Review Article | Published:

Antimicrobial resistance in nephrology

Nature Reviews Nephrology (2019) | Download Citation


The prevalence of antimicrobial resistance among many common bacterial pathogens is increasing. The emergence and global dissemination of these antibiotic-resistant bacteria (ARB) is fuelled by antibiotic selection pressure, inter-organism transmission of resistance determinants, suboptimal infection prevention practices and increasing ease and frequency of international travel, among other factors. Patients with chronic kidney disease, particularly those with end-stage renal disease who require dialysis and/or kidney transplantation, have some of the highest rates of colonization and infection with ARB worldwide. These ARB include methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus spp. and several multidrug-resistant Gram-negative organisms. Antimicrobial resistance limits treatment options and increases the risk of infection-related morbidity and mortality. Several new antibiotic agents with activity against some of the most common ARB have been developed, but resistance to these agents is already emerging and highlights the dire need for new treatment options as well as consistent implementation and improvement of basic infection prevention practices. Clinicians involved in the care of patients with renal disease must be familiar with the local epidemiology of ARB, remain vigilant for the emergence of novel resistance patterns and adhere strictly to practices proven to prevent transmission of ARB and other pathogens.

Key points

  • Infections caused by antibiotic-resistant bacteria (ARB) are associated with higher mortality, longer hospitalization and a greater economic burden than those caused by antibiotic-susceptible bacteria of the same species.

  • The growing global burden of antimicrobial resistance is particularly relevant to patients with chronic kidney disease who are disproportionally affected by antimicrobial resistance when compared with the general population.

  • Consistent implementation of basic infection prevention strategies is a crucial element in the effort to prevent transmission of and infection by ARB.

  • Critical infection prevention practices include hand hygiene, cleaning and disinfection of the environment and medical equipment, and use of evidence-based practices for insertion, use and maintenance of invasive devices.

  • Novel mechanisms of antimicrobial resistance continue to emerge and spread, leading to infections that are difficult to treat and highlighting the need for development of new antimicrobial agents.

  • Antimicrobial treatment of ARB infections is a complex and evolving topic. Consultation with an infectious disease specialist should be considered in order to optimize antimicrobial agent selection and patient outcomes.

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  1. 1.

    Review on Antimicrobial Resistance. Tackling drug-resistant infections globally: final report and recommendations. amr-review (2016).

  2. 2.

    World Health Organization. Antimicrobial resistance: global report on surveillance 2014. WHO (2014).

  3. 3.

    Magiorakos, A. P. et al. Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: an international expert proposal for interim standard definitions for acquired resistance. Clin. Microbiol. Infect. 18, 268–281 (2012).

  4. 4.

    Saran, R. et al. US Renal Data System 2017 Annual Data Report: epidemiology of kidney disease in the United States. Am. J. Kidney Dis. 71, A7 (2018).

  5. 5.

    Calfee, D. P. Multidrug-resistant organisms in dialysis patients. Semin. Dial. 26, 447–456 (2013).

  6. 6.

    Blair, J. M., Webber, M. A., Baylay, A. J., Ogbolu, D. O. & Piddock, L. J. Molecular mechanisms of antibiotic resistance. Nat. Rev. Microbiol. 13, 42–51 (2015).

  7. 7.

    Barber, M. & Rozwadowska-Dowzenko, M. Infection by penicillin-resistant staphylococci. Lancet 2, 641–644 (1948).

  8. 8.

    Barber, M. Methicillin-resistant staphylococci. J. Clin. Pathol. 14, 385–393 (1961).

  9. 9.

    Villegas-Estrada, A., Lee, M., Hesek, D., Vakulenko, S. B. & Mobashery, S. Co-opting the cell wall in fighting methicillin-resistant Staphylococcus aureus: potent inhibition of PBP 2a by two anti-MRSA beta-lactam antibiotics. J. Am. Chem. Soc. 130, 9212–9213 (2008).

  10. 10.

    Deleo, F., Otto, M., Kreiswirth, B. & Chambers, H. Community-associated meticillin-resistant Staphylococcus aureus. Lancet 375, 1557–1568 (2010).

  11. 11.

    European Centre for Disease Prevention and Control. Surveillance of antimicrobial resistance in Europe 2017. ECDC (2018).

  12. 12.

    Rosenthal, V. D. et al. International Nosocomial Infection Control Consortium report, data summary of 50 countries for 2010-2015: device-associated module. Am. J. Infect. Control 44, 1495–1504 (2016).

  13. 13.

    Zacharioudakis, I. M., Zervou, F. N., Ziakas, P. D. & Mylonakis, E. Meta-analysis of methicillin-resistant Staphylococcus aureus colonization and risk of infection in dialysis patients. J. Am. Soc. Nephrol. 25, 2131–2141 (2014).

  14. 14.

    Lu, P. et al. Methicillin-resistant Staphylococcus aureus carriage, infection and transmission in dialysis patients, healthcare workers and their family members. Nephrol. Dial. Transplant. 23, 1659–1665 (2008).

  15. 15.

    Nguyen, D. B. et al. Invasive methicillin-resistant Staphylococcus aureus infections among chronic dialysis patients in the United States, 2005–2011. Clin. Infect. Dis. 57, 1392–1400 (2013).

  16. 16.

    Giarola, L. B., Dos Santos, R. R., Tognim, M. C., Borelli, S. D. & Bedendo, J. Carriage frequency, phenotypic and genotypic characteristics of Staphylococcus aureus isolated from dialysis and kidney tranplant patients at a hosptial in northern Paraná. Braz. J. Microbiol. 43, 923–930 (2012).

  17. 17.

    Moore, C. et al. Colonisation with methicillin-resistant Staphylococcus aureus prior to renal transplantation is associated with long-term renal allograft failure. Transpl. Int. 27, 926–930 (2014).

  18. 18.

    Hiramatsu, K. et al. Methicillin-resistant Staphylococcus aureus clinical strain with reduced vancomycin susceptibility. J. Antimicrob. Chemother. 40, 135–136 (1997).

  19. 19.

    Zhang, S., Sun, X., Chang, W., Dai, Y. & Ma, X. Systematic review and meta-analysis of the epidemiology of vancomycin-intermediate and heterogeneous vancomycin-intermediate Staphylococcus aureus isolates. PLOS ONE 10, e0136082 (2015).

  20. 20.

    Bae, I. G. et al. Heterogeneous vancomycin-intermediate susceptibility phenotype in bloodstream methicillin-resistant Staphylococcus aureus isolates from an international cohort of patients with infective endocarditis: prevalence, genotype, and clinical significance. J. Infect. Dis. 200, 1355–1366 (2009).

  21. 21.

    Gomes, D. M., Ward, K. E. & LaPlante, K. L. Clinical implications of vancomycin heteroresistant and intermediately susceptible Staphylococcus aureus. Pharmacotherapy 35, 424–432 (2015).

  22. 22.

    Howden, B. P., Peleg, A. Y. & Stinear, T. P. The evolution of vancomycin intermediate Staphylococcus aureus (VISA) and heterogenous-VISA. Infect. Genet. Evol. 21, 575–582 (2014).

  23. 23.

    Smith, T. L. et al. Emergence of vancomycin resistance in Staphylococcus aureus. Glycopeptide-Intermediate Staphylococcus aureus Working Group. N. Engl. J. Med. 340, 493–501 (1999).

  24. 24.

    Centers for Disease Control and Prevention. Staphylococcus aureus resistant to vancomycin —-United States, 2002. MMWR Morb. Mortal. Wkly Rep. 51, 565–567 (2002).

  25. 25.

    Walters, M. S. et al. Vancomycin-resistant Staphylococcus aureus -Delaware, 2015. MMWR Morb. Mortal. Wkly Rep. 64, 1056 (2015).

  26. 26.

    Melo-Cristino, J., Resina, C., Manuel, V., Lito, L. & Ramirez, M. First case of infection with vancomycin-resistant Staphylococcus aureus in Europe. Lancet 382, 205 (2013).

  27. 27.

    Moravvej, Z. et al. Update on the global number of vancomycin-resistant Staphylococcus aureus (VRSA) strains. Int. J. Antimicrob. Agents 42, 370–371 (2013).

  28. 28.

    Centers Disease Control and Prevention. VISA/VRSA in healthcare settings. CDC (updated 21 Jul 2015).

  29. 29.

    Murray, B. E. The life and times of the Enterococcus. Clin. Microbiol. Rev. 3, 46–65 (1990).

  30. 30.

    Foster, T. J. Antibiotic resistance in Staphylococcus aureus. Current status and future prospects. FEMS Microbiol. Rev. 41, 430–449 (2017).

  31. 31.

    The Center for Disease Dynamics Economics & Policy. ResistanceMap: antibiotic resistance. CDDEP (2018).

  32. 32.

    Zacharioudakis, I. M., Zervou, F. N., Ziakas, P. D., Rice, L. B. & Mylonakis, E. Vancomycin-resistant enterococci colonization among dialysis patients: a meta-analysis of prevalence, risk factors, and significance. Am. J. Kidney Dis. 65, 88–97 (2015).

  33. 33.

    Freitas, M. C. et al. Prevalence of vancomycin-resistant Enterococcus fecal colonization among kidney transplant patients. BMC Infect. Dis. 6, 133 (2006).

  34. 34.

    Nguyen, D. B. et al. National Healthcare Safety Network (NHSN) Dialysis Event Surveillance Report for 2014. Clin. J. Am. Soc. Nephrol. 12, 1139–1146 (2017).

  35. 35.

    Greene, M. H. et al. Risk factors and outcomes associated with acquisition of daptomycin and linezolid-nonsusceptible vancomycin-resistant Enterococcus. Open Forum Infect. Dis 5, ofy185 (2018).

  36. 36.

    Marshall, S. H., Donskey, C. J., Hutton-Thomas, R., Salata, R. A. & Rice, L. B. Gene dosage and linezolid resistance in Enterococcus faecium and Enterococcus faecalis. Antimicrob. Agents Chemother. 46, 3334–3336 (2002).

  37. 37.

    Mendes, R. E., Hogan, P. A., Jones, R. N., Sader, H. S. & Flamm, R. K. Surveillance for linezolid resistance via the Zyvox® Annual Appraisal of Potency and Spectrum (ZAAPS) programme (2014): evolving resistance mechanisms with stable susceptibility rates. J. Antimicrob. Chemother. 71, 1860–1865 (2016).

  38. 38.

    Sader, H. S., Farrell, D. J., Flamm, R. K. & Jones, R. N. Daptomycin activity tested against 164457 bacterial isolates from hospitalised patients: summary of 8 years of a Worldwide Surveillance Programme (2005–2012). Int. J. Antimicrob. Agents 43, 465–469 (2014).

  39. 39.

    Kamboj, M. et al. Emergence of daptomycin-resistant VRE: experience of a single institution. Infect. Control Hosp. Epidemiol. 32, 391–394 (2011).

  40. 40.

    Tran, T. T., Munita, J. M. & Arias, C. A. Mechanisms of drug resistance: daptomycin resistance. Ann. NY Acad. Sci. 1354, 32–53 (2015).

  41. 41.

    Kelesidis, T., Humphries, R., Uslan, D. Z. & Pegues, D. De novo daptomycin-nonsusceptible enterococcal infections. Emerg. Infect. Dis. 18, 674–676 (2012).

  42. 42.

    Pop-Vicas, A., Strom, J., Stanley, K. & D’Agata, E. M. Multidrug-resistant gram-negative bacteria among patients who require chronic hemodialysis. Clin. J. Am. Soc. Nephrol. 3, 752–758 (2008).

  43. 43.

    Paterson, D. L. & Lipman, J. Returning to the pre-antibiotic era in the critically ill: the XDR problem. Crit. Care Med. 35, 1789–1791 (2007).

  44. 44.

    Patel, G. & Bonomo, R. A. “Stormy waters ahead”: global emergence of carbapenemases. Front. Microbiol. 4, 48 (2013).

  45. 45.

    Gomi, R. et al. Occurrence of clinically important lineages, including the sequence type 131 C1-M27 subclone, among extended-spectrum-β-lactamase-producing Escherichia coli in wastewater. Antimicrob. Agents Chemother. 61, e00564-17 (2017).

  46. 46.

    Liu, Y. Y. et al. Emergence of plasmid-mediated colistin resistance mechanism MCR-1 in animals and human beings in China: a microbiological and molecular biological study. Lancet Infect. Dis. 16, 161–168 (2016).

  47. 47.

    Lübbert, C. et al. Environmental pollution with antimicrobial agents from bulk drug manufacturing industries in Hyderabad, South India, is associated with dissemination of extended-spectrum beta-lactamase and carbapenemase-producing pathogens. Infection 45, 479–491 (2017).

  48. 48.

    Harris, P. et al. Effect of piperacillin-tazobactam versus meropenem on 30-day mortality for patients with E coli or Klebsiella pneumoniae bloodstream infection and ceftriaxone resistance. JAMA 320, 984–994 (2018).

  49. 49.

    Doi, Y., Iovleva, A. & Bonomo, R. A. The ecology of extended-spectrum β-lactamases (ESBLs) in the developed world. J. Travel Med. 24, S44–S51 (2017).

  50. 50.

    Jacoby, G. A. AmpC beta-lactamases. Clin. Microbiol. Rev. 22, 161–182 (2009).

  51. 51.

    Pascual, V. et al. Epidemiology and risk factors for infections due to AmpC β-lactamase-producing Escherichia coli. J. Antimicrob. Chemother. 70, 899–904 (2015).

  52. 52.

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

  53. 53.

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

  54. 54.

    Johnson, A. P. & Woodford, N. Global spread of antibiotic resistance: the example of New Delhi metallo-β-lactamase (NDM)-mediated carbapenem resistance. J. Med. Microbiol. 62, 499–513 (2013).

  55. 55.

    Logan, L. K. & Weinstein, R. A. The epidemiology of carbapenem-resistant Enterobacteriaceae: the impact and evolution of a global menace. J. Infect. Dis. 215, S28–S36 (2017).

  56. 56.

    Woodworth, K. R. et al. Vital signs: containment of novel multidrug-resistant organisms and resistance mechanisms -United States, 2006–2017. MMWR Morb. Mortal. Wkly Rep. 67, 396–401 (2018).

  57. 57.

    Centers for Disease Control and Prevention. Antibiotic resistance threats in the United States, 2013. CDC (2013).

  58. 58.

    Weiner, L. M. et al. Antimicrobial-resistant pathogens associated with healthcare-associated infections: summary of data reported to the National Healthcare Safety Network at the Centers for Disease Control and Prevention, 2011–2014. Infect. Control Hosp. Epidemiol. 37, 1288–1301 (2016).

  59. 59.

    Aldred, K. J., Kerns, R. J. & Osheroff, N. Mechanism of quinolone action and resistance. Biochemistry 53, 1565–1574 (2014).

  60. 60.

    Morrill, H. J. et al. Antimicrobial resistance of Escherichia coli urinary isolates in the Veterans Affairs Health Care System. Antimicrob. Agents Chemother. 61, e02236-16 (2017).

  61. 61.

    Doi, Y., Wachino, J. I. & Arakawa, Y. Aminoglycoside resistance: the emergence of acquired 16S ribosomal RNA methyltransferases. Infect. Dis. Clin. North Am. 30, 523–537 (2016).

  62. 62.

    Leclercq, R. et al. EUCAST expert rules in antimicrobial susceptibility testing. Clin. Microbiol. Infect. 19, 141–160 (2013).

  63. 63.

    Haidar, G. et al. Association between the presence of aminoglycoside-modifying enzymes and in vitro activity of gentamicin, tobramycin, amikacin, and plazomicin against Klebsiella pneumoniae carbapenemase-and extended-spectrum-β-lactamase-producing Enterobacter species. Antimicrob. Agents Chemother. 60, 5208–5214 (2016).

  64. 64.

    Klein, E. Y. et al. Global increase and geographic convergence in antibiotic consumption between 2000 and 2015. Proc. Natl Acad. Sci. USA 115, E3463–E3470 (2018).

  65. 65.

    Rojas, L. J. et al. Colistin resistance in carbapenem-resistant Klebsiella pneumoniae: laboratory detection and impact on mortality. Clin. Infect. Dis. 64, 711–718 (2017).

  66. 66.

    Baron, S., Hadjadj, L., Rolain, J. M. & Olaitan, A. O. Molecular mechanisms of polymyxin resistance: knowns and unknowns. Int. J. Antimicrob. Agents 48, 583–591 (2016).

  67. 67.

    Giamarellou, H. Epidemiology of infections caused by polymyxin-resistant pathogens. Int. J. Antimicrob. Agents 48, 614–621 (2016).

  68. 68.

    Al-Tawfiq, J. A., Laxminarayan, R. & Mendelson, M. How should we respond to the emergence of plasmid-mediated colistin resistance in humans and animals? Int. J. Infect. Dis. 54, 77–84 (2017).

  69. 69.

    Pang, Z., Raudonis, R., Glick, B. R., Lin, T. J. & Cheng, Z. Antibiotic resistance in Pseudomonas aeruginosa: mechanisms and alternative therapeutic strategies. Biotechnol. Adv. 37, 177–192 (2019).

  70. 70.

    Yusuf, E. et al. Emergence of antimicrobial resistance to Pseudomonas aeruginosa in the intensive care unit: association with the duration of antibiotic exposure and mode of administration. Ann. Intensive Care 7, 72 (2017).

  71. 71.

    Wong, D. et al. Clinical and pathophysiological overview of Acinetobacter infections: a century of challenges. Clin. Microbiol. Rev. 30, 409–447 (2017).

  72. 72.

    Towner, K. J. Acinetobacter: an old friend, but a new enemy. J. Hosp. Infect. 73, 355–363 (2009).

  73. 73.

    Morgan, D. J. et al. Multidrug-resistant Acinetobacter baumannii in New York City -10 years into the epidemic. Infect. Control Hosp. Epidemiol. 30, 196–197 (2009).

  74. 74.

    Lob, S. H. et al. Susceptibility patterns and ESBL rates of Escherichia coli from urinary tract infections in Canada and the United States, SMART 2010–2014. Diagn. Microbiol. Infect. Dis. 85, 459–465 (2016).

  75. 75.

    United States Renal Data System. 2018 Annual Data Report. USRDS (2018).

  76. 76.

    ANZDATA Registry. 40th Annual ANZDATA Report (2017). ANZDATA (updated 18 Aug 2018).

  77. 77.

    Nguyen, D. B. et al. Completeness of methicillin-resistant Staphylococcus aureus bloodstream infection reporting from outpatient hemodialysis facilities to the National Healthcare Safety Network, 2013. Infect. Control Hosp. Epidemiol. 37, 205–207 (2016).

  78. 78.

    Dalgaard, L. et al. Risk and prognosis of bloodstream infections among patients on chronic hemodialysis: a population-based cohort study. PLOS ONE 10, e0124547 (2015).

  79. 79.

    Fysaraki, M. et al. Incidence, clinical, microbiological features and outcome of bloodstream infections in patients undergoing hemodialysis. Int. J. Med. Sci. 10, 1632–1638 (2013).

  80. 80.

    Sahli, F., Feidjel, R. & Laalaoui, R. Hemodialysis catheter-related infection: rates, risk factors and pathogens. J. Infect. Public Health 10, 403–408 (2017).

  81. 81.

    Worth, L. J. et al. Epidemiology of infections and antimicrobial use in Australian haemodialysis outpatients: findings from a Victorian surveillance network, 2008–2015. J. Hosp. Infect. 97, 93–98 (2017).

  82. 82.

    Akoh, J. A. Peritoneal dialysis associated infections: an update on diagnosis and management. World J. Nephrol. 1, 106–122 (2012).

  83. 83.

    Prasad, K. N. et al. Microbiology and outcomes of peritonitis in northern India. Perit. Dial. Int. 34, 188–194 (2014).

  84. 84.

    McGuire, A. L., Carson, C. F., Inglis, T. J. & Chakera, A. Effects of a statewide protocol for the management of peritoneal dialysis-related peritonitis on microbial profiles and antimicrobial susceptibilities: a retrospective five-year review. Perit. Dial. Int. 35, 722–728 (2015).

  85. 85.

    Kitterer, D., Latus, J., Pöhlmann, C., Alscher, M. D. & Kimmel, M. Microbiological surveillance of peritoneal dialysis associated peritonitis: antimicrobial susceptibility profiles of a referral center in GERMANY over 32 years. PLOS ONE 10, e0135969 (2015).

  86. 86.

    Fishman, J. A. Infection in organ transplantation. Am. J. Transplant. 17, 856–879 (2017).

  87. 87.

    Aguado, J. M. et al. Management of multidrug resistant Gram-negative bacilli infections in solid organ transplant recipients: SET/GESITRA-SEIMC/REIPI recommendations. Transplant. Rev. (Orlando) 32, 36–57 (2018).

  88. 88.

    Ariza-Heredia, E. J. et al. Urinary tract infections in kidney transplant recipients: role of gender, urologic abnormalities, and antimicrobial prophylaxis. Ann. Transplant. 18, 195–204 (2013).

  89. 89.

    Chuang, P., Parikh, C. R. & Langone, A. Urinary tract infections after renal transplantation: a retrospective review at two US transplant centers. Clin. Transplant. 19, 230–235 (2005).

  90. 90.

    Takai, K., Tollemar, J., Wilczek, H. E. & Groth, C. G. Urinary tract infections following renal transplantation. Clin. Transplant. 12, 19–23 (1998).

  91. 91.

    Cervera, C. et al. Multidrug-resistant bacteria in solid organ transplant recipients. Clin. Microbiol. Infect. 20 (Suppl. 7), 49–73 (2014).

  92. 92.

    Bodro, M. et al. Risk factors and outcomes of bacteremia caused by drug-resistant ESKAPE pathogens in solid-organ transplant recipients. Transplantation 96, 843–849 (2013).

  93. 93.

    van Duin, D., van Delden, C. & AST Infectious Diseases Community of Practice. Multidrug-resistant gram-negative bacteria infections in solid organ transplantation. Am. J. Transplant. 13 (Suppl. 4), 31–41 (2013).

  94. 94.

    Linares, L. et al. Epidemiology and outcomes of multiple antibiotic-resistant bacterial infection in renal transplantation. Transplant. Proc. 39, 2222–2224 (2007).

  95. 95.

    Lee, J. R. et al. Independent risk factors for urinary tract infection and for subsequent bacteremia or acute cellular rejection: a single-center report of 1166 kidney allograft recipients. Transplantation 96, 732–738 (2013).

  96. 96.

    Pinheiro, H. S., Mituiassu, A. M., Carminatti, M., Braga, A. M. & Bastos, M. G. Urinary tract infection caused by extended-spectrum beta-lactamase-producing bacteria in kidney transplant patients. Transplant. Proc. 42, 486–487 (2010).

  97. 97.

    Pouch, S. M. & Satlin, M. J. Carbapenem-resistant Enterobacteriaceae in special populations: solid organ transplant recipients, stem cell transplant recipients, and patients with hematologic malignancies. Virulence 8, 391–402 (2017).

  98. 98.

    Patel, G., Huprikar, S., Factor, S. H., Jenkins, S. G. & Calfee, D. P. Outcomes of carbapenem-resistant Klebsiella pneumoniae infection and the impact of antimicrobial and adjunctive therapies. Infect. Control Hosp. Epidemiol. 29, 1099–1106 (2008).

  99. 99.

    Burnham, J. P. et al. Infectious diseases consultation reduces 30-day and 1-year all-cause mortality for multidrug-resistant organism infections. Open Forum Infect. Dis 5, ofy026 (2018).

  100. 100.

    Zhanel, G. G. et al. Ceftaroline pharmacodynamic activity versus community-associated and healthcare-associated methicillin-resistant Staphylococcus aureus, heteroresistant vancomycin-intermediate S. aureus, vancomycin-intermediate S. aureus and vancomycin-resistant S. aureus using an in vitro model. J. Antimicrob. Chemother. 66, 1301–1305 (2011).

  101. 101.

    Sader, H. S., Flamm, R. K. & Jones, R. N. Antimicrobial activity of ceftaroline tested against staphylococci with reduced susceptibility to linezolid, daptomycin, or vancomycin from U. S. hospitals, 2008 to 2011. Antimicrob. Agents Chemother. 57, 3178–3181 (2013).

  102. 102.

    Pfaller, M. A., Shortridge, D., Sader, H. S., Flamm, R. K. & Castanheira, M. Ceftolozane-tazobactam activity against drug-resistant Enterobacteriaceae and Pseudomonas aeruginosa causing healthcare-associated infections in Australia and New Zealand: report from an Antimicrobial Surveillance Program (2013–2015). J. Glob. Antimicrob. Resist. 10, 186–194 (2017).

  103. 103.

    Sader, H. S., Farrell, D. J., Flamm, R. K. & Jones, R. N. Ceftolozane/tazobactam activity tested against aerobic gram-negative organisms isolated from intra-abdominal and urinary tract infections in European and United States hospitals (2012). J. Infect. 69, 266–277 (2014).

  104. 104.

    Solomkin, J. et al. Ceftolozane/tazobactam plus metronidazole for complicated intra-abdominal infections in an era of multidrug resistance: results from a randomized, double-blind, phase 3 trial (ASPECT-cIAI). Clin. Infect. Dis. 60, 1462–1471 (2015).

  105. 105.

    Haidar, G. et al. Ceftolozane-tazobactam for the treatment of multidrug-resistant Pseudomonas aeruginosa infections: clinical effectiveness and evolution of resistance. Clin. Infect. Dis. 65, 110–120 (2017).

  106. 106.

    Munita, J. M. et al. Multicenter evaluation of ceftolozane/tazobactam for serious infections caused by carbapenem-resistant Pseudomonas aeruginosa. Clin. Infect. Dis. 65, 158–161 (2017).

  107. 107.

    Falcone, M. & Paterson, D. Spotlight on ceftazidime/avibactam: a new option for MDR Gram-negative infections. J. Antimicrob. Chemother. 71, 2713–2722 (2016).

  108. 108.

    Carmeli, Y. et al. Ceftazidime-avibactam or best available therapy in patients with ceftazidime-resistant Enterobacteriaceae and Pseudomonas aeruginosa complicated urinary tract infections or complicated intra-abdominal infections (REPRISE): a randomised, pathogen-directed, phase 3 study. Lancet Infect. Dis. 16, 661–673 (2016).

  109. 109.

    Mazuski, J. E. et al. 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 (2016).

  110. 110.

    van Duin, D. et al. Colistin versus ceftazidime-avibactam in the treatment of infections due to carbapenem-resistant Enterobacteriaceae. Clin. Infect. Dis. 66, 163–171 (2018).

  111. 111.

    Castanheira, M., Huband, M. D., Mendes, R. E. & Flamm, R. K. 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 (2017).

  112. 112.

    Kaye, K. S. et al. Effect of meropenem-vaborbactam versus 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 (2018).

  113. 113.

    Wunderink, R. G. et al. Effect and safety of meropenem-vaborbactam versus best-available therapy in patients with carbapenem-resistant Enterobacteriaceae infections: the TANGO II randomized clinical trial. Infect. Dis. Ther. 7, 439–455 (2018).

  114. 114.

    Duncan, L. R., Sader, H. S., Smart, J. I., Flamm, R. K. & Mendes, R. E. Telavancin activity in vitro tested against a worldwide collection of gram-positive clinical isolates (2014). J. Glob. Antimicrob. Resist. 10, 271–276 (2017).

  115. 115.

    Pfaller, M. A., Sader, H. S., Castanheira, M., Flamm, R. K. & Mendes, R. E. Antimicrobial activity of oritavancin and comparator agents when tested against Gram-positive bacterial isolates causing infections in cancer patients (2014–2016). J. Antimicrob. Chemother. 73, 916–922 (2018).

  116. 116.

    Smith, J. R., Roberts, K. D. & Rybak, M. J. Dalbavancin: a novel lipoglycopeptide antibiotic with extended activity against gram-positive infections. Infect. Dis. Ther. 4, 245–258 (2015).

  117. 117.

    Rubinstein, E. et al. Telavancin versus vancomycin for hospital-acquired pneumonia due to gram-positive pathogens. Clin. Infect. Dis. 52, 31–40 (2011).

  118. 118.

    Castanheira, M. et al. Activity of plazomicin against gram-negative and gram-positive isolates collected from U. S. hospitals and comparative activities of aminoglycosides against carbapenem-resistant enterobacteriaceae and isolates carrying carbapenemase genes. Antimicrob. Agents Chemother. 62, e00313-18 (2018).

  119. 119.

    Abdul-Mutakabbir, J. C., Kebriaei, R., Jorgensen, S. C. J. & Rybak, M. J. Teaching an old class new tricks: a novel semi-synthetic aminoglycoside, plazomicin. Infect. Dis. Ther. (2019).

  120. 120.

    Connolly, L. E., Riddle, V., Cebrik, D., Armstrong, E. S. & Miller, L. G. A multicenter, randomized, double-blind, phase 2 study of the efficacy and safety of plazomicin compared with levofloxacin in the treatment of complicated urinary tract infection and acute pyelonephritis. Antimicrob. Agents Chemother. 62, e01989-17 (2018).

  121. 121.

    Zhanel, G. G. et al. Review of eravacycline, a novel fluorocycline antibacterial agent. Drugs 76, 567–588 (2016).

  122. 122.

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

  123. 123.

    Solomkin, J. et al. Assessing the efficacy and safety of eravacycline versus ertapenem in complicated intra-abdominal infections in the Investigating Gram-Negative Infections Treated With Eravacycline (IGNITE 1) trial: a randomized clinical trial. JAMA Surg. 152, 224–232 (2017).

  124. 124.

    O’Riordan, W. et al. A comparison of the efficacy and safety of intravenous followed by oral delafloxacin with vancomycin plus aztreonam for the treatment of acute bacterial skin and skin structure infections: a phase 3, multinational, double-blind, randomized study. Clin. Infect. Dis. 67, 657–666 (2018).

  125. 125.

    Centers for Disease Control and Prevention. Recommendations for preventing transmission of infections among chronic hemodialysis patients. MMWR Recomm. Rep. 50, 1–43 (2001).

  126. 126.

    Coulliette, A. D. & Arduino, M. J. Hemodialysis and water quality. Semin. Dial. 26, 427–438 (2013).

  127. 127.

    Merino, J. L. et al. Serratia marcescens bacteraemia outbreak in haemodialysis patients with tunnelled catheters due to colonisation of antiseptic solution. Experience at 4 hospitals. Nefrologia 36, 667–673 (2016).

  128. 128.

    Edens, C. et al. Hemodialyzer reuse and gram-negative bloodstream infections. Am. J. Kidney Dis. 69, 726–733 (2017).

  129. 129.

    Trépanier, P. et al. Survey of infection control practices in hemodialysis units: preventing vascular access-associated bloodstream infections. Infect. Control Hosp. Epidemiol. 35, 833–838 (2014).

  130. 130.

    Chenoweth, C. E. et al. Variation in infection prevention practices in dialysis facilities: results from the national opportunity to improve infection control in ESRD (End-Stage Renal Disease) project. Infect. Control Hosp. Epidemiol. 36, 802–806 (2015).

  131. 131.

    Patel, P. R. et al. Bloodstream infection rates in outpatient hemodialysis facilities participating in a collaborative prevention effort: a quality improvement report. Am. J. Kidney Dis. 62, 322–330 (2013).

  132. 132.

    Yi, S. H. et al. Sustained infection reduction in outpatient hemodialysis centers participating in a collaborative bloodstream infection prevention effort. Infect. Control Hosp. Epidemiol. 37, 863–866 (2016).

  133. 133.

    Lewis, V. R., Clark, L., Benda, N. & Hardwick, M. J. Reducing healthcare-associated infections in an ambulatory dialysis unit: identification and alignment of work system factors. Am. J. Infect. Control 42, S284–290 (2014).

  134. 134.

    Snyder, G. M. et al. Factors associated with the receipt of antimicrobials among chronic hemodialysis patients. Am. J. Infect. Control 44, 1269–1274 (2016).

  135. 135.

    Vassalotti, J. A. et al. Fistula first breakthrough initiative: targeting catheter last in fistula first. Semin. Dial. 25, 303–310 (2012).

  136. 136.

    Septimus, E., Weinstein, R. A., Perl, T. M., Goldmann, D. A. & Yokoe, D. S. Approaches for preventing healthcare-associated infections: go long or go wide? Infect. Control Hosp. Epidemiol. 35, 797–801 (2014).

  137. 137.

    Snyder, G. M. et al. Antimicrobial use in outpatient hemodialysis units. Infect. Control Hosp. Epidemiol. 34, 349–357 (2013).

  138. 138.

    Hui, K. et al. Patterns of use and appropriateness of antibiotics prescribed to patients receiving haemodialysis: an observational study. BMC Nephrol. 18, 156 (2017).

  139. 139.

    Wagner, B. et al. Antimicrobial stewardship programs in inpatient hospital settings: a systematic review. Infect. Control Hosp. Epidemiol. 35, 1209–1228 (2014).

  140. 140.

    D’Agata, E. M. C., Tran, D., Bautista, J., Shemin, D. & Grima, D. Clinical and economic benefits of antimicrobial stewardship programs in hemodialysis facilities: a decision analytic model. Clin. J. Am. Soc. Nephrol. 13, 1389–1397 (2018).

  141. 141.

    Barlam, T. F. et al. Implementing an antibiotic stewardship program: guidelines by the Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America. Clin. Infect. Dis. 62, e51–e77 (2016).

  142. 142.

    Cunha, C. B. & D’Agata, E. M. Implementing an antimicrobial stewardship program in out-patient dialysis units. Curr. Opin. Nephrol. Hypertens. 25, 551–555 (2016).

  143. 143.

    Grothe, C., Taminato, M., Belasco, A., Sesso, R. & Barbosa, D. Prophylactic treatment of chronic renal disease in patients undergoing peritoneal dialysis and colonized by Staphylococcus aureus: a systematic review and meta-analysis. BMC Nephrol. 17, 115 (2016).

  144. 144.

    Grothe, C., Taminato, M., Belasco, A., Sesso, R. & Barbosa, D. Screening and treatment for Staphylococcus aureus in patients undergoing hemodialysis: a systematic review and meta-analysis. BMC Nephrol. 15, 202 (2014).

  145. 145.

    Miller, M. A., Dascal, A., Portnoy, J. & Mendelson, J. Development of mupirocin resistance among methicillin-resistant Staphylococcus aureus after widespread use of nasal mupirocin ointment. Infect. Control Hosp. Epidemiol. 17, 811–813 (1996).

  146. 146.

    Saidel-Odes, L. et al. A randomized, double-blind, placebo-controlled trial of selective digestive decontamination using oral gentamicin and oral polymyxin E for eradication of carbapenem-resistant Klebsiella pneumoniae carriage. Infect. Control Hosp. Epidemiol. 33, 14–19 (2012).

  147. 147.

    Halaby, T., Al Naiemi, N., Kluytmans, J., van der Palen, J. & Vandenbroucke-Grauls, C. M. Emergence of colistin resistance in Enterobacteriaceae after the introduction of selective digestive tract decontamination in an intensive care unit. Antimicrob. Agents Chemother. 57, 3224–3229 (2013).

  148. 148.

    Rieg, S. et al. Intestinal decolonization of Enterobacteriaceae producing extended-spectrum β-lactamases (ESBL): a retrospective observational study in patients at risk for infection and a brief review of the literature. BMC Infect. Dis. 15, 475 (2015).

  149. 149.

    Czaplewski, L. et al. Alternatives to antibiotics-a pipeline portfolio review. Lancet Infect. Dis. 16, 239–251 (2016).

  150. 150.

    Fischetti, V. A. Development of phage lysins as novel therapeutics: a historical perspective. Viruses 10, 310 (2018).

  151. 151.

    Corsini, B. et al. Chemotherapy with phage lysins reduces pneumococcal colonization of the respiratory tract. Antimicrob. Agents Chemother. 62, e02212-17 (2018).

  152. 152.

    Nelson, D., Loomis, L. & Fischetti, V. A. Prevention and elimination of upper respiratory colonization of mice by group A streptococci by using a bacteriophage lytic enzyme. Proc. Natl Acad. Sci. USA 98, 4107–4112 (2001).

  153. 153.

    Cheng, M. et al. An ointment consisting of the phage lysin LysGH15 and apigenin for decolonization of methicillin-resistant Staphylococcus aureus from skin wounds. Viruses 10, 244 (2018).

  154. 154.

    Schuch, R. et al. Combination therapy with lysin CF-301 and antibiotic is superior to antibiotic alone for treating methicillin-resistant Staphylococcus aureus-induced murine bacteremia. J. Infect. Dis. 209, 1469–1478 (2014).

  155. 155.

    Lood, R. et al. Novel phage lysin capable of killing the multidrug-resistant gram-negative bacterium Acinetobacter baumannii in a mouse bacteremia model. Antimicrob. Agents Chemother. 59, 1983–1991 (2015).

  156. 156.

    Zipperer, A. et al. Human commensals producing a novel antibiotic impair pathogen colonization. Nature 535, 511–516 (2016).

  157. 157.

    Xu, D. et al. Bioprospecting deep-sea actinobacteria for novel anti-infective natural products. Front. Microbiol. 9, 787 (2018).

  158. 158.

    von Gottberg, A. et al. Effects of vaccination on invasive pneumococcal disease in South Africa. N. Engl. J. Med. 371, 1889–1899 (2014).

  159. 159.

    Schroeder, M. R. et al. A population-based assessment of the impact of 7-and 13-valent pneumococcal conjugate vaccines on macrolide-resistant invasive pneumococcal disease: emergence and decline of Streptococcus pneumoniae serotype 19A (CC320) with dual macrolide resistance mechanisms. Clin. Infect. Dis. 65, 990–998 (2017).

  160. 160.

    Rappuoli, R., Bloom, D. E. & Black, S. Deploy vaccines to fight superbugs. Nature 552, 165–167 (2017).

  161. 161.

    Fattom, A. et al. Efficacy profile of a bivalent Staphylococcus aureus glycoconjugated vaccine in adults on hemodialysis: phase III randomized study. Hum. Vaccin. Immunother. 11, 632–641 (2015).

  162. 162.

    Moustafa, M. et al. Phase IIa study of the immunogenicity and safety of the novel Staphylococcus aureus vaccine V710 in adults with end-stage renal disease receiving hemodialysis. Clin. Vaccine Immunol. 19, 1509–1516 (2012).

  163. 163.

    Fowler, V. G. et al. Effect of an investigational vaccine for preventing Staphylococcus aureus infections after cardiothoracic surgery: a randomized trial. JAMA 309, 1368–1378 (2013).

  164. 164.

    Begier, E. et al. SA4Ag, a 4-antigen Staphylococcus aureus vaccine, rapidly induces high levels of bacteria-killing antibodies. Vaccine 35, 1132–1139 (2017).

  165. 165.

    Schmidt, C. S. et al. NDV-3, a recombinant alum-adjuvanted vaccine for Candida and Staphylococcus aureus, is safe and immunogenic in healthy adults. Vaccine 30, 7594–7600 (2012).

  166. 166.

    Edwards, J. E. et al. A fungal immunotherapeutic vaccine (NDV-3A) for treatment of recurrent vulvovaginal candidiasis-a phase 2 randomized, double-blind, placebo-controlled trial. Clin. Infect. Dis. 66, 1928–1936 (2018).

  167. 167.

    Hudson, L. E., Anderson, S. E., Corbett, A. H. & Lamb, T. J. Gleaning insights from fecal microbiota transplantation and probiotic studies for the rational design of combination microbial therapies. Clin. Microbiol. Rev. 30, 191–231 (2017).

  168. 168.

    Millan, B. et al. Fecal microbial transplants reduce antibiotic-resistant genes in patients with recurrent Clostridium difficile infection. Clin. Infect. Dis. 62, 1479–1486 (2016).

  169. 169.

    Jouhten, H., Mattila, E., Arkkila, P. & Satokari, R. Reduction of antibiotic resistance genes in intestinal microbiota of patients with recurrent Clostridium difficile infection after fecal microbiota transplantation. Clin. Infect. Dis. 63, 710–711 (2016).

  170. 170.

    Leung, V., Vincent, C., Edens, T. J., Miller, M. & Manges, A. R. Antimicrobial resistance gene acquisition and depletion following fecal microbiota transplantation for recurrent Clostridium difficile infection. Clin. Infect. Dis. 66, 456–457 (2018).

  171. 171.

    Manges, A. R., Steiner, T. S. & Wright, A. J. Fecal microbiota transplantation for the intestinal decolonization of extensively antimicrobial-resistant opportunistic pathogens: a review. Infect. Dis. (Lond.) 48, 587–592 (2016).

  172. 172.

    Singh, R. et al. Fecal microbiota transplantation against intestinal colonization by extended spectrum beta-lactamase producing enterobacteriaceae: a proof of principle study. BMC Res. Notes 11, 190 (2018).

  173. 173.

    Bilinski, J. et al. Fecal microbiota transplantation in patients with blood disorders inhibits gut colonization with antibiotic-resistant bacteria: results of a prospective, single-center study. Clin. Infect. Dis. 65, 364–370 (2017).

  174. 174.

    Rangan, K. J. et al. A secreted bacterial peptidoglycan hydrolase enhances tolerance to enteric pathogens. Science 353, 1434–1437 (2016).

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T.Z.W. was supported by US National Institutes of Health, National Institute of Allergy and Infectious Disease grant T32 A1007613.

Reviewer information

Nature Reviews Nephrology thanks P. Tambyah and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Author information


  1. NewYork Presbyterian–Weill Cornell Medical Center, New York, NY, USA

    • Tina Z. Wang
    •  & David P. Calfee
  2. Department of Medicine, Division of Infectious Diseases, Weill Cornell Medicine, New York, NY, USA

    • Rosy Priya L. Kodiyanplakkal
    •  & David P. Calfee


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All authors researched data for the article, contributed substantially to the discussion of content and wrote the manuscript. R.P.L.K. and D.P.C. also reviewed and edited the manuscript before submission.

Competing interests

The authors declare no competing interests.

Corresponding author

Correspondence to David P. Calfee.



Disease states produced by a microorganism that may be symptomatic or asymptomatic.

Multidrug resistant

(MDR). Non-susceptibility to at least one agent in three or more antimicrobial categories to which an organism does not possess intrinsic resistance.

Extensively drug resistant

Non-susceptibility to at least one agent in all but two or fewer antimicrobial categories to which an organism does not possess intrinsic resistance.

Pandrug resistant

Non-susceptibility to all agents in all antimicrobial categories to which an organism does not possess intrinsic resistance.


The asymptomatic presence of a microorganism on or within the body.


Direct transfer of genetic material between bacterial cells.


Acquisition of new genetic material (DNA) via uptake from the environment.


Transfer of bacterial DNA from one bacterium to another via a viral vector.

Invasive MRSA infections

MRSA infections within a normally sterile body site, such as the blood.

Vancomycin-intermediate S. aureus

(VISA). An isolate of Staphylococcus aureus that exhibits an elevated minimum inhibitory concentration (MIC) for vancomycin but that does not reach the MIC considered to represent full resistance to vancomycin.

Heteroresistant or heterogeneous VISA

(hVISA). Subpopulations of Staphylococcus aureus with reduced susceptibility present among a larger population of fully susceptible organisms.

Drug efflux pumps

Proteins in the bacterial cell membrane that transport a drug, such as an antibiotic, out of the cell.

Haematogenous osteomyelitis

Infection of bone that results from inoculation of the bone by microorganisms present in the bloodstream.

Vesicoureteral reflux

Abnormal retrograde flow of urine from the urinary bladder into the ureter and, possibly, the kidney.

Ureterovesical junction stenosis

Narrowing at the site where the ureter enters the urinary bladder that may obstruct the flow of urine from the kidney into the bladder.

Neurogenic bladder

Dysfunction of the urinary bladder due to neurological damage.

Therapeutic drug monitoring

Measurement of medication concentrations in blood at specified time intervals in order to optimize treatment effectiveness and/or minimize toxicity.

Arteriovenous fistulas

(AVFs). Surgically created connections between an artery and a vein used for vascular access for haemodialysis.

Contact precautions

Interventions used to reduce the risk of transmission of organisms transmitted by contact with the affected patient and their environment.

Antibiotic selection pressure

Reduction or elimination of bacteria that are susceptible to an administered antibiotic, allowing antimicrobial-resistant bacterial populations to gain a survival advantage and thus become predominant members of the microbiota.

Antimicrobial stewardship

A set of coordinated strategies to improve the use of antimicrobial medications with the goal of enhancing patient health outcomes, reducing resistance to antibiotics and decreasing unnecessary costs.

Endogenous pathogens

Organisms that are part of the normal microbiota but that in some circumstances can cause symptomatic infection.

Colonization resistance

The ability of the body’s microbiota, such as commensal gut bacteria, to prevent colonization and infection with pathogenic organisms.

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