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Resistance Mechanisms: A Problem and an Approach to the Solution

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Sepsis
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Abstract

Bacterial resistance is a growing problem worldwide. Treatment of bacterial infections is more difficult every day, not only in hospitals but also in the community. If it was possible to cure infections with penicillin 60 years ago, now we require the use of three or four antibiotics in order to treat an infection caused by microorganisms resistant to several antimicrobial families (multidrug-resistance), and cases of infections due to bacteria resistant to all available antibiotics have already been described. Among the reasons that can explain the sustained increase in resistance are the indiscriminate use of antibiotics for viral infections (where they are not necessary), the use of antibiotics of very wide spectrum for infections that do not require them (e.g., carbapenems in respiratory tract infections in the community), inadequate dosage or very prolonged treatments, and, lastly, the use of antibiotics in animals that end up transmitting resistance genes in human beings during their consumption (Paulson and Zaoutis, Pediatrics 136(6):e1670–7, 2015). It is a priority to take measures to contain resistance, on the one hand, through the strategy of antibiotic management, strict adherence to the multimodal WHO multimodal hand hygiene strategy, compliance with contact isolation precautions, active surveillance of colonized patients, and cohortization of patients with infections by multidrug-resistant microorganisms.

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References

  1. Paulson JA, Zaoutis TE. Nontherapeutic use of antimicrobials agents in animal agriculture: implications for pediatrics. Council on environmental health committee. Pediatrics. 2015;136(6):e1670–7.

    Article  PubMed  Google Scholar 

  2. Bonomo RA, Szabo D. Mechanisms of multidrug resistance in acinetobacter species and Pseudomonas aeruginosa. Clin Infect Dis. 2006;1(43):S49–56.

    Article  Google Scholar 

  3. Xu H, Zhou Y, Zhai X, et al. Emergence and characterization of tigecycline resistance in multidrug-resistant Klebsiella pneumoniae isolates from blood samples of patients in intensive care units in northern China. J Med Microbiol. 2016;65(8):751–9.

    Article  PubMed  Google Scholar 

  4. Villegas MV, Pallares CJ, Escandón-Vargas K, et al. Characterization and clinical impact of bloodstream infection caused by Carbapenemase-producing Enterobacteriaceae in seven latin American countries. PLoS One. 2016;11(4):e0154092.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Nordmann P, Cuzon G, Naas T. The real threat of Klebsiella pneumoniae carbapenemase-producing bacteria. Lancet Infect Dis. 2009;9(4):228–36.

    Article  CAS  PubMed  Google Scholar 

  6. Nordmann P. Carbapenemase-producing Enterobacteriaceae: overview of a major public health challenge. Med Mal Infect. 2014;44(2):51–6.

    Article  CAS  PubMed  Google Scholar 

  7. Antimicrobial resistance: global report on surveillance 2014. http://www.who.int/drugresistance/documents/surveillancereport/en/.

  8. IDSA Antimicrobial resistance action center. http://cqrcengage.com/idsociety/antimicrobial_resistance.

  9. Boucher HW, Talbot GH, Bradley JS, et al. Bad bugs, no drugs: no ESKAPE! An update of the infectious diseases society of America. Clin Infect Dis. 2009;48(1):1–12.

    Article  PubMed  Google Scholar 

  10. Pendlenton JN, Groman SP, Gilmore BF. Clinical relevance of the ESKAPE pathogens. Expert Rev Antiinfect Ther. 2013;1(3):297–308.

    Article  Google Scholar 

  11. Lacey RW. Genetic bases, epidemiology and future significance of antibiotic resistance in Staphylococcus aureus: a review. J Clin Pathol. 1973;26(12):899–913.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Shore AC, Coleman DC. Staphylococcal cassette chromosome mec: recent advances and new insights. Int J Med Microbiol. 2013;303(6–7):350–9.

    Article  CAS  PubMed  Google Scholar 

  13. Chambers HF, Deleo FR. Waves of resistance: Staphylococcus aureus in the antibiotic era. Nat Rev Microbiol. 2009;7:620–41.

    Article  Google Scholar 

  14. Gardete S, Tomasz A. Mechanisms of vancomycin resistance in Staphylococcus aureus. J Clin Invest. 2014;124(7):2836–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Tran TT, Munita JM, Arias CA. Mechanisms of drug resistance: daptomycin resistance. Ann N Y Acad Sci. 2015;1354:32–53.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Patel JB, Levitt LA, Hageman J, et al. An association between reduced susceptibility to daptomycin and reduced susceptibility to vancomycin in Staphylococcus aureus. Clin Infect Dis. 2006;42(11):1652–3.

    Article  CAS  PubMed  Google Scholar 

  17. Meka VG, Pillai SK, Sakoulas G, et al. Linezolid resistance in sequential Staphylococcus aureus isolates associated with a T2500A mutation in the 23S rRNA gene and loss of a single copy of rRNA. J Infect Dis. 2004;190:311–7.

    Article  CAS  PubMed  Google Scholar 

  18. Rubinstein E, Keynan Y. Vancomycin resistant Enterococci. Crit Care Med. 2013;29(4):841–52.

    Google Scholar 

  19. Mederski-Samoraj BD, Murray BE. High-level resistance to gentamicin in clinical isolates of enterococci. J Infect Dis. 1983;147:751–7.

    Article  CAS  PubMed  Google Scholar 

  20. Gabalda J, Len O, Miro JM, et al. Brief communication: treatment of Enterococcus faecalis endocarditis with ampicillin plus ceftriaxone. Ann Intern Med. 2007;146:574–9.

    Article  Google Scholar 

  21. Fernandez L, Hancock R. Adaptive and mutational resistance: role of porins and efflux pumps in drug resistance. Clin Microbiol Rev. 2012;25(4):661–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Lautenbach E, Strom BL, Bilker WB, et al. Epidemiological investigation of fluoroquinolones resistance in infections due to extended-spectrum beta lactamase-producing Escherichia coli and Klebsiella pneumoniae. Clin Infect Dis. 2001;33(8):1288–94.

    Article  CAS  PubMed  Google Scholar 

  23. Pitout JD, Laupland KB. Extended-spectrum beta-lactamase-producing Enterobacteriaceae: an emerging public-health concern. Lancet Infect Dis. 2008;8(3):159–66.

    Article  CAS  PubMed  Google Scholar 

  24. Navarro F, Calvo J, Cantón R, et al. Detection of resistance phenotypes in gram-negative bacteria. Enferm Infecc Microbiol Clin. 2011;29(7):524–34.

    Article  PubMed  Google Scholar 

  25. Leal AL, Cortes JA, Arias G, et al. Emergence of resistance to third generation cephalosporins by Enterobacteriaceae causing community-onset urinary tract infection in hospitals in Colombia. Enferm Infecc Microbiol Clin. 2013;31(5):298–303.

    Article  PubMed  Google Scholar 

  26. Paterson DL, Bonomo RA. Extended-spectrum beta-lactamases: a clinical update. Clin Microbiol Rev. 2005;18(4):657–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Thomson KS. Extended-spectrum beta-lactamases, AmpC and Carbapenemase issues. J Clin Microbiol. 2010;48(4):1019–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. James CE, Mahendran KR, Molitor A, et al. How betalactam antibiotics enter bacteria: a dialogue with the porins. PLoS One. 2009;4(5):e5453.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Harris PN, Tambyah PA, Paterson DL. Beta-lactam and beta-lactamase inhibitor combinations in the treatment of extended-spectrum beta lactamase producing Enterobacteriaceae: time to a reappraisal in the era of few antibiotic options? Lancet Infect Dis. 2015;15(4):475–85.

    Article  CAS  PubMed  Google Scholar 

  30. Choi SH, Lee JE, Park SJ, et al. Emergence of antibiotic resistance during therapy for infections caused by Enterobacteriaceae producing AmpC beta-lactamase: implications for antibiotic use. Antimicrob Agents Chemother. 2008;52(3):995–1000.

    Article  CAS  PubMed  Google Scholar 

  31. Negri MC, Baquero F. In vitro selective concentrations of cefepime and ceftazidime for AmpC beta-lactamase hyperproducer Enterobacter cloacae variants. Clin Microbiol Infect. 2009;5(suppl 1):S25–8.

    Google Scholar 

  32. Harris PN, Ferguson JK. Antibiotic therapy for inducible AmpC beta-lactamase producing Gram-negative bacilli: What are the alternatives to carbapenems, quinolones and aminoglycosides? Int J Antimicrob Agents. 2012;40(4):297–305.

    Article  CAS  PubMed  Google Scholar 

  33. Harris PN, Wei JY, Shen AW, Abdile AA, et al. Carbapenems vs alternative antibiotics for the treatment of bloodstream infections caused by Enterobacter, Citrobacter or Serratia species: a systematic review and meta-analysis. J Antimicrob Chemother. 2016;71(2):296–306.

    Article  CAS  PubMed  Google Scholar 

  34. Queenan AM, Bush K. Carbapenemase: the versatile beta-lactamases. Clin Microbiol Rev. 2007;20(3):440–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Falagas ME, Bliziotis IA. Pandrug-resistant gram-negative bacteria: the dawn of the postantibiotic era? Int J Antimicrobiol Agents. 2007;29(6):630–6.

    Article  CAS  Google Scholar 

  36. Walther-Rasmussen J, Høiby N. Class A Carbapenemases. J Antimicrob Chemother. 2007;60:470–82.

    Article  CAS  PubMed  Google Scholar 

  37. Nordmann P, Poirel L. Strategies for identification of carbapenemase-producing Enterobacteriaceae. J Antimicrob Chemother. 2013;68(3):487–49.

    Article  CAS  PubMed  Google Scholar 

  38. Tzouvelekis LS, 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Levy Hara G, Gould I, Endimiani A, et al. Detection, treatment and prevention of carbapenemase-producing Enterobacteriaceae: recommendations from an international working group. J Chemother. 2013;25(3):129–40.

    Article  PubMed  Google Scholar 

  40. Roberts JA, Kirkpatrick CM, Roberts MS, et al. Meropenem. J Antimicrob Chemother. 2009;64(1):142–50.

    Article  CAS  PubMed  Google Scholar 

  41. Kuti JL, Dandekar PK, Nightingale CH, et al. Use of Monte Carlo simulation to design an optimized pharmacodynamic dosing strategy for meropenem. J Clin Pharmacol. 2003;43:1116–23.

    Article  CAS  PubMed  Google Scholar 

  42. Daikos GL, Markogiannakis A. Carbapenemase-producing Klebsiella pneumoniae (when) might we still consider treating with carbapenems. Clin Microbiol Infect. 2011;17(8):1135–41.

    Article  CAS  PubMed  Google Scholar 

  43. Daikos GL, Tsaousi S, Tzouvelekis LS, et al. Carbapenemase-producing Klebsiella pneumoniae bloodstream infections: lowering mortality by antibiotic combination schemes and the role of carbapenems. Antimicrob Agents Chemother. 2014;58(4):2322–8.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Tumbarello M, Viale P, Visconti C, et al. Predictors of mortality in bloodstream infections caused by carbapenemase-producing Klebsiella pneumoniae: importance of combination therapy. Clin Infec Dis. 2012;55(7):943–50.

    Article  CAS  Google Scholar 

  45. Zarkotou O, Pournaras S, Tselioti P, et al. Predictors of mortality in patients with bloodstream infections by KPC-producing Klebsiella pneumoniae and impact of appropriate antimicrobial treatment. Clin Microbiol Infect. 2011;17(12):1798–803.

    Article  CAS  PubMed  Google Scholar 

  46. Qureshi ZA, Paterson DL, Potoski BA, et al. Antimicrobial outcome of bacteremia due to KPC-producing Klebsiella pneumoniae: superiority of combination antimicrobial regimens. Antimicrob Agents Chemotherap. 2012;56(4):2108–13.

    Article  CAS  Google Scholar 

  47. Falagas ME, Lourida P, Poulikakos P, et al. Antimicrobial treatment for infections due to carbapenem-resistant Enterobacteriaceae: systematic evaluation of available evidence. Antimicrob Agentes Chemother. 2014;58(2):654–63.

    Article  Google Scholar 

  48. Gomez-Simmonds A, Nelson B, Eiras DP, et al. Combinations regimes for treatment of carbapenem-resistant Klebseilla pneumoniae Bloodstream infections. Antimicrob Agents Chemother. 2016;60(6):3601–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Bergen P, Landersdorfer CB, Zhang J, et al. Pharmacokinetics and pharmacodynamics of old polymyxins: what is new? Diag Microbiol Infect Dis. 2012;74(3):213–23.

    Article  CAS  Google Scholar 

  50. Morrill H, Pogue J, Kaye K, et al. Treatment options for carbapenem-resistant Enterobacteriaceae infections. Open Forum Infect Dis. 2015;2(2):1–15.

    Article  Google Scholar 

  51. Kim YJ, Kim SI, Hong KW, et al. Risk factors of mortality in patients with carbapenem-resistant Acinetobacter baumannii bacteremia: impact of appropriate antimicrobial therapy. J Korean Med Sci. 2012;27(5):471–5.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Denys GA, Callister SM, Dowzicky MJ, et al. Antimicrobial susceptibility among gram-negatives isolates collected in the USA between 2005 and 2011 as part of the Tigecycline Evaluation and Surveillance trial (T.E.S.T). Ann Clin Microbiol Antimicrob. 2013;5(12):24.

    Article  Google Scholar 

  53. Hong DJ, Bae IK, Jang IH, et al. Epidemiology and characteristics of metallo-beta-lactamase-producing Pseudomonas aeruginosa. Infect Chemother. 2015;47(2):81–97.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Gniadek TJ, Carroll KC, Simner PJ, et al. Carbapenem-resistant non-glucose fermenting Gram-negatives bacilli: the missing piece to the puzzle. J Clin Microbiol. 2016;54(7):1700–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Lister P, Wolter D, Hanson N. Antibacterial- resistant Pseudomonas aeruginosa: clinical Impact and Complex regulation of chromosomally encoded resistance mechanisms. Clin Microbiol Rev. 2009;4:582–610.

    Article  Google Scholar 

  56. Bou G, Martine-Beltran J. Cloning, nucleotide sequencing, and analysis of the gene encoding an AmpC beta-lactamase in Acinetobacter baumannii. Antimicrob Agents Chemother. 2000;44(2):428–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Higgins PG, Perez-Llarena FJ, Zander E, et al. OXA-235, a novel class D beta-lactamase involved in resistance to carbapenems in Acinetobacter baumannii. Antimicrob Agents Chemother. 2013;57(5):2121–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Rajamohan G, Srinivasan VB, Gebreyes WA. Novel role of Acinetobacter baumannii RND efflux transporters in mediating decreased susceptibility to biocides. J Antimicrob Chemother. 2010;65(2):228–32.

    Article  CAS  PubMed  Google Scholar 

  59. Lopez-Rojas R, Dominguez-Herrera J, McConnell MJ, et al. Impaired virulence and in vivo fitness of colistin-resistant Acinetobacter baumannii. J Infect Dis. 2011;203(4):545–8.

    Article  PubMed  PubMed Central  Google Scholar 

  60. 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;46:567–70.

    Article  PubMed  Google Scholar 

  61. Betrosian AP, Frantzeskaki F, Xanthaki A, et al. Efficacy and safety of high-dose ampicillin-sulbactam vs colistin as monotherapy for the treatment of multidrug-resistant Acinetobacter baumannii ventilator-associated pneumonia. J Infect. 2008;56(6):432–6.

    Article  PubMed  Google Scholar 

  62. Borisova M, Gisin J, Mayer C. Blocking peptidoglycan recycling in Pseudomonas aeruginosa attenuates intrinsic resistance to fosfomycin. Microbe Drug Resist. 2014;20:231–7.

    Article  CAS  Google Scholar 

  63. Zavascki AP, Barth AL, Gonçalves AL, et al. The influence of metallo-beta-lactamase production on mortality in nosocomial pseudomonas aeruginosa infections. J Antimicrob Chemother. 2006;58(2):387–92.

    Article  CAS  PubMed  Google Scholar 

  64. Nicolau J, Oliver A, et al. Carbapenemases in Pseudomonas. Enferm Infect Microbiol Clin. 2010;28(Suppl 1):19–28.

    Article  Google Scholar 

  65. Teleb M, Soto-Ruiz E, Domingez DC. The rapid development of ESBL E. coli resistance to ceftolozane-tazobactam in a patient with a liver abscess. The research for an omnipotent antibiotic goes on. Infect Disord Drug Targets. 2016;PMID:27411471.

    Google Scholar 

  66. Falagas ME, Kanellopoulou MD, Kargeorgpoulos DE, et al. Antimicrobial susceptibility of multidrug-resistant Gram-negative bacteria to fosfomycin. Eur J Clin Microbiol Infect Dis. 2008;27(6):439–43.

    Article  CAS  PubMed  Google Scholar 

  67. Apisarnthanarak A, Mundy LM. Use of high-dose 4-hour infusion of doripenem. Clin Infect Dis. 2010;51:1352–4.

    Article  PubMed  Google Scholar 

  68. U.S. Department of Health & Human Services. Guide to the elimination of methicillin-resistant S. aureus (MRSA) transmission in hospital settings. 2nd ed. Washington, DC: U.S. Department of Health & Human Services; 2010. p. 1–65.

    Google Scholar 

  69. Siegel J, Rhinehart E, Jackson M. Guideline for isolation precautions: preventing transmission of infecting agents in healthcare settings in. 2007. http://www.cdc.gov/ncidod/dhqp/pdf/isolation2007.pdf.

  70. Taconelli E, Cataldo M, Dancer S. ESCMID guidelines for the management of the infection control measures to reduce transmission of multidrug-resistant Gram-negative bacteria in hospitalized patients. Clin Microbiol Infect. 2014;20(Suppl. 1):1–55.

    Article  Google Scholar 

  71. Casewell M, Phillips I. Hands as a route of transmission for Klebsiella species. Br Med J. 1977;2(6098):1315–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Lemmen SW, Häfner H, Zolldan D, et al. Distribution of multi-resistant gram-negative vs gram-positive bacteria in the hospital inanimate environment. J Hosp Infect. 2004;56(3):191–7.

    Article  CAS  PubMed  Google Scholar 

  73. Bhalla A, Pulltz NJ, Gries DM, et al. Acquisition of nosocomial pathogens on hands after contact with environmental surfaces near hospitalized patients. Infect Control Hosp Epidemiol. 2004;25(2):164–7.

    Article  PubMed  Google Scholar 

  74. Dancer SJ. Controlling hospital-acquired infections: focus on the role of the environment and new technologies for decontamination. Clin Microbiol Rev. 2014;27(4):665–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Climo MW, Yokoe DS, Warren DK, et al. Effect of daily chlorhexidine bathing on hospital acquired infections. N Engl J Med. 2013;368(6):533–42.

    Article  CAS  PubMed  Google Scholar 

  76. Viray MA, Morley JC, Coopersmith CM, et al. Daily bathing th chlorhexidine-based soap and the prevention of Staphylococcus aureus transmission and infection. Infect Control Hosp Epidemiol. 2014;35(3):243–50.

    Article  PubMed  PubMed Central  Google Scholar 

  77. Noto MJ, Domenico HJ, Byrne DW, et al. Chlorhexidine bathing and health care-associated infections: a randomized clinical trial. JAMA. 2015;313(4):369–78.

    Article  PubMed  PubMed Central  Google Scholar 

  78. Noteboom Y, Ong D, Oostdijk E, et al. Antibiotic-induced within-host resistance development in gram-negative bacteria in patients receiving selective decontamination or standard care. Crit Care Med. 2015;43(12):2582–8.

    Article  CAS  PubMed  Google Scholar 

  79. Curcio DJ, et al. Antibiotic prescription in intensive care units in Latin America. Rev Argent Microbiol. 2011;43(3):203–11.

    PubMed  Google Scholar 

  80. Halaby T, Al Naiemi N, Kluymans J, et al. Emergence of colistin resistance in Enterobacteriaceae after the introduction of selective digestive tract decontamination in an intensive care unit. Antimic Agents Chemother. 2013;57(7):3224–9.

    Article  CAS  Google Scholar 

  81. File T, Srinivasan A, Bartlett J. Antimicrobial stewardship: importance for patient and public health. Clin Infect Dis. 2014;59(S3):S93–S6.

    Article  CAS  PubMed  Google Scholar 

  82. Fridkin SK, Srinivasan A. Implementing a strategy for monitoring inpatient antimicrobial use among hospitals in the United States. Clin Infect Dis. 2014;58(3):401–6.

    Article  PubMed  Google Scholar 

  83. Goff DA, File TM Jr. The evolving role of antimicrobial stewardship in management of multidrug resistant infections. Infect Dis Clin N Am. 2016;30(2):539–51.

    Article  Google Scholar 

  84. Barlam T, Cosgrove S, Abbo L, 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. 2016;62(10):e51–77.

    Article  PubMed  PubMed Central  Google Scholar 

  85. Adler A, Friedman N, Marchaim D. Multidrug-resistant gram-negative bacilli. Infect Dis Clin N Am. 2016;30(4):967–97.

    Article  Google Scholar 

  86. Spelberg B. The new antibiotic mantra: shorter is better. JAMA Intern Med. 2016;176(9):1254–5.

    Article  Google Scholar 

  87. Uranga A, España P, Bilbao A, et al. Duration of antibiotic treatment in community-acquired pneumonia. A multicenter randomized clinical trial. JAMA Intern Med. 2016;176(9):1257–65.

    Article  PubMed  Google Scholar 

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Arias-León, G. (2018). Resistance Mechanisms: A Problem and an Approach to the Solution. In: Ortiz-Ruiz, G., Dueñas-Castell, C. (eds) Sepsis. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-7334-7_7

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