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VOLUME 1 , ISSUE 2 ( April-June, 2019 ) > List of Articles


Multidrug-resistant Gram-negative Bacterial Infections in Critically Ill

Manohar Gandhi, Rakshay Shetty

Keywords : Beta lactamases, Extended spectrum beta lactamase, Multidrug resistant gram-negative bacteria

Citation Information : Gandhi M, Shetty R. Multidrug-resistant Gram-negative Bacterial Infections in Critically Ill. Pediatr Inf Dis 2019; 1 (2):62-67.

DOI: 10.5005/jp-journals-10081-1214

License: CC BY-NC 4.0

Published Online: 01-06-2019

Copyright Statement:  Copyright © 2019; Jaypee Brothers Medical Publishers (P) Ltd.


Antimicrobial resistance (AMR) in gram-negative bacteria (GNB) is persisting to be a significant cause of severe infections across the world, with increasing morbidity and mortality rates. Extended spectrum beta lactamase (ESBL) rates are alarmingly increasing in Escherichia and Klebsiella species, which is about 70% and there has been an increase in the resistance to carbapenems over the past few years in India. Current scenario of rapidly growing multidrug resistant (MDR) organisms in our Indian intensive care units is posing difficulties with regard to detecting these infections and starting appropriate empirical antibiotics. A clear understanding of the epidemiological, microbiological, and pharmacological aspects of these MDR gram-negative organisms is very important. This article tries to brief the risk factors for MDR GNB infections, spectrum of MDR GNB infections, mechanisms of resistance, and beta-lactamase enzyme classification and outlines the clinically important types and the treatment considerations for these MDR gram-negative organisms.

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  1. Boucher HW, Talbot GH, Bradley JS, et al. Bad bugs, no drugs: no ESKAPE! An update from the Infectious Diseases Society of America. Clin Infect Dis 2009;48(1):1–12. DOI: 10.1086/595011.
  2. Vasoo S, Barreto JN, Tosh PK. Emerging issues in Gram-negative bacterial resistance: an update for the practicing clinician. Mayo Clin Proc 2015;90(3):395–403. DOI: 10.1016/j.mayocp.2014.12.002.
  3. Veeraraghavan B, Jesudason M, Prakasah J, et al. Antimicrobial susceptibility profiles of gram-negative bacteria causing infections collected across India during 2014-2016: Study for monitoring antimicrobial resistance trend report. Indian J Med Microbiol 2018;36(1):32–36. DOI: 10.4103/ijmm.IJMM_17_415.
  4. Kumar SG, Adithan C, Harish BN, et al. Antimicrobial resistance in India: a review. J Nat Sci Biol Med 2013;4(2):286–291. DOI: 10.4103/0976-9668.116970.
  5. Centers for Disease Control and Prevention (CDC). Vital signs: carbapenem-resistant Enterobacteriaceae. MMWR Morb Mortal Wkly Rep 2013;62(9):165–170.
  6. Rossi F. In vitro susceptibilities of aerobic and facultatively anaerobic Gram-negative bacilli isolated from patients with intra-abdominal infections worldwide: 2004 results from SMART (Study for Monitoring Antimicrobial Resistance Trends). J Antimicrob Chemother 2006;58(1):205–210. DOI: 10.1093/jac/dkl199.
  7. Hsueh PR. Study for monitoring antimicrobial resistance trends (SMART) in the Asia-Pacific region, 2002-2010. Int J Antimicrob Agents 2012;40(Suppl):S1–S3. DOI: 10.1016/S0924-8579(12)00244-0.
  8. Doi Y, Adams J, O'Keefe A, et al. Community-acquired extended-spectrum beta-lactamase producers, United States. Emerg Infect Dis 2007;13(7):1121–1123. DOI: 10.3201/eid1307.070094.
  9. Freeman JT, McBride SJ, Heffernan H, et al. Community-onset genitourinary tract infection due to CTX-M-15-Producing Escherichia coli among travelers to the Indian subcontinent in New Zealand. Clin Infect Dis 2008;47(5):689–692. DOI: 10.1086/590941.
  10. Woodford N, Ward ME, Kaufmann ME, et al. Community and hospital spread of Escherichia coli producing CTX-M extended-spectrum beta-lactamases in the UK. J Antimicrob Chemother 2004;54(4): 735–743. DOI: 10.1093/jac/dkh424.
  11. Hawser SP, Bouchillon SK, Hoban DJ, et al. Emergence of high levels of extended spectrum beta lactamase producing gram negative Bacilli in the Asia Pacific region: data from the study for monitoring antimicrobial resistance trends (SMART) program, 2007. Antimicrob Agents Chemother 2009;53(8):3280–3284. DOI: 10.1128/AAC. 00426-09.
  12. Chaudhry D, Prajapat B. Intensive care unit bugs in India: how do they differ from the Western world? J Assoc Chest Physicians 2017;5:10–17. DOI: 10.4103/2320-8775.196645.
  13. Rodriguez-Baño J, Pascual A. Clinical significance of extended-spectrum beta-lactamases. Expert Rev Anti Infect Ther 2008;6(5): 671–683. DOI: 10.1586/14787210.6.5.671.
  14. Gasink L, Edelstein P, Lautenbach E, et al. Risk factors and clinical impact of Klebsiella pneumoniae carbapenemase-producing K. pneumoniae. Infect Control Hosp Epidemiol 2009;30(12):1180–1185. DOI: 10.1086/648451.
  15. Mouloudi E, Protonotariou E, Zagorianou A, et al. Bloodstream infections caused by metallo-β-lactamase/Klebsiella pneumoniae carbapenemase-producing K. pneumoniae among intensive care unit patients in Greece: risk factors for infection and impact of type of resistance on outcomes. Infect Control Hosp Epidemiol 2010;31(12):1250–1256. DOI: 10.1086/657135.
  16. Magiorakos A, Srinivasan A, Carey R, 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 2012;18(3):268–281. DOI: 10.1111/j.1469-0691.2011.03570.x.
  17. Jacoby GA, Munoz-Price LS. The new beta-lactamases. N Engl J Med 2005;352(4):380–391. DOI: 10.1056/NEJMra041359.
  18. Ambler R. The structure of beta-lactamases. Philos Trans R Soc Lond B Biol Sci 1980;289(1036):321–331. DOI: 10.1098/rstb.1980.0049.
  19. Bush K, Jacoby G. Updated functional classification of beta-lactamases. Antimicrob Agents Chemother 2010;54(3):969–976. DOI: 10.1128/AAC.01009-09.
  20. Canton R, Coque T. The CTX-M betalactamase pandemic. Curr Opin Microbiol 2006;9(5):466–475. DOI: 10.1016/j.mib.2006.08.011.
  21. Tzouvelekis L, Markogiannakis A, Psichogiou M, et al. Carbapenemases in Klebsiella pneumoniae and other Enterobacteriaceae:an evolving crisis of global dimensions. Clin Microbiol Rev 2012;25(4):682–707. DOI: 10.1128/CMR.05035-11.
  22. Jacoby G. AmpC beta-lactamases. Clin Microbiol Rev 2009;22(1): 161–182. DOI: 10.1128/CMR.00036-08.
  23. Navarro F, Miró E, Mirelis B. Interpretive reading of enterobacteriaantibiograms. Enferm Infecc Microbiol Clin 2010;28(9):638–645. DOI: 10.1016/j.eimc.2010.05.002.
  24. Poirel L, Heritier C, Tolun V, et al. Emergence of oxacillinase-mediated resistance to imipenem in Klebsiella pneumoniae. Antimicrob Agents Chemother 2004;48(1):15–22. DOI: 10.1128/AAC.48.1.15-22.2004.
  25. Delgado-Valverde M, Sojo-Dorado J, Pascual A, et al. Clinical management of infections caused by multidrug-resistant Enterobacteriaceae. Ther Adv Infect Dis 2013;1(2):49–69. DOI: 10.1177/2049936113476284.
  26. Pop-Vicas A, Opal SM. The clinical impact of multidrugresistant gram-negative bacilli in the management of septic shock. Virulence 2014;5(1):206–212. DOI: 10.4161/viru.26210.
  27. Cornaglia G, Giamarellou H, Rossolini GM. Metalloβ-lactamases: a last frontier for β-lactams? Lancet Infect Dis 2011;11(5):381–393. DOI: 10.1016/S1473-3099(11)70056-1.
  28. Logan LK. Carbapenem-resistant enterobacteriaceae: an emerging problem in children. Clin Infect Dis 2012;55(6):852–859. DOI: 10.1093/cid/cis543.
  29. Miriagou V, Tzouvelekis LS, Rossiter S, et al. Imipenem resistance in a Salmonella clinical strain due to plasmid-mediated class A carbapenemase KPC-2. Antimicrob Agents Chemother 2003;47(4):1297–1300. DOI: 10.1128/AAC.47.4.1297-1300.2003.
  30. Castanheira M, Deshpande LM, Mathai D, et al. Early dissemination of NDM-1- and OXA-181-producing Enterobacteriaceae in Indian hospitals: report from the SENTRY antimicrobial surveillance program, 2006-2007. Antimicrob Agents Chemother 2011;55(3): 1274–1278. DOI: 10.1128/AAC.01497-10.
  31. Pragasam AK, Vijayakumar S, Bakthavatchalam YD, et al. Molecular characterisation of antimicrobial resistance in Pseudomonas aeruginosa and Acinetobacter baumannii during 2014 and 2015 collected across India. Indian J Med Microbiol 2016;34(4):433–441. DOI: 10.4103/0255-0857.195376.
  32. Piddock LJ. Mechanisms of fluoroquinolone resistance: an update 1994-1998. Drugs 1999;58(Suppl 2):11–18. DOI: 10.2165/00003495-199958002-00003.
  33. Doi Y, Arakawa Y. 16S ribosomal RNA methylation: emerging resistance mechanism against aminoglycosides. Clin Infect Dis 2007;45(1):88–94. DOI: 10.1086/518605.
  34. Zhou Y, Yu H, Guo Q, et al. Distribution of 16S rRNA methylases among different species of Gram-negative bacilli with high-level resistance to aminoglycosides. Eur J Clin Microbiol Infect Dis 2010;29(11): 1349–1353. DOI: 10.1007/s10096-010-1004-1.
  35. Bonomo RA, Szabo D. Mechanisms of multidrug resistance in Acinetobacter species and Pseudomonas aeruginosa. Clin Infect Dis 2006;43(Suppl 2):S49–S56. DOI: 10.1086/504477.
  36. Vincent JL, Rello J, Marshall J, et al. International study of the prevalence and outcomes of infection in intensive care units. JAMA 2009;302(21):2323–2329. DOI: 10.1001/jama.2009.1754.
  37. Kumar A, Roberts D, Wood KE, et al. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med 2006;34(6): 1589–1596. DOI: 10.1097/01.CCM.0000217961.75225.E9.
  38. Tumbarello M, Sanguinetti M, Montuori E, et al. Predictors of mortality in patients with bloodstream infections caused by extended-spectrum-beta-lactamase-producing Enterobacteriaceae: importance of inadequate initial antimicrobial treatment. Antimicrob Agents Chemother 2007;51(6):1987–1994. DOI: 10.1128/AAC.01509-06.
  39. Leekha S, Standiford HC. Empiric antimicrobial therapy for Gram-negative sepsis: back to the future. Crit Care Med 2011;39(8): 1995–1996. DOI: 10.1097/CCM.0b013e318223b94b.
  40. Hawkey PM, Livermore DM. Carbapenem antibiotics for serious infections. BMJ 2012;344:e3236. DOI: 10.1136/bmj.e3236.
  41. Paterson DL, Ko WC, Von Gottberg A, et al. Antibiotic therapy for Klebsiella pneumoniae bacteremia: implications of production of extended-spectrum beta-lactamases. Clin Infect Dis 2004;39(1):31–37. DOI: 10.1086/420816.
  42. Drusano GL. Antimicrobial pharmacodynamics: critical interactions of ‘bug and drug’. Nat Rev Microbiol 2004;2(4):289–300. DOI: 10.1038/nrmicro862.
  43. Roberts JA, Kirkpatrick CM, Roberts MS, et al. Meropenem dosing in critically ill patients with sepsis and without renal dysfunction: intermittent bolus versus continuous administration? Monte Carlo dosing simulations and subcutaneous tissue distribution. J Antimicrob Chemother 2009;64(1):142–150. DOI: 10.1093/jac/dkp139.
  44. Hawkey P, Warren R, Livermore D, et al. Treatment of infections caused by multidrug-resistant Gram-negative bacteria: report of the British Society for Antimicrobial Chemotherapy/Healthcare Infection Society/British Infection Association Joint Working Party. J Antimicrob Chemother 2018;73(Suppl 3):iii2–iii78. DOI: 10.1093/jac/dky027.
  45. Falagas M, Kasiakou S, Saravolatz L. Colistin: the revival of polymyxins for the management of multidrug-resistant gram-negative bacterial infections. Clin Infect Dis 2005;40(9):1333–1341. DOI: 10.1086/429323.
  46. Kift EV, Maartens G, Bamford C. Systematic review of the evidence for rational dosing of colistin. S Afr Med J 2014;104(3):183–186. DOI: 10.7196/samj.7011.
  47. Landersdorfer CB, Nation RL. Colistin: how should it be dosed for the critically ill? Crit Care Med 2015;36(1):126–135. DOI: 10.1055/s-0034-1398390.
  48. Labuschagne Q, Schellack N, Gous A, et al. COLISTIN: adult and paediatric guideline for South Africa, 2016. S Afr J Infect Dis 2016;31(1):3–7. DOI: 10.1080/23120053.2016.1144285.
  49. Michalpulos A, Papadakis E. Inhaled anti-infective agents: emphasis on colistin. Infection 2010;38(2):81–88. DOI: 10.1007/s15010-009-9148-6.
  50. Balaji V, Jeremiah SS, Baliga PR. Polymyxins: Antimicrobial susceptibility concerns and therapeutic options. Indian J Med Microbiol 2011;29(3):230–242. DOI: 10.4103/0255-0857.83905.
  51. Falagas ME, Kastoris AC, Kapaskelis AM, et al. Fosfomycin for the treatment of multidrug-resistant, including extended-spectrum beta-lactamase producing, Enterobacteriaceae infections: a systematic review. Lancet Infect Dis 2010;10(1):43–50. DOI: 10.1016/S1473-3099(09)70325-1.
  52. Pankey GA. Tigecycline. J Antimicrob Chemother 2005;56(3):470–480. DOI: 10.1093/jac/dki248.
  53. Anthony KB, Fishman NO, Linkin DR, et al. Clinical and microbiological outcomes of serious infections with multidrug-resistant gram-negative organisms treated with tigecycline. Clin Infect Dis 2008;46(4):567–570. DOI: 10.1086/526775.
  54. Bassetti M, Righi E, Carnelutti A. New therapeutic options for respiratory tract infections. Curr Opin Infect Dis 2016;29(2):178–186. DOI: 10.1097/QCO.0000000000000251.
  55. Wagenlehner FME, Cloutier DJ, Miller LG, et al. Once-daily plazomicin for complicated urinary tract infections. N Engl J Med 2019;380(8):729–740. DOI: 10.1056/NEJMoa1801467.
  56. Tumbarello M, Trecarichi EM, Corona A, et al. Efficacy of ceftazidime-avibactam salvage therapy in patients with infections caused by KPC-producing Klebsiella pneumoniae. Clin Infect Dis 2019;68(3):355–364. DOI: 10.1093/cid/ciy492.
  57. Bassetti M, Peghin M, Vena A, et al. Treatment of infections due to MDR Gram-negative bacteria. Front Med (Lausanne) 2019;6:74. DOI: 10.3389/fmed.2019.00074.
  58. Solomkin J, Hershberger E, Miller B, et al. Ceftolozane/tazobactam plus metronidazole for complicated intraabdominal infections in an era of multidrug resistance: results from a randomized, double-blind, phase 3 trial. (ASPECT-cIAI). Clin Infect Dis 2015;60(10):1462–1471. DOI: 10.1093/cid/civ097.
  59. Wagenlehner FM, Umeh O, Steenbergen J, et al. Ceftolozane-tazobactam compared with levofloxacin in the treatment of complicated urinary-tract infections, including pyelonephritis: a randomised, double-blind, phase 3 trial (ASPECT-cUTI). Lancet 2015;385(9981):1949–1956. DOI: 10.1016/S0140-6736(14)62220-0.
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