Advertisement

Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

Carbapenem-Resistant Enterobacterales: Considerations for Treatment in the Era of New Antimicrobials and Evolving Enzymology

Abstract

Purpose of Review

Gram-negative resistance is a growing concern globally. Enterobacterales, formerly Enterobacteriaceae, have developed resistance mechanisms to carbapenems that leave very few antimicrobial options in the clinician’s armamentarium.

Recent Findings

New antimicrobials like ceftazidime-avibactam, meropenem-vaborbactam, imipenem-relebactam, cefiderocol, and plazomicin have the potential to overcome resistance mechanisms in Enterobacterales including different classes of carbapenemases.

Summary

Novel β-lactam/β-lactamase inhibitors, plazomicin, and cefiderocol give the clinician options that were once not available. Utilizing these options is of the utmost importance when treating carbapenem-resistant Enterobacterales.

This is a preview of subscription content, log in to check access.

Fig. 1

References

  1. 1.

    World Health Organization. Top ten threats to global health in 2019. 2019 [cited 2019]; Available from: https://www.who.int/emergencies/ten-threats-to-global-health-in-2019. Accessed Nov 2019.

  2. 2.

    Center for Disease Control and Prevention. Antibiotic resistance threats in the United States. 2013 [cited 2019]; Available from: https://www.cdc.gov/drugresistance/threat-report-2013/pdf/ar-threats-2013-508.pdf. Accessed Nov 2019.

  3. 3.

    Center for Disease Control and Prevention. Tracking CRE HAI. 2019 May, 9, 2019; Available from: https://www.cdc.gov/hai/organisms/cre/trackingcre.html. Accessed Nov 2019.

  4. 4.

    Thaden JT, Pogue JM, Kaye KS. Role of newer and re-emerging older agents in the treatment of infections caused by carbapenem-resistant Enterobacteriaceae. Virulence. 2017;8(4):403–16.

  5. 5.

    Trecarichi EM, et al. Bloodstream infections caused by Klebsiella pneumoniae in onco-hematological patients: clinical impact of carbapenem resistance in a multicentre prospective survey. Am J Hematol. 2016;91(11):1076–81.

  6. 6.

    Facility guidance for control of carbapenem-resistant Enterobacteriaceae (CRE). 2015 November 2015; Available from: https://www.cdc.gov/hai/pdfs/cre/CRE-guidance-508.pdf. Accessed Nov 2019.

  7. 7.

    Logan LK, Weinstein RA. The epidemiology of carbapenem-resistant Enterobacteriaceae: the impact and evolution of a global menace. J Infect Dis. 2017;215(suppl_1):S28–s36.

  8. 8.

    Tängdén T, Adler M, Cars O, Sandegren L, Löwdin E. Frequent emergence of porin-deficient subpopulations with reduced carbapenem susceptibility in ESBL-producing Escherichia coli during exposure to ertapenem in an in vitro pharmacokinetic model. J Antimicrob Chemother. 2013;68(6):1319–26.

  9. 9.

    Yang F-C, et al. Characterization of Ertapenem-resistant Enterobacter cloacae in a Taiwanese university hospital. J Clin Microbiol. 2012;50(2):223–6.

  10. 10.

    Tamma PD, Goodman KE, Harris AD, Tekle T, Roberts A, Taiwo A, et al. Comparing the outcomes of patients with carbapenemase-producing and non-carbapenemase-producing carbapenem-resistant Enterobacteriaceae bacteremia. Clin Infect Dis. 2016;64(3):257–64.

  11. 11.

    Stewart A, et al. Treatment of infections by OXA-48-producing Enterobacteriaceae. Antimicrob Agents Chemother. 2018;62(11):e01195–18.

  12. 12.

    Walther-Rasmussen J, Høiby N. OXA-type carbapenemases. J Antimicrob Chemother. 2006;57(3):373–83.

  13. 13.

    Potter RF, D'Souza AW, Dantas G. The rapid spread of carbapenem-resistant Enterobacteriaceae. Drug Resist Updat. 2016;29:30–46.

  14. 14.

    van Duin D, Doi Y. The global epidemiology of carbapenemase-producing Enterobacteriaceae. Virulence. 2017;8(4):460–9.

  15. 15.

    Walsh TR. The emergence and implications of metallo-β-lactamases in Gram-negative bacteria. Clin Microbiol Infect. 2005;11:2–9.

  16. 16.

    Yigit H, Queenan AM, Anderson GJ, Domenech-Sanchez A, Biddle JW, Steward CD, et al. Novel carbapenem-hydrolyzing β-lactamase, KPC-1, from a carbapenem-resistant strain of Klebsiella pneumoniae. Antimicrob Agents Chemother. 2001;45(4):1151–61.

  17. 17.

    Yong D, et al. Characterization of a new metallo-β-lactamase gene, Bla-NDM-1, and a novel erythromycin esterase gene carried on a unique genetic structure in Klebsiella pneumoniae sequence type 14 from India. Antimicrob Agents Chemother. 2009;53(12):5046–54.

  18. 18.

    Aloush V, Navon-Venezia S, Seigman-Igra Y, Cabili S, Carmeli Y. Multidrug-resistant Pseudomonas aeruginosa: risk factors and clinical impact. Antimicrob Agents Chemother. 2006;50(1):43–8.

  19. 19.

    Nation RL, Velkov T, Li J. Colistin and polymyxin B: peas in a pod, or chalk and cheese? Clin Infect Dis. 2014;59(1):88–94.

  20. 20.

    Tsuji BT, Pogue JM, Zavascki AP, Paul M, Daikos GL, Forrest A, et al. International Consensus guidelines for the optimal use of the polymyxins: endorsed by the American College of Clinical Pharmacy (ACCP), European Society of Clinical Microbiology and Infectious Diseases (ESCMID), Infectious Diseases Society of America (IDSA), International Society for Anti-infective Pharmacology (ISAP), Society of Critical Care Medicine (SCCM), and Society of Infectious Diseases Pharmacists (SIDP). Pharmacotherapy. 2019;39(1):10–39.

  21. 21.

    Capone A, Giannella M, Fortini D, Giordano A, Meledandri M, Ballardini M, et al. High rate of colistin resistance among patients with carbapenem-resistant Klebsiella pneumoniae infection accounts for an excess of mortality. Clin Microbiol Infect. 2013;19(1):E23–e30.

  22. 22.

    Markou N, Apostolakos H, Koumoudiou C, Athanasiou M, Koutsoukou A, Alamanos I, et al. Intravenous colistin in the treatment of sepsis from multiresistant Gram-negative bacilli in critically ill patients. Crit Care. 2003;7(5):R78–83.

  23. 23.

    Perez F, et al. Polymyxins: to combine or not to combine? Antibiotics (Basel). 2019;8(2).

  24. 24.

    Qureshi ZA, Paterson DL, Potoski BA, Kilayko MC, Sandovsky G, Sordillo E, et al. Treatment outcome of bacteremia due to KPC-producing Klebsiella pneumoniae: superiority of combination antimicrobial regimens. Antimicrob Agents Chemother. 2012;56(4):2108–13.

  25. 25.

    Sandri AM, Landersdorfer CB, Jacob J, Boniatti MM, Dalarosa MG, Falci DR, et al. Population pharmacokinetics of intravenous polymyxin B in critically ill patients: implications for selection of dosage regimens. Clin Infect Dis. 2013;57(4):524–31.

  26. 26.

    Thamlikitkul V, et al. Dosing and pharmacokinetics of polymyxin B in patients with renal insufficiency. Antimicrob Agents Chemother. 2017;61(1):e01337–16.

  27. 27.

    Krause KM, et al. Aminoglycosides: an overview. Cold Spring Harb Perspect Med. 2016;6(6).

  28. 28.

    Nicolau DP, et al. Experience with a once-daily aminoglycoside program administered to 2,184 adult patients. Antimicrob Agents Chemother. 1995;39(3):650–5.

  29. 29.

    Doi Y, Arakawa Y. 16S ribosomal RNA methylation: emerging resistance mechanism against aminoglycosides. Clin Infect Dis. 2007;45(1):88–94.

  30. 30.

    Zhou Y, Yu H, Guo Q, Xu X, Ye X, Wu S, et al. Distribution of 16S rRNA methylases among different species of Gram-negative bacilli with high-level resistance to aminoglycosides. Eur J Clin Microbiol Infect Dis. 2010;29(11):1349–53.

  31. 31.

    Abdelraouf K, et al. In vivo efficacy of plazomicin alone or in combination with meropenem or tigecycline against Enterobacteriaceae isolates exhibiting various resistance mechanisms in an immunocompetent murine septicemia model. Antimicrob Agents Chemother. 2018;62(8):e01074–18.

  32. 32.

    Castanheira M, et al. In vitro activity of plazomicin against Gram-negative and Gram-positive isolates collected from U.S. hospitals and comparative activities of aminoglycosides against carbapenem-resistant Enterobacteriaceae and isolates carrying carbapenemase genes. Antimicrob Agents Chemother. 2018;62(8).

  33. 33.

    Zhang Y, Kashikar A, Bush K. In vitro activity of plazomicin against beta-lactamase-producing carbapenem-resistant Enterobacteriaceae (CRE). J Antimicrob Chemother. 2017;72(10):2792–5.

  34. 34.

    McKinnell JA, et al. Plazomicin for infections caused by carbapenem-resistant Enterobacteriaceae. N Engl J Med. 2019;380(8):791–3.

  35. 35.

    Kuti JL, et al. Evaluation of plazomicin, tigecycline, and meropenem pharmacodynamic exposure against carbapenem-resistant Enterobacteriaceae in patients with bloodstream infection or hospital-acquired/ventilator-associated pneumonia from the CARE study (ACHN-490-007). Infect Dis Ther. 2019.

  36. 36.

    Asempa TE, et al. A simulated application of the Hartford Hospital aminoglycoside dosing nomogram for plazomicin dosing interval selection in patients with serious infections caused by carbapenem-resistant Enterobacterales. Clin Ther. 2019.

  37. 37.

    Asempa TE, et al. Application of the Hartford Hospital nomogram for plazomicin dosing interval selection in patients with complicated urinary tract infection. Antimicrob Agents Chemother. 2019;63(10):e00148–19.

  38. 38.

    Bulik CC, Nicolau DP. Double-carbapenem therapy for carbapenemase-producing Klebsiella pneumoniae. Antimicrob Agents Chemother. 2011;55(6):3002–4.

  39. 39.

    Cprek JB, Gallagher JC. Ertapenem-containing double-carbapenem therapy for treatment of infections caused by carbapenem-resistant Klebsiella pneumoniae. Antimicrob Agents Chemother. 2016;60(1):669–73.

  40. 40.

    De Pascale G, et al. Double carbapenem as a rescue strategy for the treatment of severe carbapenemase-producing Klebsiella pneumoniae infections: a two-center, matched case-control study. Crit Care. 2017;21(1):173.

  41. 41.

    Giamarellou H, Galani L, Baziaka F, Karaiskos I. Effectiveness of a double-carbapenem regimen for infections in humans due to carbapenemase-producing pandrug-resistant Klebsiella pneumoniae. Antimicrob Agents Chemother. 2013;57(5):2388–90.

  42. 42.

    Souli M, Karaiskos I, Masgala A, Galani L, Barmpouti E, Giamarellou H. Double-carbapenem combination as salvage therapy for untreatable infections by KPC-2-producing Klebsiella pneumoniae. Eur J Clin Microbiol Infect Dis. 2017;36(7):1305–15.

  43. 43.

    Coleman K. Diazabicyclooctanes (DBOs): a potent new class of non-beta-lactam beta-lactamase inhibitors. Curr Opin Microbiol. 2011;14(5):550–5.

  44. 44.

    Kazmierczak KM, et al. In vitro activity of ceftazidime-avibactam and aztreonam-avibactam against OXA-48-carrying Enterobacteriaceae isolated as part of the international network for optimal resistance monitoring (INFORM) global surveillance program from 2012 to 2015. Antimicrob Agents Chemother. 2018;62(12):e00592–18.

  45. 45.

    Karlowsky JA, et al. In vitro activity of aztreonam-avibactam against Enterobacteriaceae and Pseudomonas aeruginosa isolated by clinical laboratories in 40 countries from 2012 to 2015. Antimicrob Agents Chemother. 2017;61(9):e00472–17.

  46. 46.

    Marshall S, et al. Can ceftazidime-avibactam and aztreonam overcome β-lactam resistance conferred by metallo-β-lactamases in Enterobacteriaceae? Antimicrob Agents Chemother. 2017;61(4):e02243–16.

  47. 47.

    Wenzler E, Deraedt MF, Harrington AT, Danizger LH. Synergistic activity of ceftazidime-avibactam and aztreonam against serine and metallo-beta-lactamase-producing Gram-negative pathogens. Diagn Microbiol Infect Dis. 2017;88(4):352–4.

  48. 48.

    Castón JJ, Lacort-Peralta I, Martín-Dávila P, Loeches B, Tabares S, Temkin L, et al. Clinical efficacy of ceftazidime/avibactam versus other active agents for the treatment of bacteremia due to carbapenemase-producing Enterobacteriaceae in hematologic patients. Int J Infect Dis. 2017;59:118–23.

  49. 49.

    Shields RK, et al. Ceftazidime-avibactam is superior to other treatment regimens against carbapenem-resistant Klebsiella pneumoniae bacteremia. Antimicrob Agents Chemother. 2017;61(8):e00883–17.

  50. 50.

    Sousa A, Pérez-Rodríguez MT, Soto A, Rodríguez L, Pérez-Landeiro A, Martínez-Lamas L, et al. Effectiveness of ceftazidime/avibactam as salvage therapy for treatment of infections due to OXA-48 carbapenemase-producing Enterobacteriaceae. J Antimicrob Chemother. 2018;73(11):3170–5.

  51. 51.

    Temkin E, et al. Ceftazidime-avibactam as salvage therapy for infections caused by carbapenem-resistant organisms. Antimicrob Agents Chemother. 2017;61(2):e01964–16.

  52. 52.

    Tumbarello M, et al. Efficacy of ceftazidime-avibactam salvage therapy in patients with infections caused by Klebsiella pneumoniae Carbapenemase–producing K. pneumoniae. Clin Infect Dis. 2018;68(3):355–64.

  53. 53.

    van Duin D, et al. Colistin versus ceftazidime-avibactam in the treatment of infections due to carbapenem-resistant Enterobacteriaceae. Clin Infect Dis. 2017;66(2):163–71.

  54. 54.

    Shields RK, Potoski BA, Haidar G, Hao B, Doi Y, Chen L, et al. Clinical outcomes, drug toxicity, and emergence of ceftazidime-avibactam resistance among patients treated for carbapenem-resistant Enterobacteriaceae infections. Clin Infect Dis. 2016;63(12):1615–8.

  55. 55.

    Lomovskaya O, et al. Vaborbactam: spectrum of beta-lactamase inhibition and impact of resistance mechanisms on activity in Enterobacteriaceae. Antimicrob Agents Chemother. 2017;61(11):e01443–17.

  56. 56.

    Shields RK, et al. Pneumonia and renal replacement therapy are risk factors for ceftazidime-avibactam treatment failures and resistance among patients with carbapenem-resistant Enterobacteriaceae infections. Antimicrob Agents Chemother. 2018;62(5):e02497–17.

  57. 57.

    Sabet M, et al. Activity of meropenem-vaborbactam in mouse models of infection due to KPC-producing carbapenem-resistant Enterobacteriaceae. Antimicrob Agents Chemother. 2018;62(1):e01446–17.

  58. 58.

    Wunderink RG, et al. Effect and safety of meropenem-vaborbactam versus best-available therapy in patients with carbapenem-resistant Enterobacteriaceae infections: the TANGO II randomized clinical trial. Infect Dis Ther. 2018;7(4):439–55.

  59. 59.

    CLSI. Performance standards for antimicrobial susceptibility testing. 29th ed. Clinical and Laboratory Standards Institute: Wayne; 2019.

  60. 60.

    Canver MC, et al. Activity of imipenem-relebactam and comparator agents against genetically characterized isolates of carbapenem-resistant Enterobacteriaceae. Antimicrob Agents Chemother. 2019.

  61. 61.

    Zhanel GG, et al. Imipenem-relebactam and meropenem-vaborbactam: two novel carbapenem-beta-lactamase inhibitor combinations. Drugs. 2018;78(1):65–98.

  62. 62.

    Asempa TE, Nicolau DP, Kuti JL. Activity of imipenem-relebactam alone or in combination with amikacin or colistin against Pseudomonas aeruginosa. Antimicrob Agents Chemother. 2019;63(9):e00997–19.

  63. 63.

    Haidar G, et al. Identifying spectra of activity and therapeutic niches for ceftazidime-avibactam and imipenem-relebactam against carbapenem-resistant Enterobacteriaceae. Antimicrob Agents Chemother. 2017;61(9):e00642–17.

  64. 64.

    Lob SH, et al. In vitro activity of imipenem-relebactam against Gram-negative ESKAPE pathogens isolated by clinical laboratories in the United States in 2015 (results from the SMART global surveillance program). Antimicrob Agents Chemother. 2017;61(6):e02209–16.

  65. 65.

    Lucasti C, Vasile L, Sandesc D, Venskutonis D, McLeroth P, Lala M, et al. Phase 2, dose-ranging study of relebactam with imipenem-cilastatin in subjects with complicated intra-abdominal infection. Antimicrob Agents Chemother. 2016;60(10):6234–43.

  66. 66.

    Powles MA, et al. In vivo efficacy of relebactam (MK-7655) in combination with imipenem-cilastatin in murine infection models. Antimicrob Agents Chemother. 2018;62(8):e02577–17.

  67. 67.

    Motsch J, et al. RESTORE-IMI 1: a multicenter, randomized, double-blind trial comparing efficacy and safety of imipenem/relebactam vs colistin plus imipenem in patients with imipenem-nonsusceptible bacterial infections. Clin Infect Dis. 2019.

  68. 68.

    Monogue ML, et al. In vivo efficacy of WCK 5222 (cefepime-zidebactam) against multidrug-resistant Pseudomonas aeruginosa in the neutropenic murine thigh infection model. Antimicrob Agents Chemother. 2019;63(7):e00233–19.

  69. 69.

    Moya B, et al. In vitro and in vivo activities of β-lactams in combination with the novel β-lactam enhancers zidebactam and WCK 5153 against multidrug-resistant metallo-β-lactamase-producing Klebsiella pneumoniae. Antimicrob Agents Chemother. 2019;63(5):e00128–19.

  70. 70.

    Hackel MA, et al. In vitro activity of the siderophore cephalosporin, cefiderocol, against a recent collection of clinically relevant Gram-negative bacilli from North America and Europe, including carbapenem-nonsusceptible isolates (SIDERO-WT-2014 study). Antimicrob Agents Chemother. 2017;61(9):e00093–17.

  71. 71.

    Ito A, Nishikawa T, Matsumoto S, Yoshizawa H, Sato T, Nakamura R, et al. Siderophore cephalosporin cefiderocol utilizes ferric iron transporter systems for antibacterial activity against Pseudomonas aeruginosa. Antimicrob Agents Chemother. 2016;60(12):7396–401.

  72. 72.

    Katsube T, Echols R, Arjona Ferreira JC, Krenz HK, Berg JK, Galloway C. Cefiderocol, a siderophore cephalosporin for Gram-negative bacterial infections: pharmacokinetics and safety in subjects with renal impairment. J Clin Pharmacol. 2017;57(5):584–91.

  73. 73.

    Matsumoto S, et al. Efficacy of cefiderocol against carbapenem-resistant Gram-negative bacilli in immunocompetent-rat respiratory tract infection models recreating human plasma pharmacokinetics. Antimicrob Agents Chemother. 2017;61(9):e00700–17.

  74. 74.

    Stainton SM, et al. Efficacy of humanized cefiderocol exposures over 72 hours against a diverse group of Gram-negative isolates in the neutropenic murine thigh infection model. Antimicrob Agents Chemother. 2019;63(2):e01040–18.

  75. 75.

    Katsube T, Saisho Y, Shimada J, Furuie H. Intrapulmonary pharmacokinetics of cefiderocol, a novel siderophore cephalosporin, in healthy adult subjects. J Antimicrob Chemother. 2019;74(7):1971–4.

  76. 76.

    Portsmouth S, van Veenhuyzen D, Echols R, Machida M, Ferreira JCA, Ariyasu M, et al. Cefiderocol versus imipenem-cilastatin for the treatment of complicated urinary tract infections caused by Gram-negative uropathogens: a phase 2, randomised, double-blind, non-inferiority trial. Lancet Infect Dis. 2018;18(12):1319–28.

  77. 77.

    Falagas ME, Vouloumanou EK, Samonis G, Vardakas KZ. Fosfomycin. Clin Microbiol Rev. 2016;29(2):321–47.

  78. 78.

    Pogue JM, et al. Fosfomycin activity versus carbapenem-resistant Enterobacteriaceae and vancomycin-resistant Enterococcus, Detroit, 2008–10. J Antibiot. 2013;66:625.

  79. 79.

    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(2):184–6.

  80. 80.

    Williams PCM, Waichungo J, Gordon NC, Sharland M, Murunga S, Kamau A, et al. The potential of fosfomycin for multi-drug resistant sepsis: an analysis of in vitro activity against invasive paediatric Gram-negative bacteria. J Med Microbiol. 2019;68(5):711–9.

  81. 81.

    Kaye KS, et al. Fosfomycin for injection (ZTI-01) vs piperacillin-tazobactam (PIP-TAZ) for the treatment of complicated urinary tract infection (cUTI) including acute pyelonephritis (AP): ZEUS, a phase 2/3 randomized trial. Clin Infect Dis. 2019.

  82. 82.

    Avery LM, Sutherland CA, Nicolau DP. In vitro investigation of synergy among fosfomycin and parenteral antimicrobials against carbapenemase-producing Enterobacteriaceae. Diagn Microbiol Infect Dis. 2019.

  83. 83.

    Gutiérrez-Gutiérrez B, Salamanca E, de Cueto M, Hsueh PR, Viale P, Paño-Pardo JR, et al. Effect of appropriate combination therapy on mortality of patients with bloodstream infections due to carbapenemase-producing Enterobacteriaceae (INCREMENT): a retrospective cohort study. Lancet Infect Dis. 2017;17(7):726–34.

  84. 84.

    Clancy CJ, et al. Estimating the treatment of carbapenem-resistant Enterobacteriaceae infections in the United States using antibiotic prescription data. Open Forum Infect Dis. 2019;6(8).

  85. 85.

    Giannella M, Trecarichi EM, de Rosa FG, del Bono V, Bassetti M, Lewis RE, et al. Risk factors for carbapenem-resistant Klebsiella pneumoniae bloodstream infection among rectal carriers: a prospective observational multicentre study. Clin Microbiol Infect. 2014;20(12):1357–62.

  86. 86.

    Borer A, Saidel-Odes L, Eskira S, Nativ R, Riesenberg K, Livshiz-Riven I, et al. Risk factors for developing clinical infection with carbapenem-resistant Klebsiella pneumoniae in hospital patients initially only colonized with carbapenem-resistant K pneumoniae. Am J Infect Control. 2012;40(5):421–5.

Download references

Author information

Correspondence to David P. Nicolau.

Ethics declarations

Conflict of Interest

MJL has no conflicts of interest to declare.

DPN is a consultant, speaker’s bureau member, or have received research funding from Allergan, Bayer, Cepheid, Merck, Melinta, Pfizer, Wockhardt, Shionogi, and Tetraphase.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article is part of the Topical Collection on Antimicrobial Development and Drug Resistance

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Lasko, M.J., Nicolau, D.P. Carbapenem-Resistant Enterobacterales: Considerations for Treatment in the Era of New Antimicrobials and Evolving Enzymology. Curr Infect Dis Rep 22, 6 (2020). https://doi.org/10.1007/s11908-020-0716-3

Download citation

Keywords

  • Resistance
  • Carbapenemase
  • Enterobacterales
  • Enterobacteriaceae