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Treatment for carbapenem-resistant Enterobacterales infections: recent advances and future directions

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Abstract

Carbapenem-resistant Enterobacterales (CRE) are a growing threat to human health worldwide. CRE often carry multiple resistance genes that limit treatment options and require longer durations of therapy, are more costly to treat, and necessitate therapies with increased toxicities when compared with carbapenem-susceptible strains. Here, we provide an overview of the mechanisms of resistance in CRE, the epidemiology of CRE infections worldwide, and available treatment options for CRE. We review recentlyapproved agents for the treatment of CRE, including ceftazidime-avibactam, meropenem-vaborbactam, imipenem-relebactam, cefiderocol, and novel aminoglycosides and tetracyclines. We also discuss recent advances in phage therapy and antibiotics that are currently in development targeted to CRE. The potential for the development of resistance to these therapies remains high, and enhanced antimicrobial stewardship is imperative both to reduce the spread of CRE worldwide and to ensure continued access to efficacious treatment options.

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References

  1. The World Health Organization . Antibiotic resistance. https://www.who.int/news-room/fact-sheets/detail/antibiotic-resistance. Accessed 25 Feb 2021

  2. United States Centers for Disease Control and Prevention. Clinicians: Information about CRE. https://www.cdc.gov/hai/organisms/cre/cre-clinicians.html (2019). Accessed 25 Feb 2021

  3. Papp-Wallace KM, Endimiani A, Taracila MA, Bonomo RA (2011) Carbapenems: past, present, and future. Antimicrob Agents Chemother 55:4943–4960

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. van Duin D, Doi Y (2017) The global epidemiology of carbapenemase-producing Enterobacteriaceae. Virulence 8:460–469

    Article  PubMed  CAS  Google Scholar 

  5. Nordmann P, Poirel L (2014) The difficult-to-control spread of carbapenemase producers among Enterobacteriaceae worldwide. Clin Microbiol Infect 20:821–830

    Article  CAS  PubMed  Google Scholar 

  6. Nordmann P, Naas T, Poirel L (2011) Global spread of Carbapenemase-producing Enterobacteriaceae. Emerg Infect Dis 17:1791–1798

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Bonomo RA et al (2018) Carbapenemase-Producing Organisms: A Global Scourge. Clin Infect Dis 66:1290–1297

    Article  CAS  PubMed  Google Scholar 

  8. Kelly AM, Mathema B, Larson EL (2017) Carbapenem-resistant Enterobacteriaceae in the community: a scoping review. Int J Antimicrob Agents 50:127–134

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Barbadoro P et al (2021) Carriage of Carbapenem-Resistant Enterobacterales in Adult Patients Admitted to a University Hospital in Italy. Antibiotics (Basel) 10:61

    Article  Google Scholar 

  10. Hu H et al (2020) Clinical and microbiological characteristics of community-onset Carbapenem-resistant Enterobacteriaceae isolates. Infect Drug Resist 13:3131–3143

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. van Duin D, Paterson DL (2020) Multidrug-resistant bacteria in the community: an update. Infect Dis Clin North Am 34:709–722

    Article  PubMed  PubMed Central  Google Scholar 

  12. Taggar G, Attiq Rheman M, Boerlin P, Diarra MS (2020) Molecular Epidemiology of Carbapenemases in Enterobacteriales from Humans, Animals Food and the Environment. Antibiotics (Basel) 9:693

    Article  CAS  Google Scholar 

  13. Martin A, Fahrbach K, Zhao Q, Lodise T (2018) Association Between Carbapenem Resistance and Mortality Among Adult, Hospitalized Patients With Serious Infections Due to Enterobacteriaceae: Results of a Systematic Literature Review and Meta-analysis. Open Forum Infect Dis 5:ofy150

    Article  PubMed  PubMed Central  Google Scholar 

  14. Kohler PP et al (2017) Carbapenem resistance, initial antibiotic therapy, and mortality in Klebsiella pneumoniae bacteremia: a systematic review and meta-analysis. Infect Control Hosp Epidemiol 38:1319–1328

    Article  PubMed  Google Scholar 

  15. Zilberberg MD, Nathanson BH, Sulham K, Fan W, Shorr AF (2017) Carbapenem resistance, inappropriate empiric treatment and outcomes among patients hospitalized with Enterobacteriaceae urinary tract infection, pneumonia and sepsis. BMC Infect Dis 17:279

    Article  PubMed  PubMed Central  Google Scholar 

  16. Bartsch SM et al (2017) Potential economic burden of carbapenem-resistant Enterobacteriaceae (CRE) in the United States. Clin Microbiol Infect 23(48):e9-48.e16

    Google Scholar 

  17. Igbinosa O, Dogho P, Osadiaye N (2020) Carbapenem-resistant Enterobacteriaceae: A retrospective review of treatment and outcomes in a long-term acute care hospital. Am J Infect Control 48:7–12

    Article  PubMed  Google Scholar 

  18. Adar A et al (2021) Clinical and Demographic Characteristics of Patients With a New Diagnosis of Carriage or Clinical Infection With Carbapenemase-Producing Enterobacterales: A Retrospective Study. Front Public Health 9:616793

    Article  PubMed  PubMed Central  Google Scholar 

  19. Voor In’t Holt AF, Severin JA, Lesaffre EMEH, Vos MC (2014) A systematic review and meta-analyses show that carbapenem use and medical devices are the leading risk factors for carbapenem-resistant Pseudomonas aeruginosa. Antimicrob Agents Chemother 58:2626–2637

    Article  CAS  Google Scholar 

  20. Tamma PD et al (2020) Infectious Diseases Society of America Guidance on the Treatment of Extended-Spectrum β-lactamase Producing Enterobacterales (ESBL-E), Carbapenem-Resistant Enterobacterales (CRE), and Pseudomonas aeruginosa with Difficult-to-Treat Resistance (DTR-P. aeruginosa). Clin Infect Dis doi:https://doi.org/10.1093/cid/ciaa1478

  21. Ruppé É, Woerther P-L, Barbier F (2015) Mechanisms of antimicrobial resistance in Gram-negative bacilli. Ann Intensive Care 5:61

    Article  PubMed  CAS  Google Scholar 

  22. Nordmann P, Poirel L (2019) Epidemiology and Diagnostics of Carbapenem Resistance in Gram-negative Bacteria. Clin Infect Dis 69:S521–S528

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Queenan AM, Bush K (2007) Carbapenemases: the versatile beta-lactamases. Clin Microbiol Rev 20:440–58 (table of contents)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Bush K, Bradford PA (2020) Epidemiology of β-Lactamase-Producing Pathogens. Clin Microbio Rev 33:e00047-19

    CAS  Google Scholar 

  25. Kazmierczak KM, Karlowsky JA, de Jonge BLM, Stone GG, Sahm DF (2021) Epidemiology of Carbapenem Resistance Determinants Identified in Meropenem-nonsusceptible Enterobacterales collected as part of a Global Surveillance Program, 2012–2017. Antimicrob Agents Chemother. https://doi.org/10.1128/AAC.02000-20

    Article  PubMed  PubMed Central  Google Scholar 

  26. van Duin D et al (2020) Molecular and clinical epidemiology of carbapenem-resistant Enterobacterales in the USA (CRACKLE-2): a prospective cohort study. Lancet Infect Dis 20:731–741

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  28. Palzkill T (2018) Structural and Mechanistic Basis for Extended-Spectrum Drug-Resistance Mutations in Altering the Specificity of TEM, CTX-M, and KPC β-lactamases. Front Mol Biosci 5:16

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Walther-Rasmussen J, Høiby N (2007) Class A carbapenemases. J Antimicrob Chemother 60:470–482

    Article  CAS  PubMed  Google Scholar 

  30. Hossain A et al (2004) Plasmid-mediated carbapenem-hydrolyzing enzyme KPC-2 in an Enterobacter sp. Antimicrob Agents Chemother 48:4438–4440

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Yigit H et al (2001) Novel carbapenem-hydrolyzing beta-lactamase, KPC-1, from a carbapenem-resistant strain of Klebsiella pneumoniae. Antimicrob Agents Chemother 45:1151–1161

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Deshpande LM, Jones RN, Fritsche TR, Sader HS (2006) Occurrence and Characterization of Carbapenemase-Producing Enterobacteriaceae: Report from the SENTRY Antimicrobial Surveillance Program (2000–2004). Microb Drug Resist 12:223–230

    Article  CAS  PubMed  Google Scholar 

  33. Castanheira M, Farrell SE, Deshpande LM, Mendes RE, Jones RN (2013) Prevalence of β-lactamase-encoding genes among Enterobacteriaceae bacteremia isolates collected in 26 U.S. hospitals: report from the SENTRY Antimicrobial Surveillance Program (2010). Antimicrob Agents Chemother 57:3012–3020

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Villegas MV et al (2006) First detection of the plasmid-mediated class A carbapenemase KPC-2 in clinical isolates of Klebsiella pneumoniae from South America. Antimicrob Agents Chemother 50:2880–2882

    Article  CAS  PubMed  Google Scholar 

  35. Rada AM et al (2020) Dynamics of blaKPC-2 Dissemination from Non-CG258 Klebsiella pneumoniae to Other Enterobacterales via IncN Plasmids in an Area of High Endemicity. Antimicrob Agents Chemother 64:e01743-20

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Navon-Venezia S et al (2009) First report on a hyperepidemic clone of KPC-3-producing Klebsiella pneumoniae in Israel genetically related to a strain causing outbreaks in the United States. Antimicrob Agents Chemother 53:818–820

    Article  CAS  PubMed  Google Scholar 

  37. Karampatakis T, Antachopoulos C, Iosifidis E, Tsakris A, Roilides E (2016) Molecular epidemiology of carbapenem-resistant Klebsiella pneumoniae in Greece. Future Microbiol 11:809–823

    Article  CAS  PubMed  Google Scholar 

  38. Gartzonika K et al (2018) Identification of a KPC-9-producing Klebsiella pneumoniae ST258 cluster among KPC-2-producing isolates of an ongoing outbreak in Northwestern Greece: a retrospective study. Clin Microbiol Infect 24:558–560

    Article  CAS  PubMed  Google Scholar 

  39. Vubil D et al (2017) Outbreak of KPC-3-producing ST15 and ST348 Klebsiella pneumoniae in a Portuguese hospital. Epidemiol Infect 145:595–599

    Article  CAS  PubMed  Google Scholar 

  40. Baraniak A et al (2017) Multiregional dissemination of KPC-producing Klebsiella pneumoniae ST258/ST512 genotypes in Poland, 2010–14. J Antimicrob Chemother 72:1610–1616

    Article  CAS  PubMed  Google Scholar 

  41. Tooke CL et al (2019) β-Lactamases and β-Lactamase Inhibitors in the 21st Century. J Mol Biol 431:3472–3500

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  43. Walsh TR, Toleman MA, Poirel L, Nordmann P (2005) Metallo-beta-lactamases: the quiet before the storm? Clin Microbiol Rev 18:306–325

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  45. Wu W, Feng Y, Tang G, Qiao F, McNally A, Zong Z (2019) NDM metallo-β-lactamases and their bacterial producers in health care settings. Clin Microbiol Rev 32. https://doi.org/10.1128/CMR.00115-18

  46. Watanabe M, Iyobe S, Inoue M, Mitsuhashi S (1991) Transferable imipenem resistance in Pseudomonas aeruginosa. Antimicrob Agents Chemother 35:147–151

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Malchione MD, Torres LM, Hartley DM, Koch M, Goodman JL (2019) Carbapenem and colistin resistance in Enterobacteriaceae in Southeast Asia: Review and mapping of emerging and overlapping challenges. Int J Antimicrob Agents 54:381–399

    Article  CAS  PubMed  Google Scholar 

  48. Matsumura Y et al (2017) Global Molecular Epidemiology of IMP-Producing Enterobacteriaceae. Antimicrob Agents Chemother 61:e02729-16

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Lauretti L et al (1999) Cloning and characterization of blaVIM, a new integron-borne metallo-beta-lactamase gene from a Pseudomonas aeruginosa clinical isolate. Antimicrob Agents Chemother 43:1584–1590

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Albiger B, Glasner C, Struelens MJ, Grundmann H, Monnet DL (2015) European survey of carbapenemase-producing enterobacteriaceae (EuSCAPE) working group. Carbapenemase-producing Enterobacteriaceae in Europe: assessment by national experts from 38 countries, May 2015. Euro Surveill 20. https://doi.org/10.2807/1560-7917.ES.2015.20.45.30062

  51. Yong D et al (2009) Characterization of a new metallo-beta-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 53:5046–5054

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Mairi A, Pantel A, Sotto A, Lavigne J-P, Touati A (2018) OXA-48-like carbapenemases producing Enterobacteriaceae in different niches. Eur J Clin Microbiol Infect Dis 37:587–604

    Article  CAS  PubMed  Google Scholar 

  53. Poirel L, Potron A, Nordmann P (2012) OXA-48-like carbapenemases: the phantom menace. J Antimicrob Chemother 67:1597–1606

    Article  CAS  PubMed  Google Scholar 

  54. Pitout JDD, Peirano G, Kock MM, Strydom K-A, Matsumura Y (2019) The Global Ascendency of OXA-48-Type Carbapenemases. Clin Microbiol Rev 33:e00102-19

    Article  PubMed  PubMed Central  Google Scholar 

  55. Walther-Rasmussen J, Høiby N (2006) OXA-type carbapenemases. J Antimicrob Chemother 57:373–383

    Article  CAS  PubMed  Google Scholar 

  56. Nordmann P, Dortet L, Poirel L (2012) Carbapenem resistance in Enterobacteriaceae: here is the storm! Trends Mol Med 18:263–272

    Article  CAS  PubMed  Google Scholar 

  57. Guzmán-Puche J et al (2021) Characterization of OXA-48-producing Klebsiella oxytoca isolates from a hospital outbreak in Tunisia. J Glob Antimicrob Resist 24:306–310

    Article  PubMed  Google Scholar 

  58. Heireman L et al (2020) Toilet drain water as a potential source of hospital room-to-room transmission of carbapenemase-producing Klebsiella pneumoniae. J Hosp Infect 106:232–239

    Article  CAS  PubMed  Google Scholar 

  59. Shaidullina E et al (2020) Antimicrobial Resistance and Genomic Characterization of OXA-48- and CTX-M-15-Co-Producing Hypervirulent Klebsiella pneumoniae ST23 Recovered from Nosocomial Outbreak. Antibiotics (Basel) 9:862

    Article  CAS  Google Scholar 

  60. Lyman M et al (2015) Notes from the Field: Carbapenem-resistant Enterobacteriaceae Producing OXA-48-like Carbapenemases-United States, 2010–2015. MMWR Morb Mortal Wkly Rep 64:1315–1316

    Article  PubMed  Google Scholar 

  61. Jean S-S et al (2015) Carbapenemase-producing Gram-negative bacteria: current epidemics, antimicrobial susceptibility and treatment options. Future Microbiol 10:407–425

    Article  CAS  PubMed  Google Scholar 

  62. Ract P et al (2019) Synergistic in vitro activity between aztreonam and amoxicillin-clavulanate against Enterobacteriaceae-producing class B and/or class D carbapenemases with or without extended-spectrum β-lactamases. J Med Microbiol 68:1292–1298

    Article  CAS  PubMed  Google Scholar 

  63. Biswas S, Brunel J-M, Dubus J-C, Reynaud-Gaubert M, Rolain J-M (2012) Colistin: an update on the antibiotic of the 21st century. Expert Rev Anti Infect Ther 10:917–934

    Article  CAS  PubMed  Google Scholar 

  64. Capone A et al (2013) High rate of colistin resistance among patients with carbapenem-resistant Klebsiella pneumoniae infection accounts for an excess of mortality. Clin Microbiol Infect 19:E23–E30

    Article  CAS  PubMed  Google Scholar 

  65. Giacobbe DR et al (2015) Risk factors for bloodstream infections due to colistin-resistant KPC-producing Klebsiella pneumoniae: results from a multicenter case-control-control study. Clin Microbiol Infect 21(1106):e1-8

    Google Scholar 

  66. Kai J, Wang S (2020) Recent progress on elucidating the molecular mechanism of plasmid-mediated colistin resistance and drug design. Int Microbiol 23:355–366

    Article  PubMed  Google Scholar 

  67. Band VI et al (2021) Colistin Heteroresistance Is Largely Undetected among Carbapenem-Resistant Enterobacterales in the United States. MBio 12:e02881-20

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Seo J, Wi YM, Kim JM, Kim Y-J, Ko KS (2021) Detection of colistin-resistant populations prior to antibiotic exposure in KPC-2-producing Klebsiella pneumoniae clinical isolates. J Microbiol 59:590–597

    Article  CAS  PubMed  Google Scholar 

  69. Motsch J et al (2020) 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 70:1799–1808

    Article  CAS  PubMed  Google Scholar 

  70. Wunderink RG et al (2018) 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 7:439–455

    Article  PubMed  PubMed Central  Google Scholar 

  71. van Duin D et al (2018) Colistin Versus Ceftazidime-Avibactam in the Treatment of Infections Due to Carbapenem-Resistant Enterobacteriaceae. Clin Infect Dis 66:163–171

    Article  PubMed  Google Scholar 

  72. Olowo-Okere A, Yacouba A (2020) Molecular mechanisms of colistin resistance in Africa: A systematic review of literature. Germs 10:367–379

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Osei Sekyere J, Reta MA (2020) Genomic and resistance epidemiology of gram-negative bacteria in Africa: a Systematic review and phylogenomic analyses from a one health perspective. mSystems 5. https://doi.org/10.1128/mSystems.00897-20

  74. World Health Organization (2018) The detection and reporting of colistin resistance. https://apps.who.int/iris/bitstream/handle/10665/277175/WHO-WSI-AMR-2018.4-eng.pdf. Accessed 1 Jun 2021

  75. WHO | Highest Priority Critically Important Antimicrobials (2019) World health organization. Available: https://www.who.int/foodsafety/cia/en/. Accessed 1 Jun 2021

  76. Silver LL (2017) Fosfomycin: Mechanism and Resistance. Cold Spring Harb Perspect Med 7:a025262

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  77. Falagas ME, Vouloumanou EK, Samonis G, Vardakas KZ (2016) Fosfomycin. Clin Microbiol Rev 29:321–347

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Ito R et al (2017) Widespread Fosfomycin Resistance in Gram-Negative Bacteria Attributable to the Chromosomal fosA Gene. MBio 8:e00749-17

    Article  PubMed  PubMed Central  Google Scholar 

  79. Huang L et al (2021) Prevalence and mechanisms of fosfomycin resistance among KPC-producing Klebsiella pneumoniae clinical isolates in China. Int J Antimicrob Agents 57:106226

    Article  CAS  PubMed  Google Scholar 

  80. Michalopoulos AS, Livaditis IG, Gougoutas V (2011) The revival of fosfomycin. Int J Infect Dis 15:e732–e739

    Article  CAS  PubMed  Google Scholar 

  81. Falagas ME, Giannopoulou KP, Kokolakis GN, Rafailidis PI (2008) Fosfomycin: use beyond urinary tract and gastrointestinal infections. Clin Infect Dis 46:1069–1077

    Article  PubMed  Google Scholar 

  82. Michalopoulos A et al (2010) Intravenous fosfomycin for the treatment of nosocomial infections caused by carbapenem-resistant Klebsiella pneumoniae in critically ill patients: a prospective evaluation. Clin Microbiol Infect 16:184–186

    Article  CAS  PubMed  Google Scholar 

  83. Pontikis K et al (2014) 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 43:52–59

    Article  CAS  PubMed  Google Scholar 

  84. US Food and Drug Administration. MONUROL. US Food and Drug Administration https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/050717s007lbl.pdf. Accessed 1 Jun 2021

  85. Dimitrova EK (2018) Fosfomycin-containing medicinal products. https://www.ema.europa.eu/en/medicines/human/referrals/fosfomycin-containing-medicinal-products. Accessed 1 Jun 2021

  86. Seifert H, Blondeau J, Dowzicky MJ (2018) In vitro activity of tigecycline and comparators (2014-2016) among key WHO ‘priority pathogens’ and longitudinal assessment (2014-2016) of antimicrobial resistance: a report from the T.E.S.T. study. Int J Antimicrob Agents 52:474–484

    Article  CAS  PubMed  Google Scholar 

  87. Ni W et al (2016) Tigecycline Treatment for Carbapenem-Resistant Enterobacteriaceae Infections: A Systematic Review and Meta-Analysis. Medicine 95:e3126

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Sbrana F et al (2013) Carbapenem-sparing antibiotic regimens for infections caused by Klebsiella pneumoniae carbapenemase-producing K. pneumoniae in intensive care unit. Clin Infect Dis 56:697–700

    Article  CAS  PubMed  Google Scholar 

  89. importance of combination therapy (2012) Tumbarello, M. et al. Predictors of mortality in bloodstream infections caused by Klebsiella pneumoniae carbapenemase-producing K. pneumoniae. Clin Infect Dis 55:943–950

    Article  CAS  Google Scholar 

  90. Pournaras S, Koumaki V, Spanakis N, Gennimata V, Tsakris A (2016) Current perspectives on tigecycline resistance in Enterobacteriaceae: susceptibility testing issues and mechanisms of resistance. Int J Antimicrob Agents 48:11–18

    Article  CAS  PubMed  Google Scholar 

  91. Yoon EJ, Oh Y, Jeong SH (2020) Development of Tigecycline Resistance in Carbapenemase-Producing Klebsiella pneumoniae Sequence Type 147 via AcrAB Overproduction Mediated by Replacement of the ramA Promoter. Ann Lab Med 40:15–20

    Article  CAS  PubMed  Google Scholar 

  92. Sun J et al (2019) Plasmid-encoded tet(X) genes that confer high-level tigecycline resistance in Escherichia coli. Nat Microbiol 4:1457–1464

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. He T et al (2019) Emergence of plasmid-mediated high-level tigecycline resistance genes in animals and humans. Nat Microbiol 4:1450–1456

    Article  CAS  PubMed  Google Scholar 

  94. Peyclit L, Baron SA, Rolain J-M (2019) Drug Repurposing to Fight Colistin and Carbapenem-Resistant Bacteria. Front Cell Infect Microbiol 9:193

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. MacNair CR et al (2018) Overcoming mcr-1 mediated colistin resistance with colistin in combination with other antibiotics. Nat Commun 9:458

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  96. Hu Y, Liu Y, Coates A (2019) Azidothymidine produces synergistic activity in combination with colistin against antibiotic-resistant enterobacteriaceae. Antimicrob Agents Chemother 63. https://doi.org/10.1128/AAC.01630-18

  97. Ng SMS et al (2018) Repurposing Zidovudine in combination with Tigecycline for treating carbapenem-resistant Enterobacteriaceae infections. Eur J Clin Microbiol Infect Dis 37:141–148

    Article  CAS  PubMed  Google Scholar 

  98. Cebrero-Cangueiro T et al (2018) In vitro Activity of Pentamidine Alone and in Combination With Aminoglycosides, Tigecycline, Rifampicin, and Doripenem Against Clinical Strains of Carbapenemase-Producing and/or Colistin-Resistant Enterobacteriaceae. Front Cell Infect Microbiol 8:363

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Otto RG et al (2019) An alternative strategy for combination therapy: Interactions between polymyxin B and non-antibiotics. Int J Antimicrob Agents 53:34–39

    Article  CAS  PubMed  Google Scholar 

  100. Zhanel GG et al (2013) Ceftazidime-Avibactam: a Novel Cephalosporin/b-lactamase Inhibitor Combination. Drugs; Auckland 73:159–177

    Article  CAS  Google Scholar 

  101. Ehmann DE et al (2012) Avibactam is a covalent, reversible, non-β-lactam β-lactamase inhibitor. Proc Natl Acad Sci U S A 109:11663–11668

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Sousa A et al (2018) Effectiveness of ceftazidime/avibactam as salvage therapy for treatment of infections due to OXA-48 carbapenemase-producing Enterobacteriaceae. J Antimicrob Chemother 73:3170–3175

    Article  CAS  PubMed  Google Scholar 

  103. De la Calle C et al (2019) Clinical characteristics and prognosis of infections caused by OXA-48 carbapenemase-producing Enterobacteriaceae in patients treated with ceftazidime-avibactam. Int J Antimicrob Agents 53:520–524

    Article  PubMed  CAS  Google Scholar 

  104. Shields RK et al (2017) Ceftazidime-Avibactam Is Superior to Other Treatment Regimens against Carbapenem-Resistant Klebsiella pneumoniae Bacteremia. Antimicrob Agents Chemother 61:e00883-17

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Tumbarello M et al (2021) Ceftazidime-avibactam use for KPC-Kp infections: a retrospective observational multicenter study. Clin Infect Dis. https://doi.org/10.1093/cid/ciab176

    Article  PubMed  Google Scholar 

  106. Wilson GM et al (2021) Meta-analysis of Clinical Outcomes Using Ceftazidime/Avibactam, Ceftolozane/Tazobactam, and Meropenem/Vaborbactam for the Treatment of Multidrug-Resistant Gram-Negative Infections. Open Forum Infect Dis 8:ofaa651

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  107. United States Food and Drug Administration. AVYCAZ safely and effectively. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/206494s005,s006lbl.pdf. Accessed 4 Mar 2021

  108. Mazuski JE et al (2016) Efficacy and Safety of Ceftazidime-Avibactam Plus Metronidazole Versus Meropenem in the Treatment of Complicated Intra-abdominal Infection: Results From a Randomized, Controlled, Double-Blind, Phase 3 Program. Clin Infect Dis 62:1380–1389

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Wagenlehner FM et al (2016) Ceftazidime-avibactam Versus Doripenem for the Treatment of Complicated Urinary Tract Infections, Including Acute Pyelonephritis: RECAPTURE, a Phase 3 Randomized Trial Program. Clin Infect Dis 63:754–762

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Torres A et al (2018) Ceftazidime-avibactam versus meropenem in nosocomial pneumonia, including ventilator-associated pneumonia (REPROVE): a randomised, double-blind, phase 3 non-inferiority trial. Lancet Infect Dis 18:285–295

    Article  CAS  PubMed  Google Scholar 

  111. de Jonge BLM et al (2016) In Vitro Susceptibility to Ceftazidime-Avibactam of Carbapenem-Nonsusceptible Enterobacteriaceae Isolates Collected during the INFORM Global Surveillance Study (2012 to 2014). Antimicrob Agents Chemother 60:3163–3169

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  112. Spiliopoulou I, Kazmierczak K, Stone GG (2020) In vitro activity of ceftazidime/avibactam against isolates of carbapenem-non-susceptible Enterobacteriaceae collected during the INFORM global surveillance programme (2015–17). J Antimicrob Chemother 75:384–391

    Article  CAS  PubMed  Google Scholar 

  113. Nelson K et al (2017) Resistance to Ceftazidime-Avibactam Is Due to Transposition of KPC in a Porin-Deficient Strain of Klebsiella pneumoniae with Increased Efflux Activity. Antimicrob Agents Chemother 61:e00989-17

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Humphries RM, Hemarajata P (2017) Resistance to Ceftazidime-Avibactam in Klebsiella pneumoniae Due to Porin Mutations and the Increased Expression of KPC-3. Antimicrob Agents Chemother 61:e00537-17

    PubMed  PubMed Central  Google Scholar 

  115. Humphries RM et al (2015) First Report of Ceftazidime-Avibactam Resistance in a KPC-3-Expressing Klebsiella pneumoniae Isolate. Antimicrob Agents Chemother 59:6605–6607

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Shields RK et al (2017) Emergence of Ceftazidime-Avibactam Resistance Due to Plasmid-Borne blaKPC-3 Mutations during Treatment of Carbapenem-Resistant Klebsiella pneumoniae Infections. Antimicrob Agents Chemother 61:e02097-16

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Poirel L et al (2020) KPC-50 Confers Resistance to Ceftazidime-Avibactam Associated with Reduced Carbapenemase Activity. Antimicrob Agents Chemother 64:e00321-20

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Winkler ML, Papp-Wallace KM, Bonomo RA (2015) Activity of ceftazidime/avibactam against isogenic strains of Escherichia coli containing KPC and SHV β-lactamases with single amino acid substitutions in the Ω-loop. J Antimicrob Chemother 70:2279–2286

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Shields RK et al (2016) Clinical Outcomes, Drug Toxicity, and Emergence of Ceftazidime-Avibactam Resistance Among Patients Treated for Carbapenem-Resistant Enterobacteriaceae Infections. Clin Infect Dis 63:1615–1618

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Zhang Y, Kashikar A, Brown CA, Denys G, Bush K (2017) Unusual Escherichia coli PBP 3 Insertion Sequence Identified from a Collection of Carbapenem-Resistant Enterobacteriaceae Tested In Vitro with a Combination of Ceftazidime-, Ceftaroline-, or Aztreonam-Avibactam. Antimicrob Agents Chemother 61:e00389-17

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Maraki S et al (2021) Ceftazidime-avibactam, meropenen-vaborbactam, and imipenem-relebactam in combination with aztreonam against multidrug-resistant, metallo-β-lactamase-producing Klebsiella pneumoniae. Eur J Clin Microbiol Infect Dis. https://doi.org/10.1007/s10096-021-04197-3

    Article  PubMed  Google Scholar 

  122. Shields RK, Doi Y (2020) Aztreonam Combination Therapy: An Answer to Metallo-β-Lactamase-Producing Gram-Negative Bacteria? Clin Infect Dis 71:1099–1101

    Article  CAS  PubMed  Google Scholar 

  123. Karlowsky JA et al (2017) 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 61:e00472-17

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Shaw E et al (2018) Clinical outcomes after combination treatment with ceftazidime/avibactam and aztreonam for NDM-1/OXA-48/CTX-M-15-producing Klebsiella pneumoniae infection. J Antimicrob Chemother 73:1104–1106

    Article  CAS  PubMed  Google Scholar 

  125. Falcone M et al (2020) Efficacy of ceftazidime-avibactam plus aztreonam in patients with bloodstream infections caused by MBL- producing Enterobacterales. Clin Infect Dis. https://doi.org/10.1093/cid/ciaa586

    Article  Google Scholar 

  126. Alghoribi MF et al (2021) Successful treatment of infective endocarditis due to pandrug-resistant Klebsiella pneumoniae with ceftazidime-avibactam and aztreonam. Sci Rep 11:9684

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Efficacy, Safety, and Tolerability of ATM-AVI in the Treatment of Serious Infection Due to MBL-producing Gram-negative Bacteria. https://clinicaltrials.gov/ct2/show/NCT03580044. Accessed 28 May 2021

  128. Cornely OA et al (2020) Pharmacokinetics and safety of aztreonam/avibactam for the treatment of complicated intra-abdominal infections in hospitalized adults: results from the REJUVENATE study. J Antimicrob Chemother 75:618–627

    Article  CAS  PubMed  Google Scholar 

  129. United States Food and Drug Administration. VABOMERE (meropenem and vaborbactam) for injection. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/209776lbl.pdf. Accessed 12 Mar 2021

  130. European Medicines Agency (2018) Vaborem. https://www.ema.europa.eu/en/medicines/human/EPAR/vaborem. Accessed 12 Mar 2021

  131. Cho JC, Zmarlicka MT, Shaeer KM, Pardo J (2018) Meropenem/Vaborbactam, the First Carbapenem/β-Lactamase Inhibitor Combination. Ann Pharmacother 52:769–779

    Article  CAS  PubMed  Google Scholar 

  132. Hecker SJ et al (2015) Discovery of a Cyclic Boronic Acid β-Lactamase Inhibitor (RPX7009) with Utility vs Class A Serine Carbapenemases. J Med Chem 58:3682–3692

    Article  CAS  PubMed  Google Scholar 

  133. Lomovskaya O et al (2017) Vaborbactam: Spectrum of Beta-Lactamase Inhibition and Impact of Resistance Mechanisms on Activity in Enterobacteriaceae. Antimicrob Agents Chemother 61:e01443-17

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Castanheira M, Huband MD, Mendes RE, Flamm RK (2017) Meropenem-Vaborbactam Tested against Contemporary Gram-Negative Isolates Collected Worldwide during 2014, Including Carbapenem-Resistant, KPC-Producing, Multidrug-Resistant, and Extensively Drug-Resistant Enterobacteriaceae. Antimicrob Agents Chemother 61:e00567-17

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Kaye KS et al (2018) Effect of Meropenem-Vaborbactam vs Piperacillin-Tazobactam on Clinical Cure or Improvement and Microbial Eradication in Complicated Urinary Tract Infection: The TANGO I Randomized Clinical Trial. JAMA 319:788–799

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Sun D, Rubio-Aparicio D, Nelson K, Dudley MN, Lomovskaya O (2017) Meropenem-Vaborbactam Resistance Selection, Resistance Prevention, and Molecular Mechanisms in Mutants of KPC-Producing Klebsiella pneumoniae. Antimicrob Agents Chemother 61:e01694-17

    CAS  PubMed  PubMed Central  Google Scholar 

  137. Wilson WR, Kline EG, Jones CE, Morder KT, Mettus RT, Doi Y et al (2019) Effects of KPC Variant and porin genotype on the in vitro activity of meropenem-vaborbactam against carbapenem-resistant enterobacteriaceae. Antimicrob Agents Chemother 63. https://doi.org/10.1128/AAC.02048-18

  138. Dulyayangkul P, Wan Nur Ismah WAK, Douglas EJA, Avison MB (2020) Mutation of kvrA Causes OmpK35 and OmpK36 Porin Downregulation and Reduced Meropenem-Vaborbactam Susceptibility in KPC-Producing Klebsiella pneumoniae. Antimicrob Agents Chemother 64:e02208-19

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Olsen I (2015) New promising β-lactamase inhibitors for clinical use. Eur J Clin Microbiol Infect Dis 34:1303–1308

    Article  CAS  PubMed  Google Scholar 

  140. Zhanel GG et al (2018) Imipenem-Relebactam and Meropenem–Vaborbactam: Two Novel Carbapenem-ß-Lactamase Inhibitor Combinations. Drugs; Auckland 78:65–98

    Article  CAS  Google Scholar 

  141. Campanella TA, Gallagher JC (2020) A Clinical Review and Critical Evaluation of Imipenem-Relebactam: Evidence to Date. Infect Drug Resist 13:4297–4308

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Lob SH et al (2020) In vitro activity of imipenem-relebactam against resistant phenotypes of Enterobacteriaceae and Pseudomonas aeruginosa isolated from intraabdominal and urinary tract infection samples - SMART Surveillance Europe 2015–2017. J Med Microbiol 69:207–217

    Article  CAS  PubMed  Google Scholar 

  143. United States Food and Drug Administration. RECARBRIO. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/212819s000lbl.pdf. Accessed 4 Mar 2021

  144. Smith JR, Rybak JM, Claeys KC (2020) Imipenem-Cilastatin-Relebactam: A Novel β-Lactam-β-Lactamase Inhibitor Combination for the Treatment of Multidrug-Resistant Gram-Negative Infections. Pharmacotherapy 40:343–356

    Article  CAS  PubMed  Google Scholar 

  145. Titov I et al (2020) A Randomized, Double-blind, Multicenter Trial Comparing Efficacy and Safety of Imipenem/Cilastatin/Relebactam Versus Piperacillin/Tazobactam in Adults With Hospital-acquired or Ventilator-associated Bacterial Pneumonia (RESTORE-IMI 2 Study). Clin Infect Dis. https://doi.org/10.1093/cid/ciaa803

    Article  PubMed Central  Google Scholar 

  146. van Duin D, Bonomo RA (2016) Ceftazidime/Avibactam and Ceftolozane/Tazobactam: Second-generation β-Lactam/β-Lactamase Inhibitor Combinations. Clin Infect Dis 63:234–241

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  147. Armstrong ES, Miller GH (2010) Combating evolution with intelligent design: the neoglycoside ACHN-490. Curr Opin Microbiol 13:565–573

    Article  CAS  PubMed  Google Scholar 

  148. Livermore DM et al (2011) Activity of aminoglycosides, including ACHN-490, against carbapenem-resistant Enterobacteriaceae isolates. J Antimicrob Chemother 66:48–53

    Article  CAS  PubMed  Google Scholar 

  149. Eljaaly K, Alharbi A, Alshehri S, Ortwine JK, Pogue JM (2019) Plazomicin: A Novel Aminoglycoside for the Treatment of Resistant Gram-Negative Bacterial Infections. Drugs 79:243–269

    Article  CAS  PubMed  Google Scholar 

  150. Walkty A et al (2014) In vitro activity of plazomicin against 5,015 gram-negative and gram-positive clinical isolates obtained from patients in canadian hospitals as part of the CANWARD study, 2011–2012. Antimicrob Agents Chemother 58:2554–2563

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. United States Food and Drug Administration. Zemdri. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210303orig1s000lbl.pdf. Accessed 5 Mar 2021

  152. Wagenlehner FME et al (2019) Once-Daily Plazomicin for Complicated Urinary Tract Infections. N Engl J Med 380:729–740

    Article  CAS  PubMed  Google Scholar 

  153. McKinnell JA et al (2019) Plazomicin for Infections Caused by Carbapenem-Resistant Enterobacteriaceae. N Engl J Med 380:791–793

    Article  PubMed  Google Scholar 

  154. Theuretzbacher U, Paul M (2018) Developing a new antibiotic for extensively drug-resistant pathogens: the case of plazomicin. Clin Microbiol Infect 24:1231–1233

    Article  CAS  PubMed  Google Scholar 

  155. Dimitrova EK (2020) Zemdri: Withdrawn application - European Medicines Agency. https://www.ema.europa.eu/en/medicines/human/withdrawn-applications/zemdri. Accessed 5 Mar 2021

  156. Mullard A (2019) Achaogen bankruptcy highlights antibacterial development woes. Nat Rev Drug Discov 18:411

    PubMed  Google Scholar 

  157. Shaeer KM, Zmarlicka MT, Chahine EB, Piccicacco N, Cho J (2019) C. Plazomicin: A Next-Generation Aminoglycoside. Pharmacotherapy 39:77–93

    Article  CAS  PubMed  Google Scholar 

  158. Zhanel GG et al (2012) Comparison of the next-generation aminoglycoside plazomicin to gentamicin, tobramycin and amikacin. Expert Rev Anti Infect Ther 10:459–473

    Article  CAS  PubMed  Google Scholar 

  159. Roch M et al (2020) Vertical and horizontal dissemination of an IncC plasmid harbouring rmtB 16S rRNA methylase gene, conferring resistance to plazomicin, among invasive ST258 and ST16 KPC-producing Klebsiella pneumoniae. J Glob Antimicrob Resist 24:183–189

    Article  PubMed  Google Scholar 

  160. Xiao X-Y et al (2012) Fluorocyclines 1. 7-fluoro-9-pyrrolidinoacetamido-6-demethyl-6-deoxytetracycline: a potent, broad spectrum antibacterial agent. J Med Chem 55:597–605

    Article  CAS  PubMed  Google Scholar 

  161. Zhanel GG et al (2016) Review of Eravacycline, a Novel Fluorocycline Antibacterial Agent. Drugs 76:567–588

    Article  CAS  PubMed  Google Scholar 

  162. Zhang Y, Lin X, Bush K (2016) In vitro susceptibility of β-lactamase-producing carbapenem-resistant Enterobacteriaceae (CRE) to eravacycline. J Antibiot 69:600–604

    Article  CAS  Google Scholar 

  163. Livermore DM, Mushtaq S, Warner M, Woodford N (2016) In Vitro Activity of Eravacycline against Carbapenem-Resistant Enterobacteriaceae and Acinetobacter baumannii. Antimicrob Agents Chemother 60:3840–3844

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Clark JA, Kulengowski B, Burgess DS (2020) In vitro activity of eravacycline compared with tigecycline against carbapenem-resistant Enterobacteriaceae. Int. J Antimicrob Agents 56:106178

    Article  CAS  PubMed  Google Scholar 

  165. Solomkin JS et al (2019) Eravacycline: a new treatment option for complicated intra-abdominal infections in the age of multidrug resistance. Future Microbiol 14:1293–1308

    Article  CAS  PubMed  Google Scholar 

  166. United States Food and Drug Administration. XERAVA (eravacycline) for injection. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/211109lbl.pdf. Accessed 8 Mar 2021

  167. European Medicines Agency. Xerava, INN-eravacycline. https://www.ema.europa.eu/en/documents/product-information/xerava-epar-product-information_en.pdf. Accessed 8 Mar 2021

  168. Grossman TH, O’Brien W, Kerstein KO, Sutcliffe JA (2015) Eravacycline (TP-434) is active in vitro against biofilms formed by uropathogenic Escherichia coli. Antimicrob Agents Chemother 59:2446–2449

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Efficacy and Safety Study of Eravacycline Compared With Levofloxacin in Complicated Urinary Tract Infections. https://clinicaltrials.gov/ct2/show/NCT01978938. Accessed 8 Mar 2021

  170. Heaney M, Mahoney MV, Gallagher JC (2019) Eravacycline: The Tetracyclines Strike Back. Ann Pharmacother 53:1124–1135

    Article  CAS  PubMed  Google Scholar 

  171. Grossman TH et al (2012) Target- and resistance-based mechanistic studies with TP-434, a novel fluorocycline antibiotic. Antimicrob Agents Chemother 56:2559–2564

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Park J et al (2017) Plasticity, dynamics, and inhibition of emerging tetracycline resistance enzymes. Nat Chem Biol 13:730–736

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Ding Y et al (2020) Emergence of tigecycline- and eravacycline-resistant Tet(X4)-producing Enterobacteriaceae in the gut microbiota of healthy Singaporeans. J Antimicrob Chemother 75:3480–3484

    Article  CAS  PubMed  Google Scholar 

  174. Honeyman L et al (2015) Structure-activity relationship of the aminomethylcyclines and the discovery of omadacycline. Antimicrob Agents Chemother 59:7044–7053

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Zhanel GG et al (2020) Omadacycline: A Novel Oral and Intravenous Aminomethylcycline Antibiotic Agent. Drugs 80:285–313

    Article  CAS  PubMed  Google Scholar 

  176. O’Riordan W et al (2019) Omadacycline for Acute Bacterial Skin and Skin-Structure Infections. N Engl J Med 380:528–538

    Article  PubMed  Google Scholar 

  177. Stets R et al (2019) Omadacycline for Community-Acquired Bacterial Pneumonia. N Engl J Med 380:517–527

    Article  CAS  PubMed  Google Scholar 

  178. O’Riordan W et al (2019) Once-daily oral omadacycline versus twice-daily oral linezolid for acute bacterial skin and skin structure infections (OASIS-2): a phase 3, double-blind, multicentre, randomised, controlled, non-inferiority trial. Lancet Infect Dis 19:1080–1090

    Article  PubMed  Google Scholar 

  179. United States Food and Drug Administration. NUZYRA (omadacycline). https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/209816_209817lbl.pdf. Accessed 8 Mar 2021

  180. Francisco EM (2019) Nuzyra: Withdrawn application - European Medicines Agency. https://www.ema.europa.eu/en/medicines/human/withdrawn-applications/nuzyra. Accessed 8 Mar 2021

  181. Lutgring JD et al (2020) Antibiotic Susceptibility of NDM-Producing Enterobacterales Collected in the United States in 2017 and 2018. Antimicrob. Agents Chemother 64:e00499-20

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Möllmann U, Heinisch L, Bauernfeind A, Köhler T, Ankel-Fuchs D (2009) Siderophores as drug delivery agents: application of the ‘Trojan Horse’ strategy. Biometals 22:615–624

    Article  PubMed  CAS  Google Scholar 

  183. El-Lababidi RM, Rizk JG (2020) Cefiderocol: A Siderophore Cephalosporin. Ann Pharmacother 54:1215–1231

    Article  CAS  PubMed  Google Scholar 

  184. Ito-Horiyama T et al (2016) Stability of Novel Siderophore Cephalosporin S-649266 against Clinically Relevant Carbapenemases. Antimicrob Agents Chemother 60:4384–4386

    Article  PubMed  PubMed Central  Google Scholar 

  185. Poirel L, Kieffer N, Nordmann P (2018) Stability of cefiderocol against clinically significant broad-spectrum oxacillinases. Int J Antimicrob Agents 52:866–867

    Article  CAS  PubMed  Google Scholar 

  186. Katsube T, Echols R, Wajima T (2019) Pharmacokinetic and Pharmacodynamic Profiles of Cefiderocol, a Novel Siderophore Cephalosporin. Clin Infect Dis 69:S552–S558

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Kohira N et al (2016) In Vitro Antimicrobial Activity of a Siderophore Cephalosporin, S-649266, against Enterobacteriaceae Clinical Isolates Including Carbapenem-Resistant Strains. Antimicrob Agents Chemother 60:729–734

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Zhanel GG et al (2019) Cefiderocol: A Siderophore Cephalosporin with Activity Against Carbapenem-Resistant and Multidrug-Resistant Gram-Negative Bacilli. Drugs 79:271–289

    Article  CAS  PubMed  Google Scholar 

  189. United States Food and Drug Administration. FETROJA (cefiderocol) for injection, for intravenous use. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/209445s002lbl.pdf. Accessed 8 Mar 2021

  190. Portsmouth S et al (2018) 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 18:1319–1328

    Article  CAS  PubMed  Google Scholar 

  191. Wunderink RG et al (2021) Cefiderocol versus high-dose, extended-infusion meropenem for the treatment of Gram-negative nosocomial pneumonia (APEKS-NP): a randomised, double-blind, phase 3, non-inferiority trial. Lancet Infect Dis 21:213–225

    Article  CAS  PubMed  Google Scholar 

  192. Dimitrova EK (2020) Fetcroja. https://www.ema.europa.eu/en/medicines/human/EPAR/fetcroja. Accessed 8 Mar 2021

  193. Bassetti M et al (2021) Efficacy and safety of cefiderocol or best available therapy for the treatment of serious infections caused by carbapenem-resistant Gram-negative bacteria (CREDIBLE-CR): a randomised, open-label, multicentre, pathogen-focused, descriptive, phase 3 trial. Lancet Infect Dis 21:226–240

    Article  CAS  PubMed  Google Scholar 

  194. Yamano Y (2019) In Vitro Activity of Cefiderocol Against a Broad Range of Clinically Important Gram-negative Bacteria. Clin Infect Dis 69:S544–S551

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Hackel MA et al (2017) 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 61:e00093-17

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Hackel MA et al (2018) In Vitro Activity of the Siderophore Cephalosporin, Cefiderocol, against Carbapenem-Nonsusceptible and Multidrug-Resistant Isolates of Gram-Negative Bacilli Collected Worldwide in 2014 to 2016. Antimicrob Agents Chemother 62:e01968-17

    PubMed  PubMed Central  Google Scholar 

  197. Kohira N et al (2020) Reduced susceptibility mechanism to cefiderocol, a siderophore cephalosporin, among clinical isolates from a global surveillance programme (SIDERO-WT-2014). J Glob Antimicrob Resist 22:738–741

    Article  PubMed  Google Scholar 

  198. Kortright KE, Chan BK, Koff JL, Turner PE (2019) Phage Therapy: A Renewed Approach to Combat Antibiotic-Resistant Bacteria. Cell Host Microbe 25:219–232

    Article  CAS  PubMed  Google Scholar 

  199. Dedrick RM et al (2019) Engineered bacteriophages for treatment of a patient with a disseminated drug-resistant Mycobacterium abscessus. Nat Med 25:730–733

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. Gordillo Altamirano FL, Barr JJ (2019) Phage Therapy in the Postantibiotic Era. Clin Microbiol Rev 32:e00066-18

    Article  PubMed  PubMed Central  Google Scholar 

  201. Rehman S, Ali Z, Khan M, Bostan N, Naseem S (2019) The dawn of phage therapy. Rev Med Virol 29:e2041

    Article  PubMed  Google Scholar 

  202. Reindel R, Fiore CR (2017) Phage therapy: considerations and challenges for development. Clin Infect Dis 64:1589–1590

  203. Sweere JM et al (2019) Bacteriophage trigger antiviral immunity and prevent clearance of bacterial infection. Science 363:eaat9691

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. Chanishvili N (2012) Phage therapy–history from Twort and d’Herelle through Soviet experience to current approaches. Adv Virus Res 83:3–40

    Article  CAS  PubMed  Google Scholar 

  205. Jault P et al (2019) Efficacy and tolerability of a cocktail of bacteriophages to treat burn wounds infected by Pseudomonas aeruginosa (PhagoBurn): a randomised, controlled, double-blind phase 1/2 trial. Lancet Infect Dis 19:35–45

    Article  PubMed  Google Scholar 

  206. Aslam S et al (2020) Lessons Learned From the First 10 Consecutive Cases of Intravenous Bacteriophage Therapy to Treat Multidrug-Resistant Bacterial Infections at a Single Center in the United States. Open Forum Infect Dis 7:ofaa389

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  207. Amarillas L et al (2017) Isolation and Characterization of phiLLS, a Novel Phage with Potential Biocontrol Agent against Multidrug-Resistant Escherichia coli. Front Microbiol 8:1355

    Article  PubMed  PubMed Central  Google Scholar 

  208. Oliveira H et al (2016) Characterization and genome sequencing of a Citrobacter freundii phage CfP1 harboring a lysin active against multidrug-resistant isolates. Appl Microbiol Biotechnol 100:10543–10553

    Article  CAS  PubMed  Google Scholar 

  209. Li M et al (2020) Characterization and genome analysis of Klebsiella phage P509, with lytic activity against clinical carbapenem-resistant Klebsiella pneumoniae of the KL64 capsular type. Arch Virol 165:2799–2806

    Article  CAS  PubMed  Google Scholar 

  210. Li M et al (2020) Isolation and Characterization of Novel Lytic Bacteriophages Infecting Epidemic Carbapenem-Resistant Klebsiella pneumoniae Strains. Front Microbiol 11:1554

    Article  PubMed  PubMed Central  Google Scholar 

  211. Horváth M et al (2020) Identification of a newly isolated lytic bacteriophage against K24 capsular type, carbapenem resistant Klebsiella pneumoniae isolates. Sci Rep 10:5891

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  212. Ciacci N et al (2018) Characterization of vB_Kpn_F48, a Newly Discovered Lytic Bacteriophage for Klebsiella pneumoniae of Sequence Type 101. Viruses 10:482

    Article  PubMed Central  CAS  Google Scholar 

  213. Anand T et al (2020) Phage therapy for treatment of virulent Klebsiella pneumoniae infection in a mouse model. J Glob Antimicrob Resist 21:34–41

    Article  PubMed  Google Scholar 

  214. Labrie SJ, Samson JE, Moineau S (2010) Bacteriophage resistance mechanisms. Nat Rev Microbiol 8:317–327

    Article  CAS  PubMed  Google Scholar 

  215. Guo D et al (2021) Genetic and Chemical Engineering of Phages for Controlling Multidrug-Resistant Bacteria. Antibiotics (Basel) 10:202

    Article  CAS  Google Scholar 

  216. World Health Organization (2017) Antibacterial Agents in Clinical Development: An analysis of the antibacterial clinical development pipeline, including tuberculosis. Available: https://apps.who.int/iris/bitstream/handle/10665/258965/WHO-EMP-IAU-2017.11-eng.pdf?sequence=1

  217. Livermore DM, Mushtaq S, Warner M, Vickers A, Woodford N (2017) In vitro activity of cefepime/zidebactam (WCK 5222) against Gram-negative bacteria. J Antimicrob Chemother 72:1373–1385

    Article  CAS  PubMed  Google Scholar 

  218. Thomson KS, AbdelGhani S, Snyder JW, Thomson GK (2019) Activity of Cefepime-Zidebactam against Multidrug-Resistant (MDR) Gram-Negative Pathogens. Antibiotics (Basel) 8:32

    Article  CAS  Google Scholar 

  219. Sader HS, Castanheira M, Huband M, Jones RN, Flamm RK (2017) WCK 5222 (Cefepime-Zidebactam) Antimicrobial Activity against Clinical Isolates of Gram-Negative Bacteria Collected Worldwide in 2015. Antimicrob Agents Chemother 61:e00072-17

    CAS  PubMed  PubMed Central  Google Scholar 

  220. Rodvold KA et al (2018) Plasma and Intrapulmonary Concentrations of Cefepime and Zidebactam following Intravenous Administration of WCK 5222 to Healthy Adult Subjects. Antimicrob Agents Chemother 62:e00682-18

    CAS  PubMed  PubMed Central  Google Scholar 

  221. Preston RA et al (2019) Single-Center Evaluation of the Pharmacokinetics of WCK 5222 (Cefepime-Zidebactam Combination) in Subjects with Renal Impairment. Antimicrob Agents Chemother 63:e01484-18

    CAS  PubMed  Google Scholar 

  222. Liu B et al (2020) Discovery of Taniborbactam (VNRX-5133): A Broad-Spectrum Serine- and Metallo-β-lactamase Inhibitor for Carbapenem-Resistant Bacterial Infections. J Med Chem 63:2789–2801

    Article  CAS  PubMed  Google Scholar 

  223. Krajnc A et al (2019) Bicyclic Boronate VNRX-5133 Inhibits Metallo- and Serine-β-Lactamases. J Med Chem 62:8544–8556

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  224. Hamrick JC et al (2020) VNRX-5133 (Taniborbactam), a Broad-Spectrum Inhibitor of Serine- and Metallo-β-Lactamases, Restores Activity of Cefepime in Enterobacterales and Pseudomonas aeruginosa. Antimicrob Agents Chemother 64:e01963-19

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  225. Abdelraouf K, Almarzoky Abuhussain S, Nicolau DP (2020) In vivo pharmacodynamics of new-generation β-lactamase inhibitor taniborbactam (formerly VNRX-5133) in combination with cefepime against serine-β-lactamase-producing Gram-negative bacteria. J Antimicrob Chemother 75:3601–3610

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  226. Reck F et al (2018) Optimization of novel monobactams with activity against carbapenem-resistant Enterobacteriaceae - Identification of LYS228. Bioorg Med Chem Lett 28:748–755

    Article  CAS  PubMed  Google Scholar 

  227. Blais J et al (2018) In Vitro Activity of LYS228, a Novel Monobactam Antibiotic, against Multidrug-Resistant Enterobacteriaceae. Antimicrob Agents Chemother 62:e00552-18

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  228. Dean CR et al (2018) Mode of Action of the Monobactam LYS228 and Mechanisms Decreasing In Vitro Susceptibility in Escherichia coli and Klebsiella pneumoniae. Antimicrob Agents Chemother 62:e01200-18

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  229. Osborn M et al (2019) A First-in-Human Study To Assess the Safety and Pharmacokinetics of LYS228, a Novel Intravenous Monobactam Antibiotic in Healthy Volunteers. Antimicrob Agents Chemother 63:e02592-18

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  230. Novartis licenses three novel anti-infective programs to Boston Pharmaceuticals. https://www.novartis.com/news/media-releases/novartis-licenses-three-novel-anti-infective-programs-boston-pharmaceuticals. Accessed 12 Mar 2021

  231. Barnes MD et al (2019) Nacubactam Enhances Meropenem Activity against Carbapenem-Resistant Klebsiella pneumoniae Producing KPC. Antimicrob Agents Chemother 63:e00432-19

    CAS  PubMed  PubMed Central  Google Scholar 

  232. Davies DT et al (2020) Discovery of ANT3310, a Novel Broad-Spectrum Serine β-Lactamase Inhibitor of the Diazabicyclooctane Class, Which Strongly Potentiates Meropenem Activity against Carbapenem-Resistant Enterobacterales and Acinetobacter baumannii. J Med Chem 63:15802–15820

    Article  CAS  PubMed  Google Scholar 

  233. Mushtaq S, Vickers A, Woodford N, Haldimann A, Livermore DM (2019) Activity of nacubactam (RG6080/OP0595) combinations against MBL-producing Enterobacteriaceae. J Antimicrob Chemother 74:953–960

    Article  CAS  PubMed  Google Scholar 

  234. Mallalieu NL et al (2020) Safety and Pharmacokinetic Characterization of Nacubactam, a Novel β-Lactamase Inhibitor, Alone and in Combination with Meropenem, in Healthy Volunteers. Antimicrob Agents Chemother 64:e02229-19

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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  1. Division of Global Health and Infectious Diseases, University of North Carolina, Chapel Hill, NC, USA

    Kathleen Tompkins & David van Duin

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  1. Kathleen Tompkins
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  2. David van Duin
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Tompkins, K., van Duin, D. Treatment for carbapenem-resistant Enterobacterales infections: recent advances and future directions. Eur J Clin Microbiol Infect Dis 40, 2053–2068 (2021). https://doi.org/10.1007/s10096-021-04296-1

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