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Der Anaesthesist

, Volume 66, Issue 10, pp 737–761 | Cite as

Bakterielle Sepsis

Diagnostik und kalkulierte Antibiotikatherapie
  • D. C. Richter
  • A. Heininger
  • T. Brenner
  • M. Hochreiter
  • M. Bernhard
  • J. Briegel
  • S. Dubler
  • B. Grabein
  • A. Hecker
  • W. A. Krüger
  • K. Mayer
  • M. W. Pletz
  • D. Störzinger
  • N. Pinder
  • T. Hoppe-Tichy
  • S. Weiterer
  • S. Zimmermann
  • A. Brinkmann
  • M. A. Weigand
  • Christoph Lichtenstern
Leitthema

Zusammenfassung

Die Sterblichkeit von Patienten mit Sepsis und septischem Schock ist weiterhin inakzeptabel hoch. Eine effektive, kalkulierte Antibiotikatherapie binnen der ersten Stunde nach Erkennen der Sepsis ist ein wichtiges Ziel der effektiven Sepsistherapie. Verzögerungen führen zum deutlichen Anstieg der Sterblichkeit. Daher bilden strukturierte Behandlungskonzepte eine rationale Grundlage unter Beachtung relevanter Diagnose- und Behandlungsschritte. Neben dem vermuteten Focus und individuellen Risiken einzelner Patienten müssen lokale Resistenzmuster und spezifische Problemerreger bei der Wahl der antiinfektiven Therapie berücksichtigt werden. Vielfältige pathophysiologische Veränderungen beeinflussen im Rahmen der Sepsis die substanzspezifische Pharmakokinetik (PK) vieler Antibiotika. Daher sollte das Prinzip der „Standarddosierung“ verlassen und durch einen individuelleren Therapieansatz mit stärkerer Gewichtung der Pharmakokinetik(PK)‑/Pharmakodynamik(PD)-Indizes der Substanzgruppen ersetzt werden. Wenngleich dies noch nicht der klinische Standard ist, können Applikationsformen wie die prolongierte (oder kontinuierliche) Infusion von β‑Lactamen und ein therapeutisches Drugmonitoring (TDM) helfen, definierte PK-Ziele zu erreichen. Während die prolongierte Infusion auch ohne TDM auskommt, ist TDM bei kontinuierlicher Infusion grundsätzlich notwendig. Ein weiteres Argument für den individuellen, PK/PD-orientierten Antibiotikaeinsatz ist die Zunahme komplizierter Infektionen durch multiresistente Erreger (MRE) auf Intensivstationen. Zur effektiveren Behandlung etablieren sich dort zunehmend „antibiotic stewardship teams“ (ABS-Team). Die interprofessionelle Zusammenarbeit des Behandlungsteams mit Infektiologen/Mikrobiologen und klinischen Pharmazeuten führt nicht nur zum rationaleren Antibiotikaeinsatz, sondern beeinflusst das Behandlungsergebnis positiv. Den Goldstandard der Erregerdiagnostik stellen weiterhin der kulturbasierte Nachweis aus Probenmaterial und die mikrobiologische Resistenztestung auf die verschiedenen Antibiotikagruppen dar. Neue Polymerase-Kettenreaktion(PCR)-basierte Verfahren der Erregeridentifikation und Resistenzbestimmung ergänzen trotz hoher Untersuchungsgeschwindigkeit aufgrund der limitierten aktuellen Studienlage, der hohen Kosten und der eingeschränkten Verfügbarkeit derzeit die Sepsisroutinediagnostik lediglich. Bei komplizierten, septischen Krankheitsverläufen mit mehrfacher, antiinfektiver Vorbehandlung oder rekurrenter Sepsis können PCR-basierte Verfahren ergänzend zu Therapie-Monitoring und Diagnostik eingesetzt werden. Neue Antibiotika stellen potente Alternativen in der Behandlung von MRE-Infektionen dar. Aufgrund des oftmals definierten Erregerspektrums und der praktisch (noch) nicht vorhandenen Resistenzen sind diese zur gezielten Behandlung schwerer MRE-Infektionen geeignet (Therapieeskalation).

Schlüsselwörter

Medikamentenresistenz, multipel, bakteriell Lactame Prolongierte und kontinuierliche β‑Lactam-Infusion Therapeutisches Drugmonitoring Patientenversorgungsbündel 

Bacterial sepsis

Diagnostics and calculated antibiotic therapy

Abstract

The mortality of patients with sepsis and septic shock is still unacceptably high. An effective antibiotic treatment within 1 h of recognition of sepsis is an important target of sepsis treatment. Delays lead to an increase in mortality; therefore, structured treatment concepts form a rational foundation, taking relevant diagnostic and treatment steps into consideration. In addition to the assumed focus and individual risks of each patient, local resistance patterns and specific problem pathogens must be taken into account for selection of anti-infection treatment. Many pathophysiological alterations influence the pharmacokinetics of antibiotics during sepsis. The principle of standard dosing should be abandoned and replaced by an individual treatment approach with stronger weighting of the pharmacokinetics/pharmacodynamics (PK/PD) index of the substance groups. Although this is not yet the clinical standard, prolonged (or continuous) infusion of beta-lactam antibiotics and therapeutic drug monitoring (TDM) can help to achieve defined PK targets. Prolonged infusion is sufficient without TDM but for continuous infusion TDM is basically necessary. A further argument for individual PK/PD-oriented antibiotic approaches is the increasing number of infections due to multidrug resistant pathogens (MDR) in the intensive care unit. For effective treatment antibiotic stewardship teams (ABS team) are becoming more established. Interdisciplinary cooperation of the ABS team with infectiologists, microbiologists and clinical pharmacists leads not only to a rational administration of antibiotics but also has a positive influence on the outcome. The gold standards for pathogen detection are still culture-based detection and microbiological resistance testing for the various antibiotic groups. Despite the rapid investigation time, novel polymerase chain reaction (PCR)-based procedures for pathogen identification and resistance determination, are currently only an adjunct to routine sepsis diagnostics due to the limited number of studies, high costs and limited availability. In complicated septic courses with multiple anti-infective treatment or recurrent sepsis, PCR-based procedures can be used in addition to therapy monitoring and diagnostics. Novel antibiotics represent potent alternatives in the treatment of MDR infections. Due to the often defined spectrum of pathogens and the practically absent resistance, they are suitable for targeted treatment of severe MDR infections (therapy escalation).

Keywords

Drug resistance, multiple, bacterial Lactams Prolonged and continuous β‑lactam infusion Therapeutic drug monitoring Patient care bundles 

Notes

Einhaltung ethischer Richtlinien

Interessenkonflikt

D.C. Richter, A. Heininger, T. Brenner, M. Hochreiter, M. Bernhard, J. Briegel, S. Dubler, B. Grabein, A. Hecker, W.A. Krüger, K. Mayer, M.W. Pletz, D. Störzinger, N. Pinder, T. Hoppe-Tichy, S. Weiterer, S. Zimmermann, A. Brinkmann, M.A. Weigand und C. Lichtenstern geben an, dass kein Interessenkonflikt besteht.

Dieser Beitrag beinhaltet keine von den Autoren durchgeführten Studien an Menschen oder Tieren. Für die aufgeführten Studien gelten die jeweils dort angegebenen ethischen Richtlinien.

Literatur

  1. 1.
    Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM et al (2013) Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012. Intensive Care Med 39(2):165–228.  https://doi.org/10.1007/s00134-012-2769-8 PubMedCrossRefGoogle Scholar
  2. 2.
    Kaukonen KM, Bailey M, Pilcher D, Cooper DJ, Bellomo R (2015) Systemic inflammatory response syndrome criteria in defining severe sepsis. N Engl J Med 372(17):1629–1638.  https://doi.org/10.1056/NEJMoa1415236 PubMedCrossRefGoogle Scholar
  3. 3.
    Dellinger RP, Carlet JM, Masur H, Gerlach H, Calandra T, Cohen J et al (2004) Surviving sepsis campaign guidelines for management of severe sepsis and septic shock. Intensive Care Med 30(4):536–555.  https://doi.org/10.1007/s00134-004-2210-z PubMedCrossRefGoogle Scholar
  4. 4.
    Churpek MM, Zadravecz FJ, Winslow C, Howell MD, Edelson DP (2015) Incidence and prognostic value of the systemic inflammatory response syndrome and organ dysfunctions in ward patients. Am J Respir Crit Care Med 192(8):958–964PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    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.  https://doi.org/10.1001/jama.2016.0287 PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Bloos F, Thomas-Rüddel D, Rüddel 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.  https://doi.org/10.1186/cc13755 PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    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):34–377.  https://doi.org/10.1007/s00134-017-4683-6 CrossRefGoogle Scholar
  8. 8.
    Schmoch T, Bernhard M, Uhle F, Gründling M, Brenner T, Weigand M (2017) Neue SEPSIS-3-Definition. Anaesthesist 1(8):614–621.  https://doi.org/10.1007/s00101-017-0316-2 CrossRefGoogle Scholar
  9. 9.
    Seymour CW, Liu VX, Iwashyna TJ, Brunkhorst FM, Rea TD, Scherag A et al (2016) Assessment of clinical criteria for sepsis: for the Third International Consensus Definitions for sepsis and septic shock (Sepsis-3). JAMA 315(8):762–774.  https://doi.org/10.1001/jama.2016.0288 PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Shankar-Hari M, Phillips GS, Levy ML, Seymour CW, Liu VX, Deutschman CS et al (2016) Developing a new definition and assessing new clinical criteria for septic shock: for the third international consensus definitions for sepsis and septic shock (sepsis-3). JAMA 315(8):775–787.  https://doi.org/10.1001/jama.2016.0289 PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Seymour CW, Rosengart MR (2015) Septic shock: advances in diagnosis and treatment. JAMA 314(7):708–717.  https://doi.org/10.1001/jama.2015.7885 PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Fleischmann C, Scherag A, Adhikari NK, Hartog CS, Tsaganos T, Schlattmann P et al (2016) Assessment of global incidence and mortality of hospital-treated sepsis. Current estimates and limitations. Am J Respir Crit Care Med 193(3):259–272.  https://doi.org/10.1164/rccm.201504-0781OC PubMedCrossRefGoogle Scholar
  13. 13.
    Fleischmann C, Thomas-Rueddel DO, Hartmann M, Hartog CS, Welte T, Heublein S et al (2016) Hospital incidence and mortality rates of sepsis. Dtsch Arztebl Int 113(10):159–166.  https://doi.org/10.3238/arztebl.2016.0159 PubMedPubMedCentralGoogle Scholar
  14. 14.
    Martin GS, Mannino DM, Eaton S, Moss M (2003) The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med 348(16):1546–1554.  https://doi.org/10.1056/NEJMoa022139 PubMedCrossRefGoogle Scholar
  15. 15.
    Vincent J‑L, Rello J, Marshall J, Silva E, Anzueto A, Martin CD et al (2009) International study of the prevalence and outcomes of infection in intensive care units. JAMA 302(21):2323–2329.  https://doi.org/10.1001/jama.2009.1754 PubMedCrossRefGoogle Scholar
  16. 16.
    Friedman G, Silva E, Vincent J‑L (1998) Has the mortality of septic shock changed with time? Crit Care Med 26(12):2078–2086PubMedCrossRefGoogle Scholar
  17. 17.
    Group SCCT (2016) Incidence of severe sepsis and septic shock in German intensive care units: the prospective, multicentre INSEP study. Intensive Care Med 42(12):1980–1989.  https://doi.org/10.1007/s00134-016-4504-3 CrossRefGoogle Scholar
  18. 18.
    Mouncey PR, Osborn TM, Power GS, Harrison DA, Sadique MZ, Grieve RD et al (2015) Protocolised Management In Sepsis (ProMISe): a multicentre randomised controlled trial of the clinical effectiveness and cost-effectiveness of early, goal-directed, protocolised resuscitation for emerging septic shock. Health Technol Assess.  https://doi.org/10.3310/hta19970 PubMedPubMedCentralGoogle Scholar
  19. 19.
    Delaney AP, Peake SL, Bellomo R, Cameron P, Holdgate A, Howe B et al (2013) The Australasian Resuscitation in Sepsis Evaluation (ARISE) trial statistical analysis plan. Crit Care Resusc 15(3):162–171PubMedGoogle Scholar
  20. 20.
    Pro CI, Yealy DM, Kellum JA, Huang DT, Barnato AE, Weissfeld LA et al (2014) A randomized trial of protocol-based care for early septic shock. N Engl J Med 370(18):1683–1693.  https://doi.org/10.1056/NEJMoa1401602 CrossRefGoogle Scholar
  21. 21.
    Gaieski DF, Edwards JM, Kallan MJ, Carr BG (2013) Benchmarking the incidence and mortality of severe sepsis in the United States. Crit Care Med 41(5):1167–1174PubMedCrossRefGoogle Scholar
  22. 22.
    Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR (2001) Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med 29(7):1303–1310PubMedCrossRefGoogle Scholar
  23. 23.
    Graf J, Reinhold A, Brunkhorst FM, Ragaller M, Reinhart K, Loeffler M et al (2010) Variability of structures in German intensive care units—a representative, nationwide analysis. Wien Klin Wochenschr 122(19–20):572–578.  https://doi.org/10.1007/s00508-010-1452-8 PubMedCrossRefGoogle Scholar
  24. 24.
    Engel C, Brunkhorst FM, Bone HG, Brunkhorst R, Gerlach H, Grond S et al (2007) Epidemiology of sepsis in Germany: results from a national prospective multicenter study. Intensive Care Med 33(4):606–618.  https://doi.org/10.1007/s00134-006-0517-7 PubMedCrossRefGoogle Scholar
  25. 25.
    Engel C, Brunkhorst FM, Löffler M, Reinhart K (2007) Diagnose und Epidemiologie der Sepsis. Med Welt 58:307–310Google Scholar
  26. 26.
    DeFrances CJ, Lucas CA, Buie VC, Golosinskiy A (2006) National hospital discharge survey. Natl Health Stat Report 2008(5):1–20Google Scholar
  27. 27.
    Angus DC, van der Poll T (2013) Severe sepsis and septic shock. N Engl J Med 369(9):840–851.  https://doi.org/10.1056/NEJMra1208623 PubMedCrossRefGoogle Scholar
  28. 28.
    Opal SM, Garber GE, LaRosa SP, Maki DG, Freebairn RC, Kinasewitz GT et al (2003) Systemic host responses in severe sepsis analyzed by causative microorganism and treatment effects of drotrecogin alfa (activated). Clin Infect Dis 37(1):50–58.  https://doi.org/10.1086/375593 PubMedCrossRefGoogle Scholar
  29. 29.
    Ranieri VM, Thompson BT, Barie PS, Dhainaut J‑F, Douglas IS, Finfer S et al (2012) Drotrecogin alfa (activated) in adults with septic shock. N Engl J Med 366(22):2055–2064.  https://doi.org/10.1056/NEJMoa1202290 PubMedCrossRefGoogle Scholar
  30. 30.
    Geffers C, Maechler F, Behnke M, Gastmeier P (2016) Multiresistente Erreger – Epidemiologie, Surveillance und Bedeutung. Anasthesiol Intensivmed Notfallmed Schmerzther 51(02):104–111.  https://doi.org/10.1055/s-0041-103348 PubMedCrossRefGoogle Scholar
  31. 31.
    Woerther P‑L, Burdet C, Chachaty E, Andremont A (2013) Trends in human fecal carriage of extended-spectrum β‑lactamases in the community: toward the globalization of CTX-M. Clin Microbiol Rev 26(4):744–758.  https://doi.org/10.1128/CMR.00023-13 PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Munoz-Price LS, Poirel L, Bonomo RA, Schwaber MJ, Daikos GL, Cormican M et al (2013) Clinical epidemiology of the global expansion of klebsiella pneumoniae carbapenemases. Lancet Infect Dis 13(9):785–796.  https://doi.org/10.1016/S1473-3099(13)70190-7 PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Karam G, Chastre J, Wilcox MH, Vincent J‑L (2016) Antibiotic strategies in the era of multidrug resistance. Crit Care 20(1):136.  https://doi.org/10.1186/s13054-016-1320-7 PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Gastmeier P, Schroder C, Behnke M, Meyer E, Geffers C (2014) Dramatic increase in vancomycin-resistant enterococci in Germany. J Antimicrob Chemother 69(6):1660–1664.  https://doi.org/10.1093/jac/dku035 PubMedCrossRefGoogle Scholar
  35. 35.
    van der Bij AK, Pitout JD (2012) The role of international travel in the worldwide spread of multiresistant enterobacteriaceae. J Antimicrob Chemother 67(9):2090–2100.  https://doi.org/10.1093/jac/dks214 PubMedCrossRefGoogle Scholar
  36. 36.
    Arcilla MS, van Hattem JM, Haverkate MR, Bootsma MC, van Genderen PJ, Goorhuis A et al (2017) Import and spread of extended-spectrum β‑lactamase-producing enterobacteriaceae by international travellers (COMBAT study): a prospective, multicentre cohort study. Lancet Infect Dis 17(1):78–85.  https://doi.org/10.1016/S1473-3099(16)30319-X PubMedCrossRefGoogle Scholar
  37. 37.
    Mendelson M (2015) The World Health Organization global action plan for antimicrobial resistance: guest editorial. S Afr Med J 105(5):325.  https://doi.org/10.7196/SAMJ.9644 PubMedCrossRefGoogle Scholar
  38. 38.
    Rivers E, Nguyen B, Havstad S, Ressler J, Muzzin A, Knoblich B et al (2001) Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 345(19):1368–1377.  https://doi.org/10.1056/NEJMoa010307 PubMedCrossRefGoogle Scholar
  39. 39.
    Investigators A, Group ACT, Peake SL, Delaney A, Bailey M, Bellomo R et al (2014) Goal-directed resuscitation for patients with early septic shock. N Engl J Med 371(16):1496–1506.  https://doi.org/10.1056/NEJMoa1404380 CrossRefGoogle Scholar
  40. 40.
    Lilly CM (2014) The ProCESS trial—a new era of sepsis management. N Engl J Med 370(18):1750–1751.  https://doi.org/10.1056/NEJMe1402564 PubMedCrossRefGoogle Scholar
  41. 41.
    Bernhard M, Brenner T, Brunkhorst FM, Weigand MA (2015) Frühe innerklinische Sepsistherapie. Notf Rettungsmed 18(7):595–605.  https://doi.org/10.1007/s10049-015-0098-5 CrossRefGoogle Scholar
  42. 42.
    Dellinger RP (2015) The future of sepsis performance improvement. Crit Care Med 43(9):1787–1789.  https://doi.org/10.1097/CCM.0000000000001231 PubMedCrossRefGoogle Scholar
  43. 43.
    Seymour CW, Kahn JM, Martin-Gill C, Callaway CW, Yealy DM, Scales D et al (2017) Delays from first medical contact to antibiotic administration for sepsis. Crit Care Med 45(5):759–765.  https://doi.org/10.1097/CCM.0000000000002264 PubMedCrossRefGoogle Scholar
  44. 44.
    Damiani E, Donati A, Serafini G, Rinaldi L, Adrario E, Pelaia P et al (2015) Effect of performance improvement programs on compliance with sepsis bundles and mortality: a systematic review and meta-analysis of observational studies. PLOS ONE 10(5):e125827.  https://doi.org/10.1371/journal.pone.0125827 PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Rhodes A, Phillips G, Beale R, Cecconi M, Chiche JD, De Backer D et al (2015) The surviving sepsis campaign bundles and outcome: results from the international Multicentre Prevalence Study on Sepsis (the IMpreSS study). Intensive Care Med 41(9):1620–1628.  https://doi.org/10.1007/s00134-015-3906-y PubMedCrossRefGoogle Scholar
  46. 46.
    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.  https://doi.org/10.1056/NEJMoa1703058 PubMedCrossRefGoogle Scholar
  47. 47.
    Jones SL, Ashton CM, Kiehne L, Gigliotti E, Bell-Gordon C, Disbot M et al (2015) Reductions in sepsis mortality and costs after design and implementation of a nurse-based early recognition and response program. Jt Comm J Qual Patient Saf 41(11):483PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Levy MM, Rhodes A, Phillips GS, Townsend SR, Schorr CA, Beale R et al (2015) Surviving Sepsis Campaign: association between performance metrics and outcomes in a 7.5-year study. Crit Care Med 43(1):3–12.  https://doi.org/10.1007/s00134-014-3496-0 PubMedCrossRefGoogle Scholar
  49. 49.
    Pierrakos C, Vincent J‑L (2010) Sepsis biomarkers: a review. Crit Care 14(1):R15.  https://doi.org/10.1186/cc8872 PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Lichtenstern C, Brenner T, Bardenheuer HJ, Weigand MA (2012) Predictors of survival in sepsis: what is the best inflammatory marker to measure? Curr Opin Infect Dis 25(3):328–336.  https://doi.org/10.1097/QCO.0b013e3283522038 PubMedCrossRefGoogle Scholar
  51. 51.
    Jones AE, Shapiro NI, Trzeciak S, Arnold RC, Claremont HA, Kline JA et al (2010) Lactate clearance vs central venous oxygen saturation as goals of early sepsis therapy: a randomized clinical trial. JAMA 303(8):739–746.  https://doi.org/10.1001/jama.2010.158 PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Thomas-Rueddel DO, Poidinger B, Weiss M, Bach F, Dey K, Häberle H et al (2015) Hyperlactatemia is an independent predictor of mortality and denotes distinct subtypes of severe sepsis and septic shock. J Crit Care 30(2):439.e1–439.e6.  https://doi.org/10.1016/j.jcrc.2014.10.027 CrossRefGoogle Scholar
  53. 53.
    Casserly B, Phillips GS, Schorr C, Dellinger RP, Townsend SR, Osborn TM et al (2015) Lactate measurements in sepsis-induced tissue hypoperfusion: results from the Surviving Sepsis Campaign database. Crit Care Med 43(3):567–573.  https://doi.org/10.1097/CCM.0000000000000742 PubMedCrossRefGoogle Scholar
  54. 54.
    Reichert M, Hecker M, Hörbelt R, Lerner S, Höller J, Hecker C et al (2015) Die Rolle von Biomarkern in der Diagnostik der akuten Mesenterialischämie. Chirurg 86(1):47–55.  https://doi.org/10.1007/s00104-014-2906-8 PubMedCrossRefGoogle Scholar
  55. 55.
    Reichert M, Hecker M, Hörbelt R, Lerner S, Holler J, Hecker C et al (2015) Erratum zu: Die Rolle von Biomarkern in der Diagnostik der akuten Mesenterialischämie. Chirurg 86(1):55–55.  https://doi.org/10.1007/s00104-014-2906-8 PubMedCrossRefGoogle Scholar
  56. 56.
    Henriquez-Camacho C, Losa J (2014) Biomarkers for sepsis. Biomed Res Int 2014:547818.  https://doi.org/10.1155/2014/547818 PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Limper M, De Kruif M, Duits A, Brandjes D, van Gorp E (2010) The diagnostic role of procalcitonin and other biomarkers in discriminating infectious from non-infectious fever. J Infect 60(6):409–416.  https://doi.org/10.1016/j.jinf.2010.03.016 PubMedCrossRefGoogle Scholar
  58. 58.
    Wacker C, Prkno A, Brunkhorst FM, Schlattmann P (2013) Procalcitonin as a diagnostic marker for sepsis: a systematic review and meta-analysis. Lancet Infect Dis 13(5):426–435.  https://doi.org/10.1016/S1473-3099(12)70323-7 PubMedCrossRefGoogle Scholar
  59. 59.
    Siegler BH, Weiterer S, Lichtenstern C, Stumpp D, Brenner T, Hofer S et al (2014) Use of biomarkers in sepsis. Update and perspectives. Anaesthesist 63(8–9):678–690.  https://doi.org/10.1007/s00101-014-2347-2 PubMedCrossRefGoogle Scholar
  60. 60.
    Uzzan B, Cohen R, Nicolas P, Cucherat M, Perret GY (2006) Procalcitonin as a diagnostic test for sepsis in critically ill adults and after surgery or trauma: a systematic review and meta-analysis. Crit Care Med 34(7):1996–2003PubMedCrossRefGoogle Scholar
  61. 61.
    Liu D, Su L, Han G, Yan P, Xie L (2015) Prognostic value of procalcitonin in adult patients with sepsis: a systematic review and meta-analysis. PLOS ONE 10(6):e129450.  https://doi.org/10.1371/journal.pone.0129450 PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Ugarte H, Silva E, Mercan D, De Mendonca A, Vincent J‑L (1999) Procalcitonin used as a marker of infection in the intensive care unit. Crit Care Med 27(3):498–504PubMedCrossRefGoogle Scholar
  63. 63.
    Suprin E, Camus C, Gacouin A, Le Tulzo Y, Lavoue S, Feuillu A et al (2000) Procalcitonin: a valuable indicator of infection in a medical ICU? Intensive Care Med 26(9):1232–1238.  https://doi.org/10.1007/s001340000580 PubMedCrossRefGoogle Scholar
  64. 64.
    Panacek EA, Kaul M (1999) IL-6 as a marker of excessive TNF-α activity in sepsis. Sepsis 3(1):65–73.  https://doi.org/10.1023/A:1009878726176 CrossRefGoogle Scholar
  65. 65.
    Wakefield C, Barclay G, Fearon K, Goldie A, Ross J, Grant I et al (1998) Proinflammatory mediator activity, endogenous antagonists and the systemic inflammatory response in intra-abdominal sepsis. Br J Surg 85(6):818–825PubMedCrossRefGoogle Scholar
  66. 66.
    Jekarl DW, Lee S‑Y, Lee J, Park Y‑J, Kim Y, Park JH et al (2013) Procalcitonin as a diagnostic marker and IL-6 as a prognostic marker for sepsis. Diagn Microbiol Infect Dis 75(4):342–347.  https://doi.org/10.1016/j.diagmicrobio.2012.12.011 PubMedCrossRefGoogle Scholar
  67. 67.
    Oliveira CF, Botoni FA, Oliveira CR, Silva CB, Pereira HA, Serufo JC et al (2013) Procalcitonin versus C‑reactive protein for guiding antibiotic therapy in sepsis: a randomized trial. Crit Care Med 41(10):2336–2343.  https://doi.org/10.1097/CCM.0b013e31828e969f PubMedCrossRefGoogle Scholar
  68. 68.
    Welsch T, Frommhold K, Hinz U, Weigand MA, Kleeff J, Friess H et al (2008) Persisting elevation of C‑reactive protein after pancreatic resections can indicate developing inflammatory complications. Surgery 143(1):20–28.  https://doi.org/10.1016/j.surg.2007.06.010 PubMedCrossRefGoogle Scholar
  69. 69.
    Suberviola B, Castellanos A, Astudillo LG, Iglesias D, Melon FO (2011) Prognostic value of proadrenomedullin in severe sepsis and septic shock patients with community-acquired pneumonia. Crit Care 15(Suppl 1):276.  https://doi.org/10.1186/cc9696 CrossRefGoogle Scholar
  70. 70.
    Suberviola B, Castellanos-Ortega A, Ruiz AR, Lopez-Hoyos M, Santibanez M (2013) Hospital mortality prognostication in sepsis using the new biomarkers suPAR and proADM in a single determination on ICU admission. Intensive Care Med 39(11):1945–1952.  https://doi.org/10.1007/s00134-013-3056-z PubMedCrossRefGoogle Scholar
  71. 71.
    Morgenthaler NG, Struck J, Alonso C, Bergmann A (2005) Measurement of midregional proadrenomedullin in plasma with an immunoluminometric assay. Clin Chem 51(10):1823–1829.  https://doi.org/10.1373/clinchem.2005.051110 PubMedCrossRefGoogle Scholar
  72. 72.
    Yaegashi Y, Sato N, Suzuki Y, Kojika M, Imai S, Takahashi G et al (2005) Evaluation of a newly identified soluble CD14 subtype as a marker for sepsis. J Infect Chemother 11(5):234–238.  https://doi.org/10.1007/s10156-005-0400-4 PubMedCrossRefGoogle Scholar
  73. 73.
    Shozushima T, Takahashi G, Matsumoto N, Kojika M, Endo S, Okamura Y (2011) Usefulness of presepsin (sCD14-ST) measurements as a marker for the diagnosis and severity of sepsis that satisfied diagnostic criteria of systemic inflammatory response syndrome. J Infect Chemother 17(6):764–769.  https://doi.org/10.1007/s10156-011-0254-x PubMedCrossRefGoogle Scholar
  74. 74.
    Endo S, Suzuki Y, Takahashi G, Shozushima T, Ishikura H, Murai A et al (2012) Usefulness of presepsin in the diagnosis of sepsis in a multicenter prospective study. J Infect Chemother 18(6):891–897.  https://doi.org/10.1007/s10156-012-0435-2 PubMedCrossRefGoogle Scholar
  75. 75.
    Ulla M, Pizzolato E, Lucchiari M, Loiacono M, Soardo F, Forno D et al (2013) Diagnostic and prognostic value of presepsin in the management of sepsis in the emergency department: a multicenter prospective study. Crit Care 17(4):R168.  https://doi.org/10.1186/cc12847 PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Ferrer R, Martin-Loeches I, Phillips G, Osborn TM, Townsend S, Dellinger RP et al (2014) 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 42(8):1749–1755.  https://doi.org/10.1097/CCM.0000000000000330 PubMedCrossRefGoogle Scholar
  77. 77.
    Asfar P, Meziani F, Hamel JF, Grelon F, Megarbane B, Anguel N et al (2014) High versus low blood-pressure target in patients with septic shock. N Engl J Med 370(17):1583–1593.  https://doi.org/10.1056/NEJMoa1312173 PubMedCrossRefGoogle Scholar
  78. 78.
    Reinhart K, Brunkhorst F, Bone H, Bardutzky J, Dempfle C, Forst H et al (2010) Prävention, Diagnose, Therapie und Nachsorge der Sepsis. 1. Revision der S‑2k Leitlinien der Deutschen Sepsis-Gesellschaft eV (DSG) und der Deutschen Interdisziplinären Vereinigung für Intensiv-und Notfallmedizin (DIVI). Anaesthesist 59(4):347–370PubMedCrossRefGoogle Scholar
  79. 79.
    Surviving Sepsis Campaign (2015) Updated bundles in response to new evidence. http://www.survivingsepsis.org/SiteCollectionDocuments/SSC_Bundle.pdf. Zugegriffen: 22.09.2017
  80. 80.
    Cockerill Fr WJ, Vetter E, Goodman K, Torgerson C, Harmsen W et al (2004) Optimal testing parameters for blood cultures. Clin Infect Dis 38(12):1724–1730.  https://doi.org/10.1086/421087 PubMedCrossRefGoogle Scholar
  81. 81.
    Lee A, Mirrett S, Reller LB, Weinstein MP (2007) Detection of bloodstream infections in adults: how many blood cultures are needed? J Clin Microbiol 45(11):3546–3548.  https://doi.org/10.1128/JCM.01555-07 PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Zadroga R, Williams DN, Gottschall R, Hanson K, Nordberg V, Deike M et al (2013) Comparison of 2 blood culture media shows significant differences in bacterial recovery for patients on antimicrobial therapy. Clin Infect Dis 56(6):790–797.  https://doi.org/10.1093/cid/cis1021 PubMedCrossRefGoogle Scholar
  83. 83.
    Kanegaye JT, Soliemanzadeh P, Bradley JS (2001) Lumbar puncture in pediatric bacterial meningitis: defining the time interval for recovery of cerebrospinal fluid pathogens after parenteral antibiotic pretreatment. Pediatrics 108(5):1169–1174PubMedGoogle Scholar
  84. 84.
    Cardoso T, Carneiro AH, Ribeiro O, Teixeira-Pinto A, Costa-Pereira A (2010) Reducing mortality in severe sepsis with the implementation of a core 6‑hour bundle: results from the Portuguese community-acquired sepsis study (SACiUCI study). Crit Care 14(3):R83.  https://doi.org/10.1186/cc9008 PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    de Sousa AG, Junior CJF, Santos GPD, Laselva CR, Polessi J, Lisboa LF et al (2008) The impact of each action in the Surviving Sepsis Campaign measures on hospital mortality of patients with severe sepsis/septic shock. Einstein (Sao Paulo) 6(3):323–327Google Scholar
  86. 86.
    Hansen S, Schwab F, Behnke M, Carsauw H, Heczko P, Klavs I et al (2009) National influences on catheter-associated bloodstream infection rates: practices among national surveillance networks participating in the European HELICS project. J Hosp Infect 71(1):66–73.  https://doi.org/10.1016/j.jhin.2008.07.014 PubMedCrossRefGoogle Scholar
  87. 87.
    Karch A, Castell S, Schwab F, Geffers C, Bongartz H, Brunkhorst FM et al (2015) Proposing an empirically justified reference threshold for blood culture sampling rates in intensive care units. J Clin Microbiol 53(2):648–652.  https://doi.org/10.1128/JCM.02944-14 PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Li J, Plorde JJ, Carlson LG (1994) Effects of volume and periodicity on blood cultures. J Clin Microbiol 32(11):2829–2831PubMedPubMedCentralGoogle Scholar
  89. 89.
    Baron EJ, Miller JM, Weinstein MP, Richter SS, Gilligan PH, Thomson RB et al (2013) A guide to utilization of the microbiology laboratory for diagnosis of infectious diseases: 2013 recommendations by the Infectious Diseases Society of America (IDSA) and the American Society for Microbiology (ASM). Clin Infect Dis 57(4):e22–e121.  https://doi.org/10.1093/cid/cit278 PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Munson EL, Diekema DJ, Beekmann SE, Chapin KC, Doern GV (2003) Detection and treatment of bloodstream infection: laboratory reporting and antimicrobial management. J Clin Microbiol 41(1):495–497.  https://doi.org/10.1128/JCM.41.1.495-497.2003 PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    Brandt C, Braun SD, Stein C, Slickers P, Ehricht R, Pletz MW et al (2017) In silico serine β‑lactamases analysis reveals a huge potential resistome in environmental and pathogenic species. Sci Rep.  https://doi.org/10.1038/srep43232 Google Scholar
  92. 92.
    Pletz MW, Wellinghausen N, Welte T (2011) Will polymerase chain reaction (PCR)-based diagnostics improve outcome in septic patients? A clinical view. Intensive Care Med 37(7):1069–1076.  https://doi.org/10.1007/s00134-011-2245-x PubMedCrossRefGoogle Scholar
  93. 93.
    Skvarc M, Stubljar D, Rogina P, Kaasch AJ (2013) Non-culture-based methods to diagnose bloodstream infection: does it work? Eur J Microbiol Immunol (Bp) 3(2):97–104.  https://doi.org/10.1556/EuJMI.3.2013.2.2 CrossRefGoogle Scholar
  94. 94.
    Bloos F, Sachse S, Kortgen A, Pletz MW, Lehmann M, Straube E et al (2012) Evaluation of a polymerase chain reaction assay for pathogen detection in septic patients under routine condition: an observational study. PLOS ONE 7(9):e46003.  https://doi.org/10.1371/journal.pone.0046003 PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Hebart H, Klingspor L, Klingebiel T, Loeffler J, Tollemar J, Ljungman P et al (2009) A prospective randomized controlled trial comparing PCR-based and empirical treatment with liposomal amphotericin B in patients after allo-SCT. Bone Marrow Transplant 43(7):553–561.  https://doi.org/10.1038/bmt.2008.355 PubMedCrossRefGoogle Scholar
  96. 96.
    Bhat BV, Prasad P, Kumar VBR, Harish B, Krishnakumari K, Rekha A et al (2016) Syndrome Evaluation System (SES) versus Blood Culture (BACTEC) in the diagnosis and management of neonatal sepsis—a randomized controlled trial. Indian J Pediatr 83(5):370–379.  https://doi.org/10.1007/s12098-015-1956-3 PubMedCrossRefGoogle Scholar
  97. 97.
    Vincent JL, Brealey D, Libert N, Abidi NE, O’Dwyer M, Zacharowski K et al (2015) Rapid diagnosis of infection in the critically ill, a multicenter study of molecular detection in bloodstream infections, pneumonia, and sterile site infections. Crit Care Med 43(11):2283–2291.  https://doi.org/10.1097/CCM.0000000000001249 PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Grumaz S, Stevens P, Grumaz C, Decker SO, Weigand MA, Hofer S et al (2016) Next-generation sequencing diagnostics of bacteremia in septic patients. Genome Med 8(1):73.  https://doi.org/10.1186/s13073-016-0326-8 PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Retamar P, López-Cerero L, Muniain MA, Pascual Á, Rodríguez-Baño J (2013) Impact of the MIC of piperacillin-tazobactam on the outcome of patients with bacteremia due to extended-spectrum-β-lactamase-producing escherichia coli. Antimicrob Agents Chemother 57(7):3402–3404.  https://doi.org/10.1128/AAC.00135-13 PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Retamar P, Portillo MM, López-Prieto MD, Rodríguez-López F, de Cueto M, García MV et al (2012) Impact of inadequate empirical therapy on the mortality of patients with bloodstream infections: a propensity score-based analysis. Antimicrob Agents Chemother 56(1):472–478.  https://doi.org/10.1128/AAC.00462-11 PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Cohen J, Vincent J‑L, Adhikari NK, Machado FR, Angus DC, Calandra T et al (2015) Sepsis: a roadmap for future research. Lancet Infect Dis 15(5):581–614.  https://doi.org/10.1016/S1473-3099(15)70112-X PubMedCrossRefGoogle Scholar
  102. 102.
    Vincent J‑L, Bassetti M, François B, Karam G, Chastre J, Torres A et al (2016) Advances in antibiotic therapy in the critically ill. Crit Care 20(133):1.  https://doi.org/10.1186/s13054-016-1285-6 Google Scholar
  103. 103.
    Ehrlich P (1913) Chemotherapeutics: scientific principles, methods and results. Lancet 2(445):353–359Google Scholar
  104. 104.
    Kollef MH, Sherman G, Ward S, Fraser VJ (1999) Inadequate antimicrobial treatment of infections: a risk factor for hospital mortality among critically ill patients. Chest 115(2):462–474.  https://doi.org/10.1378/chest.115.2.462 PubMedCrossRefGoogle Scholar
  105. 105.
    Kumar A, Kethireddy S (2013) Emerging concepts in optimizing antimicrobial therapy of septic shock: speed is life but a hammer helps too. Crit Care 17(1):104.  https://doi.org/10.1186/cc11890 PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Bloos F, Rüddel H, Thomas-Rüddel 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.  https://doi.org/10.1007/s00134-017-4782-4 PubMedGoogle Scholar
  107. 107.
    Scheer CS, Fuchs C, Kuhn S‑O, Vollmer M, Rehberg S, Friesecke S et al (2017) Quality improvement initiative for severe sepsis and septic shock reduces 90-day mortality: a 7.5-year observational study. Crit Care Med 45(2):241–252.  https://doi.org/10.1097/CCM.0000000000002069 PubMedCrossRefGoogle Scholar
  108. 108.
    Ibrahim EH, Sherman G, Ward S, Fraser VJ, Kollef MH (2000) The influence of inadequate antimicrobial treatment of bloodstream infections on patient outcomes in the ICU setting. Chest 118(1):146–155.  https://doi.org/10.1378/chest.118.1.146 PubMedCrossRefGoogle Scholar
  109. 109.
    Spanish Collaborative Group for Infections in Intensive Care Units of Sociedad Española de Medicina Intensiva, Crítica y Unidades Coronarias, Vallés J, Rello J, Ochagavía A, Garnacho J, Alcalá M (2003) Community-acquired bloodstream infection in critically ill adult patients: Impact of shock and inappropriate antibiotic therapy on survival. Chest 123(5):1615–1624CrossRefGoogle Scholar
  110. 110.
    Society AT, IDSo A (2005) Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med 171(4):388–416.  https://doi.org/10.1164/rccm.200405-644ST CrossRefGoogle Scholar
  111. 111.
    Bowers DR, Liew Y‑X, Lye DC, Kwa AL, Hsu L‑Y, Tam VH (2013) Outcomes of appropriate empiric combination versus monotherapy for pseudomonas aeruginosa bacteremia. Antimicrob Agents Chemother 57(3):1270–1274.  https://doi.org/10.1128/AAC.02235-12 PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    Bagshaw SM, Lapinsky S, Dial S, Arabi Y, Dodek P, Wood G et al (2009) Acute kidney injury in septic shock: clinical outcomes and impact of duration of hypotension prior to initiation of antimicrobial therapy. Intensive Care Med 35(5):871–881.  https://doi.org/10.1007/s00134-008-1367-2 PubMedCrossRefGoogle Scholar
  113. 113.
    Iscimen R, Yilmaz M, Cartin-Ceba R, Hubmayr R, Afessa B, Gajic O et al (2008) Risk factors for the development of acute lung injury in patients with septic shock: an observational cohort study. Crit Care.  https://doi.org/10.1186/cc6708 PubMedCentralGoogle Scholar
  114. 114.
    Garnacho-Montero J, Aldabo-Pallas T, Garnacho-Montero C, Cayuela A, Jiménez R, Barroso S et al (2006) Timing of adequate antibiotic therapy is a greater determinant of outcome than are TNF and IL-10 polymorphisms in patients with sepsis. Crit Care 10(4):R111.  https://doi.org/10.1186/cc4995 PubMedPubMedCentralCrossRefGoogle Scholar
  115. 115.
    Kumar A, Roberts D, Wood KE, Light B, Parrillo JE, Sharma S et al (2006) Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med 34(6):1589–1596PubMedCrossRefGoogle Scholar
  116. 116.
    Kumar A, Ellis P, Arabi Y, Roberts D, Light B, Parrillo JE et al (2009) Initiation of inappropriate antimicrobial therapy results in a fivefold reduction of survival in human septic shock. Chest 136(5):1237–1248.  https://doi.org/10.1378/chest.09-0087 PubMedCrossRefGoogle Scholar
  117. 117.
    Gaieski DF, Mikkelsen ME, Band RA, Pines JM, Massone R, Furia FF et al (2010) 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 38(4):1045–1053.  https://doi.org/10.1097/CCM.0b013e3181cc4824 PubMedCrossRefGoogle Scholar
  118. 118.
    Barie PS, Hydo LJ, Shou J, Larone DH, Eachempati SR (2005) Influence of antibiotic therapy on mortality of critical surgical illness caused or complicated by infection. Surg Infect (Larchmt) 6(1):41–54.  https://doi.org/10.1089/sur.2005.6.41 CrossRefGoogle Scholar
  119. 119.
    Barochia AV, Cui X, Vitberg D, Suffredini AF, O’Grady NP, Banks SM et al (2010) Bundled care for septic shock: an analysis of clinical trials. Crit Care Med 38(2):668–678.  https://doi.org/10.1097/CCM.0b013e3181cb0ddf PubMedPubMedCentralCrossRefGoogle Scholar
  120. 120.
    Ferrer R, Artigas A, Suarez D, Palencia E, Levy MM, Arenzana A et al (2009) Effectiveness of treatments for severe sepsis: a prospective, multicenter, observational study. Am J Respir Crit Care Med 180(9):861–866.  https://doi.org/10.1164/rccm.200812-1912OC PubMedCrossRefGoogle Scholar
  121. 121.
    Singer M (2017) Antibiotics for Sepsis—Does Each Hour Really Count? Or is it Incestuous Amplification? Am J Respir Crit Care Med.  https://doi.org/10.1164/rccm.201703-0621ED PubMedGoogle Scholar
  122. 122.
    Pletz M, Tacconelli E, Welte T (2017) Antibiotic Stewardship 2.0. Internist (Berl) 58(7):657–665.  https://doi.org/10.1007/s00108-017-0258-4 CrossRefGoogle Scholar
  123. 123.
    Schuts EC, Hulscher ME, Mouton JW, Verduin CM, Stuart JWC, Overdiek HW et al (2016) Current evidence on hospital antimicrobial stewardship objectives: a systematic review and meta-analysis. Lancet Infect Dis 16(7):847–856.  https://doi.org/10.1016/S1473-3099(16)00065-7 PubMedCrossRefGoogle Scholar
  124. 124.
    Allerberger F, Amann S, Apfalter P, Brodt H‑R, Eckmanns T, Fellhauer M et al (2016) Strategies to enhance rational use of antibiotics in hospital: a guideline by the German Society for Infectious Diseases. Infection 44(3):395–439.  https://doi.org/10.1007/s15010-016-0885-z PubMedPubMedCentralCrossRefGoogle Scholar
  125. 125.
    Sandiumenge A, Diaz E, Bodí M, Rello J (2003) Therapy of ventilator-associated pneumonia. Intensive Care Med 29(6):876–883.  https://doi.org/10.1007/s00134-003-1715-1 PubMedCrossRefGoogle Scholar
  126. 126.
    Garcin F, Leone M, Antonini F, Charvet A, Albanese J, Martin C (2010) Non-adherence to guidelines: an avoidable cause of failure of empirical antimicrobial therapy in the presence of difficult-to-treat bacteria. Intensive Care Med 36(1):75–82.  https://doi.org/10.1007/s00134-009-1660-8 PubMedCrossRefGoogle Scholar
  127. 127.
    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.  https://doi.org/10.1097/CCM.0b013e3181e96b91 PubMedCrossRefGoogle Scholar
  128. 128.
    Kumar A, Zarychanski R, Light B, Parrillo J, Maki D, Simon D et al (2010) Early combination antibiotic therapy yields improved survival compared with monotherapy in septic shock: a propensity-matched analysis. Crit Care Med 38(9):1773–1785.  https://doi.org/10.1097/CCM.0b013e3181eb3ccd PubMedCrossRefGoogle Scholar
  129. 129.
    Al-Hasan MN, Wilson JW, Lahr BD, Thomsen KM, Eckel-Passow JE, Vetter EA et al (2009) β‑lactam and fluoroquinolone combination antibiotic therapy for bacteremia caused by gram-negative bacilli. Antimicrob Agents Chemother 53(4):1386–1394.  https://doi.org/10.1128/AAC.01231-08 PubMedPubMedCentralCrossRefGoogle Scholar
  130. 130.
    Delannoy P‑Y, Boussekey N, Devos P, Alfandari S, Turbelin C, Chiche A et al (2012) Impact of combination therapy with aminoglycosides on the outcome of ICU-acquired bacteraemias. Eur J Clin Microbiol Infect Dis 31(9):2293–2299.  https://doi.org/10.1007/s10096-012-1568-z PubMedCrossRefGoogle Scholar
  131. 131.
    Díaz-Martín A, Martínez-González ML, Ferrer R, Ortiz-Leyba C, Piacentini E, Lopez-Pueyo MJ et al (2012) Antibiotic prescription patterns in the empiric therapy of severe sepsis: combination of antimicrobials with different mechanisms of action reduces mortality. Crit Care 16(6):R223.  https://doi.org/10.1186/cc11869 PubMedPubMedCentralCrossRefGoogle Scholar
  132. 132.
    Martin-Loeches I, Lisboa T, Rodriguez A, Putensen C, Annane D, Garnacho-Montero J et al (2010) Combination antibiotic therapy with macrolides improves survival in intubated patients with community-acquired pneumonia. Intensive Care Med 36(4):612–620.  https://doi.org/10.1007/s00134-009-1730-y PubMedCrossRefGoogle Scholar
  133. 133.
    Brunkhorst FM, Oppert M, Marx G, Bloos F, Ludewig K, Putensen C et al (2012) Effect of empirical treatment with moxifloxacin and meropenem vs meropenem on sepsis-related organ dysfunction in patients with severe sepsis: a randomized trial. JAMA 307(22):2390–2399.  https://doi.org/10.1001/jama.2012.5833 PubMedCrossRefGoogle Scholar
  134. 134.
    Braykov NP, Morgan DJ, Schweizer ML, Uslan DZ, Kelesidis T, Weisenberg SA et al (2014) Assessment of empirical antibiotic therapy optimisation in six hospitals: an observational cohort study. Lancet Infect Dis 14(12):1220–1227.  https://doi.org/10.1016/S1473-3099(14)70952-1 PubMedPubMedCentralCrossRefGoogle Scholar
  135. 135.
    Bender JK, Fleige C, Klare I, Fiedler S, Mischnik A, Mutters NT et al (2016) Detection of a cfr (B) variant in German enterococcus faecium clinical isolates and the impact on linezolid resistance in enterococcus spp. PLOS ONE 11(11):e167042.  https://doi.org/10.1371/journal.pone.0167042 PubMedPubMedCentralCrossRefGoogle Scholar
  136. 136.
    Heyland DK, Johnson AP, Reynolds SC, Muscedere J (2011) Procalcitonin for reduced antibiotic exposure in the critical care setting: a systematic review and an economic evaluation. Crit Care Med 39(7):1792–1799.  https://doi.org/10.1097/CCM.0b013e31821201a5 PubMedCrossRefGoogle Scholar
  137. 137.
    Bouadma L, Luyt C‑E, Tubach F, Cracco C, Alvarez A, Schwebel C et al (2010) Use of procalcitonin to reduce patients’ exposure to antibiotics in intensive care units (PRORATA trial): a multicentre randomised controlled trial. Lancet 375(9713):463–474.  https://doi.org/10.1016/S0140-6736(09)61879-1 PubMedCrossRefGoogle Scholar
  138. 138.
    de Jong E, van Oers JA, Beishuizen A, Vos P, Vermeijden WJ, Haas LE et al (2016) Efficacy and safety of procalcitonin guidance in reducing the duration of antibiotic treatment in critically ill patients: a randomised, controlled, open-label trial. Lancet Infect Dis 16(7):819–827.  https://doi.org/10.1016/S1473-3099(16)00053-0 PubMedCrossRefGoogle Scholar
  139. 139.
    Schuetz P, Muller B, Christ-Crain M, Stolz D, Tamm M, Bouadma L et al (2013) Procalcitonin to initiate or discontinue antibiotics in acute respiratory tract infections. Evid Based Child Health.  https://doi.org/10.1002/14651858.CD007498 Google Scholar
  140. 140.
    Schuetz P, Briel M, Christ-Crain M, Stolz D, Bouadma L, Wolff M et al (2012) Procalcitonin to guide initiation and duration of antibiotic treatment in acute respiratory infections: an individual patient data meta-analysis. Clin Infect Dis 55(5):651–662.  https://doi.org/10.1093/cid/cis464 PubMedPubMedCentralCrossRefGoogle Scholar
  141. 141.
    Schuetz P, Birkhahn R, Sherwin R, Jones AE, Singer A, Kline JA et al (2017) Serial Procalcitonin predicts mortality in severe sepsis patients: results from the Multicenter Procalcitonin MOnitoring SEpsis (MOSES) study. Crit Care Med 45(5):781–789.  https://doi.org/10.1097/CCM.0000000000002321 PubMedPubMedCentralCrossRefGoogle Scholar
  142. 142.
    Andriolo BN, Andriolo RB, Salomão R, Atallah ÁN (2017) Effectiveness and safety of procalcitonin evaluation for reducing mortality in adults with sepsis, severe sepsis or septic shock. Cochrane Libr.  https://doi.org/10.1002/14651858.CD010959.pub2 Google Scholar
  143. 143.
    Westwood M, Ramaekers B, Whiting P, Tomini F, Joore M, Armstrong N et al (2015) Procalcitonin testing to guide antibiotic therapy for the treatment of sepsis in intensive care settings and for suspected bacterial infection in emergency department settings: a systematic review and cost-effectiveness analysis. Health Technol Assess 19(96):1–236.  https://doi.org/10.3310/hta19960 CrossRefGoogle Scholar
  144. 144.
    Matthaiou DK, Ntani G, Kontogiorgi M, Poulakou G, Armaganidis A, Dimopoulos G (2012) An ESICM systematic review and meta-analysis of procalcitonin-guided antibiotic therapy algorithms in adult critically ill patients. Intensive Care Med 38(6):940–949.  https://doi.org/10.1007/s00134-012-2563-7 PubMedCrossRefGoogle Scholar
  145. 145.
    Gomes Silva BN, Andriolo RB, Atallah ÁN, Salomão R (2010) De-escalation of antimicrobial treatment for adults with sepsis, severe sepsis or septic shock. Cochrane Libr.  https://doi.org/10.1002/14651858.CD007934.pub2 Google Scholar
  146. 146.
    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.  https://doi.org/10.1007/s00134-014-3411-8 PubMedCrossRefGoogle Scholar
  147. 147.
    Turza KC, Politano AD, Rosenberger LH, Riccio LM, McLeod M, Sawyer RG (2016) De-escalation of antibiotics does not increase mortality in critically ill surgical patients. Surg Infect (Larchmt) 17(1):48–52.  https://doi.org/10.1089/sur.2014.202 CrossRefGoogle Scholar
  148. 148.
    Havey TC, Fowler RA, Daneman N (2011) Duration of antibiotic therapy for bacteremia: a systematic review and meta-analysis. Crit Care 15(6):R267.  https://doi.org/10.1186/cc10545 PubMedPubMedCentralCrossRefGoogle Scholar
  149. 149.
    Sawyer RG, Claridge JA, Nathens AB, Rotstein OD, Duane TM, Evans HL et al (2015) Trial of short-course antimicrobial therapy for intraabdominal infection. N Engl J Med 372(21):1996–2005.  https://doi.org/10.1056/NEJMoa1411162 PubMedPubMedCentralCrossRefGoogle Scholar
  150. 150.
    Chastre J, Wolff M, Fagon J‑Y, 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.  https://doi.org/10.1001/jama.290.19.2588 PubMedCrossRefGoogle Scholar
  151. 151.
    Garnacho-Montero J, Gutiérrez-Pizarraya A, Escoresca-Ortega A, Corcia-Palomo Y, Fernández-Delgado E, Herrera-Melero I et al (2014) De-escalation of empirical therapy is associated with lower mortality in patients with severe sepsis and septic shock. Intensive Care Med 40(1):32–40.  https://doi.org/10.1007/s00134-013-3077-7 PubMedCrossRefGoogle Scholar
  152. 152.
    Weiss CH, Persell SD, Wunderink RG, Baker DW (2012) Empiric antibiotic, mechanical ventilation, and central venous catheter duration as potential factors mediating the effect of a checklist prompting intervention on mortality: an exploratory analysis. Bmc Health Serv Res 12(198).  https://doi.org/10.1186/1472-6963-12-198 Google Scholar
  153. 153.
    Bodmann K, Grabein B (2010) Empfehlungen zur kalkulierten parenteralen Initialtherapie bakterieller Erkrankungen bei ErwachsenenGoogle Scholar
  154. 154.
    Sartelli M, Weber DG, Ruppé E, Bassetti M, Wright BJ, Ansaloni L et al (2016) Antimicrobials: a global alliance for optimizing their rational use in intra-abdominal infections (AGORA). World J Emerg Surg 11(33).  https://doi.org/10.1186/s13017-016-0089-y Google Scholar
  155. 155.
    Brook I (1989) Inoculum effect. Reviews of infectious diseases. Clin Infect Dis 11(3):361–368.  https://doi.org/10.1093/clinids/11.3.361 CrossRefGoogle Scholar
  156. 156.
    Ruppé É, Woerther P‑L, Barbier F (2015) Mechanisms of antimicrobial resistance in gram-negative bacilli. Ann Intensive Care 5(21).  https://doi.org/10.1186/s13613-015-0061-0 PubMedPubMedCentralGoogle Scholar
  157. 157.
    Perez F, Bonomo RA (2012) Can we really use ß‑lactam/ß-lactam inhibitor combinations for the treatment of infections caused by extended-spectrum ß‑lactamase—producing bacteria? Clin Infect Dis 54(2):175–177.  https://doi.org/10.1093/cid/cir793 PubMedCrossRefGoogle Scholar
  158. 158.
    Hanrahan T, Whitehouse T, Lipman J, Roberts JA (2015) Vancomycin-associated nephrotoxicity: a meta-analysis of administration by continuous versus intermittent infusion. Int J Antimicrob Agents 46(3):249–253.  https://doi.org/10.1016/j.ijantimicag.2015.04.013 PubMedCrossRefGoogle Scholar
  159. 159.
    Brinkmann A, Röhr A, Köberer A, Fuchs T, Preisenberger J, Krüger W et al (2016) Therapeutisches Drug Monitoring und individualisierte Dosierung von Antibiotika bei der Sepsis. Med Klin Notfallmed:1–12.  https://doi.org/10.1007/s00063-016-0213-5 Google Scholar
  160. 160.
    Benvenuto M, Benziger DP, Yankelev S, Vigliani G (2006) Pharmacokinetics and tolerability of daptomycin at doses up to 12 milligrams per kilogram of body weight once daily in healthy volunteers. Antimicrob Agents Chemother 50(10):3245–3249.  https://doi.org/10.1128/AAC.00247-06 PubMedPubMedCentralCrossRefGoogle Scholar
  161. 161.
    Schweizer ML, Furuno JP, Harris AD, Johnson JK, Shardell MD, McGregor JC et al (2011) Comparative effectiveness of nafcillin or cefazolin versus vancomycin in methicillin-susceptible staphylococcus aureus bacteremia. BMC Infect Dis 11(279).  https://doi.org/10.1186/1471-2334-11-279 Google Scholar
  162. 162.
    Nissen JL, Skov R, Knudsen JD, Østergaard C, Schønheyder HC, Frimodt-Møller N et al (2013) Effectiveness of penicillin, dicloxacillin and cefuroxime for penicillin-susceptible staphylococcus aureus bacteraemia: a retrospective, propensity-score-adjusted case—control and cohort analysis. J Antimicrob Chemother 68(8):1894–1900.  https://doi.org/10.1093/jac/dkt108 PubMedCrossRefGoogle Scholar
  163. 163.
    Liu C, Bayer A, Cosgrove SE, Daum RS, Fridkin SK, Gorwitz RJ et al (2011) Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant staphylococcus aureus infections in adults and children. Clin Infect Dis 52(3):e18–e55.  https://doi.org/10.1093/cid/ciq146 PubMedCrossRefGoogle Scholar
  164. 164.
    Jongsma K, Joson J, Heidari A (2013) Ceftaroline in the treatment of concomitant methicillin-resistant and daptomycin-non-susceptible staphylococcus aureus infective endocarditis and osteomyelitis: case report. J Antimicrob Chemother 68(6):1444–1445.  https://doi.org/10.1093/jac/dkt009 PubMedCrossRefGoogle Scholar
  165. 165.
    Tattevin P, Boutoille D, Vitrat V, Van Grunderbeeck N, Revest M, Dupont M et al (2014) Salvage treatment of methicillin-resistant staphylococcal endocarditis with ceftaroline: a multicentre observational study. J Antimicrob Chemother 69(7):2010–2013.  https://doi.org/10.1093/jac/dku085 PubMedCrossRefGoogle Scholar
  166. 166.
    Raad I, Darouiche R, Vazquez J, Lentnek A, Hachem R, Hanna H et al (2005) Efficacy and safety of weekly dalbavancin therapy for catheter-related bloodstream infection caused by gram-positive pathogens. Clin Infect Dis 40(3):374–380.  https://doi.org/10.1086/427283 PubMedCrossRefGoogle Scholar
  167. 167.
    Roberts KD, Sulaiman RM, Dalbavancin Oritavancin RMJ (2015) An innovative approach to the treatment of gram-positive infections. Pharmacotherapy 35(10):935–948.  https://doi.org/10.1002/phar.1641 PubMedCrossRefGoogle Scholar
  168. 168.
    López-Cortés LE, del Toro MD, Gálvez-Acebal J, Bereciartua-Bastarrica E, Fariñas MC, Sanz-Franco M et al (2013) Impact of an evidence-based bundle intervention in the quality-of-care management and outcome of staphylococcus aureus bacteremia. Clin Infect Dis 57(9):1225–1233.  https://doi.org/10.1093/cid/cit499 PubMedCrossRefGoogle Scholar
  169. 169.
    Habib G, Lancellotti P, Antunes MJ, Bongiorni MG, Casalta J‑P, Del Zotti F et al (2015) 2015 Esc Guidelines for the management of infective endocarditis: The Task Force for the Management of Infective Endocarditis of the European Society of Cardiology (esc). Endorsed by: European Association for Cardio-thoracic Surgery (eacts), the European Association of Nuclear Medicine (eanm). Eur Heart J 36(44):3075–3128.  https://doi.org/10.1093/eurheartj/ehv319 PubMedCrossRefGoogle Scholar
  170. 170.
    Kalil AC, Metersky ML, Klompas M, Muscedere J, Sweeney DA, Palmer LB et al (2016) Management of adults with hospital-acquired and ventilator-associated pneumonia: 2016 clinical practice guidelines by the Infectious Diseases Society of America and the American Thoracic Society. Clin Infect Dis 63(5):e61–e111.  https://doi.org/10.1093/cid/ciw353 PubMedPubMedCentralCrossRefGoogle Scholar
  171. 171.
    Magill SS, Edwards JR, Bamberg W, Beldavs ZG, Dumyati G, Kainer MA et al (2014) Multistate point-prevalence survey of health care—associated infections. N Engl J Med 370(13):1198–1208.  https://doi.org/10.1056/NEJMoa1306801 PubMedPubMedCentralCrossRefGoogle Scholar
  172. 172.
    Melsen WG, Rovers MM, Groenwold RH, Bergmans DC, Camus C, Bauer TT et al (2013) Attributable mortality of ventilator-associated pneumonia: a meta-analysis of individual patient data from randomised prevention studies. Lancet Infect Dis 13(8):665–671.  https://doi.org/10.1016/S1473-3099(13)70081-1 PubMedCrossRefGoogle Scholar
  173. 173.
    Kollef MH, Hamilton CW, Ernst FR (2012) Economic impact of ventilator-associated pneumonia in a large matched cohort. Infect Control Hosp Epidemiol 33(03):250–256.  https://doi.org/10.1086/664049 PubMedCrossRefGoogle Scholar
  174. 174.
    Muscedere JG, Day A, Heyland DK (2010) Mortality, attributable mortality, and clinical events as end points for clinical trials of ventilator-associated pneumonia and hospital-acquired pneumonia. Clin Infect Dis 51(Supplement 1):S120–S125.  https://doi.org/10.1086/653060 PubMedCrossRefGoogle Scholar
  175. 175.
    Sopena N, Sabrià M (2005) Multicenter study of hospital-acquired pneumonia in non-ICU patients. Chest 127(1):213–219.  https://doi.org/10.1378/chest.127.1.213 PubMedCrossRefGoogle Scholar
  176. 176.
    Esperatti M, Ferrer M, Giunta V, Ranzani OT, Saucedo LM, Bassi GL et al (2013) Validation of predictors of adverse outcomes in hospital-acquired pneumonia in the ICU. Crit Care Med 41(9):2151–2161.  https://doi.org/10.1097/CCM.0b013e31828a674a PubMedCrossRefGoogle Scholar
  177. 177.
    Dalhoff K, Abele-Horn M, Andreas S, Bauer T, von Baum H, Deja M et al (2012) Epidemiologie, Diagnostik und Therapie erwachsener Patienten mit nosokomialer Pneumonie. Pneumologie 66(12):707–765.  https://doi.org/10.1055/s-0032-1325924 PubMedCrossRefGoogle Scholar
  178. 178.
    Dalhoff K, Abele-Horn M, Andreas S, Bauer T, von Baum H, Deja M et al (2012) Epidemiology, diagnosis and treatment of adult patients with nosocomial pneumonia. S‑3 Guideline of the German Society for Anaesthesiology and Intensive Care Medicine, the German Society for Infectious Diseases, the German Society for Hygiene and Microbiology, the German Respiratory Society and the Paul-Ehrlich-Society for Chemotherapy. Pneumologie 66(12):707–765.  https://doi.org/10.1055/s-0032-1325924 PubMedCrossRefGoogle Scholar
  179. 179.
    Chavanet P (2013) The ZEPHyR study: a randomized comparison of linezolid and vancomycin for MRSA pneumonia. Med Mal Infect 43(11-12):451–455.  https://doi.org/10.1016/j.medmal.2013.09.011 PubMedCrossRefGoogle Scholar
  180. 180.
    Liapikou A, Cilloniz C, Torres A (2015) Ceftobiprole for the treatment of pneumonia: a European perspective. Drug Des Devel Ther 9:4565–4572.  https://doi.org/10.2147/DDDT.S56616 PubMedPubMedCentralGoogle Scholar
  181. 181.
    Pugh R, Grant C, Cooke RP, Dempsey G (2011) Short-course versus prolonged-course antibiotic therapy for hospital-acquired pneumonia in critically ill adults. Cochrane Libr.  https://doi.org/10.1002/14651858.CD007577.pub2 Google Scholar
  182. 182.
    Dimopoulos G, Poulakou G, Pneumatikos IA, Armaganidis A, Kollef MH, Matthaiou DK (2013) Short- vs long-duration antibiotic regimens for ventilator-associated pneumonia: a systematic review and meta-analysis. Chest 144(6):1759–1767.  https://doi.org/10.1378/chest.13-0076 PubMedCrossRefGoogle Scholar
  183. 183.
    Solomkin JS, Mazuski JE, Bradley JS, Rodvold KA, Goldstein EJ, Baron EJ et al (2010) Diagnosis and management of complicated intra-abdominal infection in adults and children: guidelines by the Surgical Infection Society and the Infectious Diseases Society of America. Surg Infect (Larchmt) 11(1):79–109.  https://doi.org/10.1089/sur.2009.9930 CrossRefGoogle Scholar
  184. 184.
    Torrens G, Cabot G, Ocampo-Sosa AA, Conejo MC, Zamorano L, Navarro F et al (2016) Activity of ceftazidime-avibactam against clinical and isogenic laboratory pseudomonas aeruginosa isolates expressing combinations of most relevant β‑lactam resistance mechanisms. Antimicrob Agents Chemother 60(10):6407–6410.  https://doi.org/10.1128/AAC.01282-16 PubMedPubMedCentralCrossRefGoogle Scholar
  185. 185.
    Mazuski JE, Gasink LB, Armstrong J, Broadhurst H, Stone GG, Rank D et al (2016) Efficacy and safety of ceftazidime-avibactam plus metronidazole versus meropenem in the treatment of complicated intra-abdominal infection: results from a randomized, controlled, double-blind, phase 3 program. Clin Infect Dis 62(11):1380–1389.  https://doi.org/10.1093/cid/ciw133 PubMedPubMedCentralCrossRefGoogle Scholar
  186. 186.
    Solomkin J, Hershberger E, Miller B, Popejoy M, Friedland I, Steenbergen J et al (2015) Ceftolozane/tazobactam plus metronidazole for complicated intra-abdominal infections in an era of multidrug resistance: results from a randomized, double-blind, phase 3 trial (ASPECT-cIAI). Clin Infect Dis 60(10):1462–1471.  https://doi.org/10.1093/cid/civ097 PubMedPubMedCentralCrossRefGoogle Scholar
  187. 187.
    Schöfer H et al (2011) Diagnostik und Therapie Staphylococcus aureus bedingter Infektionen der Haut und Schleimhäute. J Deutsch Dermatol Ges 9(11):953–968Google Scholar
  188. 188.
    Rhodes NJ, MacVane SH, Kuti JL, Scheetz MH (2014) Impact of loading doses on the time to adequate predicted beta-lactam concentrations in prolonged and continuous infusion dosing schemes. Clin Infect Dis 59(6):905–907.  https://doi.org/10.1093/cid/ciu402 PubMedCrossRefGoogle Scholar
  189. 189.
    Craig WA (1998) Pharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing of mice and men. Clin Infect Dis 26(1):1–10.  https://doi.org/10.1086/516284 PubMedCrossRefGoogle Scholar
  190. 190.
    Roberts JA, Abdul-Aziz MH, Lipman J, Mouton JW, Vinks AA, Felton TW et al (2014) Individualised antibiotic dosing for patients who are critically ill: challenges and potential solutions. Lancet Infect Dis 14(6):498–509.  https://doi.org/10.1016/S1473-3099(14)70036-2 PubMedPubMedCentralCrossRefGoogle Scholar
  191. 191.
    Pletz MW, Bloos F, Burkhardt O, Brunkhorst FM, Bode-Boger SM, Martens-Lobenhoffer J et al (2010) Pharmacokinetics of moxifloxacin in patients with severe sepsis or septic shock. Intensive Care Med 36(6):979–983.  https://doi.org/10.1007/s00134-010-1864-y PubMedCrossRefGoogle Scholar
  192. 192.
    van Zanten AR, Polderman KH, van Geijlswijk IM, van der Meer GY, Schouten MA, Girbes AR (2008) Ciprofloxacin pharmacokinetics in critically ill patients: a prospective cohort study. J Crit Care 23(3):422–430.  https://doi.org/10.1016/j.jcrc.2007.11.011 PubMedCrossRefGoogle Scholar
  193. 193.
    Blot S, Koulenti D, Akova M, Bassetti M, De Waele JJ, Dimopoulos G et al (2014) Does contemporary vancomycin dosing achieve therapeutic targets in a heterogeneous clinical cohort of critically ill patients? Data from the multinational DALI study. Crit Care 18(3):R99.  https://doi.org/10.1186/cc13874 PubMedPubMedCentralCrossRefGoogle Scholar
  194. 194.
    Moore RD, Smith CR, Lietman PS (1984) Association of aminoglycoside plasma levels with therapeutic outcome in gram-negative pneumonia. Am J Med 77(4):657–662.  https://doi.org/10.1016/0002-9343(84)90358-9 PubMedCrossRefGoogle Scholar
  195. 195.
    Men P, Li H‑B, Zhai S‑D, Zhao R‑S (2016) Association between the AUC 0‑24/MIC ratio of vancomycin and its clinical effectiveness: a systematic review and meta-analysis. PLOS ONE 11(1):e146224.  https://doi.org/10.1371/journal.pone.0146224 PubMedPubMedCentralCrossRefGoogle Scholar
  196. 196.
    Chelluri L, Jastremski MS (1987) Inadequacy of standard aminoglycoside loading doses in acutely ill patients. Crit Care Med 15(12):1143–1145PubMedCrossRefGoogle Scholar
  197. 197.
    Kohanski MA, DePristo MA, Collins JJ (2010) Sublethal antibiotic treatment leads to multidrug resistance via radical-induced mutagenesis. Mol Cell 37(3):311–320.  https://doi.org/10.1016/j.molcel.2010.01.003 PubMedPubMedCentralCrossRefGoogle Scholar
  198. 198.
    Drusano GL (2004) Antimicrobial pharmacodynamics: critical interactions of ‘bug and drug’. Nat Rev Microbiol 2(4):289–300.  https://doi.org/10.1038/nrmicro862 PubMedCrossRefGoogle Scholar
  199. 199.
    Olofsson SK, Cars O (2007) Optimizing drug exposure to minimize selection of antibiotic resistance. Clin Infect Dis 45(Supplement 2):S129–S136.  https://doi.org/10.1086/519256 PubMedCrossRefGoogle Scholar
  200. 200.
    Udy AA, Lipman J, Jarrett P, Klein K, Wallis SC, Patel K et al (2015) Are standard doses of piperacillin sufficient for critically ill patients with augmented creatinine clearance? Crit Care 19(1).  https://doi.org/10.1186/s13054-015-0750-y PubMedPubMedCentralGoogle Scholar
  201. 201.
    Mouton JW, Ambrose PG, Canton R, Drusano GL, Harbarth S, MacGowan A et al (2011) Conserving antibiotics for the future: new ways to use old and new drugs from a pharmacokinetic and pharmacodynamic perspective. Drug Resist Updat 14(2):107–117.  https://doi.org/10.1016/j.drup.2011.02.005 PubMedCrossRefGoogle Scholar
  202. 202.
    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.  https://doi.org/10.1093/cid/ciu027 PubMedCrossRefGoogle Scholar
  203. 203.
    McKinnon PS, Paladino JA, Schentag JJ (2008) Evaluation of area under the inhibitory curve (AUIC) and time above the minimum inhibitory concentration (T>MIC) as predictors of outcome for cefepime and ceftazidime in serious bacterial infections. Int J Antimicrob Agents 31(4):345–351.  https://doi.org/10.1016/j.ijantimicag.2007.12.009 PubMedCrossRefGoogle Scholar
  204. 204.
    Drusano G, Lodise T, Melnick D, Liu W, Oliver A, Mena A et al (2011) Meropenem penetration into epithelial lining fluid in mice and humans and delineation of exposure targets. Antimicrob Agents Chemother 55(7):3406–3412.  https://doi.org/10.1128/AAC.01559-10 PubMedPubMedCentralCrossRefGoogle Scholar
  205. 205.
    Lodise T, Sorgel F, Melnick D, Mason B, Kinzig M, Drusano G (2011) Penetration of meropenem into epithelial lining fluid of patients with ventilator-associated pneumonia. Antimicrob Agents Chemother 55(4):1606–1610.  https://doi.org/10.1128/AAC.01330-10 PubMedPubMedCentralCrossRefGoogle Scholar
  206. 206.
    Lodise T, Nau R, Kinzig M, Drusano G, Jones R, Sörgel F (2007) Pharmacodynamics of ceftazidime and meropenem in cerebrospinal fluid: results of population pharmacokinetic modelling and Monte Carlo simulation. J Antimicrob Chemother 60(5):1038–1044.  https://doi.org/10.1093/jac/dkm325 PubMedCrossRefGoogle Scholar
  207. 207.
    Lodise TP, Butterfield J (2011) Use of pharmacodynamic principles to inform β‑lactam dosing: “S” does not always mean success. J Hosp Med 6(S1):S16–S23PubMedCrossRefGoogle Scholar
  208. 208.
    Tam VH, Schilling AN, Neshat S, Poole K, Melnick DA, Coyle EA (2005) Optimization of meropenem minimum concentration/MIC ratio to suppress in vitro resistance of pseudomonas aeruginosa. Antimicrob Agents Chemother 49(12):4920–4927.  https://doi.org/10.1128/AAC.49.12.4920-4927.2005 PubMedPubMedCentralCrossRefGoogle Scholar
  209. 209.
    Taccone FS, Laterre P‑F, Dugernier T, Spapen H, Delattre I, Wittebole X et al (2010) Insufficient β‑lactam concentrations in the early phase of severe sepsis and septic shock. Crit Care 14(4):R126.  https://doi.org/10.1186/cc9091 PubMedPubMedCentralCrossRefGoogle Scholar
  210. 210.
    Udy AA, Varghese JM, Altukroni M, Briscoe S, McWhinney BC, Ungerer JP et al (2012) Subtherapeutic initial beta-lactam concentrations in select critically ill patients: association between augmented renal clearance and low trough drug concentrations. Chest 142(1):30–39.  https://doi.org/10.1378/chest.11-1671 PubMedCrossRefGoogle Scholar
  211. 211.
    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.  https://doi.org/10.1093/jac/dkv201 PubMedGoogle Scholar
  212. 212.
    Lodise TP, Lomaestro B, Drusano GL (2007) Piperacillin-tazobactam for Pseudomonas aeruginosa infection: clinical implications of an extended-infusion dosing strategy. Clin Infect Dis 44(3):357–363.  https://doi.org/10.1086/510590 PubMedCrossRefGoogle Scholar
  213. 213.
    Lee LS, Kinzig-Schippers M, Nafziger AN, Ma L, Sorgel F, Jones RN et al (2010) Comparison of 30-min and 3‑h infusion regimens for imipenem/cilastatin and for meropenem evaluated by Monte Carlo simulation. Diagn Microbiol Infect Dis 68(3):251–258.  https://doi.org/10.1016/j.diagmicrobio.2010.06.012 PubMedCrossRefGoogle Scholar
  214. 214.
    Abdul-Aziz MH, Lipman J, Akova M, Bassetti M, De Waele JJ, Dimopoulos G et al (2016) Is prolonged infusion of piperacillin/tazobactam and meropenem in critically ill patients associated with improved pharmacokinetic/pharmacodynamic and patient outcomes? An observation from the Defining Antibiotic Levels in Intensive care unit patients (DALI) cohort. J Antimicrob Chemother 71(1):196–207.  https://doi.org/10.1093/jac/dkv288 PubMedCrossRefGoogle Scholar
  215. 215.
    Taubert M, Zander J, Frechen S, Scharf C, Frey L, Vogeser M et al (2017) Optimization of linezolid therapy in the critically ill: the effect of adjusted infusion regimens. J Antimicrob Chemother 72(8):2304–2310.  https://doi.org/10.1093/jac/dkx149 PubMedGoogle Scholar
  216. 216.
    Carlier M, Carrette S, Roberts JA, Stove V, Verstraete A, Hoste E et al (2013) Meropenem and piperacillin/tazobactam prescribing in critically ill patients: does augmented renal clearance affect pharmacokinetic/pharmacodynamic target attainment when extended infusions are used? Crit Care 17(3):R84.  https://doi.org/10.1186/cc12705 PubMedPubMedCentralCrossRefGoogle Scholar
  217. 217.
    Patel BM, Paratz J, See NC, Muller MJ, Rudd M, Paterson D et al (2012) Therapeutic drug monitoring of beta-lactam antibiotics in burns patients—a one-year prospective study. Ther Drug Monit 34(2):160–164.  https://doi.org/10.1097/FTD.0b013e31824981a6 PubMedCrossRefGoogle Scholar
  218. 218.
    Dulhunty JM, Roberts JA, Davis JS, Webb SA, Bellomo R, Gomersall C et al (2015) A multicenter randomized trial of continuous versus intermittent β‑lactam infusion in severe sepsis. Am J Respir Crit Care Med 192(11):1298–1305.  https://doi.org/10.1164/rccm.201505-0857OC PubMedCrossRefGoogle Scholar
  219. 219.
    Frey OR, Köberer A, Röhr AC, Preisenberger JA, Brinkmann A (2013) Optimale Dosierung und Applikation von Antiinfektiva. intensiv 21(05):264–267.  https://doi.org/10.1055/s-0033-1355148 CrossRefGoogle Scholar
  220. 220.
    Hayashi Y, Lipman J, Udy AA, Ng M, McWhinney B, Ungerer J et al (2013) β‑lactam therapeutic drug monitoring in the critically ill: optimising drug exposure in patients with fluctuating renal function and hypoalbuminaemia. Int J Antimicrob Agents 41(2):162–166.  https://doi.org/10.1016/j.ijantimicag.2012.10.002 PubMedCrossRefGoogle Scholar
  221. 221.
    Nosseir N, Michels G, Pfister R, Adam R, Wiesen M, Müller C (2014) Therapeutisches Drug Monitoring (TDM) von Antiinfektiva in der Intensivmedizin. Dtsch Med Wochenschr 139(38):1889–1894.  https://doi.org/10.1055/s-0034-1387215 PubMedCrossRefGoogle Scholar
  222. 222.
    Roberts JA, Norris R, Paterson DL, Martin JH (2012) Therapeutic drug monitoring of antimicrobials. Br J Clin Pharmacol 73(1):27–36.  https://doi.org/10.1111/j.1365-2125.2011.04080.x PubMedPubMedCentralCrossRefGoogle Scholar
  223. 223.
    Wong G, Sime FB, Lipman J, Roberts JA (2014) How do we use therapeutic drug monitoring to improve outcomes from severe infections in critically ill patients? BMC Infect Dis.  https://doi.org/10.1186/1471-2334-14-288 Google Scholar
  224. 224.

Copyright information

© Springer Medizin Verlag GmbH 2017

Authors and Affiliations

  • D. C. Richter
    • 1
  • A. Heininger
    • 2
  • T. Brenner
    • 1
  • M. Hochreiter
    • 1
  • M. Bernhard
    • 3
  • J. Briegel
    • 4
  • S. Dubler
    • 1
  • B. Grabein
    • 5
  • A. Hecker
    • 6
  • W. A. Krüger
    • 7
  • K. Mayer
    • 8
  • M. W. Pletz
    • 9
  • D. Störzinger
    • 8
  • N. Pinder
    • 8
  • T. Hoppe-Tichy
    • 2
  • S. Weiterer
    • 1
  • S. Zimmermann
    • 2
  • A. Brinkmann
    • 10
  • M. A. Weigand
    • 1
  • Christoph Lichtenstern
    • 1
  1. 1.Klinik für AnästhesiologieUniversitätsklinikum HeidelbergHeidelbergDeutschland
  2. 2.Zentrum für Infektiologie, Sektion für Krankenhaus- und UmwelthygieneUniversitätsklinikum HeidelbergHeidelbergDeutschland
  3. 3.Zentrale NotaufnahmeUniversitätsklinikum LeipzigLeipzigDeutschland
  4. 4.Klinik für AnästhesiologieKlinikum der Universität MünchenMünchenDeutschland
  5. 5.Stabsstelle „Klinische Mikrobiologie und Krankenhaushygiene“Klinikum der Universität MünchenMünchenDeutschland
  6. 6.Klinik für Allgemein‑, Viszeral‑, Thorax‑, Transplantations- und KinderchirurgieUniversitätsklinikum Gießen und Marburg, Standort GießenGießenDeutschland
  7. 7.Klinik für Anästhesiologie und operative IntensivmedizinGesundheitsverbund Landkreis Konstanz, Klinikum KonstanzKonstanzDeutschland
  8. 8.Apotheke des Universitätsklinikums HeidelbergHeidelbergDeutschland
  9. 9.Zentrum für Infektionsmedizin und KrankenhaushygieneUniversitätsklinikum JenaJenaDeutschland
  10. 10.Klinik für Anästhesie, operative Intensivmedizin und spezielle SchmerztherapieKlinikum HeidenheimHeidenheimDeutschland

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