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Antimicrobial Therapy

  • Thierry Calandra
  • Benoît Guery
Chapter

Abstract

The management of septic patients requires a comprehensive, multidisciplinary approach. The antibiotic therapy is one of the main determinants associated to prognosis. Several studies have shown that inappropriate antimicrobial therapy was associated to increased mortality. An appropriate empiric antibiotic therapy includes, not only the susceptibility of the potential pathogen(s) to the agent(s), but also a correct timing for administration and the optimization of each molecule regarding pharmacokinetic/pharmacodynamics (PK/PD) principles. Focusing on the two main agents prescribed in septic shock, a high maximum serum concentration/minimum inhibitory concentration (MIC) is expected for aminoglycosides, and the optimization of the time over the MIC is required for beta-lactams favoring continuous or extended time of infusion. In targeted therapy, a large number of studies suggest that monotherapy is as efficient as associations supporting for a rapid de-escalation. Finally to limit antibiotic pressure, there is now a trend to propose shorter duration of treatment for the patient where the source control is adequate. Antimicrobial therapy remains a challenge in the intensive care unit. Timing of administration, adequate antimicrobial spectrum, PK/PD, and duration of therapy are all linked to prognosis. Antimicrobial stewardship programs with dedicated management teams are a priority in sepsis patients.

References

  1. 1.
    Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R, et al. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock: 2016. Intensive Care Med. 2017;43(3):304–77.CrossRefGoogle Scholar
  2. 2.
    Bochud PY, Bonten M, Marchetti O, Calandra T. Antimicrobial therapy for patients with severe sepsis and septic shock: an evidence-based review. Crit Care Med. 2004;32(11 Suppl):S495–512.CrossRefGoogle Scholar
  3. 3.
    Ramphal R. Importance of adequate initial antimicrobial therapy. Chemotherapy. 2005;51(4):171–6.CrossRefGoogle Scholar
  4. 4.
    Freid MA, Vosti KL. The importance of underlying disease in patients with gram-negative bacteremia. Arch Intern Med. 1968;121(5):418–23.CrossRefGoogle Scholar
  5. 5.
    Bryant RE, Hood AF, Hood CE, Koenig MG. Factors affecting mortality of gram-negative rod bacteremia. Arch Intern Med. 1971;127(1):120–8.CrossRefGoogle Scholar
  6. 6.
    Kreger BE, Craven DE, McCabe WR. Gram-negative bacteremia. IV. Re-evaluation of clinical features and treatment in 612 patients. Am J Med. 1980;68(3):344–55.CrossRefGoogle Scholar
  7. 7.
    Barie PS, Hydo LJ, Shou J, Larone DH, Eachempati SR. Influence of antibiotic therapy on mortality of critical surgical illness caused or complicated by infection. Surg Infect (Larchmt). 2005;6(1):41–54.CrossRefGoogle Scholar
  8. 8.
    Kumar A, Roberts D, Wood KE, Light B, Parrillo JE, Sharma S, 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):1589–96.CrossRefGoogle Scholar
  9. 9.
    Castellanos-Ortega A, Suberviola B, Garcia-Astudillo LA, Holanda MS, Ortiz F, Llorca J, et al. Impact of the Surviving Sepsis Campaign protocols on hospital length of stay and mortality in septic shock patients: results of a three-year follow-up quasi-experimental study. Crit Care Med. 2010;38(4):1036–43.CrossRefGoogle Scholar
  10. 10.
    El Solh AA, Akinnusi ME, Alsawalha LN, Pineda LA. Outcome of septic shock in older adults after implementation of the sepsis “bundle”. J Am Geriatr Soc. 2008;56(2):272–8.CrossRefGoogle Scholar
  11. 11.
    Ferrer R, Artigas A, Suarez D, Palencia E, Levy MM, Arenzana A, et al. Effectiveness of treatments for severe sepsis: a prospective, multicenter, observational study. Am J Respir Crit Care Med. 2009;180(9):861–6.CrossRefGoogle Scholar
  12. 12.
    Gurnani PK, Patel GP, Crank CW, Vais D, Lateef O, Akimov S, et al. Impact of the implementation of a sepsis protocol for the management of fluid-refractory septic shock: a single-center, before-and-after study. Clin Ther. 2010;32(7):1285–93.CrossRefGoogle Scholar
  13. 13.
    Larsen GY, Mecham N, Greenberg R. An emergency department septic shock protocol and care guideline for children initiated at triage. Pediatrics. 2011;127(6):e1585–92.CrossRefGoogle Scholar
  14. 14.
    Puskarich MA, Trzeciak S, Shapiro NI, Arnold RC, Horton JM, Studnek JR, et al. Association between timing of antibiotic administration and mortality from septic shock in patients treated with a quantitative resuscitation protocol. Crit Care Med. 2011;39(9):2066–71.CrossRefGoogle Scholar
  15. 15.
    Ferrer R, Martin-Loeches I, Phillips G, Osborn TM, Townsend S, Dellinger RP, et al. Empiric antibiotic treatment reduces mortality in severe sepsis and septic shock from the first hour: results from a guideline-based performance improvement program. Crit Care Med. 2014;42(8):1749–55.CrossRefGoogle Scholar
  16. 16.
    Seymour CW, Gesten F, Prescott HC, Friedrich ME, Iwashyna TJ, Phillips GS, et al. Time to Treatment and Mortality during Mandated Emergency Care for Sepsis. N Engl J Med. 2017;376(23):2235–44.CrossRefGoogle Scholar
  17. 17.
    Kim SH, Park WB, Lee CS, Kang CI, Bang JW, Kim HB, et al. Outcome of inappropriate empirical antibiotic therapy in patients with Staphylococcus aureus bacteraemia: analytical strategy using propensity scores. Clin Microbiol Infect. 2006;12(1):13–21.CrossRefGoogle Scholar
  18. 18.
    Shorr AF, Micek ST, Kollef MH. Inappropriate therapy for methicillin-resistant Staphylococcus aureus: resource utilization and cost implications. Crit Care Med. 2008;36(8):2335–40.CrossRefGoogle Scholar
  19. 19.
    Paul M, Kariv G, Goldberg E, Raskin M, Shaked H, Hazzan R, et al. Importance of appropriate empirical antibiotic therapy for methicillin-resistant Staphylococcus aureus bacteraemia. J Antimicrob Chemother. 2010;65(12):2658–65.CrossRefGoogle Scholar
  20. 20.
    Morrell M, Fraser VJ, Kollef MH. Delaying the empiric treatment of candida bloodstream infection until positive blood culture results are obtained: a potential risk factor for hospital mortality. Antimicrob Agents Chemother. 2005;49(9):3640–5.CrossRefGoogle Scholar
  21. 21.
    Garey KW, Rege M, Pai MP, Mingo DE, Suda KJ, Turpin RS, et al. Time to initiation of fluconazole therapy impacts mortality in patients with candidemia: a multi-institutional study. Clin Infect Dis. 2006;43(1):25–31.CrossRefGoogle Scholar
  22. 22.
    Labelle AJ, Micek ST, Roubinian N, Kollef MH. Treatment-related risk factors for hospital mortality in Candida bloodstream infections. Crit Care Med. 2008;36(11):2967–72.CrossRefGoogle Scholar
  23. 23.
    Zilberberg MD, Kollef MH, Arnold H, Labelle A, Micek ST, Kothari S, et al. Inappropriate empiric antifungal therapy for candidemia in the ICU and hospital resource utilization: a retrospective cohort study. BMC Infect Dis. 2010;10:150.CrossRefGoogle Scholar
  24. 24.
    Fang CT, Shau WY, Hsueh PR, Chen YC, Wang JT, Hung CC, et al. Early empirical glycopeptide therapy for patients with methicillin-resistant Staphylococcus aureus bacteraemia: impact on the outcome. J Antimicrob Chemother. 2006;57(3):511–9.CrossRefGoogle Scholar
  25. 25.
    Osih RB, McGregor JC, Rich SE, Moore AC, Furuno JP, Perencevich EN, et al. Impact of empiric antibiotic therapy on outcomes in patients with Pseudomonas aeruginosa bacteremia. Antimicrob Agents Chemother. 2007;51(3):839–44.CrossRefGoogle Scholar
  26. 26.
    Corona A, Bertolini G, Lipman J, Wilson AP, Singer M. Antibiotic use and impact on outcome from bacteraemic critical illness: the BActeraemia Study in Intensive Care (BASIC). J Antimicrob Chemother. 2010;65(6):1276–85.CrossRefGoogle Scholar
  27. 27.
    Cain SE, Kohn J, Bookstaver PB, Albrecht H, Al-Hasan MN. Stratification of the impact of inappropriate empirical antimicrobial therapy for Gram-negative bloodstream infections by predicted prognosis. Antimicrob Agents Chemother. 2015;59(1):245–50.CrossRefGoogle Scholar
  28. 28.
    Fitzpatrick JM, Biswas JS, Edgeworth JD, Islam J, Jenkins N, Judge R, et al. Gram-negative bacteraemia; a multi-centre prospective evaluation of empiric antibiotic therapy and outcome in English acute hospitals. Clin Microbiol Infect. 2016;22(3):244–51.CrossRefGoogle Scholar
  29. 29.
    McGregor JC, Rich SE, Harris AD, Perencevich EN, Osih R, Lodise TP Jr, et al. A systematic review of the methods used to assess the association between appropriate antibiotic therapy and mortality in bacteremic patients. Clin Infect Dis. 2007;45(3):329–37.CrossRefGoogle Scholar
  30. 30.
    Retamar P, Portillo MM, Lopez-Prieto MD, Rodriguez-Lopez F, de Cueto M, Garcia MV, et al. Impact of inadequate empirical therapy on the mortality of patients with bloodstream infections: a propensity score-based analysis. Antimicrob Agents Chemother. 2012;56(1):472–8.CrossRefGoogle Scholar
  31. 31.
    Paul M, Shani V, Muchtar E, Kariv G, Robenshtok E, Leibovici L. Systematic review and meta-analysis of the efficacy of appropriate empiric antibiotic therapy for sepsis. Antimicrob Agents Chemother. 2010;54(11):4851–63.CrossRefGoogle Scholar
  32. 32.
    Gaieski DF, Mikkelsen ME, Band RA, Pines JM, Massone R, Furia FF, et al. Impact of time to antibiotics on survival in patients with severe sepsis or septic shock in whom early goal-directed therapy was initiated in the emergency department. Crit Care Med. 2010;38(4):1045–53.CrossRefGoogle Scholar
  33. 33.
    Kaasch AJ, Rieg S, Kuetscher J, Brodt HR, Widmann T, Herrmann M, et al. Delay in the administration of appropriate antimicrobial therapy in Staphylococcus aureus bloodstream infection: a prospective multicenter hospital-based cohort study. Infection. 2013;41(5):979–85.CrossRefGoogle Scholar
  34. 34.
    Sterling SA, Miller WR, Pryor J, Puskarich MA, Jones AE. The impact of timing of antibiotics on outcomes in severe sepsis and septic shock: a systematic review and meta-analysis. Crit Care Med. 2015;43(9):1907–15.CrossRefGoogle Scholar
  35. 35.
    Carlet J, Rambaud C, Pulcini C, isotAClddBM-r W. WAAR (world alliance against antibiotic resistance): safeguarding antibiotics. Antimicrob Resist Infect Control. 2012;1(1):25.CrossRefGoogle Scholar
  36. 36.
    Pakyz AL, Oinonen M, Polk RE. Relationship of carbapenem restriction in 22 university teaching hospitals to carbapenem use and carbapenem-resistant Pseudomonas aeruginosa. Antimicrob Agents Chemother. 2009;53(5):1983–6.CrossRefGoogle Scholar
  37. 37.
    Seah XF, Ong YL, Tan SW, Krishnaswamy G, Chong CY, Tan NW, et al. Impact of an antimicrobial stewardship program on the use of carbapenems in a tertiary women’s and children’s hospital, Singapore. Pharmacotherapy. 2014;34(11):1141–50.CrossRefGoogle Scholar
  38. 38.
    Roberts JA, Lipman J. Pharmacokinetic issues for antibiotics in the critically ill patient. Crit Care Med. 2009;37(3):840–51. quiz 59CrossRefGoogle Scholar
  39. 39.
    Moore RD, Lietman PS, Smith CR. Clinical response to aminoglycoside therapy: importance of the ratio of peak concentration to minimal inhibitory concentration. J Infect Dis. 1987;155(1):93–9.CrossRefGoogle Scholar
  40. 40.
    Kashuba AD, Nafziger AN, Drusano GL, Bertino JS Jr. Optimizing aminoglycoside therapy for nosocomial pneumonia caused by gram-negative bacteria. Antimicrob Agents Chemother. 1999;43(3):623–9.PubMedPubMedCentralGoogle Scholar
  41. 41.
    Karlowsky JA, Zhanel GG, Davidson RJ, Hoban DJ. Postantibiotic effect in Pseudomonas aeruginosa following single and multiple aminoglycoside exposures in vitro. J Antimicrob Chemother. 1994;33(5):937–47.CrossRefGoogle Scholar
  42. 42.
    Xiong YQ, Caillon J, Kergueris MF, Drugeon H, Baron D, Potel G, et al. Adaptive resistance of Pseudomonas aeruginosa induced by aminoglycosides and killing kinetics in a rabbit endocarditis model. Antimicrob Agents Chemother. 1997;41(4):823–6.PubMedPubMedCentralGoogle Scholar
  43. 43.
    Allou N, Charifou Y, Augustin P, Galas T, Valance D, Corradi L, et al. A study to evaluate the first dose of gentamicin needed to achieve a peak plasma concentration of 30 mg/l in patients hospitalized for severe sepsis. Eur J Clin Microbiol Infect Dis. 2016;35(7):1187–93.CrossRefGoogle Scholar
  44. 44.
    Marik PE. Aminoglycoside volume of distribution and illness severity in critically ill septic patients. Anaesth Intensive Care. 1993;21(2):172–3.PubMedGoogle Scholar
  45. 45.
    Triginer C, Izquierdo I, Fernandez R, Rello J, Torrent J, Benito S, et al. Gentamicin volume of distribution in critically ill septic patients. Intensive Care Med. 1990;16(5):303–6.CrossRefGoogle Scholar
  46. 46.
    Taccone FS, Laterre PF, Spapen H, Dugernier T, Delattre I, Layeux B, et al. Revisiting the loading dose of amikacin for patients with severe sepsis and septic shock. Crit Care. 2010;14(2):R53.CrossRefGoogle Scholar
  47. 47.
    Forrest A, Nix DE, Ballow CH, Goss TF, Birmingham MC, Schentag JJ. Pharmacodynamics of intravenous ciprofloxacin in seriously ill patients. Antimicrob Agents Chemother. 1993;37(5):1073–81.CrossRefGoogle Scholar
  48. 48.
    Zelenitsky SA, Ariano RE. Support for higher ciprofloxacin AUC 24/MIC targets in treating Enterobacteriaceae bloodstream infection. J Antimicrob Chemother. 2010;65(8):1725–32.CrossRefGoogle Scholar
  49. 49.
    Roberts JA, Cotta MO, Cojutti P, Lugano M, Della Rocca G, Pea F. Does critical illness change levofloxacin pharmacokinetics? Antimicrob Agents Chemother. 2015;60(3):1459–63.CrossRefGoogle Scholar
  50. 50.
    Delattre IK, Taccone FS, Jacobs F, Hites M, Dugernier T, Spapen H, et al. Optimizing beta-lactams treatment in critically-ill patients using pharmacokinetics/pharmacodynamics targets: are first conventional doses effective? Expert Rev Anti Infect Ther. 2017;15(7):677–88.CrossRefGoogle Scholar
  51. 51.
    Roberts JA, Paul SK, Akova M, Bassetti M, De Waele JJ, Dimopoulos G, et al. DALI: defining antibiotic levels in intensive care unit patients: are current beta-lactam antibiotic doses sufficient for critically ill patients? Clin Infect Dis. 2014;58(8):1072–83.CrossRefGoogle Scholar
  52. 52.
    Dulhunty JM, Roberts JA, Davis JS, Webb SA, Bellomo R, Gomersall C, et al. Continuous infusion of beta-lactam antibiotics in severe sepsis: a multicenter double-blind, randomized controlled trial. Clin Infect Dis. 2013;56(2):236–44.CrossRefGoogle Scholar
  53. 53.
    Dulhunty JM, Roberts JA, Davis JS, Webb SA, Bellomo R, Gomersall C, et al. A multicenter randomized trial of continuous versus intermittent beta-lactam infusion in severe sepsis. Am J Respir Crit Care Med. 2015;192(11):1298–305.CrossRefGoogle Scholar
  54. 54.
    Abdul-Aziz MH, Sulaiman H, Mat-Nor MB, Rai V, Wong KK, Hasan MS, et al. Beta-Lactam Infusion in Severe Sepsis (BLISS): a prospective, two-centre, open-labelled randomised controlled trial of continuous versus intermittent beta-lactam infusion in critically ill patients with severe sepsis. Intensive Care Med. 2016;42(10):1535–45.CrossRefGoogle Scholar
  55. 55.
    Roberts JA, Abdul-Aziz MH, Davis JS, Dulhunty JM, Cotta MO, Myburgh J, et al. Continuous versus intermittent beta-lactam infusion in severe sepsis. A meta-analysis of individual patient data from randomized trials. Am J Respir Crit Care Med. 2016;194(6):681–91.CrossRefGoogle Scholar
  56. 56.
    Falagas ME, Tansarli GS, Ikawa K, Vardakas KZ. Clinical outcomes with extended or continuous versus short-term intravenous infusion of carbapenems and piperacillin/tazobactam: a systematic review and meta-analysis. Clin Infect Dis. 2013;56(2):272–82.CrossRefGoogle Scholar
  57. 57.
    Roberts JA, Webb S, Paterson D, Ho KM, Lipman J. A systematic review on clinical benefits of continuous administration of beta-lactam antibiotics. Crit Care Med. 2009;37(6):2071–8.CrossRefGoogle Scholar
  58. 58.
    Shiu J, Wang E, Tejani AM, Wasdell M. Continuous versus intermittent infusions of antibiotics for the treatment of severe acute infections. Cochrane Database Syst Rev. 2013;3:CD008481.Google Scholar
  59. 59.
    Rybak MJ. The pharmacokinetic and pharmacodynamic properties of vancomycin. Clin Infect Dis. 2006;42(Suppl 1):S35–9.CrossRefGoogle Scholar
  60. 60.
    Wysocki M, Delatour F, Faurisson F, Rauss A, Pean Y, Misset B, et al. Continuous versus intermittent infusion of vancomycin in severe Staphylococcal infections: prospective multicenter randomized study. Antimicrob Agents Chemother. 2001;45(9):2460–7.CrossRefGoogle Scholar
  61. 61.
    Roberts JA, Taccone FS, Udy AA, Vincent JL, Jacobs F, Lipman J. Vancomycin dosing in critically ill patients: robust methods for improved continuous-infusion regimens. Antimicrob Agents Chemother. 2011;55(6):2704–9.CrossRefGoogle Scholar
  62. 62.
    Liu P, Muller M, Derendorf H. Rational dosing of antibiotics: the use of plasma concentrations versus tissue concentrations. Int J Antimicrob Agents. 2002;19(4):285–90.CrossRefGoogle Scholar
  63. 63.
    Robatel C, Decosterd LA, Biollaz J, Eckert P, Schaller MD, Buclin T. Pharmacokinetics and dosage adaptation of meropenem during continuous venovenous hemodiafiltration in critically ill patients. J Clin Pharmacol. 2003;43(12):1329–40.CrossRefGoogle Scholar
  64. 64.
    Jenkins A, Thomson AH, Brown NM, Semple Y, Sluman C, MacGowan A, et al. Amikacin use and therapeutic drug monitoring in adults: do dose regimens and drug exposures affect either outcome or adverse events? A systematic review. J Antimicrob Chemother. 2016;71(10):2754–9.CrossRefGoogle Scholar
  65. 65.
    Ong LZ, Tambyah PA, Lum LH, Low ZJ, Cheng I, Murali TM, et al. Aminoglycoside-associated acute kidney injury in elderly patients with and without shock. J Antimicrob Chemother. 2016;71(11):3250–7.CrossRefGoogle Scholar
  66. 66.
    Blondeau JM, Hansen G, Metzler K, Hedlin P. The role of PK/PD parameters to avoid selection and increase of resistance: mutant prevention concentration. J Chemother. 2004;16(Suppl 3):1–19.CrossRefGoogle Scholar
  67. 67.
    Zhao X, Drlica K. Restricting the selection of antibiotic-resistant mutant bacteria: measurement and potential use of the mutant selection window. J Infect Dis. 2002;185(4):561–5.CrossRefGoogle Scholar
  68. 68.
    Etienne M, Croisier D, Charles PE, Lequeu C, Piroth L, Portier H, et al. Effect of low-level resistance on subsequent enrichment of fluoroquinolone-resistant Streptococcus pneumoniae in rabbits. J Infect Dis. 2004;190(8):1472–5.CrossRefGoogle Scholar
  69. 69.
    Drlica K, Zhao X. Mutant selection window hypothesis updated. Clin Infect Dis. 2007;44(5):681–8.CrossRefGoogle Scholar
  70. 70.
    Kumar A, Safdar N, Kethireddy S, Chateau D. A survival benefit of combination antibiotic therapy for serious infections associated with sepsis and septic shock is contingent only on the risk of death: a meta-analytic/meta-regression study. Crit Care Med. 2010;38(8):1651–64.CrossRefGoogle Scholar
  71. 71.
    Paul M, Lador A, Grozinsky-Glasberg S, Leibovici L. Beta lactam antibiotic monotherapy versus beta lactam-aminoglycoside antibiotic combination therapy for sepsis. Cochrane Database Syst Rev. 2014;1:CD003344.Google Scholar
  72. 72.
    Pena C, Suarez C, Ocampo-Sosa A, Murillas J, Almirante B, Pomar V, et al. Effect of adequate single-drug vs combination antimicrobial therapy on mortality in Pseudomonas aeruginosa bloodstream infections: a post Hoc analysis of a prospective cohort. Clin Infect Dis. 2013;57(2):208–16.CrossRefGoogle Scholar
  73. 73.
    Vardakas KZ, Tansarli GS, Bliziotis IA, Falagas ME. beta-Lactam plus aminoglycoside or fluoroquinolone combination versus beta-lactam monotherapy for Pseudomonas aeruginosa infections: a meta-analysis. Int J Antimicrob Agents. 2013;41(4):301–10.CrossRefGoogle Scholar
  74. 74.
    Heyland DK, Dodek P, Muscedere J, Day A, Cook D, Canadian Critical Care Trials G. Randomized trial of combination versus monotherapy for the empiric treatment of suspected ventilator-associated pneumonia. Crit Care Med. 2008;36(3):737–44.CrossRefGoogle Scholar
  75. 75.
    Brunkhorst FM, Oppert M, Marx G, Bloos F, Ludewig K, Putensen C, et al. Effect of empirical treatment with moxifloxacin and meropenem vs meropenem on sepsis-related organ dysfunction in patients with severe sepsis: a randomized trial. JAMA. 2012;307(22):2390–9.CrossRefGoogle Scholar
  76. 76.
    Silva BN, Andriolo RB, Atallah AN, Salomao R. De-escalation of antimicrobial treatment for adults with sepsis, severe sepsis or septic shock. Cochrane Database Syst Rev. 2013;3:CD007934.Google Scholar
  77. 77.
    Garnacho-Montero J, Gutierrez-Pizarraya A, Escoresca-Ortega A, Corcia-Palomo Y, Fernandez-Delgado E, Herrera-Melero I, et al. De-escalation of empirical therapy is associated with lower mortality in patients with severe sepsis and septic shock. Intensive Care Med. 2014;40(1):32–40.CrossRefGoogle Scholar
  78. 78.
    Leone M, Bechis C, Baumstarck K, Lefrant JY, Albanese J, Jaber S, et al. De-escalation versus continuation of empirical antimicrobial treatment in severe sepsis: a multicenter non-blinded randomized noninferiority trial. Intensive Care Med. 2014;40(10):1399–408.CrossRefGoogle Scholar
  79. 79.
    Timsit JF, Harbarth S, Carlet J. De-escalation as a potential way of reducing antibiotic use and antimicrobial resistance in ICU. Intensive Care Med. 2014;40(10):1580–2.CrossRefGoogle Scholar
  80. 80.
    Tabah A, Cotta MO, Garnacho-Montero J, Schouten J, Roberts JA, Lipman J, et al. A systematic review of the definitions, determinants, and clinical outcomes of antimicrobial de-escalation in the intensive care unit. Clin Infect Dis. 2016;62(8):1009–17.CrossRefGoogle Scholar
  81. 81.
    Paul M, Dickstein Y, Raz-Pasteur A. Antibiotic de-escalation for bloodstream infections and pneumonia: systematic review and meta-analysis. Clin Microbiol Infect. 2016;22(12):960–7.CrossRefGoogle Scholar

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© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Infectious Diseases Service, Department of MedicineUniversity Hospital and University of LausanneLausanneSwitzerland

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