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Rationalizing antimicrobial therapy in the ICU: a narrative review

Jean-François Timsit| Matteo Bassetti| Olaf Cremer| George Daikos| Jan de Waele| Andre Kallil| Eric Kipnis| Marin Kollef| Kevin Laupland| Jose-Artur Paiva| Jesús Rodríguez-Baño| Étienne Ruppé| Jorge Salluh| Fabio Silvio Taccone| Emmanuel Weiss| François Barbier
Volume 45, Issue 2 / February , 2019

Pages 172 - 189


The massive consumption of antibiotics in the ICU is responsible for substantial ecological side effects that promote the dissemination of multidrug-resistant bacteria (MDRB) in this environment. Strikingly, up to half of ICU patients receiving empirical antibiotic therapy have no definitively confirmed infection, while de-escalation and shortened treatment duration are insufficiently considered in those with documented sepsis, highlighting the potential benefit of implementing antibiotic stewardship programs (ASP) and other quality improvement initiatives. The objective of this narrative review is to summarize the available evidence, emerging options, and unsolved controversies for the optimization of antibiotic therapy in the ICU. Published data notably support the need for better identification of patients at risk of MDRB infection, more accurate diagnostic tools enabling a rule-in/rule-out approach for bacterial sepsis, an individualized reasoning for the selection of single-drug or combination empirical regimen, the use of adequate dosing and administration schemes to ensure the attainment of pharmacokinetics/pharmacodynamics targets, concomitant source control when appropriate, and a systematic reappraisal of initial therapy in an attempt to minimize collateral damage on commensal ecosystems through de-escalation and treatment-shortening whenever conceivable. This narrative review also aims at compiling arguments for the elaboration of actionable ASP in the ICU, including improved patient outcomes and a reduction in antibiotic-related selection pressure that may help to control the dissemination of MDRB in this healthcare setting.



  1. Versporten A, Zarb P, Caniaux I, Gros MF, Drapier N, Miller M et al (2018) Antimicrobial consumption and resistance in adult hospital inpatients in 53 countries: results of an internet-based global point prevalence survey. Lancet Glob Health 6(6):e619–e629
  2. Detsis M, Karanika S, Mylonakis E (2017) ICU acquisition rate, risk factors, and clinical significance of digestive tract colonization with extended-spectrum beta-lactamase-producing Enterobacteriaceae: a systematic review and meta-analysis. Crit Care Med 45(4):705–714
  3. Kollef MH, Chastre J, Fagon JY, Francois B, Niederman MS, Rello J et al (2014) Global prospective epidemiologic and surveillance study of ventilator-associated pneumonia due to Pseudomonas aeruginosa. Crit Care Med 42(10):2178–2187
  4. Bulens SN, Yi SH, Walters MS, Jacob JT, Bower C, Reno J et al (2018) Carbapenem-nonsusceptible Acinetobacter baumannii, 8 US metropolitan areas, 2012-2015. Emerg Infect Dis 24(4):727–734
  5. Hsu LY, Apisarnthanarak A, Khan E, Suwantarat N, Ghafur A, Tambyah PA (2017) Carbapenem-resistant Acinetobacter baumannii and Enterobacteriaceae in South and Southeast Asia. Clin Microbiol Rev 30(1):1–22
  6. Rodriguez CH, Balderrama Yarhui N, Nastro M, Nunez Quezada T, Castro Canarte G, Magne Ventura R et al (2016) Molecular epidemiology of carbapenem-resistant Acinetobacter baumannii in South America. J Med Microbiol 65(10):1088–1091
  7. Nowak J, Zander E, Stefanik D, Higgins PG, Roca I, Vila J et al (2017) High incidence of pandrug-resistant Acinetobacter baumannii isolates collected from patients with ventilator-associated pneumonia in Greece, Italy and Spain as part of the MagicBullet clinical trial. J Antimicrob Chemother 72(12):3277–3282
  8. Lob SH, Biedenbach DJ, Badal RE, Kazmierczak KM, Sahm DF (2015) Antimicrobial resistance and resistance mechanisms of Enterobacteriaceae in ICU and non-ICU wards in Europe and North America: SMART 2011-2013. J Glob Antimicrob Resist 3(3):190–197
  9. Bonomo RA, Burd EM, Conly J, Limbago BM, Poirel L, Segre JA et al (2018) Carbapenemase-producing organisms: a global scourge. Clini Infect Dis 66(8):1290–1297
  10. Rosenthal VD, Al-Abdely HM, El-Kholy AA, AlKhawaja SAA, Leblebicioglu H, Mehta Y et al (2016) International nosocomial infection control consortium report, data summary of 50 countries for 2010–2015: device-associated module. Am J Infect Control 44(12):1495–1504
  11. Weiner LM, Webb AK, Limbago B, Dudeck MA, Patel J, Kallen AJ et al (2016) 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(11):1288–1301
  12. Gao L, Lyu Y, Li Y (2017) Trends in drug resistance of Acinetobacter baumannii over a 10-year period: nationwide data from the China surveillance of antimicrobial resistance program. Chin Med J (Engl) 130(6):659–664
  13. Bonell A, Azarrafiy R, Huong VTL, Viet TL, Phu VD, Dat VQ et al (2018) A systematic review and meta-analysis of ventilator associated pneumonia in adults in Asia; an analysis of national income level on incidence and etiology. Clin Infect Dis. https://doi.org/10.1093/cid/ciy543
  14. Hu FP, Guo Y, Zhu DM, Wang F, Jiang XF, Xu YC et al (2016) Resistance trends among clinical isolates in China reported from CHINET surveillance of bacterial resistance, 2005-2014. Clin Microbiol Infect 22(Suppl 1):S9–S14
  15. Bitterman R, Hussein K, Leibovici L, Carmeli Y, Paul M (2016) Systematic review of antibiotic consumption in acute care hospitals. Clin Microbiol Infect 22(6):561
  16. Holmes AH, Moore LS, Sundsfjord A, Steinbakk M, Regmi S, Karkey A et al (2016) Understanding the mechanisms and drivers of antimicrobial resistance. Lancet 387(10014):176–187
  17. Barbier F, Luyt CE (2016) Understanding resistance. Intensive Care Med 42(12):2080–2083
  18. Ruppé E, Woerther PL, Barbier F (2015) Mechanisms of antimicrobial resistance in Gram-negative bacilli. Ann Intensive Care 5:21
  19. Abdallah M, Badawi M, Amirah MF, Rasheed A, Mady AF, Alodat M et al (2017) Impact of carbapenem restriction on the antimicrobial susceptibility pattern of Pseudomonas aeruginosa isolates in the ICU. J Antimicrob Chemother 72(11):3187–3190
  20. Zagorianou A, Sianou E, Iosifidis E, Dimou V, Protonotariou E, Miyakis S et al (2012) Microbiological and molecular characteristics of carbapenemase-producing Klebsiella pneumoniae endemic in a tertiary Greek hospital during 2004–2010. Euro Surveill 17(7):20088
  21. Meyer E, Schwab F, Schroeren-Boersch B, Gastmeier P (2010) Dramatic increase of third-generation cephalosporin-resistant E. coli in German intensive care units: secular trends in antibiotic drug use and bacterial resistance, 2001–2008. Crit Care 14(3):R113
  22. Bassetti M, Cruciani M, Righi E, Rebesco B, Fasce R, Costa A et al (2006) Antimicrobial use and resistance among Gram-negative bacilli in an Italian intensive care unit. J Chemother 18(3):261–267
  23. Samonis G, Korbila IP, Maraki S, Michailidou I, Vardakas KZ, Kofteridis D et al (2014) Trends in isolation of intrinsically resistant to colistin Enterobacteriaceae and association with colistin use un a tertiary hospital. Eur J Clin Microbiol Infect Dis 33(9):1505–1510
  24. Jacoby TS, Kuchenbecker RS, Dos Santos RP, Magedanz L, Guzatto P, Moreira LB (2010) Impact of hospital-wide infection rate, invasive procedures use and antimicrobial consumption on bacterial resistance inside an intensive care unit. J Hosp Infect 75(1):23–27
  25. Fihman V, Messika J, Hajage D, Tournier V, Gaudry S, Magdoud F et al (2015) Five-year trends for ventilator-associated pneumonia: correlation between microbiological findings and antimicrobial drug consumption. Int J Antimicrob Agents 46(5):518–525
  26. Kaki R, Elligsen M, Walker S, Simor A, Palmay L, Daneman N (2011) Impact of antimicrobial stewardship in critical care: a systematic review. J Antimicrob Chemother 66(6):1223–1230
  27. Bell BG, Schellevis F, Stobberingh E, Goossens H, Pringle M (2014) A systematic review and meta-analysis of the effects of antibiotic consumption on antibiotic resistance. BMC Infect Dis 14:13
  28. Nijssen S, Fluit AC, van de Vijver D, Top J, Willems R, Bonten MJM (2010) Effects of reducing beta-lactam antibiotic pressure on intestinal colonization of antibiotic-resistant Gram-negative bacteria. Intensive Care Med 36(3):512–519
  29. Ruppe E, Burdet C, Grall N, de Lastours V, Lescure FX, Andremont A et al (2018) Impact of antibiotics on the intestinal microbiota needs to be re-defined to optimize antibiotic usage. Clin Microbiol Infect 24(1):3–5
  30. Pamer EG (2016) Resurrecting the intestinal microbiota to combat antibiotic-resistant pathogens. Science 352(6285):535–538
  31. Razazi K, Derde LP, Verachten M, Legrand P, Lesprit P, Brun-Buisson C (2012) Clinical impact and risk factors for colonization with extended-spectrum beta-lactamase-producing bacteria in the intensive care unit. Intensive Care Med 38(11):1769–1778
  32. Poignant S, Guinard J, Guiguon A, Bret L, Poisson D-M, Boulain T et al (2015) Risk factors and outcomes of intestinal carriage of AmpC-hyperproducing Enterobacteriaceae in ICU patients. Antimicrob Agents Chemother 60(3):1883–1887
  33. Hilliquin D, Le Guern R, Thepot Seegers V, Neulier C, Lomont A, Marie V et al (2018) Risk factors for acquisition of OXA-48-producing Klebsiella pneumoniae among contact patients: a multicentre study. J Hosp Infect 98(3):253–259
  34. Papadimitriou-Olivgeris M, Marangos M, Fligou F, Christofidou M, Bartzavali C, Anastassiou ED et al (2012) Risk factors for KPC-producing Klebsiella pneumoniae enteric colonization upon ICU admission. J Antimicrob Chemother 67(12):2976–2981
  35. Tan BK, Vivier E, Ait Bouziad K, Zahar JR, Pommier C, Parmeland L et al (2018) A hospital-wide intervention replacing ceftriaxone with cefotaxime to reduce rate of healthcare-associated infections caused by extended-spectrum beta-lactamase-producing Enterobacteriaceae in the intensive care unit. Intensive Care Med 44(5):672–673
  36. Grohs P, Kerneis S, Sabatier B, Lavollay M, Carbonnelle E, Rostane H et al (2014) Fighting the spread of AmpC-hyperproducing Enterobacteriaceae: beneficial effect of replacing ceftriaxone with cefotaxime. J Antimicrob Chemother 69(3):786–789
  37. Woerther PL, Lepeule R, Burdet C, Decousser JW, Ruppe E, Barbier F (2018) Carbapenems and alternative beta-lactams for the treatment of infections due to ESBL-producing Enterobacteriaceae: what impact on intestinal colonization resistance? Int J Antimicrob Agents 52:762–770
  38. Kao KC, Chen CB, Hu HC, Chang HC, Huang CC, Huang YC (2015) Risk factors of methicillin-resistant Staphylococcus aureus infection and correlation with nasal colonization based on molecular genotyping in medical intensive care units: a prospective observational study. Medicine (Baltimore) 94(28):e1100
  39. Ziakas PD, Anagnostou T, Mylonakis E (2014) The prevalence and significance of methicillin-resistant Staphylococcus aureus colonization at admission in the general ICU setting: a meta-analysis of published studies. Crit Care Med 42(2):433–444
  40. Raman G, Avendano EE, Chan J, Merchant S, Puzniak L (2018) Risk factors for hospitalized patients with resistant or multidrug-resistant Pseudomonas aeruginosa infections: a systematic review and meta-analysis. Antimicrob Resist Infect Control 7:79
  41. Zahar JR, Blot S, Nordmann P, Martischang R, Timsit JF, Harbarth S et al (2018) Screening for intestinal carriage of ESBL-producing Enterobacteriaceae in critically ill patients: expected benefits and evidence-based controversies. Clin Infect Dis. https://doi.org/10.1093/cid/ciy864
  42. Mazzeffi M, Gammie J, Taylor B, Cardillo S, Haldane-Lutterodt N, Amoroso A et al (2017) Healthcare-associated infections in cardiac surgery patients with prolonged intensive care unit stay. Ann Thorac Surg 103(4):1165–1170
  43. van Vught LA, Klein Klouwenberg PM, Spitoni C, Scicluna BP, Wiewel MA, Horn J et al (2016) Incidence, risk factors, and attributable mortality of secondary infections in the intensive care unit after admission for sepsis. JAMA 315(14):1469–1479
  44. Tabah A, Koulenti D, Laupland K, Misset B, Valles J, de Bruzzi Carvalho F et al (2012) Characteristics and determinants of outcome of hospital-acquired bloodstream infections in intensive care units: the EUROBACT International Cohort Study. Intensive Care Med 38(12):1930–1945
  45. Sterling SA, Puskarich MA, Glass AF, Guirgis F, Jones AE (2017) The impact of the Sepsis-3 septic shock definition on previously defined septic shock patients. Crit Care Med 45(9):1436–1442
  46. Ferrer R, Martinez ML, Goma G, Suarez D, Alvarez-Rocha L, de la Torre MV et al (2018) Improved empirical antibiotic treatment of sepsis after an educational intervention: the ABISS-Edusepsis study. Crit Care 22(1):167
  47. Liu VX, Fielding-Singh V, Greene JD, Baker JM, Iwashyna TJ, Bhattacharya J et al (2017) The timing of early antibiotics and hospital mortality in sepsis. Am J Respir Crit Care Med 196(7):856–863
  48. Seymour CW, Gesten F, Prescott HC, Friedrich ME, Iwashyna TJ, Phillips GS et al (2017) Time to treatment and mortality during mandated emergency care for sepsis. N Engl J Med 376(23):2235–2244
  49. Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R et al (2017) Surviving Sepsis Campaign: international guidelines for management of sepsis and septic shock: 2016. Intensive Care Med 43(3):304–377
  50. Laupland KB, Zahar JR, Adrie C, Schwebel C, Goldgran-Toledano D, Azoulay E et al (2012) Determinants of temperature abnormalities and influence on outcome of critical illness. Crit Care Med 40(1):145–151
  51. Lam SW, Bauer SR, Fowler R, Duggal A (2018) Systematic review and meta-analysis of procalcitonin-guidance versus usual care for antimicrobial management in critically ill patients: focus on subgroups based on antibiotic initiation, cessation, or mixed strategies. Crit Care Med 46(5):684–690
  52. Schuetz P, Wirz Y, Sager R, Christ-Crain M, Stolz D, Tamm M et al (2018) Effect of procalcitonin-guided antibiotic treatment on mortality in acute respiratory infections: a patient level meta-analysis. Lancet Infect Dis 18(1):95–107
  53. van Someren Greve F, Juffermans NP, Bos LDJ, Binnekade JM, Braber A, Cremer OL et al (2018) Respiratory viruses in invasively ventilated critically ill patients—a prospective multicenter observational study. Crit Care Med 46(1):29–36
  54. Loubet P, Voiriot G, Houhou-Fidouh N, Neuville M, Bouadma L, Lescure FX et al (2017) Impact of respiratory viruses in hospital-acquired pneumonia in the intensive care unit: a single-center retrospective study. J Clin Virol 91:52–57
  55. Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M et al (2016) The third international consensus definitions for sepsis and septic shock (Sepsis-3). JAMA 315(8):801–810
  56. Fernando SM, Tran A, Taljaard M, Cheng W, Rochwerg B, Seely AJE et al (2018) Prognostic accuracy of the quick sequential organ failure assessment for mortality in patients with suspected infection: a systematic review and meta-analysis. Ann Intern Med 168(4):266–275
  57. Williams JM, Greenslade JH, McKenzie JV, Chu K, Brown AFT, Lipman J (2017) Systemic inflammatory response syndrome, quick sequential organ function assessment, and organ dysfunction: insights from a prospective database of ED patients with infection. Chest 151(3):586–596
  58. Klein Klouwenberg PM, Cremer OL, van Vught LA, Ong DS, Frencken JF, Schultz MJ et al (2015) Likelihood of infection in patients with presumed sepsis at the time of intensive care unit admission: a cohort study. Crit Care 19:319
  59. Hranjec T, Rosenberger LH, Swenson B, Metzger R, Flohr TR, Politano AD et al (2012) Aggressive versus conservative initiation of antimicrobial treatment in critically ill surgical patients with suspected intensive-care-unit-acquired infection: a quasi-experimental, before and after observational cohort study. Lancet Infect Dis 12(10):774–780
  60. Parlato M, Cavaillon JM (2015) Host response biomarkers in the diagnosis of sepsis: a general overview. Methods Mol Biol 1237:149–211
  61. Parlato M, Philippart F, Rouquette A, Moucadel V, Puchois V, Blein S et al (2018) Circulating biomarkers may be unable to detect infection at the early phase of sepsis in ICU patients: the CAPTAIN prospective multicenter cohort study. Intensive Care Med 44(7):1061–1070
  62. Layios N, Lambermont B, Canivet JL, Morimont P, Preiser JC, Garweg C et al (2012) Procalcitonin usefulness for the initiation of antibiotic treatment in intensive care unit patients. Crit Care Med 40(8):2304–2309
  63. Mearelli F, Fiotti N, Giansante C, Casarsa C, Orso D, De Helmersen M et al (2018) Derivation and validation of a biomarker-based clinical algorithm to rule out sepsis from noninfectious systemic inflammatory response syndrome at emergency department admission: a multicenter prospective study. Crit Care Med 46(9):1421–1429
  64. Kalil AC, Syed A, Rupp ME, Chambers H, Vargas L, Maskin A et al (2015) Is bacteremic sepsis associated with higher mortality in transplant recipients than in nontransplant patients? A matched case-control propensity-adjusted study. Clin Infect Dis 60(2):216–222
  65. Kalil AC, Sandkovsky U, Florescu DF (2018) Severe infections in critically ill solid organ transplant recipients. Clin Microbiol Infect 24:1257–1263
  66. NCCN (2018) Clinical practice guidelines in oncology. prevention and treatment of cancer-related infections. version 1.2018. https://www.nccn.org/store/login/login.aspx?ReturnURL=https://www.nccn.org/professionals/physician_gls/pdf/infections.pdf. Accessed 1 Sept 2018
  67. Schnell D, Azoulay E, Benoit D, Clouzeau B, Demaret P, Ducassou S et al (2016) Management of neutropenic patients in the intensive care unit (NEWBORNS EXCLUDED) recommendations from an expert panel from the French Intensive Care Society (SRLF) with the French Group for Pediatric Intensive Care Emergencies (GFRUP), the French Society of Anesthesia and Intensive Care (SFAR), the French Society of Hematology (SFH), the French Society for Hospital Hygiene (SF2H), and the French Infectious Diseases Society (SPILF). Ann Intensive Care 6(1):90
  68. European AIDS Clinical Society guidelines. Updated yearly. http://www.eacsociety.org/Guidelines.aspx. Accessed 1 Sept 2018
  69. Singh JA, Cameron C, Noorbaloochi S, Cullis T, Tucker M, Christensen R et al (2015) Risk of serious infection in biological treatment of patients with rheumatoid arthritis: a systematic review and meta-analysis. Lancet 386(9990):258–265
  70. Venet F, Monneret G (2018) Advances in the understanding and treatment of sepsis-induced immunosuppression. Nat Rev Nephrol 14(2):121–137
  71. Martin S, Perez A, Aldecoa C (2017) Sepsis and immunosenescence in the elderly patient: a review. Front Med 4:20
  72. Ramanan P, Bryson AL, Binnicker MJ, Pritt BS, Patel R (2018) Syndromic panel-based testing in clinical microbiology. Clin Microbiol Rev 31(1):e00024-17
  73. van de Groep K, Bos MP, Savelkoul PHM, Rubenjan A, Gazenbeek C, Melchers WJG et al (2018) Development and first evaluation of a novel multiplex real-time PCR on whole blood samples for rapid pathogen identification in critically ill patients with sepsis. Eur J Clin Microbiol Infect Dis 37(7):1333–1344
  74. Ruppe E, Baud D, Schicklin S, Guigon G, Schrenzel J (2016) Clinical metagenomics for the management of hospital- and healthcare-acquired pneumonia. Future Microbiol 11(3):427–439
  75. Charalampous T, Richardson H, Kay GL, Baldan R, Jeanes C, Rae D et al (2018) Rapid diagnosis of lower respiratory infection using nanopore-based clinical metagenomics. BioRXIV. https://doi.org/10.1101/387548
  76. Pendleton KM, Erb-Downward JR, Bao Y, Branton WR, Falkowski NR, Newton DW et al (2017) Rapid pathogen identification in bacterial pneumonia using real-time metagenomics. Am J Respir Crit Care Med 196(12):1610–1612
  77. Langelier C, Zinter MS, Kalantar K, Yanik GA, Christenson S, O’Donovan B et al (2018) Metagenomic sequencing detects respiratory pathogens in hematopoietic cellular transplant patients. Am J Respir Crit Care Med 197(4):524–528
  78. Le Dorze M, Gault N, Foucrier A, Ruppe E, Mourvillier B, Woerther PL et al (2015) Performance and impact of a rapid method combining mass spectrometry and direct antimicrobial susceptibility testing on treatment adequacy of patients with ventilator-associated pneumonia. Clin Microbiol Infect 21(5):468
  79. Lutgring JD, Bittencourt C, McElvania TeKippe E, Cavuoti D, Hollaway R, Burd EM (2018) Evaluation of the accelerate pheno system: results from two academic medical centers. J Clin Microbiol 56(4):e01672-17
  80. Timbrook TT, Morton JB, McConeghy KW, Caffrey AR, Mylonakis E, LaPlante KL (2017) The effect of molecular rapid diagnostic testing on clinical outcomes in bloodstream infections: a systematic review and meta-analysis. Clin Infect Dis 64(1):15–23
  81. Roberts JA, Paul SK, Akova M, Bassetti M, De Waele JJ, Dimopoulos G et al (2014) DALI: defining antibiotic levels in intensive care unit patients: are current beta-lactam antibiotic doses sufficient for critically ill patients? Clin Infect Dis 58(8):1072–1083
  82. Roberts JA, Taccone FS, Lipman J (2016) Understanding PK/PD. Intensive Care Med 42(11):1797–1800
  83. De Waele JJ, Lipman J, Carlier M, Roberts JA (2015) Subtleties in practical application of prolonged infusion of beta-lactam antibiotics. Int J Antimicrob Agents 45(5):461–463
  84. Bergen PJ, Bulitta JB, Kirkpatrick CM, Rogers KE, McGregor MJ, Wallis SC et al (2017) Substantial impact of altered pharmacokinetics in critically ill patients on the antibacterial effects of meropenem evaluated via the dynamic hollow-fiber infection model. Antimicrob Agents Chemother 61(5):e02642-16
  85. Tangden T, Ramos Martin V, Felton TW, Nielsen EI, Marchand S, Bruggemann RJ et al (2017) The role of infection models and PK/PD modelling for optimising care of critically ill patients with severe infections. Intensive Care Med 43(7):1021–1032
  86. Huttner A, Harbarth S, Hope WW, Lipman J, Roberts JA (2015) Therapeutic drug monitoring of the beta-lactam antibiotics: what is the evidence and which patients should we be using it for? J Antimicrob Chemother 70(12):3178–3183
  87. Duszynska W, Taccone FS, Hurkacz M, Kowalska-Krochmal B, Wiela-Hojenska A, Kubler A (2013) Therapeutic drug monitoring of amikacin in septic patients. Crit Care 17(4):R165
  88. Brasseur A, Hites M, Roisin S, Cotton F, Vincent JL, De Backer D et al (2016) A high-dose aminoglycoside regimen combined with renal replacement therapy for the treatment of MDR pathogens: a proof-of-concept study. J Antimicrob Chemother 71(5):1386–1394
  89. Pajot O, Burdet C, Couffignal C, Massias L, Armand-Lefevre L, Foucrier A et al (2015) Impact of imipenem and amikacin pharmacokinetic/pharmacodynamic parameters on microbiological outcome of Gram-negative bacilli ventilator-associated pneumonia. J Antimicrob Chemother 70(5):1487–1494
  90. Prybylski JP (2015) Vancomycin trough concentration as a predictor of clinical outcomes in patients with Staphylococcus aureus bacteremia: a meta-analysis of observational studies. Pharmacotherapy 35(10):889–898
  91. Wong G, Brinkman A, Benefield RJ, Carlier M, De Waele JJ, El Helali N et al (2014) An international, multicentre survey of beta-lactam antibiotic therapeutic drug monitoring practice in intensive care units. J Antimicrob Chemother 69(5):1416–1423
  92. Mouton JW, Muller AE, Canton R, Giske CG, Kahlmeter G, Turnidge J (2018) MIC-based dose adjustment: facts and fables. J Antimicrob Chemother 73(3):564–568
  93. Beumier M, Casu GS, Hites M, Wolff F, Cotton F, Vincent JL et al (2015) Elevated beta-lactam concentrations associated with neurological deterioration in ICU septic patients. Minerva Anestesiol 81(5):497–506
  94. Imani S, Buscher H, Marriott D, Gentili S, Sandaradura I (2017) Too much of a good thing: a retrospective study of beta-lactam concentration-toxicity relationships. J Antimicrob Chemother 72(10):2891–2897
  95. Torres A, Zhong N, Pachl J, Timsit JF, Kollef M, Chen Z et al (2018) Ceftazidime-avibactam versus meropenem in nosocomial pneumonia, including ventilator-associated pneumonia (REPROVE): a randomised, double-blind, phase 3 non-inferiority trial. Lancet Infect Dis 18(3):285–295
  96. Harris PNA, Tambyah PA, Lye DC, Mo Y, Lee TH, Yilmaz M et al (2018) Effect of piperacillin-tazobactam vs meropenem on 30-day mortality for patients with E. coli or Klebsiella pneumoniae bloodstream infection and ceftriaxone resistance: a randomized clinical trial. JAMA 320(10):984–994
  97. Bertolini G, Nattino G, Tascini C, Poole D, Viaggi B, Carrara G et al (2018) Mortality attributable to different Klebsiella susceptibility patterns and to the coverage of empirical antibiotic therapy: a cohort study on patients admitted to the ICU with infection. Intensive Care Med 44(10):1709–1719
  98. Murray KP, Zhao JJ, Davis SL, Kullar R, Kaye KS, Lephart P et al (2013) Early use of daptomycin versus vancomycin for methicillin-resistant Staphylococcus aureus bacteremia with vancomycin minimum inhibitory concentration > 1 mg/L: a matched cohort study. Clin Infect Dis 56(11):1562–1569
  99. Wunderink RG, Niederman MS, Kollef MH, Shorr AF, Kunkel MJ, Baruch A et al (2012) Linezolid in methicillin-resistant Staphylococcus aureus nosocomial pneumonia: a randomized, controlled study. Clin Infect Dis 54(5):621–629
  100. Abbas M, Paul M, Huttner A (2017) New and improved? A review of novel antibiotics for Gram-positive bacteria. Clin Microbiol Infect 23(10):697–703
  101. Tamma PD, Cosgrove SE, Maragakis LL (2012) Combination therapy for treatment of infections with gram-negative bacteria. Clin Microbiol Rev 25(3):450–470
  102. Paul M, Lador A, Grozinsky-Glasberg S, Leibovici L (2014) Beta lactam antibiotic monotherapy versus beta lactam-aminoglycoside antibiotic combination therapy for sepsis. Cochrane Database Syst Rev 1:CD003344
  103. Kumar A, Safdar N, Kethireddy S, Chateau D (2010) 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 38(8):1651–1664
  104. Ripa M, Rodriguez-Nunez O, Cardozo C, Naharro-Abellan A, Almela M, Marco F et al (2017) Influence of empirical double-active combination antimicrobial therapy compared with active monotherapy on mortality in patients with septic shock: a propensity score-adjusted and matched analysis. J Antimicrob Chemother 72(12):3443–3452
  105. Daikos GL, Tsaousi S, Tzouvelekis LS, Anyfantis I, Psichogiou M, Argyropoulou A et al (2014) Carbapenemase-producing Klebsiella pneumoniae bloodstream infections: lowering mortality by antibiotic combination schemes and the role of carbapenems. Antimicrob Agents Chemother 58(4):2322–2328
  106. Tumbarello M, Trecarichi EM, De Rosa FG, Giannella M, Giacobbe DR, Bassetti M et al (2015) Infections caused by KPC-producing Klebsiella pneumoniae: differences in therapy and mortality in a multicentre study. J Antimicrob Chemother 70(7):2133–2143
  107. Falcone M, Russo A, Iacovelli A, Restuccia G, Ceccarelli G, Giordano A et al (2016) Predictors of outcome in ICU patients with septic shock caused by Klebsiella pneumoniae carbapenemase-producing K. pneumoniae. Clin Microbiol Infect 22(5):444–450
  108. Gutierrez-Gutierrez B, Salamanca E, de Cueto M, Hsueh PR, Viale P, Pano-Pardo JR et al (2017) Effect of appropriate combination therapy on mortality of patients with bloodstream infections due to carbapenemase-producing Enterobacteriaceae (INCREMENT): a retrospective cohort study. Lancet Infect Dis 17(7):726–734
  109. Tumbarello M, Viale P, Viscoli C, Trecarichi EM, Tumietto F, Marchese A et al (2012) Predictors of mortality in bloodstream infections caused by Klebsiella pneumoniae carbapenemase-producing K. pneumoniae: importance of combination therapy. Clin Infect Dis 55(7):943–950
  110. Aydemir H, Akduman D, Piskin N, Comert F, Horuz E, Terzi A et al (2013) Colistin vs. the combination of colistin and rifampicin for the treatment of carbapenem-resistant Acinetobacter baumannii ventilator-associated pneumonia. Epidemiol Infect 141(6):1214–1222
  111. Durante-Mangoni E, Signoriello G, Andini R, Mattei A, De Cristoforo M, Murino P et al (2013) Colistin and rifampicin compared with colistin alone for the treatment of serious infections due to extensively drug-resistant Acinetobacter baumannii: a multicenter, randomized clinical trial. Clin Infect Dis 57(3):349–358
  112. Sirijatuphat R, Thamlikitkul V (2014) Preliminary study of colistin versus colistin plus fosfomycin for treatment of carbapenem-resistant Acinetobacter baumannii infections. Antimicrob Agents Chemother 58(9):5598–5601
  113. Paul M, Daikos GL, Durante-Mangoni E, Yahav D, Carmeli Y, Benattar YD et al (2018) Colistin alone versus colistin plus meropenem for treatment of severe infections caused by carbapenem-resistant gram-negative bacteria: an open-label, randomised controlled trial. Lancet Infect Dis 18(4):391–400
  114. Zusman O, Altunin S, Koppel F, Dishon Benattar Y, Gedik H, Paul M (2017) Polymyxin monotherapy or in combination against carbapenem-resistant bacteria: systematic review and meta-analysis. J Antimicrob Chemother 72(1):29–39
  115. Makris D, Petinaki E, Tsolaki V, Manoulakas E, Mantzarlis K, Apostolopoulou O et al (2018) Colistin versus colistin combined with ampicillin-sulbactam for multiresistant Acinetobacter baumannii ventilator-associated pneumonia treatment: an open-label prospective study. Indian J Crit Care Med 22(2):67–77
  116. Vardakas KZ, Mavroudis AD, Georgiou M, Falagas ME (2018) Intravenous colistin combination antimicrobial treatment vs. monotherapy: a systematic review and meta-analysis. Int J Antimicrob Agents 51(4):535–547
  117. Sime FB, Roberts MS, Roberts JA (2015) Optimization of dosing regimens and dosing in special populations. Clin Microbiol Infect 21(10):886–893
  118. Vardakas KZ, Voulgaris GL, Maliaros A, Samonis G, Falagas ME (2018) Prolonged versus short-term intravenous infusion of antipseudomonal beta-lactams for patients with sepsis: a systematic review and meta-analysis of randomised trials. Lancet Infect Dis 18(1):108–120
  119. Hao JJ, Chen H, Zhou JX (2016) Continuous versus intermittent infusion of vancomycin in adult patients: a systematic review and meta-analysis. Int J Antimicrob Agents 47(1):28–35
  120. Tabah A, Cotta MO, Garnacho-Montero J, Schouten J, Roberts JA, Lipman J et al (2016) A systematic review of the definitions, determinants, and clinical outcomes of antimicrobial de-escalation in the intensive care unit. Clin Infect Dis 62(8):1009–1017
  121. Weiss E, Zahar JR, Lesprit P, Ruppe E, Leone M, Chastre J et al (2015) Elaboration of a consensual definition of de-escalation allowing a ranking of beta-lactams. Clin Microbiol Infect. 21(7):649
  122. Silva BN, Andriolo RB, Atallah AN, Salomao R (2013) De-escalation of antimicrobial treatment for adults with sepsis, severe sepsis or septic shock. Cochrane Database Syst Rev 3:CD007934
  123. Mokart D, Slehofer G, Lambert J, Sannini A, Chow-Chine L, Brun JP et al (2014) De-escalation of antimicrobial treatment in neutropenic patients with severe sepsis: results from an observational study. Intensive Care Med 40(1):41–49
  124. Paul M, Dickstein Y, Raz-Pasteur A (2016) Antibiotic de-escalation for bloodstream infections and pneumonia: systematic review and meta-analysis. Clin Microbiol Infect 22(12):960–967
  125. Leone M, Bechis C, Baumstarck K, Lefrant JY, Albanese J, Jaber S et al (2014) De-escalation versus continuation of empirical antimicrobial treatment in severe sepsis: a multicenter non-blinded randomized noninferiority trial. Intensive Care Med 40(10):1399–1408
  126. Weiss E, Zahar JR, Garrouste-Orgeas M, Ruckly S, Essaied W, Schwebel C et al (2016) De-escalation of pivotal beta-lactam in ventilator-associated pneumonia does not impact outcome and marginally affects MDR acquisition. Intensive Care Med 42(12):2098–2100
  127. De Bus L, Denys W, Catteeuw J, Gadeyne B, Vermeulen K, Boelens J et al (2016) Impact of de-escalation of beta-lactam antibiotics on the emergence of antibiotic resistance in ICU patients: a retrospective observational study. Intensive Care Med 42(6):1029–1039
  128. Ruppe E, Martin-Loeches I, Rouze A, Levast B, Ferry T, Timsit JF (2018) What’s new in restoring the gut microbiota in ICU patients? Potential role of faecal microbiota transplantation. Clin Microbiol Infect 24(8):803–805
  129. D’Agata EM, Magal P, Olivier D, Ruan S, Webb GF (2007) Modeling antibiotic resistance in hospitals: the impact of minimizing treatment duration. J Theor Biol 249(3):487–499
  130. Chastre J, Wolff M, Fagon JY, Chevret S, Thomas F, Wermert D et al (2003) Comparison of 8 vs 15 days of antibiotic therapy for ventilator-associated pneumonia in adults: a randomized trial. JAMA 290(19):2588–2598
  131. Klompas M, Li L, Menchaca JT, Gruber S (2017) Ultra-short-course antibiotics for patients with suspected ventilator-associated pneumonia but minimal and stable ventilator settings. Clin Infect Dis 64(7):870–876
  132. Sandberg T, Skoog G, Hermansson AB, Kahlmeter G, Kuylenstierna N, Lannergard A et al (2012) Ciprofloxacin for 7 days versus 14 days in women with acute pyelonephritis: a randomised, open-label and double-blind, placebo-controlled, non-inferiority trial. Lancet 380(9840):484–490
  133. Chotiprasitsakul D, Han JH, Cosgrove SE, Harris AD, Lautenbach E, Conley AT et al (2018) Comparing the outcomes of adults with enterobacteriaceae bacteremia receiving short-course versus prolonged-course antibiotic therapy in a multicenter, propensity score-matched cohort. Clin Infect Dis 66(2):172–177
  134. Montravers P, Tubach F, Lescot T, Veber B, Esposito-Farese M, Seguin P et al (2018) Short-course antibiotic therapy for critically ill patients treated for postoperative intra-abdominal infection: the DURAPOP randomised clinical trial. Intensive Care Med 44(3):300–310
  135. Royer S, DeMerle KM, Dickson RP, Prescott HC (2018) Shorter versus longer courses of antibiotics for infection in hospitalized patients: a systematic review and meta-analysis. J Hosp Med 13(5):336–342
  136. Hanretty AM, Gallagher JC (2018) Shortened courses of antibiotics for bacterial infections: a systematic review of randomized controlled trials. Pharmacotherapy. 38(6):674–687
  137. Huang DT, Yealy DM, Filbin MR, Brown AM, Chang CH, Doi Y et al (2018) Procalcitonin-guided use of antibiotics for lower respiratory tract infection. N Engl J Med 379(3):236–249
  138. Mazuski JE, Tessier JM, May AK, Sawyer RG, Nadler EP, Rosengart MR et al (2017) The surgical infection society revised guidelines on the management of intra-abdominal infection. Surg Infect 18(1):1–76
  139. Woodhead M, Blasi F, Ewig S, Garau J, Huchon G, Ieven M et al (2011) Guidelines for the management of adult lower respiratory tract infections—full version. Clin Microbiol Infect 17(Suppl 6):E1–E59
  140. Mandell LA, Wunderink RG, Anzueto A, Bartlett JG, Campbell GD, Dean NC et al (2007) Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis 44(Suppl 2):S27–S72
  141. Gupta K, Hooton TM, Naber KG, Wullt B, Colgan R, Miller LG et al (2011) International clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women: a 2010 update by the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases. Clin Infect Dis 52(5):e103–e120
  142. Torres A, Niederman MS, Chastre J, Ewig S, Fernandez-Vandellos P, Hanberger H et al (2017) International ERS/ESICM/ESCMID/ALAT guidelines for the management of hospital-acquired pneumonia and ventilator-associated pneumonia: Guidelines for the management of hospital-acquired pneumonia (HAP)/ventilator-associated pneumonia (VAP) of the European Respiratory Society (ERS), European Society of Intensive Care Medicine (ESICM), European Society of Clinical Microbiology and Infectious Diseases (ESCMID) and Asociacion Latinoamericana del Torax (ALAT). Eur Respir J 50(3):1700582
  143. Klein EY, Van Boeckel TP, Martinez EM, Pant S, Gandra S, Levin SA et al (2018) Global increase and geographic convergence in antibiotic consumption between 2000 and 2015. Proc Natl Acad Sci USA 115(15):E3463–E3470
  144. ECDC. Summary of the latest data on antibiotic consumption in the European Union ESAC-Net surveillance data November 2017. https://ecdc.europa.eu/sites/portal/files/documents/Final_2017_EAAD_ESAC-Net_Summary-edited%20-%20FINALwith%20erratum.pdf2017. Accessed 13 Oct 2018
  145. Kollef MH, Chastre J, Clavel M, Restrepo MI, Michiels B, Kaniga K et al (2012) A randomized trial of 7-day doripenem versus 10-day imipenem-cilastatin for ventilator-associated pneumonia. Crit Care 16(6):R218
  146. Schein M, Marshall J (2004) Source control for surgical infections. World J Surg 28(7):638–645
  147. Martinez ML, Ferrer R, Torrents E, Guillamat-Prats R, Goma G, Suarez D et al (2017) Impact of source control in patients with severe sepsis and septic shock. Crit Care Med 45(1):11–19
  148. Chao WN, Tsai CF, Chang HR, Chan KS, Su CH, Lee YT et al (2013) Impact of timing of surgery on outcome of Vibrio vulnificus-related necrotizing fasciitis. Am J Surg 206(1):32–39
  149. Karvellas CJ, Abraldes JG, Zepeda-Gomez S, Moffat DC, Mirzanejad Y, Vazquez-Grande G et al (2016) The impact of delayed biliary decompression and anti-microbial therapy in 260 patients with cholangitis-associated septic shock. Aliment Pharmacol Ther 44(7):755–766
  150. Bloos F, Ruddel H, Thomas-Ruddel D, Schwarzkopf D, Pausch C, Harbarth S et al (2017) Effect of a multifaceted educational intervention for anti-infectious measures on sepsis mortality: a cluster randomized trial. Intensive Care Med 43(11):1602–1612
  151. Bloos F, Thomas-Ruddel D, Ruddel H, Engel C, Schwarzkopf D, Marshall JC et al (2014) Impact of compliance with infection management guidelines on outcome in patients with severe sepsis: a prospective observational multi-center study. Crit Care 18(2):R42
  152. Azuhata T, Kinoshita K, Kawano D, Komatsu T, Sakurai A, Chiba Y et al (2014) Time from admission to initiation of surgery for source control is a critical determinant of survival in patients with gastrointestinal perforation with associated septic shock. Crit Care 18(3):R87
  153. Boyer A, Vargas F, Coste F, Saubusse E, Castaing Y, Gbikpi-Benissan G et al (2009) Influence of surgical treatment timing on mortality from necrotizing soft tissue infections requiring intensive care management. Intensive Care Med 35(5):847–853
  154. Karanika S, Paudel S, Grigoras C, Kalbasi A, Mylonakis E (2016) Systematic review and meta-analysis of clinical and economic outcomes from the implementation of hospital-based antimicrobial stewardship programs. Antimicrob Agents Chemother 60(8):4840–4852
  155. Baur D, Gladstone BP, Burkert F, Carrara E, Foschi F, Dobele S et al (2017) Effect of antibiotic stewardship on the incidence of infection and colonisation with antibiotic-resistant bacteria and Clostridium difficile infection: a systematic review and meta-analysis. Lancet Infect Dis 17(9):990–1001
  156. Dyar OJ, Huttner B, Schouten J, Pulcini C (2017) What is antimicrobial stewardship? Clin Microbiol Infect 23(11):793–798
  157. Pulcini C, Binda F, Lamkang AS, Trett A, Charani E, Goff DA et al (2018) Developing core elements and checklist items for global hospital antimicrobial stewardship programmes: a consensus approach. Clin Microbiol Infect 25(1):20–25
  158. Kollef MH, Bassetti M, Francois B, Burnham J, Dimopoulos G, Garnacho-Montero J et al (2017) The intensive care medicine research agenda on multidrug-resistant bacteria, antibiotics, and stewardship. Intensive Care Med 43(9):1187–1197
  159. De Waele JJ, Akova M, Antonelli M, Canton R, Carlet J, De Backer D et al (2018) Antimicrobial resistance and antibiotic stewardship programs in the ICU: insistence and persistence in the fight against resistance. A position statement from ESICM/ESCMID/WAAAR round table on multi-drug resistance. Intensive Care Med 44(2):189–196
  160. Flottorp SA, Oxman AD, Krause J, Musila NR, Wensing M, Godycki-Cwirko M et al (2013) A checklist for identifying determinants of practice: a systematic review and synthesis of frameworks and taxonomies of factors that prevent or enable improvements in healthcare professional practice. Implement Sci IS 8:35
  161. Bailly S, Meyfroidt G, Timsit JF (2018) What’s new in ICU in 2050: big data and machine learning. Intensive Care Med 44(9):1524–1527
  162. Salluh JIF, Chiche JD, Reis CE, Soares M (2018) New perspectives to improve critical care benchmarking. Ann Inten Care 8(1):17
  163. Naidus E, Celi LA (2016) Big data in healthcare: are we close to it? Rev Bras Ter Intensiva 28(1):8–10
  164. Bremmer DN, Trienski TL, Walsh TL, Moffa MA (2018) Role of technology in antimicrobial stewardship. Med Clin N Am 102(5):955–963
  165. Emberger J, Tassone D, Stevens MP, Markley JD (2018) The current state of antimicrobial stewardship: challenges, successes, and future directions. Curr Infect Dis Rep 20(9):31
  166. Doernberg SB, Chambers HF (2017) Antimicrobial stewardship approaches in the intensive care unit. Infect Dis Clin N Am 31(3):513–534
  167. Teerawattanapong N, Kengkla K, Dilokthornsakul P, Saokaew S, Apisarnthanarak A, Chaiyakunapruk N (2017) Prevention and control of multidrug-resistant Gram-negative bacteria in adult intensive care units: a systematic review and network meta-analysis. Clin Infect Dis 64(suppl_2):S51–S60
  168. Ruppe E, Lisboa T, Barbier F (2018) The gut microbiota of critically ill patients: first steps in an unexplored world. Intensive Care Med 44:1561–1564
  169. de Gunzburg J, Ghozlane A, Ducher A, Le Chatelier E, Duval X, Ruppe E et al (2018) Protection of the human gut microbiome from antibiotics. J Infect Dis 217(4):628–636
  170. Haak BW, Wiersinga WJ (2017) The role of the gut microbiota in sepsis. Lancet Gastroenterol Hepatol 2(2):135–143
  171. World Health Organization. Antimicrobial resistance—Global report of surveillance. http://www.who.int/antimicrobial-resistance/publications/surveillancereport/en/. 2014
  172. European Center for Disease Control and Prevention. European Antimicrobial Resistance Surveillance Network (EARS-Net)—Annual report. http://www.ecdc.europa.eu/en/healthtopics/antimicrobial_resistance). 2016
  173. Luyt CE, Brechot N, Trouillet JL, Chastre J (2014) Antibiotic stewardship in the intensive care unit. Crit Care 18(5):480
  174. Alobaid AS, Hites M, Lipman J, Taccone FS, Roberts JA (2016) Effect of obesity on the pharmacokinetics of antimicrobials in critically ill patients: a structured review. Int J Antimicrob Agents 47(4):259–268

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