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Is it time to move away from polymyxins?: evidence and alternatives

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Abstract

Increasing burden of carbapenem resistance and resultant difficult-to-treat infections are of particular concern due to the lack of effective and safe treatment options. More recently, several new agents with activity against certain multidrug-resistant (MDR) and extensive drug-resistant (XDR) Gram-negative pathogens have been approved for clinical use. These include ceftazidime-avibactam, meropenem-vaborbactam, imipenem-cilastatin-relebactam, plazomicin, and cefiderocol. For the management of MBL infections, clinically used triple combination comprising ceftazidime-avibactam and aztreonam is hindered due to non-availability of antimicrobial susceptibility testing methods and lack of information on potential drug-drug interaction leading to PK changes impacting its safety and efficacy. Moreover, in several countries including Indian subcontinent and developing countries, these new agents are yet to be made available. Under these circumstances, polymyxins are the only last resort for the treatment of carbapenem-resistant infections. With the recent evidence of suboptimal PK/PD particularly in lung environment, limited efficacy and increased nephrotoxicity associated with polymyxin use, the Clinical and Laboratory Standards Institute (CLSI) has revised both colistin and polymyxin B breakpoints. Thus, polymyxins ‘intermediate’ breakpoint for Enterobacterales, P. aeruginosa, and Acinetobacter spp. are now set at ≤ 2 mg/L, implying limited clinical efficacy even for isolates with the MIC value 2 mg/L. This change has questioned the dependency on polymyxins in treating XDR infections. In this context, recently approved cefiderocol and phase 3 stage combination drug cefepime-zidebactam assume greater significance due to their potential to act as polymyxin-supplanting therapies.

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References

  1. World Health Organization (2017) Global priority list of antibiotic-resistant bacteria to guide research, discovery, and development of new antibiotics. Available at: https://www.who.int/medicines/publications/WHO-PPL-Short_Summary_25Feb-ET_NM_WHO.pdf?ua=1. Accessed 9 July 2020

  2. El-Sayed Ahmed MAE, Zhong LL, Shen C, Yang Y, Doi Y, Tian GB (2020) Colistin and its role in the era of antibiotic resistance: an extended review (2000-2019). Emerg Microbes Infect 9(1):868–885

    PubMed  PubMed Central  Google Scholar 

  3. Karaiskos I, Galani I, Souli M, Giamarellou H (2019) Novel β-lactam-β-lactamase inhibitor combinations: expectations for the treatment of carbapenem-resistant Gram-negative pathogens. Expert Opin Drug Metab Toxicol 15(2):133–149

    CAS  PubMed  Google Scholar 

  4. Bilinskaya A, Linder KE, Kuti JL (2020) Plazomicin: an intravenous aminoglycoside antibacterial for the treatment of complicated urinary tract infections. Expert Rev Anti-Infect Ther 18(8):705–720

    CAS  PubMed  Google Scholar 

  5. 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(5):1373–1385

    CAS  PubMed  Google Scholar 

  6. Kohira N, Hackel MA, Ishioka Y, Kuroiwa M, Sahm DF, Sato T et al (2020) Reduced susceptibility mechanism to cefiderocol, a siderophore cephalosporin, among clinical isolates from global surveillance program (SIDERO-WT-2014). J Glob Antimicrob Resist S2213-7165(20):30184–30183

    Google Scholar 

  7. Sheu CC, Chang YT, Lin SY, Chen YH, Hsueh PR (2019) Infections caused by carbapenem-resistant Enterobacteriaceae: an update on therapeutic options. Front Microbiol 10:80

    PubMed  PubMed Central  Google Scholar 

  8. Zasowski EJ, Rybak JM, Rybak MJ (2015) The β-lactams strike back: ceftazidime-avibactam. Pharmacotherapy 35(8):755–770

    CAS  PubMed  PubMed Central  Google Scholar 

  9. van Duin D, Bonomo RA (2016) Ceftazidime/avibactam and ceftolozane/tazobactam: second-generation β-lactam/β-lactamase inhibitor combinations. Clin Infect Dis 63(2):234–241

    PubMed  PubMed Central  Google Scholar 

  10. Clinical and Laboratory Standards Institute (2020) Performance standards for antimicrobial susceptibility testing; 24th informational supplement. CLSI document M100-S30. Clinical and Laboratory Standards Institute, Wayne, PA

  11. Shields RK (2020) Case commentary: the need for cefiderocol is clear, but are the supporting clinical data? Antimicrob Agents Chemother 64(4):e00059–e00020

    PubMed  PubMed Central  Google Scholar 

  12. Echols R, Ariyasu M, Nagata TD (2019) Pathogen-focused clinical development to address unmet medical need: cefiderocol targeting carbapenem resistance. Clin Infect Dis 69(Suppl 7):S559–S564

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Humphries RM (2015) Susceptibility testing of the polymyxins: where are we now? Pharmacotherapy 35(1):22–27

    CAS  PubMed  Google Scholar 

  15. Tsuji BT, Pogue JM, Zavascki AP, Paul M, Daikos GL, Forrest A et al (2019) 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 39(1):10–39

    PubMed  PubMed Central  Google Scholar 

  16. Nation RL, Rigatto MHP, Falci DR, Zavascki AP (2019) Polymyxin acute kidney injury: dosing and other strategies to reduce toxicity. Antibiotics (Basel) 8(1):24

    CAS  Google Scholar 

  17. Garonzik SM, Li J, Thamlikitkul V, Paterson DL, Shoham S, Jacob J et al (2011) 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 55(7):3284–3294

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Miglis C, Rhodes NJ, Avedissian SN, Kubin CJ, Yin MT, Nelson BC et al (2018) Population pharmacokinetics of polymyxin B in acutely ill adult patients. Antimicrob Agents Chemother 62(3):e01475–e01417

    PubMed  PubMed Central  Google Scholar 

  19. Forrest A, Garonzik SM, Thamlikitkul V, Giamarellos-Bourboulis EJ, Paterson DL, Li J et al (2017) Pharmacokinetic/toxicodynamic analysis of colistin-associated acute kidney injury in critically ill patients. Antimicrob Agents Chemother 61(11):e01367–e01317

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Landersdorfer CB, Nation RL (2015) Colistin: how should it be dosed for the critically ill? Semin Respir Crit Care Med 36(1):126–135

    PubMed  Google Scholar 

  21. Landersdorfer CB, Wang J, Wirth V, Chen K, Kaye KS, Tsuji BT et al (2018) Pharmacokinetics/pharmacodynamics of systemically administered polymyxin B against Klebsiella pneumoniae in mouse thigh and lung infection models. J Antimicrob Chemother 73(2):462–468

    CAS  PubMed  Google Scholar 

  22. Rattanaumpawan P, Lorsutthitham J, Ungprasert P, Angkasekwinai N, Thamlikitkul V (2010) Randomized controlled trial of nebulized colistimethate sodium as adjunctive therapy of ventilator-associated pneumonia caused by Gram-negative bacteria. J Antimicrob Chemother 12:2645–2649

    Google Scholar 

  23. Nation RL, Li J, Cars O, Couet W, Dudley MN, Kaye KS et al (2015) Framework for optimisation of the clinical use of colistin and polymyxin B: the Prato polymyxin consensus. Lancet Infect Dis 15(2):225–234

    CAS  PubMed  Google Scholar 

  24. Pogue JM, Lee J, Marchaim D, Yee V, Zhao JJ, Chopra T et al (2011) Incidence of and risk factors for colistin-associated nephrotoxicity in a large academic health system. Clin Infect Dis 53(9):879–884

    CAS  PubMed  Google Scholar 

  25. Lee SH, Kim JS, Ravichandran K, Gil HW, Song HY, Hong SY (2015) P-glycoprotein induction ameliorates colistin induced nephrotoxicity in cultured human proximal tubular cells. PLoS One 10(8):e0136075

    PubMed  PubMed Central  Google Scholar 

  26. Rattanaumpawan P, Ungprasert P, Thamlikitkul V (2011) Risk factors for colistin-associated nephrotoxicity. J Inf Secur 62(2):187–190

    Google Scholar 

  27. Balkan II, Dogan M, Durdu B, Batirel A, Hakyemez IN, Cetin B et al (2014) Colistin nephrotoxicity increases with age. Scand J Infect Dis 46(10):678–685

    CAS  PubMed  Google Scholar 

  28. Miano TA, Lautenbach E, Wilson FP, Guo W, Borovskiy Y, Hennessy S (2018) Attributable risk and time course of colistin-associated acute kidney injury. Clin J Am Soc Nephrol 13(4):542–550

    PubMed  PubMed Central  Google Scholar 

  29. Phe K, Shields RK, Tverdek FP, Aitken SL, Guervil DJ, Lam WM et al (2016) Predicting the risk of nephrotoxicity in patients receiving colistimethate sodium: a multicentre, retrospective, cohort study. J Antimicrob Chemother 71(12):3585–3587

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Akajagbor DS, Wilson SL, Shere-Wolfe KD, Dakum P, Charurat ME, Gilliam BL (2013) Higher incidence of acute kidney injury with intravenous colistimethate sodium compared with polymyxin B in critically ill patients at a tertiary care medical center. Clin Infect Dis 57(9):1300–1303

    CAS  PubMed  Google Scholar 

  31. Tuon FF, Rigatto MH, Lopes CK, Kamei LK, Rocha JL, Zavascki AP (2014) Risk factors for acute kidney injury in patients treated with polymyxin B or colistin methanesulfonate sodium. Int J Antimicrob Agents 43(4):349–352

    CAS  PubMed  Google Scholar 

  32. Rigatto MH, Behle TF, Falci DR, Freitas T, Lopes NT, Nunes M et al (2015) Risk factors for acute kidney injury (AKI) in patients treated with polymyxin B and influence of AKI on mortality: a multicentre prospective cohort study. J Antimicrob Chemother 70(5):1552–1557

    CAS  PubMed  Google Scholar 

  33. Aggarwal R, Dewan A (2018) Comparison of nephrotoxicity of colistin with polymyxin B administered in currently recommended doses: a prospective study. Ann Clin Microbiol Antimicrob 17(1):15

    PubMed  PubMed Central  Google Scholar 

  34. Ngamprasertchai T, Boonyasiri A, Charoenpong L, Nimitvilai S, Lorchirachoonkul N, Wattanamongkonsil L et al (2018) Effectiveness and safety of polymyxin B for the treatment of infections caused by extensively drug-resistant Gram-negative bacteria in Thailand. Infect Drug Resist 11:1219–1224

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Maniara BP, Healy LE, Doan TL (2020) Risk of nephrotoxicity associated with nonrenally adjusted intravenous polymyxin B compared to traditional dosing. J Pharm Pract 33(3):287–292

    PubMed  Google Scholar 

  36. Mattos KPH, Gouvêa IR, Quintanilha JCF, Cursino MA, Vasconcelos PENS, Moriel P (2019) Polymyxin B clinical outcomes: a prospective study of patients undergoing intravenous treatment. J Clin Pharm Ther 44(3):415–419

    CAS  PubMed  Google Scholar 

  37. McKinnell JA, Dwyer JP, Talbot GH, Connolly LE, Friedland I, Smith A et al (2019) Plazomicin for infections caused by carbapenem-resistant Enterobacteriaceae. N Engl J Med 380(8):791–793

    PubMed  Google Scholar 

  38. Motsch J, Murta de Oliveira C, Stus V, Köksal I, Lyulko O, Boucher HW 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(9):1799–1808

    CAS  PubMed  Google Scholar 

  39. Wunderink RG, Giamarellos-Bourboulis EJ, Rahav G, Mathers AJ, Bassetti M, Vazquez J 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(4):439–455

    PubMed  PubMed Central  Google Scholar 

  40. van Duin D, Lok JJ, Earley M, Cober E, Richter SS, Perez F et al (2018) Colistin versus ceftazidime-avibactam in the treatment of infections due to carbapenem-resistant Enterobacteriaceae. Clin Infect Dis 66(2):163–171

    PubMed  Google Scholar 

  41. Dubrovskaya Y, Prasad N, Lee Y, Esaian D, Figueroa DA, Tam VH (2015) Risk factors for nephrotoxicity onset associated with polymyxin B therapy. J Antimicrob Chemother 70(6):1903–1907

    CAS  PubMed  Google Scholar 

  42. Nelson BC, Eiras DP, Gomez-Simmonds A, Loo AS, Satlin MJ, Jenkins SG et al (2015) Clinical outcomes associated with polymyxin B dose in patients with bloodstream infections due to carbapenem-resistant Gram-negative rods. Antimicrob Agents Chemother 59(11):7000–7006

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Rigatto MH, Falci DR, Lopes NT, Zavascki AP (2016) Clinical features and mortality of patients on renal replacement therapy receiving polymyxin B. Int J Antimicrob Agents 47(2):146–150

    CAS  PubMed  Google Scholar 

  44. Ismail B, Shafei MN, Harun A, Ali S, Omar M, Deris ZZ (2018) Predictors of polymyxin B treatment failure in Gram-negative healthcare-associated infections among critically ill patients. J Microbiol Immunol Infect 51(6):763–769

    CAS  PubMed  Google Scholar 

  45. Teo JQ, Chang CW, Leck H, Tang CY, Lee SJ, Cai Y et al (2019) Risk factors and outcomes associated with the isolation of polymyxin B and carbapenem-resistant Enterobacteriaceae spp.: a case-control study. Int J Antimicrob Agents 53(5):657–662

    CAS  PubMed  Google Scholar 

  46. Pogue JM, Kaye KS, Veve MP, Patel TS, Gerlach AT, Davis SL et al (2020) Ceftolozane/tazobactam vs polymyxin or aminoglycoside-based regimens for the treatment of drug-resistant Pseudomonas aeruginosa. Clin Infect Dis 71(2):304–310

    CAS  PubMed  Google Scholar 

  47. Satlin MJ, Lewis JS, Weinstein MP, Patel J, Humphries RM, Kahlmeter G et al (2020) Clinical and Laboratory Standards Institute (CLSI) and European Committee on Antimicrobial Susceptibility Testing (EUCAST) position statements on polymyxin B and colistin clinical breakpoints. Clin Infect Dis: ciaa121. https://doi.org/10.1093/cid/ciaa121

  48. Poirel L, Jayol A, Nordmann P (2017) Polymyxins: antibacterial activity, susceptibility testing, and resistance mechanisms encoded by plasmids or chromosomes. Clin Microbiol Rev 30(2):557–596

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Ezadi F, Ardebili A, Mirnejad R (2019) Antimicrobial susceptibility testing for polymyxins: challenges, issues, and recommendations. J Clin Microbiol 57(4):e01390–e01318

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Simner PJ, Bergman Y, Trejo M, Roberts AA, Marayan R, Tekle T et al (2019) Two-site evaluation of the colistin broth disk elution test to determine colistin in vitro activity against Gram-negative bacilli. J Clin Microbiol 57(2):e01163–e01118

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Dortet L, Potron A, Bonnin RA, Plesiat P, Naas T, Filloux A et al (2018) Rapid detection of colistin resistance in Acinetobacter baumannii using MALDI-TOF-based lipidomics on intact bacteria. Sci Rep 8:16910

    PubMed  PubMed Central  Google Scholar 

  52. Lescat M, Poirel L, Jayol A, Nordmann P (2019) Performances of the rapid polymyxin Acinetobacter and Pseudomonas tests for colistin susceptibility testing. Microb Drug Resist 25(4):520–523

    CAS  PubMed  Google Scholar 

  53. Matuschek E, Ahman J, Webster C, Kahlmeter G (2018) Antimicrobial susceptibility testing of colistin - evaluation of seven commercial MIC products against standard broth microdilution for Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa and Acinetobacter spp. Clin Microbiol Infect 24:865–870

    CAS  PubMed  Google Scholar 

  54. Falagas ME, Rafailidis PI, Kasiakou SK, Hatzopoulou P, Michalopoulos A (2006) Effectiveness and nephrotoxicity of colistin monotherapy vs. colistin-meropenem combination therapy for multidrug-resistant Gram-negative bacterial infections. Clin Microbiol Infect 12(12):1227–1230

    CAS  PubMed  Google Scholar 

  55. Paul M, Daikos GL, Durante-Mangoni E, Yahav D, Carmeli Y, Benattar YD et al (2018) Colistin alone versus colistin plus meropenem for treatment of severe infections caused by carbapenem-resistant Gram-negative bacteria: an open-label, randomised controlled trial. Lancet Infect Dis 18(4):391–400

    CAS  PubMed  Google Scholar 

  56. Dickstein Y, Lellouche J, Schwartz D, Nutman A, Rakovitsky N, Dishon Benattar Y et al (2019) Colistin resistance development following colistin-meropenem combination therapy vs. colistin monotherapy in patients with infections caused by carbapenem-resistant organisms. Clin Infect Dis: ciz1146. https://doi.org/10.1093/cid/ciz1146

  57. Dickstein Y, Lellouche J, Ben Dalak Amar M, Schwartz D, Nutman A et al (2019) Treatment outcomes of colistin- and carbapenem-resistant Acinetobacter baumannii infections: an exploratory subgroup analysis of a randomized clinical trial. Clin Infect Dis 69(5):769–776

    CAS  PubMed  Google Scholar 

  58. Kelesidis T, Falagas ME (2015) The safety of polymyxin antibiotics. Expert Opin Drug Saf 14(11):1687–1701

    CAS  PubMed  PubMed Central  Google Scholar 

  59. European Committee on Antimicrobial Susceptibility Testing (2020) Breakpoint tables for interpretation of MICs and zone diameters, version 10.0. https://www.eucast.org/fileadmin/src/media/PDFs/EUCAST_files/Breakpoint_tables/v_10.0_Breakpoint_Tables.pdf. Accessed Aug 2020

  60. Doern GV, Brecher SM (2011) The clinical predictive value (or lack thereof) of the results of in vitro antimicrobial susceptibility tests. J Clin Microbiol 49(9 Suppl):S11–S14. https://doi.org/10.1128/JCM.00580-11

    Article  PubMed Central  Google Scholar 

  61. Drusano GL, Fregeau C, Liu W, Brown DL, Louie A (2010) Impact of burden on granulocyte clearance of bacteria in a mouse thigh infection model. Antimicrob Agents Chemother 54(10):4368–4372

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Drusano GL, Liu W, Fikes S, Cirz R, Robbins N, Kurhanewicz S et al (2014) Interaction of drug- and granulocyte-mediated killing of Pseudomonas aeruginosa in a murine pneumonia model. J Infect Dis 210(8):1319–1324

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Thaden JT, Pogue JM, Kaye KS (2017) Role of newer and re-emerging older agents in the treatment of infections caused by carbapenem-resistant Enterobacteriaceae. Virulence 8(4):403–416

    CAS  PubMed  Google Scholar 

  64. Lashinsky JN, Henig O, Pogue JM, Kaye KS (2017) Minocycline for the treatment of multidrug and extensively drug-resistant A. baumannii: a review. Infect Dis Ther 6(2):199–211

    PubMed  PubMed Central  Google Scholar 

  65. Pogue JM, Mann T, Barber KE, Kaye KS (2013) Carbapenem-resistant Acinetobacter baumannii: epidemiology, surveillance and management. Expert Rev Anti-Infect Ther 11(4):383–393

    CAS  PubMed  Google Scholar 

  66. Fragkou PC, Poulakou G, Blizou A, Blizou M, Rapti V, Karageorgopoulos DE et al (2019) The role of minocycline in the treatment of nosocomial infections caused by multidrug, extensively drug and pandrug resistant Acinetobacter baumannii: a systematic review of clinical evidence. Microorganisms 7(6):159

    CAS  PubMed Central  Google Scholar 

  67. Pogue JM, Neelakanta A, Mynatt RP, Sharma S, Lephart P, Kaye KS (2014) Carbapenem-resistance in gram-negative bacilli and intravenous minocycline: an antimicrobial stewardship approach at the Detroit Medical Center. Clin Infect Dis 59(Suppl 6):S388–S393

    CAS  PubMed  Google Scholar 

  68. Dixit D, Madduri RP, Sharma R (2014) The role of tigecycline in the treatment of infections in light of the new black box warning. Expert Rev Anti-Infect Ther 12(4):397–400

    CAS  PubMed  Google Scholar 

  69. Freire AT, Melnyk V, Kim MJ, Datsenko O, Dzyublik O, Glumcher F et al (2010) Comparison of tigecycline with imipenem/cilastatin for the treatment of hospital-acquired pneumonia. Diagn Microbiol Infect Dis 68(2):140–151

    CAS  PubMed  Google Scholar 

  70. Bassetti M, Giacobbe DR, Taramasso L (2012) Tigecycline use in hospital and its potential role in infection control. Eur Infect Dis 6(1):57–60

    Google Scholar 

  71. Ramirez J, Dartois N, Gandjini H, Yan JL, Korth-Bradley J, McGovern PC (2013) 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 57(4):1756–1762

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Bassetti M, Peghin M, Pecori D (2016) The management of multidrug-resistant Enterobacteriaceae. Curr Opin Infect Dis 29(6):583–594

    CAS  PubMed  Google Scholar 

  73. Baron J, Cai S, Klein N, Cunha BA (2018) Once daily high dose tigecycline is optimal: tigecycline PK/PD parameters predict clinical effectiveness. J Clin Med 7(3):49

    PubMed Central  Google Scholar 

  74. Cunha BA, Baron J, Cunha CB (2017) Once daily high dose tigecycline - pharmacokinetic/pharmacodynamic based dosing for optimal clinical effectiveness: dosing matters, revisited. Expert Rev Anti-Infect Ther 15(3):257–267

    CAS  PubMed  Google Scholar 

  75. Falagas ME, Vardakas KZ, Tsiveriotis KP, Triarides NA, Tansarli GS (2014) Effectiveness and safety of high-dose tigecycline-containing regimens for the treatment of severe bacterial infections. Int J Antimicrob Agents 44(1):1–7

    CAS  PubMed  Google Scholar 

  76. Cai Y, Wang R (2011) Tigecycline: benefits and risks. Lancet Infect Dis 11(11):804–805

    PubMed  Google Scholar 

  77. Vardakas KZ, Rafailidis PI, Falagas ME (2012) Effectiveness and safety of tigecycline: focus on use for approved indications. Clin Infect Dis 54(11):1672–1674

    CAS  PubMed  Google Scholar 

  78. Tasina E, Haidich AB, Kokkali S, Arvanitidou M (2011) Efficacy and safety of tigecycline for the treatment of infectious diseases: a meta-analysis. Lancet Infect Dis 11(11):834–844

    CAS  PubMed  Google Scholar 

  79. Yahav D, Lador A, Paul M, Leibovici L (2012) Tigecycline and overall mortality. Clin Infect Dis 55(12):1739

    PubMed  Google Scholar 

  80. Michalopoulos A, Virtzili S, Rafailidis P, Chalevelakis G, Damala M, Falagas ME (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

    CAS  PubMed  Google Scholar 

  81. Pontikis K, Karaiskos I, Bastani S, Dimopoulos G, Kalogirou M, Katsiari M 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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  83. Florent A, Chichmanian RM, Cua E, Pulcini C (2011) Adverse events associated with intravenous fosfomycin. Int J Antimicrob Agents 37(1):82–83

    CAS  PubMed  Google Scholar 

  84. Falagas ME, Vouloumanou EK, Samonis G, Vardakas KZ (2016) Fosfomycin. Clin Microbiol Rev 29(2):321–347

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Zhanel GG, Zhanel MA, Karlowsky JA (2018) Intravenous fosfomycin: an assessment of its potential for use in the treatment of systemic infections in Canada. Can J Infect Dis Med Microbiol 2018:8912039

    PubMed  PubMed Central  Google Scholar 

  86. Livermore DM, Nicolau DP, Hopkins KL, Meunier D (2020) CRE, CRO, CPE and CPO': terminology past its ‘sell-by-date’ in an era of new antibiotics and regional carbapenemase epidemiology. Clin Infect Dis: ciaa122. https://doi.org/10.1093/cid/ciaa122

  87. Logan LK, Weinstein RA (2017) The epidemiology of carbapenem-resistant Enterobacteriaceae: the impact and evolution of a global menace. J Infect Dis 215(suppl_1):S28–S36

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Kazmierczak KM, Rabine S, Hackel M, McLaughlin RE, Biedenbach DJ, Bouchillon SK et al (2016) Multiyear, multinational survey of the incidence and global distribution of metallo-β-lactamase-producing Enterobacteriaceae and Pseudomonas aeruginosa. Antimicrob Agents Chemother 60(2):1067–1078

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Zarrilli R, Pournaras S, Giannouli M, Tsakris A (2013) Global evolution of multidrugresistant Acinetobacter baumannii clonal lineages. Int J Antimicrob Agents 41:11–19

    CAS  PubMed  Google Scholar 

  90. Shields RK, Nguyen MH, Chen L, Press EG, Potoski BA, Marini RV, Doi Y et al (2017) Ceftazidime-avibactam is superior to other treatment regimens against carbapenem-resistant Klebsiella pneumoniae bacteremia. Antimicrob Agents Chemother 61(8):e00883–e00817

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Räisänen K, Koivula I, Ilmavirta H, Puranen S, Kallonen T, Lyytikäinen O et al (2018) Emergence of ceftazidime-avibactam-resistant Klebsiella pneumoniae during treatment, Finland, December 2018. Euro Surveill 24(19):1900256

    Google Scholar 

  92. Oueslati S, Tlili L, Exilie C, Bernabeu S, Iorga B, Bonnin RA et al (2020) Different phenotypic expression of KPC b-lactamase variants and challenges in their detection. J Antimicrob Chemother 75(3):769–771

    CAS  PubMed  Google Scholar 

  93. Oueslati S, Iorga B, Tlili L, Exilie C, Zavala A, Dortet L et al (2019) Unravelling ceftazidime/avibactam resistance of KPC-28, a KPC-2 variant lacking carbapenemase activity. J Antimicrob Chemother 74(8):2239–2246

    CAS  PubMed  Google Scholar 

  94. Athans V, Neuner EA, Hassouna H, Richter SS, Keller G, Castanheira M et al (2018) Meropenem-vaborbactam as salvage therapy for ceftazidime-avibactam-resistant Klebsiella pneumoniae bacteremia and abscess in a liver transplant recipient. Antimicrob Agents Chemother 63(1):e01551–e01518

    PubMed  PubMed Central  Google Scholar 

  95. Tumbarello M, Trecarichi EM, Corona A, De Rosa FG, Bassetti M, Mussini C et al (2019) Efficacy of ceftazidime-avibactam salvage therapy in patients with infections caused by Klebsiella pneumoniae carbapenemase-producing K. pneumoniae. Clin Infect Dis 68(3):355–364

    CAS  PubMed  Google Scholar 

  96. Onorato L, Di Caprio G, Signoriello S, Coppola N (2019) Efficacy of ceftazidime/avibactam in monotherapy or combination therapy against carbapenem-resistant Gram-negative bacteria: a meta-analysis. Int J Antimicrob Agents 54(6):735–740

    CAS  PubMed  Google Scholar 

  97. Jorgensen SCJ, Trinh TD, Zasowski EJ, Lagnf AM, Bhatia S, Melvin SM et al (2019) Real-world experience with ceftazidime-avibactam for multidrug-resistant gram-negative bacterial infections. Open Forum Infect Dis 6(12):ofz522

    PubMed  PubMed Central  Google Scholar 

  98. Ackley R, Roshdy D, Meredith J, Minor S, Anderson WE, Capraro GA et al (2020) Meropenem-vaborbactam versus ceftazidime-avibactam for treatment of carbapenem-resistant Enterobacteriaceae infections. Antimicrob Agents Chemother 64(5):e02313–e02319

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Tsivkovski R, Lomovskaya O (2020) Potency of vaborbactam is less affected than that of avibactam in strains producing KPC-2 mutations that confer resistance to ceftazidime-avibactam. Antimicrob Agents Chemother 64(4):e01936–e01919

    CAS  PubMed  PubMed Central  Google Scholar 

  100. 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(7):e02208–e02219

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Pogue JM, Bonomo RA, Kaye KS (2019) Ceftazidime/avibactam, meropenem/vaborbactam, or both? Clinical and formulary considerations. Clin Infect Dis 68(3):519–524

    CAS  PubMed  Google Scholar 

  102. Noval M, Banoub M, Claeys KC, Heil E (2020) The battle is on: new beta-lactams for the treatment of multidrug-resistant Gram-negative organisms. Curr Infect Dis Rep 22(1):1

    PubMed  Google Scholar 

  103. Serio AW, Keepers T, Krause KM (2019) Plazomicin is active against metallo-β-lactamase-producing Enterobacteriaceae. Open Forum Infect Dis 6(4):ofz12

    Google Scholar 

  104. Papp-Wallace KM (2019) The latest advances in β-lactam/β-lactamase inhibitor combinations for the treatment of Gram-negative bacterial infections. Expert Opin Pharmacother 20(17):2169–2184

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Sader HS, Rhomberg PR, Flamm RK, Jones RN, Castanheira M (2017) WCK 5222 (cefepime/zidebactam) antimicrobial activity tested against Gram-negative organisms producing clinically relevant β-lactamases. J Antimicrob Chemother 72(6):1696–1703

    CAS  PubMed  Google Scholar 

  106. Kidd JM, Livermore DM, Nicolau DP (2020) The difficulties of identifying and treating Enterobacterales with OXA-48-like carbapenemases. Clin Microbiol Infect 26(4):401–403

    CAS  PubMed  Google Scholar 

  107. Stewart A, Harris P, Henderson A, Paterson D (2018) Treatment of infections by OXA-48-producing Enterobacteriaceae. Antimicrob Agents Chemother 62(11):e01195–e01118

    PubMed  PubMed Central  Google Scholar 

  108. Sousa A, Pérez-Rodríguez MT, Soto A, Rodríguez L, Pérez-Landeiro A, Martínez-Lamas L 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(11):3170–3175

    CAS  PubMed  Google Scholar 

  109. De la Calle C, Rodríguez O, Morata L, Marco F, Cardozo C, García-Vidal 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(4):520–524

    PubMed  Google Scholar 

  110. Wu JY, Srinivas P, Pogue JM (2020) Cefiderocol: a novel agent for the management of multidrug-resistant Gram-negative organisms. Infect Dis Ther 9(1):17–40

    PubMed  PubMed Central  Google Scholar 

  111. Shields R, Doi Y (2019) Aztreonam combination therapy: a long-awaited answer to metallo-β-lactamase-producing gram-negatives? Clin Infect Dis 2019:ciz1159

    Google Scholar 

  112. Emeraud C, Escaut L, Boucly A, Fortineau N, Bonnin RA, Naas T et al (2019) Aztreonam plus clavulanate, tazobactam, or avibactam for treatment of infections caused by metallo-β-lactamase-producing Gram-negative bacteria. Antimicrob Agents Chemother 63(5):e00010–e00019

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Falcone M, Daikos GL, Tiseo G, Bassoulis D, Giordano C, Galfo V et al Efficacy of ceftazidime-avibactam plus aztreonam in patients with bloodstream infections caused by MBL- producing Enterobacterales. Clin Infect Dis: ciaa586. https://doi.org/10.1093/cid/ciaa586

  114. Sieswerda E, van den Brand M, van den Berg RB, Sträter J, Schouls L, van Dijk K et al (2020) Successful rescue treatment of sepsis due to a pandrug-resistant, NDM-producing Klebsiella pneumoniae using aztreonam powder for nebulizer solution as intravenous therapy in combination with ceftazidime/avibactam. J Antimicrob Chemother 75(3):773–775

    CAS  PubMed  Google Scholar 

  115. Yasmin M, Fouts DE, Jacobs MR, Haydar H, Marshall SH, White R et al (2019) Monitoring ceftazidime-avibactam (CAZ-AVI) and aztreonam (ATM) concentrations in the treatment of a bloodstream infection caused by a multidrug-resistant Enterobacter sp. carrying both KPC-4 and NDM-1 carbapenemases. Clin Infect Dis: ciz1155

  116. Alm RA, Johnstone MR, Lahiri SD (2015) Characterization of Escherichia coli NDM isolates with decreased susceptibility to aztreonam/avibactam: role of a novel insertion in PBP3. J Antimicrob Chemother 70(5):1420–1428

    CAS  PubMed  Google Scholar 

  117. Biagi M, Wu T, Lee M, Patel S, Butler D, Wenzler E (2019) Searching for the optimal treatment for metallo- and serine-β-lactamase producing Enterobacteriaceae: aztreonam in combination with ceftazidime-avibactam or meropenem-vaborbactam. Antimicrob Agents Chemother 63(12):e01426–e01419

    CAS  PubMed Central  Google Scholar 

  118. Lutgring JD, Balbuena R, Reese N, Gilbert SE, Ansari U, Bhatnagar A et al (2020) Antibiotic susceptibility of NDM-producing Enterobacterales collected in the United States, 2017-2018. Antimicrob Agents Chemother. https://doi.org/10.1128/AAC.00499-20

  119. Hamrick JC, Docquier JD, Uehara T, Myers CL, Six DA, Chatwin CL 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(3):e01963–e01919

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Wang X, Zhao C, Wang Q, Wang Z, Liang X, Zhang F et al (2020) In vitro activity of the novel β-lactamase inhibitor taniborbactam (VNRX-5133), in combination with cefepime or meropenem, against MDR Gram-negative bacterial isolates from China. J Antimicrob Chemother 75(7):1850–1858

    CAS  PubMed  Google Scholar 

  121. 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(3):e02048–e02018

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Aitken SL, Tarrand JJ, Deshpande LM, Tverdek FP, Jones AL, Shelburne SA et al (2016) High rates of nonsusceptibility to ceftazidime-avibactam and identification of New Delhi metallo-β-lactamase production in Enterobacteriaceae bloodstream infections at a major cancer center. Clin Infect Dis 63(7):954–958

    CAS  PubMed  Google Scholar 

  123. Humphries RM, Yang S, Hemarajata P, Ward KW, Hindler JA, Miller SA et al (2015) First report of ceftazidime-avibactam resistance in a KPC-3-expressing Klebsiella pneumoniae isolate. Antimicrob Agents Chemother 59(10):6605–6607

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Nelson K, Hemarajata P, Sun D, Rubio-Aparicio D, Tsivkovski R, Yang S 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(10):e00989–e00917

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Shen Z, Ding B, Ye M, Wang P, Bi Y, Wu S et al (2017) High ceftazidime hydrolysis activity and porin OmpK35 deficiency contribute to the decreased susceptibility to ceftazidime/avibactam in KPC-producing Klebsiella pneumoniae. J Antimicrob Chemother 72(7):1930–1936

    CAS  PubMed  Google Scholar 

  126. 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(8):e00389–e00317

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Fröhlich C, Sørum V, Thomassen AM, Johnsen PJ, Leiros HS, Samuelsen Ø (2019) OXA-48-mediated ceftazidime-avibactam resistance is associated with evolutionary trade-offs. mSphere 4(2):e00024–e00019

    PubMed  PubMed Central  Google Scholar 

  128. Periasamy H, Joshi P, Palwe S, Shrivastava R, Bhagwat S, Patel M (2020) High prevalence of Escherichia coli clinical isolates in India harbouring four amino acid inserts in PBP3 adversely impacting activity of aztreonam/avibactam. J Antimicrob Chemother 75(6):1650–1651

    CAS  PubMed  Google Scholar 

  129. Maraolo AE, Mazzitelli M, Trecarichi EM, Buonomo AR, Torti C, Gentile I (2020) Ceftolozane/tazobactam for difficult-to-treat Pseudomonas aeruginosa infections: a systematic review of its efficacy and safety for off-label indications. Int J Antimicrob Agents 55(3):105891

    CAS  PubMed  Google Scholar 

  130. Wi YM, Greenwood-Quaintance KE, Schuetz AN, Ko KS, Peck KR, Song JH et al (2017) Activity of ceftolozane-tazobactam against carbapenem-resistant, non-carbapenemase-producing Pseudomonas aeruginosa and associated resistance mechanisms. Antimicrob Agents Chemother 62(1):e01970–e01917

    PubMed  PubMed Central  Google Scholar 

  131. Dantas RCC, Silva RTE, Ferreira ML, Gonçalves IR, Araújo BF, Campos PA et al (2017) Molecular epidemiological survey of bacteremia by multidrug resistant Pseudomonas aeruginosa: the relevance of intrinsic resistance mechanisms. PLoS One 12(5):e0176774

    PubMed  PubMed Central  Google Scholar 

  132. Arca-Suárez J, Vázquez-Ucha JC, Fraile-Ribot PA, Lence E, Cabot G, Martínez-Guitián M et al (2020) Molecular and biochemical insights into the in vivo evolution of AmpC-mediated resistance to ceftolozane/tazobactam during treatment of an MDR Pseudomonas aeruginosa infection. J Antimicrob Chemother: dkaa291. https://doi.org/10.1093/jac/dkaa291

  133. Winkler ML, Papp-Wallace KM, Hujer AM, Domitrovic TN, Hujer KM, Hurless KN et al (2015) Unexpected challenges in treating multidrug-resistant Gram-negative bacteria: resistance to ceftazidime-avibactam in archived isolates of Pseudomonas aeruginosa. Antimicrob Agents Chemother 59(2):1020–1029

    PubMed  PubMed Central  Google Scholar 

  134. Skoglund E, Abodakpi H, Rios R, Diaz L, De La Cadena E, Dinh AQ et al (2018) In vivo resistance to ceftolozane/tazobactam in Pseudomonas aeruginosa arising by AmpC- and non-AmpC-mediated pathways. Case Rep Infect Dis 2018:9095203

    PubMed  PubMed Central  Google Scholar 

  135. O'Donnell JN, Bidell MR, Lodise TP (2020) Approach to the treatment of patients with serious multidrug-resistant Pseudomonas aeruginosa infections. Pharmacotherapy. https://doi.org/10.1002/phar.2449

  136. Horner C, Mushtaq S, Livermore DM, BSAC Resistance Surveillance Standing Committee (2019) Potentiation of imipenem by relebactam for Pseudomonas aeruginosa from bacteraemia and respiratory infections. J Antimicrob Chemother 74(7):1940–1944

    CAS  PubMed  Google Scholar 

  137. Pragasam AK, Raghanivedha M, Anandan S, Veeraraghavan B (2016) Characterization of Pseudomonas aeruginosa with discrepant carbapenem susceptibility profile. Ann Clin Microbiol Antimicrob 15:12

    PubMed  PubMed Central  Google Scholar 

  138. Sabet M, Tarazi Z, Griffith DC (2018) Activity of meropenem-vaborbactam against Pseudomonas aeruginosa and Acinetobacter baumannii in a neutropenic mouse thigh infection model. Antimicrob Agents Chemother 63(1):e01665–e01618

    PubMed  PubMed Central  Google Scholar 

  139. Iregui A, Khan Z, Landman D, Quale J (2020) Activity of cefiderocol against Enterobacterales, Pseudomonas aeruginosa, and Acinetobacter baumannii endemic to medical centers in New York City. Microb Drug Resist 26(7):722–726

    CAS  PubMed  PubMed Central  Google Scholar 

  140. Delgado-Valverde M, Conejo MDC, Serrano L, Fernández-Cuenca F, Pascual Á (2020) Activity of cefiderocol against high-risk clones of multidrug-resistant Enterobacterales, Acinetobacter baumannii, Pseudomonas aeruginosa and Stenotrophomonas maltophilia. J Antimicrob Chemother 75(7):1840–1849

    CAS  PubMed  PubMed Central  Google Scholar 

  141. Hackel MA, Tsuji M, Yamano Y, Echols R, Karlowsky JA, Sahm DF (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(9):e00093–e00017

    CAS  PubMed  PubMed Central  Google Scholar 

  142. Hackel MA, Tsuji M, Yamano Y, Echols R, Karlowsky JA, Sahm DF (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(2):e01968–e01917

  143. Moya B, Bhagwat S, Cabot G, Bou G, Patel M, Oliver A (2020) Effective inhibition of PBPs by cefepime and zidebactam in the presence of VIM-1 drives potent bactericidal activity against MBL-expressing Pseudomonas aeruginosa. J Antimicrob Chemother 75(6):1474–1478

    CAS  PubMed  Google Scholar 

  144. Thomson KS, AbdelGhani S, Snyder JW, Thomson GK (2019) Activity of cefepime-zidebactam against multidrug-resistant (MDR) Gram-negative pathogens. Antibiotics (Basel) 8(1):32

    CAS  Google Scholar 

  145. Sader HS, Carvalhaes CG, Duncan LR, Ryan Arends SR, Mendes RE, Castanheira M (2019) Cefepime-zidebactam (WCK 5222) activity against clinical isolates of non-fermentative Gram-negative bacilli collected worldwide in 2018. Presented at ASM/ESCMID September 3–6, Boston, MA, USA Poster 69

  146. Kidd JM, Abdelraouf K, Nicolau DP (2020) Efficacy of human-simulated bronchopulmonary exposures of cefepime, zidebactam and the combination (WCK 5222) against MDR Pseudomonas aeruginosa in a neutropenic murine pneumonia model. J Antimicrob Chemother 75(1):149–155

    CAS  PubMed  Google Scholar 

  147. Monogue ML, Tabor-Rennie J, Abdelraouf K, Nicolau DP (2019) In vivo efficacy of WCK 5222 (cefepime-zidebactam) against multidrug-resistant Pseudomonas aeruginosa in the neutropenic murine thigh infection model. Antimicrob Agents Chemother 63(7):e00233–e00219

    CAS  PubMed  PubMed Central  Google Scholar 

  148. Bonomo RA (2019) Cefiderocol: a novel siderophore cephalosporin defeating carbapenem-resistant pathogens. Clin Infect Dis 69(Suppl 7):S519–S520

    CAS  PubMed  PubMed Central  Google Scholar 

  149. McCarthy MW (2020) Cefiderocol to treat complicated urinary tract infection. Drugs Today (Barc) 56(3):177–184

    CAS  Google Scholar 

  150. Dagher M, Ruffin F, Marshall S, Taracila M, Bonomo RA, Reilly R et al (2020) Case report: successful rescue therapy of extensively drug-resistant Acinetobacter baumannii osteomyelitis with cefiderocol. Open Forum Infect Dis 7(5):ofaa150

  151. Trecarichi EM, Quirino A, Scaglione V, Longhini F, Garofalo E, Bruni A et al (2019) Successful treatment with cefiderocol for compassionate use in a critically ill patient with XDR Acinetobacter baumannii and KPC-producing Klebsiella pneumoniae: a case report. J Antimicrob Chemother 74(11):3399–3401

    CAS  PubMed  Google Scholar 

  152. Stevens RW, Clancy M (2019) Compassionate use of cefiderocol in the treatment of an intraabdominal infection due to multidrug-resistant Pseudomonas aeruginosa: a case report. Pharmacotherapy 39(11):1113–1118

    PubMed  Google Scholar 

  153. Bassetti M, Ariyasu M, Binkowitz B, Nagata TD, Echols RM, Matsunaga Y et al (2019) Designing a pathogen-focused study to address the high unmet medical need represented by carbapenem-resistant gram-negative pathogens - the international, multicenter, randomized, open-label, phase 3 CREDIBLE-CR study. Infect Drug Resist 12:3607–3623

    CAS  PubMed  PubMed Central  Google Scholar 

  154. Khan Z, Iregui A, Landman D, Quale J (2019) Activity of cefepime/zidebactam (WCK 5222) against Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter baumannii endemic to New York City medical centres. J Antimicrob Chemother 74(10):2938–2942

    CAS  PubMed  Google Scholar 

  155. Lepak AJ, Zhao M, Andes DR (2019) WCK 5222 (cefepime/zidebactam) pharmacodynamic target analysis against metallo-β-lactamase producing Enterobacteriaceae in the neutropenic mouse pneumonia model. Antimicrob Agents Chemother 63(12):e01648–e01619

    CAS  PubMed Central  Google Scholar 

  156. Avery LM, Mullane EM, Nicolau DP (2020) Evaluation of the in vitro activity of WCK 5222 (cefepime/zidebactam) and currently available combination therapies against single- and double-carbapenemase producing Enterobacteriaceae: expanding the zone of hope. Int J Antimicrob Agents 55(2):105863

    CAS  PubMed  Google Scholar 

  157. Papp-Wallace KM, Nguyen NQ, Jacobs MR, Bethel CR, Barnes MD, Kumar V et al (2018) Strategic approaches to overcome resistance against Gram-negative pathogens using β-lactamase inhibitors and β-lactam enhancers: activity of three novel diazabicyclooctanes WCK 5153, zidebactam (WCK 5107), and WCK 4234. J Med Chem 61(9):4067–4086

    CAS  PubMed  PubMed Central  Google Scholar 

  158. Moya B, Barcelo IM, Bhagwat S, Patel M, Bou G, Papp-Wallace KM et al (2017) WCK 5107 (zidebactam) and WCK 5153 are novel inhibitors of PBP2 showing potent "β-lactam enhancer" activity against Pseudomonas aeruginosa, including multidrug-resistant metallo-β-lactamase-producing high-risk clones. Antimicrob Agents Chemother 61(6):e02529–e02516

    PubMed  PubMed Central  Google Scholar 

  159. Moya B, Barcelo IM, Bhagwat S, Patel M, Bou G, Papp-Wallace KM et al (2017) Potent β-lactam enhancer activity of zidebactam and WCK 5153 against Acinetobacter baumannii, including carbapenemase-producing clinical isolates. Antimicrob Agents Chemother 61(11):e01238–e01217

    CAS  PubMed  PubMed Central  Google Scholar 

  160. Bhagwat SS, Periasamy H, Takalkar SS, Palwe SR, Khande HN, Patel MV (2019) The novel β-lactam enhancer zidebactam augments the in vivo pharmacodynamic activity of cefepime in a neutropenic mouse lung Acinetobacter baumannii infection model. Antimicrob Agents Chemother 63(4):e02146–e02118

    CAS  PubMed  PubMed Central  Google Scholar 

  161. Almarzoky Abuhussain SS, Avery LM, Abdelraouf K, Nicolau DP (2018) In vivo efficacy of humanized WCK 5222 (cefepime-zidebactam) exposures against carbapenem-resistant Acinetobacter baumannii in the neutropenic thigh model. Antimicrob Agents Chemother 63(1):e01931–e01918

    PubMed  PubMed Central  Google Scholar 

  162. Avery LM, Abdelraouf K, Nicolau DP (2018) Assessment of the in vivo efficacy of WCK 5222 (cefepime-zidebactam) against carbapenem-resistant Acinetobacter baumannii in the neutropenic murine lung infection model. Antimicrob Agents Chemother 62(11):e00948–e00918

    PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Department of Infectious Diseases, Jupiter Hospital, Pune, India

    Rajeev Soman

  2. Department of Clinical Microbiology, Christian Medical College, Vellore, Tamil Nadu, 632 004, India

    Yamuna Devi Bakthavatchalam & Balaji Veeraraghavan

  3. Department of Surgery, Christian Medical College, Vellore, India

    Abinaya Nadarajan

  4. Department of Orthopaedics, Christian Medical College, Vellore, India

    Hariharan Triplicane Dwarakanathan

  5. Department of Infectious Diseases, Apollo Hospitals, Chennai, India

    Ramasubramanian Venkatasubramanian

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  1. Rajeev Soman
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Soman, R., Bakthavatchalam, Y.D., Nadarajan, A. et al. Is it time to move away from polymyxins?: evidence and alternatives. Eur J Clin Microbiol Infect Dis 40, 461–475 (2021). https://doi.org/10.1007/s10096-020-04053-w

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