therapy is not well established. Evidence to date suggests that colistin constitutes the backbone of therapy, but the unique pharmacokinetic properties of colistin have led many to suggest the use of combination antimicrobial therapy. However, the combination of agents and dosing regimens that delivers the best clinical efficacy while minimizing toxicity is yet to be defined. Carbapenems, sulbactam, rifampin and tigecycline have been the most studied in the context of combination therapy. Most data regarding therapy for invasive, resistant A. baumannii infections come from uncontrolled case series and retrospective analyses, though some clinical trials have been completed and others are underway. Early institution of appropriate antimicrobial therapy is shown to consistently improve survival of patients with carbapenem-resistant and XDR A. baumannii infection, but the choice of empiric therapy in these infections remains an open question. This review summarizes the most current knowledge regarding the epidemiology, mechanisms of resistance, and treatment considerations of carbapenem-resistant and XDR A. baumannii.

Keywords

Minocycline Colistin Bloodstream Infection Polymyxin Tigecycline 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

This work was supported in part by a research grant from the National Institutes of Health to Y.D. (R01AI104895). Y.D. has received a research grant from Merck and has served on an advisory board for Shionogi. J.A.V. has no potential conflicts of interest. M.H.N. has no potential conflicts of interest.

References

  1. 1.
    Peleg AY, Seifert H, Paterson DL. Acinetobacter baumannii: emergence of a successful pathogen. Clin Microbiol Rev. 2008;21(3):538–82.PubMedCentralPubMedGoogle Scholar
  2. 2.
    Sievert DM, Ricks P, Edwards JR, Schneider A, Patel J, Srinivasan A, et al. Antimicrobial-resistant pathogens associated with healthcare-associated infections: summary of data reported to the National Healthcare Safety Network at the Centers for Disease Control and Prevention, 2009–2010. Infect Control Hosp Epidemiol. 2013;34(1):1–14.PubMedGoogle Scholar
  3. 3.
    Chuang YC, Sheng WH, Li SY, Lin YC, Wang JT, Chen YC, et al. Influence of genospecies of Acinetobacter baumannii complex on clinical outcomes of patients with Acinetobacter bacteremia. Clin Infect Dis. 2011;52(3):352–60.PubMedGoogle Scholar
  4. 4.
    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(3):268–81.PubMedGoogle Scholar
  5. 5.
    Queenan AM, Pillar CM, Deane J, Sahm DF, Lynch AS, Flamm RK, et al. Multidrug resistance among Acinetobacter spp. in the USA and activity profile of key agents: results from CAPITAL Surveillance 2010. Diagn Microbiol Infect Dis. 2012;73(3):267–70.PubMedGoogle Scholar
  6. 6.
    Pogue JM, Mann T, Barber KE, Kaye KS. Carbapenem-resistant Acinetobacter baumannii: epidemiology, surveillance and management. Expert Rev Anti Infect Ther. 2013;11(4):383–93.PubMedGoogle Scholar
  7. 7.
    Hidron AI, Edwards JR, Patel J, Horan TC, Sievert DM, Pollock DA, et al. NHSN annual update: antimicrobial-resistant pathogens associated with healthcare-associated infections: annual summary of data reported to the National Healthcare Safety Network at the Centers for Disease Control and Prevention, 2006–2007. Infect Control Hosp Epidemiol. 2008;29(11):996–1011.PubMedGoogle Scholar
  8. 8.
    Kallen AJ, Hidron AI, Patel J, Srinivasan A. Multidrug resistance among gram-negative pathogens that caused healthcare-associated infections reported to the National Healthcare Safety Network, 2006-2008. Infect Control Hosp Epidemiol. 2010;31(5):528–31.PubMedGoogle Scholar
  9. 9.
    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(3):209–15.PubMedGoogle Scholar
  10. 10.
    Schleicher X, Higgins PG, Wisplinghoff H, Korber-Irrgang B, Kresken M, Seifert H. Molecular epidemiology of Acinetobacter baumannii and Acinetobacter nosocomialis in Germany over a 5-year period (2005–2009). Clin Microbiol Infect. 2013;19(8):737–42.PubMedGoogle Scholar
  11. 11.
    Chuang YC, Sheng WH, Lauderdale TL, Li SY, Wang JT, Chen YC, et al. Molecular epidemiology, antimicrobial susceptibility and carbapenemase resistance determinants among Acinetobacter baumannii clinical isolates in Taiwan. J Microbiol Immunol Infect. 2013; in press.Google Scholar
  12. 12.
    Wisplinghoff H, Paulus T, Lugenheim M, Stefanik D, Higgins PG, Edmond MB, et al. Nosocomial bloodstream infections due to Acinetobacter baumannii, Acinetobacter pittii and Acinetobacter nosocomialis in the United States. J Infect. 2012;64(3):282–90.PubMedGoogle Scholar
  13. 13.
    Adams-Haduch JM, Onuoha EO, Bogdanovich T, Tian GB, Marschall J, Urban CM, et al. Molecular epidemiology of carbapenem-nonsusceptible Acinetobacter baumannii in the United States. J Clin Microbiol. 2011;49(11):3849–54.PubMedCentralPubMedGoogle Scholar
  14. 14.
    Ng TM, Teng CB, Lye DC, Apisarnthanarak A. A multicenter case–case control study for risk factors and outcomes of extensively drug-resistant Acinetobacter baumannii bacteremia. Infect Control Hosp Epidemiol. 2014;35(1):49–55.PubMedGoogle Scholar
  15. 15.
    Sheng WH, Liao CH, Lauderdale TL, Ko WC, Chen YS, Liu JW, et al. A multicenter study of risk factors and outcome of hospitalized patients with infections due to carbapenem-resistant Acinetobacter baumannii. Int J Infect Dis. 2010;14(9):e764–9.PubMedGoogle Scholar
  16. 16.
    Cisneros JM, Rodriguez-Bano J, Fernandez-Cuenca F, Ribera A, Vila J, Pascual A, et al. Risk-factors for the acquisition of imipenem-resistant Acinetobacter baumannii in Spain: a nationwide study. Clin Microbiol Infect. 2005;11(11):874–9.PubMedGoogle Scholar
  17. 17.
    Lee SO, Kim NJ, Choi SH, Hyong Kim T, Chung JW, Woo JH, et al. Risk factors for acquisition of imipenem-resistant Acinetobacter baumannii: a case–control study. Antimicrob Agents Chemother. 2004;48(1):224–8.Google Scholar
  18. 18.
    Lemos EV, de la Hoz FP, Einarson TR, McGhan WF, Quevedo E, Castaneda C, et al. Carbapenem resistance and mortality in patients with Acinetobacter baumannii infection: systematic review and meta-analysis. Clin Microbiol Infect. 2014;20(5):416–23.Google Scholar
  19. 19.
    Lee HY, Chen CL, Wu SR, Huang CW, Chiu CH. Risk factors and outcome analysis of Acinetobacter baumannii complex bacteremia in critical patients. Crit Care Med. 2014;42(5):1081–8.Google Scholar
  20. 20.
    Kim SY, Jung JY, Kang YA, Lim JE, Kim EY, Lee SK, et al. Risk factors for occurrence and 30-day mortality for carbapenem-resistant Acinetobacter baumannii bacteremia in an intensive care unit. J Korean Med Sci. 2012;27(8):939–47.PubMedCentralPubMedGoogle Scholar
  21. 21.
    Kang G, Hartzell JD, Howard R, Wood-Morris RN, Johnson MD, Fraser S, et al. Mortality associated with Acinetobacter baumannii complex bacteremia among patients with war-related trauma. Infect Control Hosp Epidemiol. 2010;31(1):92–4.PubMedGoogle Scholar
  22. 22.
    Kim YJ, Kim SI, Hong KW, Kim YR, Park YJ, Kang MW. Risk factors for mortality in patients with carbapenem-resistant Acinetobacter baumannii bacteremia: impact of appropriate antimicrobial therapy. J Korean Med Sci. 2012;27(5):471–5.PubMedCentralPubMedGoogle Scholar
  23. 23.
    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):1311–22.Google Scholar
  24. 24.
    Esterly JS, Griffith M, Qi C, Malczynski M, Postelnick MJ, Scheetz MH. Impact of carbapenem resistance and receipt of active antimicrobial therapy on clinical outcomes of Acinetobacter baumannii bloodstream infections. Antimicrob Agents Chemother. 2011;55(10):4844–9.PubMedCentralPubMedGoogle Scholar
  25. 25.
    Munoz-Price LS, Zembower T, Penugonda S, Schreckenberger P, Lavin MA, Welbel S, et al. Clinical outcomes of carbapenem-resistant Acinetobacter baumannii bloodstream infections: study of a 2-state monoclonal outbreak. Infect Control Hosp Epidemiol. 2010;31(10):1057–62.PubMedGoogle Scholar
  26. 26.
    Chopra T, Marchaim D, Awali RA, Krishna A, Johnson P, Tansek R, et al. Epidemiology of bloodstream infections caused by Acinetobacter baumannii and impact of drug resistance to both carbapenems and ampicillin–sulbactam on clinical outcomes. Antimicrob Agents Chemother. 2013;57(12):6270–5.PubMedCentralPubMedGoogle Scholar
  27. 27.
    Woodford N, Turton JF, Livermore DM. Multiresistant Gram-negative bacteria: the role of high-risk clones in the dissemination of antibiotic resistance. FEMS Microbiol Rev. 2011;35(5):736–55.PubMedGoogle Scholar
  28. 28.
    Hujer KM, Hamza NS, Hujer AM, Perez F, Helfand MS, Bethel CR, et al. Identification of a new allelic variant of the Acinetobacter baumannii cephalosporinase, ADC-7 β-lactamase: defining a unique family of class C enzymes. Antimicrob Agents Chemother. 2005;49(7):2941–8.PubMedCentralPubMedGoogle Scholar
  29. 29.
    Bou G, Martinez-Beltran J. Cloning, nucleotide sequencing, and analysis of the gene encoding an AmpC β-lactamase in Acinetobacter baumannii. Antimicrob Agents Chemother. 2000;44(2):428–32.PubMedCentralPubMedGoogle Scholar
  30. 30.
    Heritier C, Poirel L, Nordmann P. Cephalosporinase over-expression resulting from insertion of ISAba1 in Acinetobacter baumannii. Clin Microbiol Infect. 2006;12(2):123–30.PubMedGoogle Scholar
  31. 31.
    Lopes BS, Amyes SG. Role of ISAba1 and ISAba125 in governing the expression of bla ADC in clinically relevant Acinetobacter baumannii strains resistant to cephalosporins. J Med Microbiol. 2012;61(Pt 8):1103–8.PubMedGoogle Scholar
  32. 32.
    Tian GB, Adams-Haduch JM, Taracila M, Bonomo RA, Wang HN, Doi Y. Extended-spectrum AmpC cephalosporinase in Acinetobacter baumannii: ADC-56 confers resistance to cefepime. Antimicrob Agents Chemother. 2011;55(10):4922–5.Google Scholar
  33. 33.
    Vahaboglu H, Ozturk R, Aygun G, Coskunkan F, Yaman A, Kaygusuz A, et al. Widespread detection of PER-1-type extended-spectrum β-lactamases among nosocomial Acinetobacter and Pseudomonas aeruginosa isolates in Turkey: a nationwide multicenter study. Antimicrob Agents Chemother. 1997;41(10):2265–9.PubMedCentralPubMedGoogle Scholar
  34. 34.
    Lee Y, Bae IK, Kim J, Jeong SH, Lee K. Dissemination of ceftazidime-resistant Acinetobacter baumannii clonal complex 92 in Korea. J Appl Microbiol. 2012;112(6):1207–11.PubMedGoogle Scholar
  35. 35.
    Naas T, Coignard B, Carbonne A, Blanckaert K, Bajolet O, Bernet C, et al. VEB-1 extended-spectrum β-lactamase-producing Acinetobacter baumannii, France. Emerg Infect Dis. 2006;12(8):1214–22.PubMedCentralPubMedGoogle Scholar
  36. 36.
    Adams-Haduch JM, Paterson DL, Sidjabat HE, Pasculle AW, Potoski BA, Muto CA, et al. Genetic basis of multidrug resistance in Acinetobacter baumannii clinical isolates at a tertiary medical center in Pennsylvania. Antimicrob Agents Chemother. 2008;52(11):3837–43.PubMedCentralPubMedGoogle Scholar
  37. 37.
    Rumbo C, Gato E, Lopez M, Ruiz de Alegria C, Fernandez-Cuenca F, Martinez-Martinez L, et al. Contribution of efflux pumps, porins, and β-lactamases to multidrug resistance in clinical isolates of Acinetobacter baumannii. Antimicrob Agents Chemother. 2013;57(11):5247–57.Google Scholar
  38. 38.
    Heritier C, Poirel L, Lambert T, Nordmann P. Contribution of acquired carbapenem-hydrolyzing oxacillinases to carbapenem resistance in Acinetobacter baumannii. Antimicrob Agents Chemother. 2005;49(8):3198–202.PubMedCentralPubMedGoogle Scholar
  39. 39.
    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(1):72–7.PubMedGoogle Scholar
  40. 40.
    Figueiredo S, Poirel L, Papa A, Koulourida V, Nordmann P. Overexpression of the naturally occurring bla OXA-51 gene in Acinetobacter baumannii mediated by novel insertion sequence ISAba9. Antimicrob Agents Chemother. 2009;53(9):4045–7.PubMedCentralPubMedGoogle Scholar
  41. 41.
    Higgins PG, Perez-Llarena FJ, Zander E, Fernandez A, Bou G, Seifert H. OXA-235, a novel class D β-lactamase involved in resistance to carbapenems in Acinetobacter baumannii. Antimicrob Agents Chemother. 2013;57(5):2121–6.PubMedCentralPubMedGoogle Scholar
  42. 42.
    Mugnier PD, Poirel L, Naas T, Nordmann P. Worldwide dissemination of the bla OXA-23 carbapenemase gene of Acinetobacter baumannii. Emerg Infect Dis. 2010;16(1):35–40.PubMedCentralPubMedGoogle Scholar
  43. 43.
    Chen Y, Zhou Z, Jiang Y, Yu Y. Emergence of NDM-1-producing Acinetobacter baumannii in China. J Antimicrob Chemother. 2011;66(6):1255–9.PubMedGoogle Scholar
  44. 44.
    Decousser JW, Jansen C, Nordmann P, Emirian A, Bonnin RA, Anais L, et al. Outbreak of NDM-1-producing Acinetobacter baumannii in France, January to May 2013. Euro Surveill. 2013;18(31):1–4.Google Scholar
  45. 45.
    Tsakris A, Ikonomidis A, Pournaras S, Tzouvelekis LS, Sofianou D, Legakis NJ, et al. VIM-1 metallo-β-lactamase in Acinetobacter baumannii. Emerg Infect Dis. 2006;12(6):981–3.PubMedCentralPubMedGoogle Scholar
  46. 46.
    Kouyama Y, Harada S, Ishii Y, Saga T, Yoshizumi A, Tateda K, et al. Molecular characterization of carbapenem-non-susceptible Acinetobacter spp. in Japan: predominance of multidrug-resistant Acinetobacter baumannii clonal complex 92 and IMP-type metallo-β-lactamase-producing non-baumannii Acinetobacter species. J Infect Chemother. 2012;18(4):522–8.PubMedGoogle Scholar
  47. 47.
    Lee K, Yum JH, Yong D, Lee HM, Kim HD, Docquier JD, et al. Novel acquired metallo-β-lactamase gene, bla SIM-1, in a class 1 integron from Acinetobacter baumannii clinical isolates from Korea. Antimicrob Agents Chemother. 2005;49(11):4485–91.PubMedCentralPubMedGoogle Scholar
  48. 48.
    Robledo IE, Aquino EE, Sante MI, Santana JL, Otero DM, Leon CF, et al. Detection of KPC in Acinetobacter spp. in Puerto Rico. Antimicrob Agents Chemother. 2010;54(3):1354–7.PubMedCentralPubMedGoogle Scholar
  49. 49.
    Moubareck C, Bremont S, Conroy MC, Courvalin P, Lambert T. GES-11, a novel integron-associated GES variant in Acinetobacter baumannii. Antimicrob Agents Chemother. 2009;53(8):3579–81.PubMedCentralPubMedGoogle Scholar
  50. 50.
    Urban C, Go E, Mariano N, Rahal JJ. Interaction of sulbactam, clavulanic acid and tazobactam with penicillin-binding proteins of imipenem-resistant and -susceptible Acinetobacter baumannii. FEMS Microbiol Lett. 1995;125:193–7.Google Scholar
  51. 51.
    Fernandez-Cuenca F, Martinez-Martinez L, Conejo MC, Ayala JA, Perea EJ, Pascual A. Relationship between β-lactamase production, outer membrane protein and penicillin-binding protein profiles on the activity of carbapenems against clinical isolates of Acinetobacter baumannii. J Antimicrob Chemother. 2003;51(3):565–74.PubMedGoogle Scholar
  52. 52.
    Krizova L, Poirel L, Nordmann P, Nemec A. TEM-1 β-lactamase as a source of resistance to sulbactam in clinical strains of Acinetobacter baumannii. J Antimicrob Chemother. 2013;68(12):2786–91.PubMedGoogle Scholar
  53. 53.
    Giannouli M, Di Popolo A, Durante-Mangoni E, Bernardo M, Cuccurullo S, Amato G, et al. Molecular epidemiology and mechanisms of rifampicin resistance in Acinetobacter baumannii isolates from Italy. Int J Antimicrob Agents. 2012;39(1):58–63.PubMedGoogle Scholar
  54. 54.
    Houang ET, Chu YW, Lo WS, Chu KY, Cheng AF. Epidemiology of rifampin ADP-ribosyltransferase (arr-2) and metallo-β-lactamase (bla IMP-4) gene cassettes in class 1 integrons in Acinetobacter strains isolated from blood cultures in 1997 to 2000. Antimicrob Agents Chemother. 2003;47(4):1382–90.PubMedCentralPubMedGoogle Scholar
  55. 55.
    Shaw KJ, Rather PN, Hare RS, Miller GH. Molecular genetics of aminoglycoside resistance genes and familial relationships of the aminoglycoside-modifying enzymes. Microbiol Rev. 1993;57(1):138–63.PubMedCentralPubMedGoogle Scholar
  56. 56.
    Landman D, Kelly P, Backer M, Babu E, Shah N, Bratu S, et al. Antimicrobial activity of a novel aminoglycoside, ACHN-490, against Acinetobacter baumannii and Pseudomonas aeruginosa from New York City. J Antimicrob Chemother. 2011;66(2):332–4.PubMedGoogle Scholar
  57. 57.
    Akers KS, Chaney C, Barsoumian A, Beckius M, Zera W, Yu X, et al. Aminoglycoside resistance and susceptibility testing errors in Acinetobacter baumannii–calcoaceticus complex. J Clin Microbiol. 2010;48(4):1132–8.PubMedCentralPubMedGoogle Scholar
  58. 58.
    Liou GF, Yoshizawa S, Courvalin P, Galimand M. Aminoglycoside resistance by ArmA-mediated ribosomal 16S methylation in human bacterial pathogens. J Mol Biol. 2006;359(2):358–64.PubMedGoogle Scholar
  59. 59.
    Yu YS, Zhou H, Yang Q, Chen YG, Li LJ. Widespread occurrence of aminoglycoside resistance due to ArmA methylase in imipenem-resistant Acinetobacter baumannii isolates in China. J Antimicrob Chemother. 2007;60(2):454–5.PubMedGoogle Scholar
  60. 60.
    Doi Y, Adams JM, Yamane K, Paterson DL. Identification of 16S rRNA methylase-producing Acinetobacter baumannii clinical strains in North America. Antimicrob Agents Chemother. 2007;51(11):4209–10.PubMedCentralPubMedGoogle Scholar
  61. 61.
    Coyne S, Rosenfeld N, Lambert T, Courvalin P, Perichon B. Overexpression of resistance-nodulation-cell division pump AdeFGH confers multidrug resistance in Acinetobacter baumannii. Antimicrob Agents Chemother. 2010;54(10):4389–93.PubMedCentralPubMedGoogle Scholar
  62. 62.
    Beceiro A, Llobet E, Aranda J, Bengoechea JA, Doumith M, Hornsey M, et al. Phosphoethanolamine modification of lipid A in colistin-resistant variants of Acinetobacter baumannii mediated by the pmrAB two-component regulatory system. Antimicrob Agents Chemother. 2011;55(7):3370–9.PubMedCentralPubMedGoogle Scholar
  63. 63.
    Pelletier MR, Casella LG, Jones JW, Adams MD, Zurawski DV, Hazlett KR, et al. Unique structural modifications are present in the lipopolysaccharide from colistin-resistant strains of Acinetobacter baumannii. Antimicrob Agents Chemother. 2013;57(10):4831–40.PubMedCentralPubMedGoogle Scholar
  64. 64.
    Arroyo LA, Herrera CM, Fernandez L, Hankins JV, Trent MS, Hancock RE. The pmrCAB operon mediates polymyxin resistance in Acinetobacter baumannii ATCC 17978 and clinical isolates through phosphoethanolamine modification of lipid A. Antimicrob Agents Chemother. 2011;55(8):3743–51.PubMedCentralPubMedGoogle Scholar
  65. 65.
    Moffatt JH, Harper M, Harrison P, Hale JD, Vinogradov E, Seemann T, et al. Colistin resistance in Acinetobacter baumannii is mediated by complete loss of lipopolysaccharide production. Antimicrob Agents Chemother. 2010;54(12):4971–7.PubMedCentralPubMedGoogle Scholar
  66. 66.
    Chopra I, Hawkey PM, Hinton M. Tetracyclines, molecular and clinical aspects. J Antimicrob Chemother. 1992;29(3):245–77.PubMedGoogle Scholar
  67. 67.
    Coyne S, Courvalin P, Perichon B. Efflux-mediated antibiotic resistance in Acinetobacter spp. Antimicrob Agents Chemother. 2011;55(3):947–53.PubMedCentralPubMedGoogle Scholar
  68. 68.
    Abbott I, Cerqueira GM, Bhuiyan S, Peleg AY. Carbapenem resistance in Acinetobacter baumannii: laboratory challenges, mechanistic insights and therapeutic strategies. Expert Rev Anti Infect Ther. 2013;11(4):395–409.PubMedGoogle Scholar
  69. 69.
    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(7):1607–15.PubMedGoogle Scholar
  70. 70.
    Akajagbor DS, Wilson SL, Shere-Wolfe KD, Dakum P, Charurat ME, Gilliam BL. Higher incidence of acute kidney injury with intravenous colistimethate sodium compared with polymyxin B in critically ill patients at a tertiary care medical center. Clin Infect Dis. 2013;57(9):1300–3.PubMedGoogle Scholar
  71. 71.
    Nation RL, Li J, Cars O, Couet W, Dudley MN, Kaye KS, et al. Consistent global approach on reporting of colistin doses to promote safe and effective use. Clin Infect Dis. 2014;58(1):139–41.PubMedGoogle Scholar
  72. 72.
    Bergen PJ, Landersdorfer CB, Zhang J, Zhao M, Lee HJ, Nation RL, et al. Pharmacokinetics and pharmacodynamics of ‘old’ polymyxins: what is new? Diagn Microbiol Infect Dis. 2012;74(3):213–23.PubMedCentralPubMedGoogle Scholar
  73. 73.
    Owen RJ, Li J, Nation RL, Spelman D. In vitro pharmacodynamics of colistin against Acinetobacter baumannii clinical isolates. J Antimicrob Chemother. 2007;59(3):473–7.PubMedGoogle Scholar
  74. 74.
    Li J, Rayner CR, Nation RL, Owen RJ, Spelman D, Tan KE, et al. Heteroresistance to colistin in multidrug-resistant Acinetobacter baumannii. Antimicrob Agents Chemother. 2006;50(9):2946–50.PubMedCentralPubMedGoogle Scholar
  75. 75.
    Mohamed AF, Karaiskos I, Plachouras D, Karvanen M, Pontikis K, Jansson B, et al. Application of a loading dose of colistin methanesulfonate in critically ill patients: population pharmacokinetics, protein binding, and prediction of bacterial kill. Antimicrob Agents Chemother. 2012;56(8):4241–9.PubMedCentralPubMedGoogle Scholar
  76. 76.
    Garonzik SM, Li J, Thamlikitkul V, Paterson DL, Shoham S, Jacob J, et al. Population pharmacokinetics of colistin methanesulfonate and formed colistin in critically ill patients from a multicenter study provide dosing suggestions for various categories of patients. Antimicrob Agents Chemother. 2011;55(7):3284–94.PubMedCentralPubMedGoogle Scholar
  77. 77.
    Plachouras D, Karvanen M, Friberg LE, Papadomichelakis E, Antoniadou A, Tsangaris I, et al. Population pharmacokinetic analysis of colistin methanesulfonate and colistin after intravenous administration in critically ill patients with infections caused by gram-negative bacteria. Antimicrob Agents Chemother. 2009;53(8):3430–6.PubMedCentralPubMedGoogle Scholar
  78. 78.
    Garnacho-Montero J, Ortiz-Leyba C, Jimenez-Jimenez FJ, Barrero-Almodovar AE, Garcia-Garmendia JL, Bernabeu-Wittel IM, et al. Treatment of multidrug-resistant Acinetobacter baumannii ventilator-associated pneumonia (VAP) with intravenous colistin: a comparison with imipenem-susceptible VAP. Clin Infect Dis. 2003;36(9):1111–8.PubMedGoogle Scholar
  79. 79.
    Oliveira MS, Prado GV, Costa SF, Grinbaum RS, Levin AS. Ampicillin/sulbactam compared with polymyxins for the treatment of infections caused by carbapenem-resistant Acinetobacter spp. J Antimicrob Chemother. 2008;61(6):1369–75.PubMedGoogle Scholar
  80. 80.
    Betrosian AP, Frantzeskaki F, Xanthaki A, Douzinas EE. Efficacy and safety of high-dose ampicillin/sulbactam vs. colistin as monotherapy for the treatment of multidrug resistant Acinetobacter baumannii ventilator-associated pneumonia. J Infect. 2008;56(6):432–6.PubMedGoogle Scholar
  81. 81.
    Yapa SW, Li J, Patel K, Wilson JW, Dooley MJ, George J, et al. Pulmonary and systemic pharmacokinetics of inhaled and intravenous colistin methanesulfonate in cystic fibrosis patients: targeting advantage of inhalational administration. Antimicrob Agents Chemother. 2014;58(5):2570–9.Google Scholar
  82. 82.
    Conway SP. Nebulized antibiotic therapy: the evidence. Chron Respir Dis. 2005;2(1):35–41.PubMedGoogle Scholar
  83. 83.
    Tumbarello M, De Pascale G, Trecarichi EM, De Martino S, Bello G, Maviglia R, et al. Effect of aerosolized colistin as adjunctive treatment on the outcomes of microbiologically documented ventilator-associated pneumonia caused by colistin-only susceptible gram-negative bacteria. Chest. 2013;144(6):1768–75.PubMedGoogle Scholar
  84. 84.
    Kuo SC, Lee YT, Yang SP, Chen CP, Chen TL, Hsieh SL, et al. Eradication of multidrug-resistant Acinetobacter baumannii from the respiratory tract with inhaled colistin methanesulfonate: a matched case–control study. Clin Microbiol Infect. 2012;18(9):870–6.PubMedGoogle Scholar
  85. 85.
    Rattanaumpawan P, Lorsutthitham J, Ungprasert P, Angkasekwinai N, Thamlikitkul V. Randomized controlled trial of nebulized colistimethate sodium as adjunctive therapy of ventilator-associated pneumonia caused by Gram-negative bacteria. J Antimicrob Chemother. 2010;65(12):2645–9.PubMedGoogle Scholar
  86. 86.
    Markantonis SL, Markou N, Fousteri M, Sakellaridis N, Karatzas S, Alamanos I, et al. Penetration of colistin into cerebrospinal fluid. Antimicrob Agents Chemother. 2009;53(11):4907–10.PubMedCentralPubMedGoogle Scholar
  87. 87.
    Imberti R, Cusato M, Accetta G, Marino V, Procaccio F, Del Gaudio A, et al. Pharmacokinetics of colistin in cerebrospinal fluid after intraventricular administration of colistin methanesulfonate. Antimicrob Agents Chemother. 2012;56(8):4416–21.PubMedCentralPubMedGoogle Scholar
  88. 88.
    Karaiskos I, Galani L, Baziaka F, Giamarellou H. Intraventricular and intrathecal colistin as the last therapeutic resort for the treatment of multidrug-resistant and extensively drug-resistant Acinetobacter baumannii ventriculitis and meningitis: a literature review. Int J Antimicrob Agents. 2013;41(6):499–508.PubMedGoogle Scholar
  89. 89.
    Noguchi JK, Gill MA. Sulbactam: a β-lactamase inhibitor. Clin Pharm. 1988;7(1):37–51.PubMedGoogle Scholar
  90. 90.
    Rafailidis PI, Ioannidou EN, Falagas ME. Ampicillin/sulbactam: current status in severe bacterial infections. Drugs. 2007;67(13):1829–49.PubMedGoogle Scholar
  91. 91.
    Meyers BR, Wilkinson P, Mendelson MH, Walsh S, Bournazos C, Hirschman SZ. Pharmacokinetics of ampicillin–sulbactam in healthy elderly and young volunteers. Antimicrob Agents Chemother. 1991;35(10):2098–101.PubMedCentralPubMedGoogle Scholar
  92. 92.
    Swenson JM, Killgore GE, Tenover FC. Antimicrobial susceptibility testing of Acinetobacter spp. by NCCLS broth microdilution and disk diffusion methods. J Clin Microbiol. 2004;42(11):5102–8.PubMedCentralPubMedGoogle Scholar
  93. 93.
    Reddy T, Chopra T, Marchaim D, Pogue JM, Alangaden G, Salimnia H, et al. Trends in antimicrobial resistance of Acinetobacter baumannii isolates from a metropolitan Detroit health system. Antimicrob Agents Chemother. 2010;54(5):2235–8.PubMedCentralPubMedGoogle Scholar
  94. 94.
    Montero A, Ariza J, Corbella X, Domenech A, Cabellos C, Ayats J, et al. Efficacy of colistin versus β-lactams, aminoglycosides, and rifampin as monotherapy in a mouse model of pneumonia caused by multiresistant Acinetobacter baumannii. Antimicrob Agents Chemother. 2002;46(6):1946–52.PubMedCentralPubMedGoogle Scholar
  95. 95.
    Rodriguez-Hernandez MJ, Cuberos L, Pichardo C, Caballero FJ, Moreno I, Jimenez-Mejias ME, et al. Sulbactam efficacy in experimental models caused by susceptible and intermediate Acinetobacter baumannii strains. J Antimicrob Chemother. 2001;47(4):479–82.PubMedGoogle Scholar
  96. 96.
    Choi JY, Kim CO, Park YS, Yoon HJ, Shin SY, Kim YK, et al. Comparison of efficacy of cefoperazone/sulbactam and imipenem/cilastatin for treatment of Acinetobacter bacteremia. Yonsei Med J. 2006;47(1):63–9.PubMedCentralPubMedGoogle Scholar
  97. 97.
    Wood GC, Hanes SD, Croce MA, Fabian TC, Boucher BA. Comparison of ampicillin-sulbactam and imipenem-cilastatin for the treatment of Acinetobacter ventilator-associated pneumonia. Clin Infect Dis. 2002;34(11):1425–30.PubMedGoogle Scholar
  98. 98.
    Oliveira MS, Costa SF, Pedri E, van der Heijden I, Levin AS. The minimal inhibitory concentration for sulbactam was not associated with the outcome of infections caused by carbapenem-resistant Acinetobacter sp. treated with ampicillin/sulbactam. Clinics (Sao Paulo). 2013;68(4):569–73.Google Scholar
  99. 99.
    Livermore DM. Tigecycline: what is it, and where should it be used? J Antimicrob Chemother. 2005;56(4):611–4.PubMedGoogle Scholar
  100. 100.
    Denys GA, Callister SM, Dowzicky MJ. Antimicrobial susceptibility among gram-negative isolates collected in the USA between 2005 and 2011 as part of the Tigecycline Evaluation and Surveillance Trial (T.E.S.T.). Ann Clin Microbiol Antimicrob. 2013;12:24.PubMedCentralPubMedGoogle Scholar
  101. 101.
    Ruzin A, Keeney D, Bradford PA. AdeABC multidrug efflux pump is associated with decreased susceptibility to tigecycline in Acinetobacter calcoaceticus-Acinetobacter baumannii complex. J Antimicrob Chemother. 2007;59(5):1001–4.PubMedGoogle Scholar
  102. 102.
    Peleg AY, Potoski BA, Rea R, Adams J, Sethi J, Capitano B, et al. Acinetobacter baumannii bloodstream infection while receiving tigecycline: a cautionary report. J Antimicrob Chemother. 2007;59(1):128–31.PubMedGoogle Scholar
  103. 103.
    Muralidharan G, Micalizzi M, Speth J, Raible D, Troy S. Pharmacokinetics of tigecycline after single and multiple doses in healthy subjects. Antimicrob Agents Chemother. 2005;49(1):220–9.PubMedCentralPubMedGoogle Scholar
  104. 104.
    Kim NH, Hwang JH, Song KH, Choe PG, Kim ES, Park SW, et al. Tigecycline in carbapenem-resistant Acinetobacter baumannii bacteraemia: susceptibility and clinical outcome. Scand J Infect Dis. 2013;45(4):315–9.PubMedGoogle Scholar
  105. 105.
    Nix DE, Matthias KR. Should tigecycline be considered for urinary tract infections? A pharmacokinetic re-evaluation. J Antimicrob Chemother. 2010;65(6):1311–2.Google Scholar
  106. 106.
    Freire AT, Melnyk V, Kim MJ, Datsenko O, Dzyublik O, Glumcher F, et al. Comparison of tigecycline with imipenem/cilastatin for the treatment of hospital-acquired pneumonia. Diagn Microbiol Infect Dis. 2010;68(2):140–51.PubMedGoogle Scholar
  107. 107.
    Pichardo C, Pachon-Ibanez ME, Docobo-Perez F, Lopez-Rojas R, Jimenez-Mejias ME, Garcia-Curiel A, et al. Efficacy of tigecycline vs. imipenem in the treatment of experimental Acinetobacter baumannii murine pneumonia. Eur J Clin Microbiol Infect Dis. 2010;29(5):527–31.PubMedGoogle Scholar
  108. 108.
    Ramirez J, Dartois N, Gandjini H, Yan JL, Korth-Bradley J, McGovern PC. Randomized phase 2 trial to evaluate the clinical efficacy of two high-dosage tigecycline regimens versus imipenem-cilastatin for treatment of hospital-acquired pneumonia. Antimicrob Agents Chemother. 2013;57(4):1756–62.PubMedCentralPubMedGoogle Scholar
  109. 109.
    Lee YT, Tsao SM, Hsueh PR. 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. 2013;32(9):1211–20.PubMedGoogle Scholar
  110. 110.
    Anthony KB, Fishman NO, Linkin DR, Gasink LB, Edelstein PH, Lautenbach E. Clinical and microbiological outcomes of serious infections with multidrug-resistant gram-negative organisms treated with tigecycline. Clin Infect Dis. 2008;46(4):567–70.PubMedGoogle Scholar
  111. 111.
    Reid GE, Grim SA, Aldeza CA, Janda WM, Clark NM. Rapid development of Acinetobacter baumannii resistance to tigecycline. Pharmacotherapy. 2007;27(8):1198–201.PubMedGoogle Scholar
  112. 112.
    Testa RT, Petersen PJ, Jacobus NV, Sum PE, Lee VJ, Tally FP. In vitro and in vivo antibacterial activities of the glycylcyclines, a new class of semisynthetic tetracyclines. Antimicrob Agents Chemother. 1993;37(11):2270–7.PubMedCentralPubMedGoogle Scholar
  113. 113.
    Agwuh KN, MacGowan A. Pharmacokinetics and pharmacodynamics of the tetracyclines including glycylcyclines. J Antimicrob Chemother. 2006;58(2):256–65.PubMedGoogle Scholar
  114. 114.
    Pei G, Mao Y, Sun Y. In vitro activity of minocycline alone and in combination with cefoperazone-sulbactam against carbapenem-resistant Acinetobacter baumannii. Microb Drug Resist. 2012;18(6):574–7.PubMedGoogle Scholar
  115. 115.
    Liang W, Liu XF, Huang J, Zhu DM, Li J, Zhang J. Activities of colistin- and minocycline-based combinations against extensive drug resistant Acinetobacter baumannii isolates from intensive care unit patients. BMC Infect Dis. 2011;11:109.PubMedCentralPubMedGoogle Scholar
  116. 116.
    Griffith ME, Yun HC, Horvath LL, Murray CK. Minocycline therapy for traumatic wound infections caused by the multidrug-resistant Acinetobacter baumanniiAcinetobacter calcoaceticus complex. Infect Dis Clin Pract. 2008;16:16–9.Google Scholar
  117. 117.
    Wood GC, Hanes SD, Boucher BA, Croce MA, Fabian TC. Tetracyclines for treating multidrug-resistant Acinetobacter baumannii ventilator-associated pneumonia. Intensive Care Med. 2003;29(11):2072–6.PubMedGoogle Scholar
  118. 118.
    Chan JD, Graves JA, Dellit TH. Antimicrobial treatment and clinical outcomes of carbapenem-resistant Acinetobacter baumannii ventilator-associated pneumonia. J Intensive Care Med. 2010;25(6):343–8.Google Scholar
  119. 119.
    Song JY, Kee SY, Hwang IS, Seo YB, Jeong HW, Kim WJ, et al. In vitro activities of carbapenem/sulbactam combination, colistin, colistin/rifampicin combination and tigecycline against carbapenem-resistant Acinetobacter baumannii. J Antimicrob Chemother. 2007;60(2):317–22.PubMedGoogle Scholar
  120. 120.
    Giamarellos-Bourboulis EJ, Xirouchaki E, Giamarellou H. Interactions of colistin and rifampin on multidrug-resistant Acinetobacter baumannii. Diagn Microbiol Infect Dis. 2001;40(3):117–20.PubMedGoogle Scholar
  121. 121.
    Pachon-Ibanez ME, Docobo-Perez F, Lopez-Rojas R, Dominguez-Herrera J, Jimenez-Mejias ME, Garcia-Curiel A, et al. 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. 2010;54(3):1165–72.PubMedCentralPubMedGoogle Scholar
  122. 122.
    Pantopoulou A, Giamarellos-Bourboulis EJ, Raftogannis M, Tsaganos T, Dontas I, Koutoukas P, et al. Colistin offers prolonged survival in experimental infection by multidrug-resistant Acinetobacter baumannii: the significance of co-administration of rifampicin. Int J Antimicrob Agents. 2007;29(1):51–5.PubMedGoogle Scholar
  123. 123.
    Bassetti M, Repetto E, Righi E, Boni S, Diverio M, Molinari MP, et al. Colistin and rifampicin in the treatment of multidrug-resistant Acinetobacter baumannii infections. J Antimicrob Chemother. 2008;61(2):417–20.PubMedGoogle Scholar
  124. 124.
    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):1214–22.PubMedGoogle Scholar
  125. 125.
    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):349–58.PubMedGoogle Scholar
  126. 126.
    Falagas ME, Kanellopoulou MD, Karageorgopoulos DE, Dimopoulos G, Rafailidis PI, Skarmoutsou ND, et al. Antimicrobial susceptibility of multidrug-resistant Gram negative bacteria to fosfomycin. Eur J Clin Microbiol Infect Dis. 2008;27(6):439–43.PubMedGoogle Scholar
  127. 127.
    Santimaleeworagun W, Wongpoowarak P, Chayakul P, Pattharachayakul S, Tansakul P, Garey KW. 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. 2011;42(4):890–900.PubMedGoogle Scholar
  128. 128.
    Sirijatuphat R, Thamlikitkul V. Colistin versus colistin plus fosfomycin for treatment of carbapenem-resistant Acinetobacter baumannii infections: a preliminary study. Antimicrob Agents Chemother. 2014; in press.Google Scholar
  129. 129.
    Li J, Nation RL, Owen RJ, Wong S, Spelman D, Franklin C. Antibiograms of multidrug-resistant clinical Acinetobacter baumannii: promising therapeutic options for treatment of infection with colistin-resistant strains. Clin Infect Dis. 2007;45(5):594–8.PubMedGoogle Scholar
  130. 130.
    Hornsey M, Wareham DW. In vivo efficacy of glycopeptide-colistin combination therapies in a Galleria mellonella model of Acinetobacter baumannii infection. Antimicrob Agents Chemother. 2011;55(7):3534–7.PubMedCentralPubMedGoogle Scholar
  131. 131.
    Hornsey M, Phee L, Longshaw C, Wareham DW. In vivo efficacy of telavancin/colistin combination therapy in a Galleria mellonella model of Acinetobacter baumannii infection. Int J Antimicrob Agents. 2013;41(3):285–7.PubMedGoogle Scholar
  132. 132.
    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(5):2103–8.PubMedCentralPubMedGoogle Scholar
  133. 133.
    Galani I, Orlandou K, Moraitou H, Petrikkos G, Souli M. Colistin/daptomycin: an unconventional antimicrobial combination synergistic in vitro against multidrug-resistant Acinetobacter baumannii. Int J Antimicrob Agents. 2014;43(4):370–4.PubMedGoogle Scholar
  134. 134.
    Garnacho-Montero J, Amaya-Villar R, Gutierrez-Pizarraya A, Espejo-Gutierrez de Tena E, Artero-Gonzalez 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. 2013;59(3):225–31.Google Scholar
  135. 135.
    Petrosillo N, Giannella M, Antonelli M, Antonini M, Barsic B, Belancic L, et al. Clinical experience of colistin–glycopeptide combination in critically ill patients infected with gram-negative bacteria. Antimicrob Agents Chemother. 2014;58(2):851–8.PubMedCentralPubMedGoogle Scholar
  136. 136.
    Lesho E, Yoon EJ, McGann P, Snesrud E, Kwak Y, Milillo M, et al. Emergence of colistin-resistance in extremely drug-resistant Acinetobacter baumannii containing a novel pmrCAB operon during colistin therapy of wound infections. J Infect Dis. 2013;208(7):1142–51.PubMedGoogle Scholar
  137. 137.
    Snitkin ES, Zelazny AM, Gupta J, Program NCS, Palmore TN, Murray PR, et al. Genomic insights into the fate of colistin resistance and Acinetobacter baumannii during patient treatment. Genome Res. 2013;23(7):1155–62.PubMedCentralPubMedGoogle Scholar
  138. 138.
    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(12):e52349.PubMedCentralPubMedGoogle Scholar
  139. 139.
    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):194–9.PubMedGoogle Scholar
  140. 140.
    Kumar A, Roberts D, Wood KE, Light B, Parrillo JE, Sharma S, et al. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med. 2006;34(6):1589–96.PubMedGoogle Scholar
  141. 141.
    Micek ST, Welch EC, Khan J, Pervez M, Doherty JA, Reichley RM, et al. Empiric combination antibiotic therapy is associated with improved outcome against sepsis due to Gram-negative bacteria: a retrospective analysis. Antimicrob Agents Chemother. 2010;54(5):1742–8.PubMedCentralPubMedGoogle Scholar
  142. 142.
    Lee YT, Kuo SC, Yang SP, Lin YT, Tseng FC, Chen TL, et al. Impact of appropriate antimicrobial therapy on mortality associated with Acinetobacter baumannii bacteremia: relation to severity of infection. Clin Infect Dis. 2012;55(2):209–15.PubMedGoogle Scholar
  143. 143.
    Erbay A, Idil A, Gozel MG, Mumcuoglu I, Balaban N. Impact of early appropriate antimicrobial therapy on survival in Acinetobacter baumannii bloodstream infections. Int J Antimicrob Agents. 2009;34(6):575–9.PubMedGoogle Scholar
  144. 144.
    de Gouvea EF, Martins IS, Halpern M, Ferreira AL, Basto ST, Goncalves RT, et al. The influence of carbapenem resistance on mortality in solid organ transplant recipients with Acinetobacter baumannii infection. BMC Infect Dis. 2012;12:351.PubMedCentralPubMedGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2014

Authors and Affiliations

  • J. Alexander Viehman
    • 4
  • M. Hong Nguyen
    • 2
    • 3
    • 5
  • Yohei Doi
    • 1
    • 2
    Email author
  1. 1.Division of Infectious Diseases, Department of MedicineUniversity of Pittsburgh Medical CenterPittsburghUSA
  2. 2.Antibiotic Management ProgramUniversity of Pittsburgh Medical CenterPittsburghUSA
  3. 3.XDR Pathogen LaboratoryUniversity of Pittsburgh Medical CenterPittsburghUSA
  4. 4.Division of Infectious Diseases, Department of MedicineUniversity of Pittsburgh Medical CenterPittsburghUSA
  5. 5.Division of Infectious Diseases, Department of MedicineUniversity of Pittsburgh Medical CenterPittsburghUSA

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