Infect Chemother.  2014 Sep;46(3):149-164. 10.3947/ic.2014.46.3.149.

Therapy of Infections due to Carbapenem-Resistant Gram-Negative Pathogens

• Lee CS
• Doi Y

• KMID: 2284972
• DOI: http://doi.org/10.3947/ic.2014.46.3.149

Abstract

The prevalence of carbapenem-resistant gram-negative bacterial pathogens (CRGNs) has increased dramatically during the last 10 years, but the optimal treatment for CRGN infections is not well established due to the relative scarcity of robust clinical data. The polymyxins remain the most consistently active agents against CRGNs in vitro. Tigecycline, based on its in vitro antibacterial spectrum, could also be considered as a therapeutic option in the treatment of infections caused by certain CRGNs. Other agents, including aminoglycosides, rifampin, trimethoprim-sulfamethoxazole, fosfomycin and fluoroquinolones, could be considered as monotherapy or combination therapy against CRGNs in appropriate contexts, as combination therapy with two or more in vitro active drugs appears to be more effective than monotherapy based on some clinical data. Several promising new agents are in late-stage clinical development, including ceftolozane-tazobactam, ceftazidime-avibactam and plazomicin. Given the shortage of adequate treatment options, containment of CRGNs should be pursued through implementation of adequate infection prevention procedures and antimicrobial stewardship to reduce the disease burden and prevent future outbreaks of CRGNs.

Keyword

Combination drug therapy; Polymyxins; Colistin; Tigecycline; Carbapenemase

MeSH Terms

Aminoglycosides
Colistin
Containment of Biohazards
Disease Outbreaks
Drug Therapy, Combination
Fluoroquinolones
Fosfomycin
Polymyxins
Prevalence
Rifampin
Trimethoprim, Sulfamethoxazole Drug Combination
Aminoglycosides
Colistin
Fluoroquinolones
Fosfomycin
Polymyxins
Rifampin

Reference

1. Akova M, Daikos GL, Tzouvelekis L, Carmeli Y. Interventional strategies and current clinical experience with carbapenemase-producing Gram-negative bacteria. Clin Microbiol Infect. 2012; 18:439–448.

2. Queenan AM, Bush K. Carbapenemases: the versatile β-lactamases. Clin Microbiol Rev. 2007; 20:440.

3. Schwaber MJ, Carmeli Y. Carbapenem-resistant Enterobacteriaceae: a potential threat. JAMA. 2008; 300:2911–2913.

4. Bratu S, Mooty M, Nichani S, Landman D, Gullans C, Pettinato B, Karumudi U, Tolaney P, Quale J. Emergence of KPC-possessing Klebsiella pneumoniae in Brooklyn, New York: epidemiology and recommendations for detection. Antimicrob Agents Chemother. 2005; 49:3018–3020.

5. Kanj SS, Kanafani ZA. Current concepts in antimicrobial therapy against resistant gram-negative organisms: extended-spectrum β-lactamase-producing Enterobacteriaceae, carbapenem-resistant Enterobacteriaceae, and multidrug-resistant Pseudomonas aeruginosa. Mayo Clin Proc. 2011; 86:250–259.

6. Peleg AY, Seifert H, Paterson DL. Acinetobacter baumannii: emergence of a successful pathogen. Clin Microbiol Rev. 2008; 21:538–582.

7. Lemos EV, de la Hoz FP, Einarson TR, McGhan WF, Quevedo E, Castañeda C, Kawai K. Carbapenem resistance and mortality in patients with Acinetobacter baumannii infection: systematic review and meta-analysis. Clin Microbiol Infect. 2014; 20:416–423.

8. Queenan AM, Pillar CM, Deane J, Sahm DF, Lynch AS, Flamm RK, Peterson J, Davies TA. Multidrug resistance among Acinetobacter spp. in the USA and activity profile of key agents: results from CAPITAL Surveillance 2010. Diagn Microbiol Infect Dis. 2012; 73:267–270.

9. Garnacho-Montero J, Ortiz-Leyba C, Jiménez-Jiménez FJ, Barrero-Almodóvar AE, García-Garmendia JL, Bernabeu-WittelI M, Gallego-Lara SL, Madrazo-Osuna J. Treatment of multidrug-resistant Acinetobacter baumannii ventilator-associated pneumonia (VAP) with intravenous colistin: a comparison with imipenem-susceptible VAP. Clin Infect Dis. 2003; 36:1111–1118.

10. 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; 61:1369–1375.

11. Garonzik SM, Li J, Thamlikitkul V, Paterson DL, Shoham S, Jacob J, Silveira FP, Forrest A, Nation RL. 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; 55:3284–3294.

12. Kuo SC, Lee YT, Yang SP, Chen CP, Chen TL, Hsieh SL, Siu LK, Fung CP. Eradication of multidrug-resistant Acinetobacter baumannii from the respiratory tract with inhaled colistin methanesulfonate: a matched case-control study. Clin Microbiol Infect. 2012; 18:870–876.

13. 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; 65:2645–2649.

14. Swenson JM, Killgore GE, Tenover FC. Antimicrobial susceptibility testing of Acinetobacter spp. by NCCLS broth microdilution and disk diffusion methods. J Clin Microbiol. 2004; 42:5102–5108.

15. Reddy T, Chopra T, Marchaim D, Pogue JM, Alangaden G, Salimnia H, Boikov D, Navon-Venezia S, Akins R, Selman P, Dhar S, Kaye KS. Trends in antimicrobial resistance of Acinetobacter baumannii isolates from a metropolitan Detroit health system. Antimicrob Agents Chemother. 2010; 54:2235–2238.

16. 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; 56:432–436.

17. 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; 49:220–229.

18. Kim NH, Hwang JH, Song KH, Choe PG, Kim ES, Park SW, Kim HB, Kim NJ, Park WB, Oh MD. Tigecycline in carbapenem-resistant Acinetobacter baumannii bacteraemia: susceptibility and clinical outcome. Scand J Infect Dis. 2013; 45:315–319.

19. 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; 32:1211–1220.

20. 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; 57:1756–1762.

21. 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.

22. Griffith ME, Yun HC, Horvath LL, Murray CK. Minocycline therapy for traumatic wound infections caused by the multidrug-resistant Acinetobacter baumannii-Acinetobacter calcoaceticus complex. Infect Dis Clin Pract. 2008; 16:16–19.

23. Wood GC, Hanes SD, Boucher BA, Croce MA, Fabian TC. Tetracyclines for treating multidrug-resistant Acinetobacter baumannii ventilator-associated pneumonia. Intensive Care Med. 2003; 29:2072–2076.

24. Aydemir H, Akduman D, Piskin N, Comert F, Horuz E, Terzi A, Kokturk F, Ornek T, Celebi G. Colistin vs. the combination of colistin and rifampicin for the treatment of carbapenem-resistant Acinetobacter baumannii ventilator-associated pneumonia. Epidemiol Infect. 2013; 141:1214–1222.

25. Durante-Mangoni E, Signoriello G, Andini R, Mattei A, De Cristoforo M, Murino P, Bassetti M, Malacarne P, Petrosillo N, Galdieri N, Mocavero P, Corcione A, Viscoli C, Zarrilli R, Gallo C, Utili R. 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; 57:349–358.

26. 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; 42:890–900.

27. Sirijatuphat R, Thamlikitkul V. Colistin versus colistin plus fosfomycin for treatment of carbapenem-resistant Acinetobacter baumannii infections : A preliminary study. Antimicrob Agents Chemother. 2014; 58:5598–5601.

28. Batirel A, Balkan II, Karabay O, Agalar C, Akalin S, Alici O, Alp E, Altay FA, Altin N, Arslan F, Aslan T, Bekiroglu N, Cesur S, Celik AD, Dogan M, Durdu B, Duygu F, Engin A, Engin DO, Gonen I, Guclu E, Guven T, Hatipoglu CA, Hosoglu S, Karahocagil MK, Kilic AU, Ormen B, Ozdemir D, Ozer S, Oztoprak N, Sezak N, Turhan V, Turker N, Yilmaz H. 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; 33:1311–1322.

29. Shields RK, Clancy CJ, Gillis LM, Kwak EJ, Silveira FP, Massih RC, Eschenauer GA, Potoski BA, Nguyen MH. Epidemiology, clinical characteristics and outcomes of extensively drug-resistant Acinetobacter baumannii infections among solid organ transplant recipients. PLoS One. 2012; 7:e52349.

30. Sutcliffe JA, O'Brien W, Fyfe C, Grossman TH. Antibacterial activity of eravacycline (TP-434), a novel fluorocycline, against hospital and community pathogens. Antimicrob Agents Chemother. 2013; 57:5548–5558.

31. Solomkin JS, Ramesh MK, Cesnauskas G, Novikovs N, Stefanova P, Sutcliffe JA, Walpole SM, Horn PT. Phase 2, randomized, double-blind study of the efficacy and safety of two dose regimens of eravacycline versus ertapenem for adult community-acquired complicated intra-abdominal infections. Antimicrob Agents Chemother. 2014; 58:1847–1854.

32. Morrow BJ, Pillar CM, Deane J, Sahm DF, Lynch AS, Flamm RK, Peterson J, Davies TA. Activities of carbapenem and comparator agents against contemporary US Pseudomonas aeruginosa isolates from the CAPITAL surveillance program. Diagn Microbiol Infect Dis. 2013; 75:412–416.

33. Linden PK, Kusne S, Coley K, Fontes P, Kramer DJ, Paterson D. Use of parenteral colistin for the treatment of serious infection due to antimicrobial-resistant Pseudomonas aeruginosa. Clin Infect Dis. 2003; 37:e154–e160.

34. Falagas ME, Rafailidis PI, Ioannidou E, Alexiou VG, Matthaiou DK, Karageorgopoulos DE, Kapaskelis A, Nikita D, Michalopoulos A. Colistin therapy for microbiologically documented multidrug-resistant Gram-negative bacterial infections: a retrospective cohort study of 258 patients. Int J Antimicrob Agents. 2010; 35:194–199.

35. Hachem RY, Chemaly RF, Ahmar CA, Jiang Y, Boktour MR, Rjaili GA, Bodey GP, Raad II. Colistin is effective in treatment of infections caused by multidrug-resistant Pseudomonas aeruginosa in cancer patients. Antimicrob Agents Chemother. 2007; 51:1905–1911.

36. Kwa AL, Loh C, Low JG, Kurup A, Tam VH. Nebulized colistin in the treatment of pneumonia due to multidrug-resistant Acinetobacter baumannii and Pseudomonas aeruginosa. Clin Infect Dis. 2005; 41:754–757.

37. Lu Q, Luo R, Bodin L, Yang J, Zahr N, Aubry A, Golmard JL, Rouby JJ. Nebulized Antibiotics Study Group. Efficacy of high-dose nebulized colistin in ventilator-associated pneumonia caused by multidrug-resistant Pseudomonas aeruginosa and Acinetobacter baumannii. Anesthesiology. 2012; 117:1335–1347.

38. Neuner EA, Sekeres J, Hall GS, van Duin D. Experience with fosfomycin for treatment of urinary tract infections due to multidrug-resistant organisms. Antimicrob Agents Chemother. 2012; 56:5744–5748.

39. Dinh A, Salomon J, Bru JP, Bernard L. Fosfomycin: efficacy against infections caused by multidrug-resistant bacteria. Scand J Infect Dis. 2012; 44:182–189.

40. Pontikis K, Karaiskos I, Bastani S, Dimopoulos G, Kalogirou M, Katsiari M, Oikonomou A, Poulakou G, Roilides E, Giamarellou H. Outcomes of critically ill intensive care unit patients treated with fosfomycin for infections due to pandrug-resistant and extensively drug-resistant carbapenemase-producing Gram-negative bacteria. Int J Antimicrob Agents. 2014; 43:52–59.

41. Apisarnthanarak A, Mundy LM. Carbapenem-resistant Pseudomonas aeruginosa pneumonia with intermediate minimum inhibitory concentrations to doripenem: combination therapy with high-dose, 4-h infusion of doripenem plus fosfomycin versus intravenous colistin plus fosfomycin. Int J Antimicrob Agents. 2012; 39:271–272.

42. Takeda S, Nakai T, Wakai Y, Ikeda F, Hatano K. In vitro and in vivo activities of a new cephalosporin, FR264205, against Pseudomonas aeruginosa. Antimicrob Agents Chemother. 2007; 51:826–830.

43. Mushtaq S, Warner M, Livermore DM. In vitro activity of ceftazidime+NXL104 against Pseudomonas aeruginosa and other non-fermenters. J Antimicrob Chemother. 2010; 65:2376–2381.

44. Sievert DM, Ricks P, Edwards JR, Schneider A, Patel J, Srinivasan A, Kallen A, Limbago B, Fridkin S. National Healthcare Safety Network (NHSN) Team and Participating NHSN Facilities. 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; 34:1–14.

45. Bratu S, Tolaney P, Karumudi U, Quale J, Mooty M, Nichani S, Landman D. Carbapenemase-producing Klebsiella pneumoniae in Brooklyn, NY: molecular epidemiology and in vitro activity of polymyxin B and other agents. J Antimicrob Chemother. 2005; 56:128–132.

46. Castanheira M, Sader HS, Deshpande LM, Fritsche TR, Jones RN. Antimicrobial activities of tigecycline and other broad-spectrum antimicrobials tested against serine carbapenemase-and metallo-β-lactamase-producing Enterobacteriaceae: report from the SENTRY Antimicrobial Surveillance Program. Antimicrob Agents Chemother. 2008; 52:570–573.

47. Satlin MJ, Calfee DP, Chen L, Fauntleroy KA, Wilson SJ, Jenkins SG, Feldman EJ, Roboz GJ, Shore TB, Helfgott DC, Soave R, Kreiswirth BN, Walsh TJ. Emergence of carbapenem-resistant Enterobacteriaceae as causes of bloodstream infections in patients with hematologic malignancies. Leuk Lymphoma. 2013; 54:799–806.

48. Pena I, Picazo JJ, Rodríguez-Avial C, Rodríguez-Avial I. Carbapenemase-producing Enterobacteriaceae in a tertiary hospital in Madrid, Spain: high percentage of colistin resistance among VIM-1-producing Klebsiella pneumoniae ST11 isolates. Int J Antimicrob Agents. 2014; 43:460–464.

49. Poulakou G, Kontopidou FV, Paramythiotou E, Kompoti M, Katsiari M, Mainas E, Nicolaou C, Yphantis D, Antoniadou A, Trikka-Graphakos E, Roussou Z, Clouva P, Maguina N, Kanellakopoulou K, Armaganidis A, Giamarellou H. Tigecycline in the treatment of infections from multi-drug resistant gram-negative pathogens. J Infect. 2009; 58:273–284.

50. Kelesidis T, Karageorgopoulos DE, Kelesidis I, Falagas ME. Tigecycline for the treatment of multidrug-resistant Enterobacteriaceae: a systematic review of the evidence from microbiological and clinical studies. J Antimicrob Chemother. 2008; 62:895–904.

51. Cobo J, Morosini MI, Pintado V, Tato M, Samaranch N, Baquero F, Cantón R. Use of tigecycline for the treatment of prolonged bacteremia due to a multiresistant VIM-1 and SHV-12 β-lactamase-producing Klebsiella pneumoniae epidemic clone. Diagn Microbiol Infect Dis. 2008; 60:319–322.

52. Nordmann P, Cuzon G, Naas T. The real threat of Klebsiella pneumoniae carbapenemase-producing bacteria. Lancet Infect Dis. 2009; 9:228–236.

53. Bogdanovich T, Adams-Haduch JM, Tian GB, Nguyen MH, Kwak EJ, Muto CA, Doi Y. Colistin-resistant, Klebsiella pneumoniae carbapenemase (KPC)-producing Klebsiella pneumoniae belonging to the international epidemic clone ST258. Clin Infect Dis. 2011; 53:373–376.

54. Arnold RS, Thom KA, Sharma S, Phillips M, Johnson JK, Morgan DJ. Emergence of Klebsiella pneumoniae carbapenemase-producing bacteria. South Med J. 2011; 104:40–45.

55. Souli M, Kontopidou FV, Papadomichelakis E, Galani I, Armaganidis A, Giamarellou H. Clinical experience of serious infections caused by Enterobacteriaceae producing VIM-1 metallo-β-lactamase in a Greek University Hospital. Clin Infect Dis. 2008; 46:847–854.

56. Souli M, Galani I, Antoniadou A, Papadomichelakis E, Poulakou G, Panagea T, Vourli S, Zerva L, Armaganidis A, Kanellakopoulou K, Giamarellou H. An outbreak of infection due to β-lactamase Klebsiella pneumoniae carbapenemase 2-producing K. pneumoniae in a Greek university hospital: molecular characterization, epidemiology, and outcomes. Clin Infect Dis. 2010; 50:364–373.

57. Daikos GL, Petrikkos P, Psichogiou M, Kosmidis C, Vryonis E, Skoutelis A, Georgousi K, Tzouvelekis LS, Tassios PT, Bamia C, Petrikkos G. Prospective observational study of the impact of VIM-1 metallo-β-lactamase on the outcome of patients with Klebsiella pneumoniae bloodstream infections. Antimicrob Agents Chemother. 2009; 53:1868–1873.

58. Kontopidou F, Giamarellou H, Katerelos P, Maragos A, Kioumis I, Trikka-Graphakos E, Valakis C, Maltezou HC. Group for the Study of KPC-producing Klebsiella pneumoniae infections in intensive care units. Infections caused by carbapenem-resistant Klebsiella pneumoniae among patients in intensive care units in Greece: a multi-centre study on clinical outcome and therapeutic options. Clin Microbiol Infect. 2014; 20:O117–O123.

59. Hirsch EB, Tam VH. Detection and treatment options for Klebsiella pneumoniae carbapenemases (KPCs): an emerging cause of multidrug-resistant infection. J Antimicrob Chemother. 2010; 65:1119–1125.

60. Daikos GL, Markogiannakis A. Carbapenemase-producing Klebsiella pneumoniae: (when) might we still consider treating with carbapenems? Clin Microbiol Infect. 2011; 17:1135–1141.

61. Clancy CJ, Chen L, Shields RK, Zhao Y, Cheng S, Chavda KD, Hao B, Hong JH, Doi Y, Kwak EJ, Silveira FP, Abdel-Massih R, Bogdanovich T, Humar A, Perlin DS, Kreiswirth BN, Hong Nguyen M. Epidemiology and molecular characterization of bacteremia due to carbapenem-resistant Klebsiella pneumoniae in transplant recipients. Am J Transplant. 2013; 13:2619–2633.

62. Endimiani A, Patel G, Hujer KM, Swaminathan M, Perez F, Rice LB, Jacobs MR, Bonomo RA. In vitro activity of fosfomycin against bla_KPC-containing Klebsiella pneumoniae isolates, including those nonsusceptible to tigecycline and/or colistin. Antimicrob Agents Chemother. 2010; 54:526–529.

63. Michalopoulos A, Virtzili S, Rafailidis P, Chalevelakis G, Damala M, Falagas ME. Intravenous fosfomycin for the treatment of nosocomial infections caused by carbapenem-resistant Klebsiella pneumoniae in critically ill patients: a prospective evaluation. Clin Microbiol Infect. 2010; 16:184–186.

64. Karageorgopoulos DE, Miriagou V, Tzouvelekis LS, Spyridopoulou K, Daikos GL. Emergence of resistance to fosfomycin used as adjunct therapy in KPC Klebsiella pneumoniae bacteraemia: report of three cases. J Antimicrob Chemother. 2012; 67:2777–2779.

65. Livermore DM, Tulkens PM. Temocillin revived. J Antimicrob Chemother. 2009; 63:243–245.

66. Adams-Haduch JM, Potoski BA, Sidjabat HE, Paterson DL, Doi Y. Activity of temocillin against KPC-producing Klebsiella pneumoniae and Escherichia coli. Antimicrob Agents Chemother. 2009; 53:2700–2701.

67. Bulik CC, Nicolau DP. In vivo efficacy of simulated human dosing regimens of prolonged-infusion doripenem against carbapenemase-producing Klebsiella pneumoniae. Antimicrob Agents Chemother. 2010; 54:4112–4115.

68. Ho VP, Jenkins SG, Afaneh CI, Turbendian HK, Nicolau DP, Barie PS. Use of meropenem by continuous infusion to treat a patient with a bla_KPC-2-positive Klebsiella pneumoniae blood stream infection. Surg Infect (Larchmt). 2011; 12:325–327.

69. Tzouvelekis LS, Markogiannakis A, Piperaki E, Souli M, Daikos GL. Treating infections caused by carbapenemase-producing Enterobacteriaceae. Clin Microbiol Infect. 2014; [Epub ahead of print].

70. Qureshi ZA, Paterson DL, Potoski BA, Kilayko MC, Sandovsky G, Sordillo E, Polsky B, Adams-Haduch JM, Doi Y. Treatment outcome of bacteremia due to KPC-producing Klebsiella pneumoniae: superiority of combination antimicrobial regimens. Antimicrob Agents Chemother. 2012; 56:2108–2113.

71. Zarkotou O, Pournaras S, Tselioti P, Dragoumanos V, Pitiriga V, Ranellou K, Prekates A, Themeli-Digalaki K, Tsakris A. Predictors of mortality in patients with bloodstream infections caused by KPC-producing Klebsiella pneumoniae and impact of appropriate antimicrobial treatment. Clin Microbiol Infect. 2011; 17:1798–1803.

72. Tumbarello M, Viale P, Viscoli C, Trecarichi EM, Tumietto F, Marchese A, Spanu T, Ambretti S, Ginocchio F, Cristini F, Losito AR, Tedeschi S, Cauda R, Bassetti M. Predictors of mortality in bloodstream infections caused by Klebsiella pneumoniae carbapenemase-producing K. pneumoniae: importance of combination therapy. Clin Infect Dis. 2012; 55:943–950.

73. Daikos GL, Tsaousi S, Tzouvelekis LS, Anyfantis I, Psichogiou M, Argyropoulou A, Stefanou I, Sypsa V, Miriagou V, Nepka M, Georgiadou S, Markogiannakis A, Goukos D, Skoutelis A. Carbapenemase-producing Klebsiella pneumoniae bloodstream infections: lowering mortality by antibiotic combination schemes and the role of carbapenems. Antimicrob Agents Chemother. 2014; 58:2322–2328.

74. Lagacé-Wiens P, Walkty A, Karlowsky JA. Ceftazidime-avibactam: an evidence-based review of its pharmacology and potential use in the treatment of Gram-negative bacterial infections. Core Evid. 2014; 9:13–25.

75. Ehmann DE, Jahic H, Ross PL, Gu RF, Hu J, Durand-Réville TF, Lahiri S, Thresher J, Livchak S, Gao N, Palmer T, Walkup GK, Fisher SL. Kinetics of avibactam inhibition against Class A, C, and D β-lactamases. J Biol Chem. 2013; 288:27960–27971.

76. Mushtaq S, Warner M, Williams G, Critchley I, Livermore DM. Activity of chequerboard combinations of ceftaroline and NXL104 versus β-lactamase-producing Enterobacteriaceae. J Antimicrob Chemother. 2010; 65:1428–1432.

77. Stachyra T, Levasseur P, Péchereau MC, Girard AM, Claudon M, Miossec C, Black MT. In vitro activity of the β-lactamase inhibitor NXL104 against KPC-2 carbapenemase and Enterobacteriaceae expressing KPC carbapenemases. J Antimicrob Chemother. 2009; 64:326–329.

78. Endimiani A, Hujer KM, Hujer AM, Armstrong ES, Choudhary Y, Aggen JB, Bonomo RA. ACHN-490, a neoglycoside with potent in vitro activity against multidrug-resistant Klebsiella pneumoniae isolates. Antimicrob Agents Chemother. 2009; 53:4504–4507.

79. Nordmann P, Poirel L. Emerging carbapenemases in Gram-negative aerobes. Clin Microbiol Infect. 2002; 8:321–331.

80. Kim YA, Qureshi ZA, Adams-Haduch JM, Park YS, Shutt KA, Doi Y. Features of infections due to Klebsiella pneumoniae carbapenemase-producing Escherichia coli: emergence of sequence type 131. Clin Infect Dis. 2012; 55:224–231.

81. Landman D, Urban C, Bäcker M, Kelly P, Shah N, Babu E, Bratu S, Quale J. Susceptibility profiles, molecular epidemiology, and detection of KPC-producing Escherichia coli isolates from the New York City vicinity. J Clin Microbiol. 2010; 48:4604–4607.

82. O'Hara JA, Hu F, Ahn C, Nelson J, Rivera JI, Pasculle AW, Doi Y. Molecular epidemiology of KPC-producing Escherichia coli: Occurrence of ST131-fimH30 subclone harboring pKpQIL-like IncFIIk plasmid. Antimicrob Agents Chemother. 2014; 58:4234–4237.

83. Zhanel GG, Denisuik A, Vashisht S, Yachison C, Adam HJ, Hoban DJ. Pharmacodynamic activity of ertapenem versus genotypically characterized extended-spectrum β-lactamase (ESBL)-, KPC- or NDM-producing Escherichia coli with reduced susceptibility or resistance to ertapenem using an in vitro model. J Antimicrob Chemother. 2014; 69:2448–2452.

84. Kaase M, Szabados F, Anders A, Gatermann SG. Fosfomycin susceptibility in carbapenem-resistant Enterobacteriaceae from Germany. J Clin Microbiol. 2014; 52:1893–1897.

85. Novak A, Goic-Barisic I, Tambic Andrasevic A, Butic I, Radic M, Jelic M, Rubic Z, Tonkic M. Monoclonal outbreak of VIM-1-carbapenemase-producing Enterobacter cloacae in intensive care unit, University Hospital Centre Split, Croatia. Microb Drug Resist. 2014; [Epub ahead of print].

86. Lee Y, Choi H, Yum JH, Kang G, Bae IK, Jeong SH, Lee K. Molecular mechanisms of carbapenem resistance in Enterobacter cloacae clinical isolates from Korea and clinical outcome. Ann Clin Lab Sci. 2012; 42:281–286.

87. Ahn C, Syed A, Hu F, O'Hara JA, Rivera JI, Doi Y. Microbiological features of KPC-producing Enterobacter isolates identified in a U.S. hospital system. Diagn Microbiol Infect Dis. 2014; 80:154–158.

88. Nicodemo AC, Paez JI. Antimicrobial therapy for Stenotrophomonas maltophilia infections. Eur J Clin Microbiol Infect Dis. 2007; 26:229–237.

89. Lai CH, Chi CY, Chen HP, Chen TL, Lai CJ, Fung CP, Yu KW, Wong WW, Liu CY. Clinical characteristics and prognostic factors of patients with Stenotrophomonas maltophilia bacteremia. J Microbiol Immunol Infect. 2004; 37:350–358.

90. Senol E, DesJardin J, Stark PC, Barefoot L, Snydman DR. Attributable mortality of Stenotrophomonas maltophilia bacteremia. Clin Infect Dis. 2002; 34:1653–1656.

91. Nseir S, Di Pompeo C, Brisson H, Dewavrin F, Tissier S, Diarra M, Boulo M, Durocher A. Intensive care unit-acquired Stenotrophomonas maltophilia: incidence, risk factors, and outcome. Crit Care. 2006; 10:R143.

92. Brooke JS. Stenotrophomonas maltophilia: an emerging global opportunistic pathogen. Clin Microbiol Rev. 2012; 25:2–41.

93. Wang YL, Scipione MR, Dubrovskaya Y, Papadopoulos J. Monotherapy with fluoroquinolone or trimethoprim-sulfamethoxazole for treatment of Stenotrophomonas maltophilia infections. Antimicrob Agents Chemother. 2014; 58:176–182.

94. Cho SY, Kang CI, Kim J, Ha YE, Chung DR, Lee NY, Peck KR, Song JH. Can levofloxacin be a useful alternative to trimethoprim-sulfamethoxazole for treating Stenotrophomonas maltophilia bacteremia? Antimicrob Agents Chemother. 2014; 58:581–583.

95. Lakatos B, Jakopp B, Widmer A, Frei R, Pargger H, Elzi L, Battegay M. Evaluation of treatment outcomes for Stenotrophomonas maltophilia bacteraemia. Infection. 2014; 42:553–558.

96. Tekçe YT, Erbay A, Cabadak H, Sen S. Tigecycline as a therapeutic option in Stenotrophomonas maltophilia infections. J Chemother. 2012; 24:150–154.