id000053
10.3205/id000053
urn:nbn:de:0183-id0000533
Leitlinie
Guideline
Kalkulierte parenterale Initialtherapie bakterieller Infektionen: Sepsis
Calculated initial parenteral treatment of bacterial infections: Sepsis
Bodmann
Bodmann
Klaus-Friedrich
KF
Dr.
Klinik für Internistische Intensiv- und Notfallmedizin und Klinische Infektiologie, Klinikum Barnim GmbH, Werner Forßmann Krankenhaus, Rudolf-Breitscheid-Straße 100, 16225 Eberswalde, DeutschlandKlinik für Internistische Intensiv- und Notfallmedizin und Klinische Infektiologie, Klinikum Barnim GmbH, Werner Forßmann Krankenhaus, Eberswalde, Deutschland
Klinik für Internistische Intensiv- und Notfallmedizin und Klinische Infektiologie, Klinikum Barnim GmbH, Werner Forßmann Krankenhaus, Rudolf-Breitscheid-Straße 100, 16225 Eberswalde, GermanyKlinik für Internistische Intensiv- und Notfallmedizin und Klinische Infektiologie, Klinikum Barnim GmbH, Werner Forßmann Krankenhaus, Eberswalde, Germany
kf.bodmann@klinikum-barnim.de
author
Höhl
Höhl
Rainer
R
Institut für Klinikhygiene, Medizinische Mikrobiologie und Klinische Infektiologie, Klinikum Nürnberg, DeutschlandInstitut für Klinikhygiene, Medizinische Mikrobiologie und Klinische Infektiologie, Klinikum Nürnberg, Deutschland
Institut für Klinikhygiene, Medizinische Mikrobiologie und Klinische Infektiologie, Klinikum Nürnberg, GermanyInstitut für Klinikhygiene, Medizinische Mikrobiologie und Klinische Infektiologie, Klinikum Nürnberg, Germany
author
Krüger
Krüger
Wolfgang
W
Klinik für Anästhesiologie und Operative Intensivmedizin, Klinikum Konstanz, DeutschlandKlinik für Anästhesiologie und Operative Intensivmedizin, Klinikum Konstanz, Deutschland
Klinik für Anästhesiologie und Operative Intensivmedizin, Klinikum Konstanz, GermanyKlinik für Anästhesiologie und Operative Intensivmedizin, Klinikum Konstanz, Germany
author
Grabein
Grabein
Beatrice
B
Stabsstelle Klinische Mikrobiologie und Krankenhaushygiene, Klinikum der Universität München, München, DeutschlandStabsstelle Klinische Mikrobiologie und Krankenhaushygiene, Klinikum der Universität München, München, Deutschland
Stabsstelle Klinische Mikrobiologie und Krankenhaushygiene, Klinikum der Universität München, Munich, GermanyStabsstelle Klinische Mikrobiologie und Krankenhaushygiene, Klinikum der Universität München, Munich, Germany
author
Graninger
Graninger
Wolfgang
W
Wien, ÖsterreichWien, Österreich
Vienna, AustriaVienna, Austria
author
German Medical Science GMS Publishing House
Düsseldorf
610
Calculated parenteral initial therapy
Kalkulierte parenterale Initialtherapie
20200326
germ
engl
This is an Open Access article distributed under the terms of the Creative Commons Attribution 4.0 License.
Dieser Artikel ist ein Open-Access-Artikel und steht unter den Lizenzbedingungen der Creative Commons Attribution 4.0 License (Namensnennung).
2195-8831
8
GMS Infectious Diseases
GMS Infect Dis
09
Dies ist das elfte Kapitel der von der Paul-Ehrlich-Gesellschaft für Chemotherapie e.V. (PEG) herausgegebenen S2k Leitlinie „Kalkulierte parenterale Initialtherapie bakterieller Erkrankungen bei Erwachsenen – Update 2018“ in der 2. aktualisierten Fassung.Sepsis als die dritthäufigste Todesursache in Deutschland mit einer Letalität von 30 bis über 50% ist definiert als lebensbedrohliche Organdysfunktion, die durch eine fehlregulierte Wirtsantwort auf eine Infektion hervorgerufen wird. Die frühe, wirksame antimikrobielle Therapie stellt neben der Fokussanierung/-kontrolle die wichtigste kausale Behandlungsoption dar, ergänzt durch die allgemeine Intensivtherapie mit ihren vor allem supportiven Maßnahmen. Eine antimikrobielle Vortherapie, die Vorgeschichte des Patienten (z.B. Risikofaktoren für multiresistente Erreger) und die Kleinraumepidemiologie sollten unbedingt in die therapeutischen und praktischen Erwägungen einbezogen werden. Eine Modifizierung der zunächst oft breit notwendigen kalkulierten Kombinationstherapie ist anzustreben. In Zukunft wird der zeitnahen Plasmakonzentrationsbestimmung von Antiinfektiva gerade beim Sepsis-Patienten mit seinen vielfältigen, teils gegenläufigen pathophysiologischen Veränderungen eine herausragende Bedeutung im Hinblick auf Wirksamkeit, Toxizität und Resistenzentwicklung zukommen. Um diese komplexen Strategien im klinischen Alltag erfolgreich umsetzen zu können, bedarf es der engen Zusammenarbeit des Intensivmediziners/Klinikers mit der klinischen Infektiologie, der Mikrobiologie und der klinischen Pharmakologie, idealerweise im Rahmen eines funktionierenden Antimicrobial Stewardship Programmes.
This is the eleventh chapter of the guideline “Calculated initial parenteral treatment of bacterial infections in adults – update 2018” in the 2nd updated version. The German guideline by the Paul-Ehrlich-Gesellschaft für Chemotherapie e.V. (PEG) has been translated to address an international audience.Sepsis, defined as a life threatening organ dysfunction caused by a misregulated host response to an infection, is the third leading cause of death in Germany with a lethality rate of 30% to over 50%. An early, effective antimicrobial therapy is, next to infectious source control, the most important causal treatment option. It should be complemented by the mainly supportive measures of general intensive care therapy. Prior antimicrobial therapy, the patient’s medical history (e.g. risk factors for multiresistant agents) and small-scale epidemiology are to be considered as part of the therapeutic and practical decisions. A modification of the often needed broad initial calculated combination therapy is desirable. In the future, prompt measurements of plasma concentrations of antiinfectives, especially for the sepsis patient with diverse and partly conflicting pathophysiological changes, will have great importance regarding efficacy, toxicity and resistance development. In order to apply those complex strategies in clinical routine, there is a requirement for a strong interdisciplinary collaboration between the intensive care unit, clinical infectiology, microbiology, and clinical pharmacology, ideally in the framework of a functional antimicrobial stewardship program.
EinleitungDie Therapie der Sepsis, vor allem mit zunehmend multiresistenten bzw. Selektions-Erregern (Akronym „ESCAPE“ ), stellt für den klinisch tätigen Arzt eine der größten Herausforderungen dar , .Insbesondere im Bereich der Intensivmedizin kommt der Sepsis und dem septischen Schock aufgrund steigender Inzidenz und leicht fallender Letalität von 30–50% bei hohen Kosten eine besondere Bedeutung zu.Im Jahr 2013 haben deutsche Krankenhäuser laut einer Erhebung von Fleischmann et al. 279.530 Sepsis-Fälle an das Institut für das Entgeltsystem im Krankenhaus (InEK) gemeldet, wobei 67.849 dieser Patienten (24,3%) verstarben. Besonders hoch erscheint die Sterblichkeitsrate bei Patienten mit schwerer Sepsis (60,3%). Die Sepsis stellt damit die dritthäufigste Todesursache in Deutschland dar.Ergänzt werden diese Daten durch eine prospektive, multizentrische Punkt-Prävalenz Studie (INSEP Study), in die 11.883 Patienten von 133 deutschen Intensivstationen eingeschlossen wurden. Davon hatten 1.503 Patienten (12,6%) die Diagnose einer schweren Sepsis oder eines septischen Schocks, wovon 860 Fälle (57,2%) nosokomialen Ursprungs waren. Die Letalität der Patienten mit Sepsis betrug 34,3% während des intensivstationären Aufenthalts, im Vergleich zu 6% der Patienten ohne Sepsis. Insgesamt bestätigte diese Studie die Tendenz zur leicht fallenden Letalität im Vergleich zu früheren Untersuchungen bei gleichzeitig steigender Prävalenz der Sepsis .Der internationale Vergleich zur Inzidenz und Letalität der Sepsis fällt schwer, da sich die Krankheitsbilder, <![CDATA[Alterss</PlainText></TextGroup>trukturen, epidemiologisch verfügbaren Daten und Kriterien für die Aufnahme in Krankenhäuser oder Intensivstationen zwischen den Ländern deutlich unterscheiden. Mit diesen Einschränkungen wird die Letalität der schweren Sepsis mit durchschnittlich 28% beziffert <TextLink reference="6"></TextLink>.</Pgraph><Pgraph>Beim nicht neutropenischen Intensivpatienten muss auch an Pilzinfektionen gedacht werden. In der deutschen Prävalenzstudie <TextLink reference="7"></TextLink> wurden in 17,8% der Fälle Pilze als Ursache der schweren Sepsis mikrobiologisch nachgewiesen. In den USA sind Candida spp. inzwischen der dritthäufigste Erreger in Blutkulturen von Patienten auf der Intensivstation <TextLink reference="8"></TextLink>, in Deutschland der vierthäufigste mit der höchsten Erreger-assoziierten Letalität <TextLink reference="9"></TextLink>.</Pgraph><Pgraph>Zu den disponierenden Erkrankungen einer Sepsis gehören alle Formen der Abwehrschwäche, z.B. Tumorleiden, Diabetes mellitus, Nieren-, Lebererkrankungen und Hämoblastosen, im Bereich der operativen Intensivmedizin z.B. Polytraumen, Verbrennungen und große risikoreiche Eingriffe wie z.B. Organtransplantationen. Die wirksame antimikrobielle Therapie stellt neben der frühen Fokussanierung die wichtigste kausale Behandlungsoption dar. Sie wird ergänzt durch die allgemeine Intensivtherapie mit ihren vor allem supportiven Maßnahmen <TextLink reference="10"></TextLink>.</Pgraph><Pgraph>Nach heutigem Kenntnisstand erscheint die mikrobielle Sepsis immer noch am besten in der Formulierung von Schuster <TextLink reference="11"></TextLink> beschrieben: „Sepsis ist die Gesamtheit der lebensbedrohlichen klinischen Krankheitserscheinungen und pathophysiologischen Veränderungen als Reaktion auf die Aktion pathogener Erreger und ihrer Produkte, die aus einem Infektionsherd in den Blutstrom eindringen, die großen biologischen Kaskadensysteme und spezielle Zellsysteme aktivieren und die Bildung und Freisetzung humoraler und zellulärer Mediatoren auslösen.“</Pgraph><Pgraph>Die bisher geltenden Kriterien zur Diagnose der Sepsis bestanden aus dem Nachweis einer Infektion und mindestens zwei der vier nachfolgenden Kriterien <TextLink reference="12"></TextLink></Pgraph><Pgraph><OrderedList><ListItem level="1" levelPosition="1" numString="1.">Fieber über 38°C oder in seltenen Fällen Hypothermie unter 36°C</ListItem><ListItem level="1" levelPosition="2" numString="2.">Tachypnoe über 20/min oder Hypokapnie mit einem PaCO<Subscript>2</Subscript><32 mm Hg</ListItem><ListItem level="1" levelPosition="3" numString="3.">Tachykardie über 90/min</ListItem><ListItem level="1" levelPosition="4" numString="4.">Leukozytose über 12.000/mm<Superscript>3</Superscript> oder Leukopenie unter 4.000/mm<Superscript>3</Superscript> oder bei normaler Leukozytenzahl Linksverschiebung im Differentialblutbild (mehr als 10% unreife Formen) </ListItem></OrderedList></Pgraph><Pgraph>Die Reduktion auf diese vier „SIRS-Kriterien“ bzw. die Notwendigkeit von ≥2 der Kriterien wurde nicht unkritisch gesehen, da einerseits bis zu einem Viertel der Sepsis-Fälle damit nicht erfasst, andererseits die SIRS-Kriterien auch bei einfachen, nicht-komplizierten Infektionen erfüllt wurden <TextLink reference="13"></TextLink>, <TextLink reference="14"></TextLink>, <TextLink reference="15"></TextLink>. Septische Zustandsbilder wurden gemäß der alten amerikanischen Konsensus-Definition in verschiedene klinische Schweregrade eingeteilt: SIRS, Sepsis, schwere Sepsis, septischer Schock.</Pgraph><Pgraph>Eine Task-Force aus 19 Experten hat im Auftrag der beiden weltweit führenden Fachgesellschaften ESICM (European Society of Intensive Care Medicine) und SCCM (So<TextGroup><PlainText>c</PlainText></TextGroup>iety of Critical Care Medicine) die Definition der Sepsis überarbeitet, die nun als „Sepsis-3“ bezeichnet wird <TextLink reference="16"></TextLink>, <TextLink reference="17"></TextLink>, <TextLink reference="18"></TextLink>. Danach wird Sepsis definiert als „lebensbedrohliche Organdysfunktion, die durch eine fehlregulierte Wirtsantwort auf eine Infektion hervorgerufen wird“, d.h. die neue „Sepsis“ ist die alte „schwere Sepsis“. Im Zentrum steht jetzt der SOFA-Score; die SIRS-Kriterien zur systemischen Entzündungsreaktion des Körpers wurden gestrichen. Ein „qSOFA“ (quick SOFA) soll ein Screening ohne Labortests bei Patienten, die nicht auf der Intensivstation liegen, erleichtern (Abbildung 1 <ImgLink imgNo="1" imgType="figure"/>):</Pgraph><Pgraph><UnorderedList><ListItem level="1">Atemfrequenz ≥22/min</ListItem><ListItem level="1">Verändertes Bewusstsein (GCS<15)</ListItem><ListItem level="1">Systolischer Blutdruck ≤100 mm Hg</ListItem></UnorderedList></Pgraph><Pgraph>Der qSOFA wird positiv gewertet, wenn ≥2 Kriterien erfüllt sind: weitere Suche nach Organdysfunktion (SOFA-Score) anschließen, Therapie beginnen bzw. eskalieren, Monitoring intensivieren.</Pgraph><Pgraph>Organdysfunktion ist definiert als eine akute Veränderung des SOFA Scores ≥2 Punkte als Folge der Infektion (Sterblichkeit ≥10%). Der Ausgangs-SOFA-Score wird bei Patienten ohne vorbekannte Organdysfunktion als Null angenommen. Die SOFA-Score-Parameter sind Respiration, Gerinnung, Leber, Herz-Kreislauf, ZNS, Niere.</Pgraph><Pgraph>Der septische Schock wird definiert als: Sepsis + Vasopressoren-Gabe erforderlich, um bei persistierender Hypotonie einen mittleren arteriellen Blutdruck <TextGroup><PlainText>≥65 mm Hg</PlainText></TextGroup> aufrecht zu erhalten + Serum-Laktat >2 mmol/l (<TextGroup><PlainText>>18 m</PlainText></TextGroup>g/dl) trotz adäquater Volumensubstitution. Bei septischem Schock übersteigt die Krankenhaussterblichkeit 40%. </Pgraph><Pgraph>Die pathophysiologischen Erkenntnisse der vergangenen Jahre zeigen, dass septische Zustandsbilder durch ein kompliziertes Netzwerk pro- und antiinflammatorischer Zytokine bedingt sind <TextLink reference="19"></TextLink>, <TextLink reference="20"></TextLink>. Das Sepsis-Geschehen ist ein dynamischer Prozess des Übergangs vom Stadium der „einfachen Sepsis“ zur „schweren Sepsis“ bzw. in den „septischen Schock“ mit Organdysfunktion bzw. Organversagen, aber auch der Entwicklung von septischen Organbesiedlungen. Eine detaillierte Darlegung der intensivmedizinischen supportiven und adjunktiven Therapie-Maßnahmen ginge über die Zielsetzung der vorliegenden Leitlinien zur kalkulierten anti-infektiven Initialtherapie deutlich hinaus. Hierzu verweisen wir auf die aktuellen Guidelines der Surviving Sepsis Campaign <TextLink reference="21"></TextLink>. </Pgraph><Pgraph>Entscheidend für das Überleben der Patienten ist die <TextGroup><PlainText>rasche</PlainText></TextGroup> adäquate antimikrobielle Therapie und, wann immer möglich, die frühe Fokussanierung in den ersten Stunden. Kumar konnte in einer retrospektiven Studie von 2006 <TextLink reference="22"></TextLink> zeigen, dass mit jeder Stunde Therapieverzögerung nach Beginn der Hypotension im septischen Schock die Sterblichkeit um 7,6% steigt. In der Folgezeit wurden z.T. widersprüchliche Studien zu diesem Thema veröffentlicht. Zuletzt scheint eine Metaanalyse <TextLink reference="23"></TextLink> nahezulegen, dass kein Letalitätsbenefit besteht, wenn Antibiotika bei Sepsis innerhalb der ersten 3 Stunden nach Ersteinschätzung in der Notfallambulanz bzw. eine Stunde nach Beginn des septischen Schocks verabreicht wurden. Neben methodischen Schwächen (7 Studien konnten wegen misslungener Kommunikation mit den Autoren nicht einbezogen werden), wurde keine einzige randomisierte, kontrollierte Studie eingeschlossen, weil eine solche nicht existierte. Darüber hinaus waren die Studien nicht limitiert auf solche mit adäquater, effektiver Therapie und es wurde keine Aussage zu multiresistenten Erregern oder zur Fokussanierung gemacht. </Pgraph><Pgraph>In den aktuellen Guidelines der Surviving Sepsis Campaign wird eine starke Empfehlung für die intravenöse Antibiotikagabe spätestens innerhalb einer Stunde nach Diagnosestellung der Sepsis oder des septischen Schocks ausgesprochen, auch wenn die Evidenz für dieses Vorgehen als moderat eingestuft wird <TextLink reference="21"></TextLink>. Dies wird durch weitere aktuelle Daten <TextLink reference="24"></TextLink>, auch aus Deutschland <TextLink reference="25"></TextLink>, unterstützt. </Pgraph><Pgraph>Aufgrund der Zunahme multiresistenter Erreger (MRSA, VRE, vor allem aber <Mark2>Acinetobacter</Mark2> <Mark2>baumannii</Mark2>, <Mark2>Pseudomonas</Mark2> <Mark2>aeruginosa</Mark2> und Enterobacteriaceae vom Typ 3MRGN und 4MRGN) <TextLink reference="26"></TextLink> muss häufig eine breit wirksame, auch kombinierte antimikrobielle Therapie begonnen werden, um das Erregerspektrum ausreichend zu erfassen <TextLink reference="27"></TextLink>. Eine antimikrobielle Vortherapie und die Vorgeschichte des Patienten (z.B. Risikofaktoren für MRGN-Erreger) sollten unbedingt in die therapeutischen und praktischen Erwägungen (z.B. Isolierung) einbezogen werden.</Pgraph><Pgraph>Die Notwendigkeit der antimikrobiellen Therapie sollte täglich überdacht <TextLink reference="28"></TextLink> und reevaluiert werden <TextLink reference="29"></TextLink>. Bei einer Kombinationstherapie sollte nach Erhalt der mikrobiologischen Befunde deeskaliert werden (weniger breit, Absetzen eines Kombinationspartners) <TextLink reference="30"></TextLink>. </Pgraph><Pgraph>In der physiologisch und pharmakologisch komplexen Situation der Sepsis wird empfohlen, zunächst (d.h. in den ersten Tagen) hochdosiert zu therapieren, um schnell suffiziente Wirkspiegel beim Sepsis-Patienten mit hohem Verteilungsvolumen und mit anfangs häufig im Rahmen der hyperdynamen Kreislaufsituation erhöhter Kreatinin-Clearance zu erzielen <TextLink reference="31"></TextLink>. Es existieren jedoch wenige Daten mit guter Evidenz zu diesem Thema. Auf Zeichen der Toxizität antimikrobieller Substanzen und mögliche Interaktionen ist stets zu achten. An den Folgetagen sollte die Dosierung an die Organinsuffizienzen (Niere, Leber) angepasst werden. In Zukunft wird der Plasmakonzentrationsbestimmung von Antibiotika und Antimykotika gerade beim Sepsis-Patienten eine herausragende Bedeutung im Hinblick auf Wirksamkeit, Toxizität und Resistenzentwicklung zukommen <TextLink reference="31"></TextLink>, <TextLink reference="32"></TextLink>, <TextLink reference="33"></TextLink>, <TextLink reference="34"></TextLink>, <TextLink reference="35"></TextLink>.</Pgraph><Pgraph>Zur Steuerung der Therapie, vor allem zur Frage der Beendigung und der Wirksamkeit einer Antibiotika-Therapie, soll nach aktuellen Erkenntnissen neben der klinischen Einschätzung die mehrmalige Bestimmung von Procalcitonin (PCT) im Serum durchgeführt werden <TextLink reference="22"></TextLink>, <TextLink reference="36"></TextLink>, <TextLink reference="37"></TextLink>, <TextLink reference="38"></TextLink>, <TextLink reference="39"></TextLink>.</Pgraph><Pgraph>Um die genannten Strategien im klinischen Alltag erfolgreich umsetzen zu können, bedarf es der engen Zusammenarbeit des Intensivmediziners/Klinikers mit der klini<TextGroup><PlainText>s</PlainText></TextGroup>chen Infektiologie, der Mikrobiologie und der klinischen Pharmakologie. Der moderne Begriff „Antimicrobial <TextGroup><PlainText>Stew</PlainText></TextGroup>ardship“ <TextLink reference="40"></TextLink>, <TextLink reference="41"></TextLink> beschreibt dieses Vorgehen. Beispielsweise steigerte die infektiologische Beratung bei einer <Mark2>Staphylococcus-aureus</Mark2>-Bakteriämie signifikant die Behandlungsqualität und verringerte Letalität und Krankenhausliegedauer <TextLink reference="42"></TextLink>.</Pgraph><Pgraph>Sepsis ist insgesamt eine heterogene Erkrankung, die in der Frühphase schwierig zu diagnostizieren und in der Spätphase schwierig zu behandeln ist. Frühe Intervention verbessert die Prognose. Rasche und adäquate antimikrobielle Therapie, mikrobiologische Diagnostik, Fokuskontrolle und supportive Behandlung der Endorgandysfunktion sind die Eckpfeiler einer erfolgreichen Sepsis-Therapie. Eine antimikrobielle Übertherapie muss wegen der zu erwartenden Kollateralschäden dennoch vermieden werden <TextLink reference="43"></TextLink>.</Pgraph></TextBlock>
<TextBlock language="en" linked="yes" name="Introduction">
<MainHeadline>Introduction</MainHeadline><Pgraph>The treatment of sepsis, especially with increasingly multidrug-resistant or selective pathogens (acronym “ESCAPE” <TextLink reference="1"></TextLink>), represents one of the greatest challenges for clinically active physicians <TextLink reference="2"></TextLink>, <TextLink reference="3"></TextLink>.</Pgraph><Pgraph>Particularly in the field of intensive care, sepsis and septic shock are of particular importance due to increasing incidence, a slight drop in mortality of 30–50% and high costs.</Pgraph><Pgraph>In 2013, according to a survey by Fleischmann et al. <TextLink reference="4"></TextLink> 279,530 cases of sepsis were reported to the Institute for the Hospital Remuneration System (InEK), with 67,849 of these patients (24.3%) dying. The mortality rate appears to be particularly high in patients with severe sepsis (60.3%). Sepsis is the third leading cause of death in Germany.</Pgraph><Pgraph>These data are complemented by a prospective, multicen<TextGroup><PlainText>t</PlainText></TextGroup>er point-prevalence study (INSEP Study), in which 11,88<TextGroup><PlainText>3 p</PlainText></TextGroup>atients from 133 German intensive care units were investigated. Of these, 1,503 patients (12.6%) had a diagnosis of severe sepsis or septic shock, of which <TextGroup><PlainText>860 c</PlainText></TextGroup>ases (57.2%) were of nosocomial origin. The mortality of patients with sepsis was 34.3% during intensive care stay, compared to 6% of patients without sepsis. Overall, this study confirmed the tendency towards slightly lower mortality compared to previous studies but increasing prevalence of sepsis <TextLink reference="5"></TextLink>.</Pgraph><Pgraph>International comparisons of the incidence and mortality of sepsis are difficult as disease patterns, age structures, epidemiologically available data, and criteria for hospitalization or intensive care units differ significantly between countries. With these limitations, the mortality of severe sepsis is estimated at an average of 28% <TextLink reference="6"></TextLink>.</Pgraph><Pgraph>Fungal infections must be a consideration in patients in non-neutropenic intensive care. In the German prevalence study <TextLink reference="7"></TextLink>, fungi were detected microbiologically as the cause of severe sepsis in 17.8% of cases. In the US <Mark2>Candida</Mark2> spp. are now the third most frequent pathogen in blood cultures from patients in intensive care units <TextLink reference="8"></TextLink>, in Germany the fourth most frequent with the highest pathogen-associated mortality <TextLink reference="9"></TextLink>.</Pgraph><Pgraph>The predisposing diseases of sepsis include all forms of immune deficiency, such as tumors, diabetes mellitus, kidney and liver diseases and hemoblastosis, in the field of surgical intensive care for example polytrauma, burns and major high-risk procedures such as organ transplants. Effective antimicrobial treatment is the most important causal treatment option in addition to early source control. It is complemented by general intensive care with its mainly supportive measures <TextLink reference="10"></TextLink>.</Pgraph><Pgraph>According to current knowledge, Schuster’s definition of microbial sepsis is still considered the best <TextLink reference="11"></TextLink>: “Sepsis is the sum of the life-threatening clinical manifestations and pathophysiological changes in response to activity of pathogens and their products entering the bloodstream from a focal point of infection, activating large biological cascade systems and specialized cell systems and triggering the formation and release of humoral and cellular mediators.”</Pgraph><Pgraph>The current criteria for the diagnosis of sepsis consist of the detection of an infection and at least two of the following four criteria <TextLink reference="12"></TextLink>:</Pgraph><Pgraph><OrderedList><ListItem level="1" levelPosition="1" numString="1.">Fever above 38°C or in rare cases hypothermia below 36°C</ListItem><ListItem level="1" levelPosition="2" numString="2.">Tachypnea above 20/min or hypocapnia with a <TextGroup><PlainText>PaCO</PlainText><Subscript>2</Subscript><PlainText> <32 mm Hg</PlainText></TextGroup></ListItem><ListItem level="1" levelPosition="3" numString="3.">Tachycardia above 90/min</ListItem><ListItem level="1" levelPosition="4" numString="4.">Leukocytosis greater than 12,000/mm<Superscript>3</Superscript> or leukopenia less than 4,000/mm<Superscript>3</Superscript> or normal white blood cell count left shift in differential blood count (more than 10% immature forms) </ListItem></OrderedList></Pgraph><Pgraph>The reduction to these four “SIRS criteria” or the necessity of ≥2 of the criteria was not uncontroversial because on the one hand up to a quarter of cases of sepsis are not covered by them and on the other hand SIRS criteria have been met even by simple, uncomplicated infections <TextLink reference="13"></TextLink>, <TextLink reference="14"></TextLink>, <TextLink reference="15"></TextLink>. Septic conditions were classified into different degrees of clinical severity according to the old American consensus definition: SIRS, sepsis, severe sepsis, septic shock.</Pgraph><Pgraph>A task force of 19 experts has revised the definition of sepsis on behalf of the two world-leading societies ESICM (European Society of Intensive Care Medicine) and SCCM (Society of Critical Care Medicine), which is now called “Sepsis-3” <TextLink reference="16"></TextLink>, <TextLink reference="17"></TextLink>, <TextLink reference="18"></TextLink>. According to this new definition, sepsis is defined as a “life threatening organ dysfunction caused by a misregulated host response to infection”, i.e. the new “sepsis” is the old “severe sepsis”. The focus is now on the SOFA score; the SIRS criteria on the systemic inflammatory response of the body have been dropped. A “qSOFA” (quick SOFA) is intended to facilitate screening without lab testing in non-intensive care patients (<TextGroup><PlainText>Figure 1 </PlainText></TextGroup><ImgLink imgNo="1" imgType="figure"/>):</Pgraph><Pgraph><UnorderedList><ListItem level="1">Respiratory rate ≥22/min</ListItem><ListItem level="1">Altered consciousness (GCS <15)</ListItem><ListItem level="1">Systolic blood pressure ≤100 mm Hg</ListItem></UnorderedList></Pgraph><Pgraph>qSOFA is considered positive if ≥2 criteria are met: follow by further search for organ dysfunction (SOFA score), start or escalate treatment, intensify monitoring.</Pgraph><Pgraph>Organ dysfunction is defined as an acute change of the SOFA score ≥2 points as a result of the infection (mortality ≥10%). The baseline SOFA score is assumed to be zero in patients with no known organ dysfunction. The SOFA score parameters are respiration, coagulation, liver, cardiovascular system, CNS, kidney.</Pgraph><Pgraph>Septic shock is defined as: Sepsis + vasopressor administration required to maintain a mean arterial blood pressure ≥65 mm Hg in persistent hypotension + serum lactate >2 mmol/l (>18 mg/dl) despite adequate volume replacement. For septic shock, hospital mortality exceeds 40%. </Pgraph><Pgraph>The pathophysiological findings of recent years show that septic conditions are caused by a complicated network of pro- and anti-inflammatory cytokines <TextLink reference="19"></TextLink>, <TextLink reference="20"></TextLink>. A sepsis event is a dynamic process of transition from the stage of “simple sepsis” to “severe sepsis” or “septic shock” with organ dysfunction or organ failure but also the development of septic organ colonization. A detailed description of intensive care supportive and adjunctive treatment measures would go far beyond the objectives of these guidelines on calculated anti-infective initial treatment. For this we refer to the current guidelines of the Surviving Sepsis Campaign <TextLink reference="21"></TextLink>. </Pgraph><Pgraph>Rapid, adequate antimicrobial treatment and, whenever possible, early source control in the first few hours is key to patient survival. In a retrospective study from 2006 <TextLink reference="22"></TextLink> Kumar was able to show that with every hour of treatment delay after onset of hypotension in septic shock mortality increases by 7.6%. To some extent conflicting studies were published on this topic in the following years. A recent meta-analysis <TextLink reference="23"></TextLink> seems to suggest that there is no benefit regarding mortality if antibiotics are administered in sepsis within the first 3 hours after initial assessment in the emergency department or one hour after the onset of septic shock. In addition to methodological weaknesses (7 studies could not be included due to failure to communicate with the authors), no single randomized, controlled study was included because there were none. In addition, the studies were not limited to those with adequate, effective treatment and no statement was made on multiresistant pathogens or on source control. </Pgraph><Pgraph>In the current guidelines of the Surviving Sepsis Campaign, a strong recommendation is made for giving intravenous antibiotics no later than one hour after the diagnosis of sepsis or septic shock, although the evidence for this procedure is considered moderate <TextLink reference="21"></TextLink>. This is supported by other current data <TextLink reference="24"></TextLink>, also from Germany <TextLink reference="25"></TextLink>. </Pgraph><Pgraph>Due to the increase in multidrug-resistant pathogens (especially MRSA, VRE but especially <Mark2>Acinetobacter</Mark2> <Mark2>baumannii</Mark2>, <Mark2>Pseudomonas</Mark2> <Mark2>aeruginosa</Mark2> and Enterobacteriaceae type 3MRGN and 4MRGN) <TextLink reference="26"></TextLink> it is often necessary to start broad or even combined, antimicrobial treatment to adequately cover the pathogen spectrum <TextLink reference="27"></TextLink>. Prior antimicrobial treatment and the patient’s history (for example risk factors for MRGN pathogens) should necessarily be included in the therapeutic and practical considerations (such as isolation).</Pgraph><Pgraph>The need for antimicrobial treatment should be reconsidered <TextLink reference="28"></TextLink> and re-evaluated <TextLink reference="29"></TextLink> daily. Combination treatment should be de-escalated once microbiological findings are available (less broad, discontinuation of a combination partner) <TextLink reference="30"></TextLink>.</Pgraph><Pgraph>In the physiologically and pharmacologically complex situation of sepsis, it is recommended to treat patients with high doses initially (i.e. in the first few days) in order to quickly reach a sufficiently effective level in sepsis patients with a high volume of distribution and creatinine clearance which is often elevated in hyperdynamic circulatory situations <TextLink reference="31"></TextLink>. However, there are few data with good evidence on this topic. Attention should always be paid to signs of antimicrobial toxicity and possible interactions. Subsequently, the dosage should be adjusted to the organ deficiencies (kidney, liver). In the future, determination of plasma concentrations of antibiotics and antimycotics will be particularly important in sepsis patients in terms of efficacy, toxicity and development of resistance <TextLink reference="31"></TextLink>, <TextLink reference="32"></TextLink>, <TextLink reference="33"></TextLink>, <TextLink reference="34"></TextLink>, <TextLink reference="35"></TextLink>.</Pgraph><Pgraph>According to the current state of knowledge, in order to manage treatment, especially regarding the question of termination and effectiveness of antibiotic treatment, repeated determination of procalcitonin (PCT) in the serum should be carried out in addition to clinical assessment <TextLink reference="22"></TextLink>, <TextLink reference="36"></TextLink>, <TextLink reference="37"></TextLink>, <TextLink reference="38"></TextLink>, <TextLink reference="39"></TextLink>.</Pgraph><Pgraph>In order to be able to successfully implement the above-mentioned strategies in everyday clinical practice, it is necessary for intensive care physicians and clinicians to work closely with clinical infectiology, microbiology and clinical pharmacology. The modern term “antimicrobial stewardship” <TextLink reference="40"></TextLink>, <TextLink reference="41"></TextLink> describes this approach. For example, infectiological advice for <Mark2>Staphylococcus</Mark2> <Mark2>aureus</Mark2> bacteremia significantly increased the quality of treatment and decreased mortality and length of hospital stay <TextLink reference="42"></TextLink>.</Pgraph><Pgraph>Overall, sepsis is a heterogeneous disease which is difficult to diagnose in the early stages and difficult to treat in the late stages. Early intervention improves the prognosis. Rapid and adequate antimicrobial therapy, microbiological diagnostics, source control and supportive treatment of internal organ dysfunction are the cornerstones of successful sepsis treatment. Nevertheless, excessive antimicrobial treatment must be avoided because of the expected collateral damage <TextLink reference="43"></TextLink>.</Pgraph></TextBlock>
<TextBlock language="de" linked="yes" name="Mikrobiologie und aktuelle Resistenzsituation">
<MainHeadline>Mikrobiologie und aktuelle Resistenzsituation</MainHeadline><Pgraph>Die aktuellen Empfehlungen zur Blutkulturdiagnostik wurden im Rahmen der „MiQ-Richtlinien“ (Qualitätsstandards in der mikrobiologisch-infektiologischen Diagnostik der Deutschen Gesellschaft für Hygiene und Mikrobiologie, DGHM) publiziert. Dort finden sich Angaben zur Entnahme von Blutkulturen, zum Entnahmeort, zur Vorgehensweise bei der Venenpunktion sowie zum Probentransport und zur Verarbeitung mit und ohne automatisches Detektionssystem. Bei der Abnahme von Blutkulturen, möglichst vor Beginn der Antibiotika-Therapie, sind vor allem folgende Punkte zu beachten:</Pgraph><Pgraph><UnorderedList><ListItem level="1">Frische Punktion einer peripheren Vene, Entnahme aus liegenden Kathetern nur zusätzlich</ListItem><ListItem level="1">Hygienische Händedesinfektion</ListItem><ListItem level="1">Wisch- oder Sprühdesinfektion der Haut auf einem mindestens 5x 5 cm großen Areal mit alkoholischem Desinfektionsmittel, Einwirkzeit 1 min</ListItem><ListItem level="1">Zweite Hautdesinfektion von innen nach außen mit sterilem Tupfer</ListItem><ListItem level="1">Anlegen von Einmalhandschuhen</ListItem><ListItem level="1">Keine erneute Palpation der Punktionsstelle</ListItem><ListItem level="1">Venenpunktion und Entnahme von 8–10 ml (5<TextGroup><PlainText>–10 ml)</PlainText></TextGroup> Blut pro Blutkulturflasche, das heißt 16–20 ml pro Blutkulturset</ListItem><ListItem level="1">Entnahme von drei Blutkultursets</ListItem><ListItem level="1">Alkoholische Wischdesinfektion des Durchstichstopfens der Blutkulturflaschen</ListItem><ListItem level="1">Trocknung des Desinfektionsmittels abwarten</ListItem><ListItem level="1">Blutkulturflaschen mit jeweils frischer Kanüle beimpfen (nicht belegt!) oder geschlossenes Entnahmesystem verwenden (TRBA!)</ListItem><ListItem level="1">Keine Belüftung der aeroben Flasche vornehmen</ListItem><ListItem level="1">Blutkulturflaschen sofort ins Labor transportieren</ListItem></UnorderedList></Pgraph><Pgraph>Das Spektrum der Sepsis-Erreger ist breit. In der deutschen SEPNET-Studie waren 55% der Fälle durch grampositive Bakterien, 54% durch gramnegative Mikroorganismen und knapp 18% durch <Mark2>Candida</Mark2>-Spezies verursacht worden. Die Summe von über 100% erklärt sich durch polymikrobielle Infektionen <TextLink reference="7"></TextLink>.</Pgraph><Pgraph>Zur Resistenzsituation bei Blutkulturisolaten in Deutschland liegen Daten aus dem Antibiotika-Resistenz-Surveillance-System ARS aus dem Jahr 2015 vor <TextLink reference="44"></TextLink> (siehe auch Kapitel 2 <TextLink reference="45"></TextLink>).</Pgraph><Pgraph>Der Anteil an Methicillin-resistenten Stämmen von <Mark2>Staphylococcus</Mark2> <Mark2>aureus</Mark2> ist in den letzten Jahren leicht gesunken und betrug zuletzt 11,8% (n=7.740). Der Anteil der Methicillin-resistenten Isolate bei Koagulase-negativen Staphylokokken ist hingegen mit 58,8% (n=27.804) weiterhin hoch. Der Anteil Glykopeptid-resistenter <Mark2>Enterococcus-faecium</Mark2>-Stämme bei Blutkulturisolaten lag in 2015 bei 12,2% (n=1.729) und ist damit nach einem bisherigen Höchststand von 14,8% (n=573) im Jahr 2011 wieder etwas gesunken.</Pgraph><Pgraph>Bei <Mark2>Escherichia</Mark2> <Mark2>coli</Mark2> ist der Anteil der Fluorchinolon-resistenten Stämme in den letzten Jahren leicht gesunken und betrug zuletzt für Ciprofloxacin 20,7% (n=11.611). Der Anteil der Cefotaxim-resistenten Isolate als Ausdruck für das Vorhandensein einer ESBL beträgt aktuell 11,5% (n=9.958). Bei <Mark2>Klebsiella</Mark2> <Mark2>pneumoniae</Mark2> ist die Ciprofloxacin-Resistenzrate in den zurückliegenden Jahren in etwa gleich geblieben und lag in 2015 bei 12,1% (n=2.051). Die Rate der ESBL-Bildner bei <Mark2>Klebsiella</Mark2> <Mark2>pneumoniae</Mark2>, wiederum gemessen an der Cefotaxim-Resistenz, war ebenfalls in den letzten Jahren nahezu unverändert und im lag letzten Jahr bei 13,0% (n=1.796). Inzwischen sind auch die ersten Carbapenem-resistenten Klebsiellen-Isolate in Blutkulturen nachgewiesen, auch wenn der Anteil mit 0,2% (Meropenem, n=2.032) noch sehr gering ist.</Pgraph><Pgraph>Bei <Mark2>Pseudomonas</Mark2> <Mark2>aeruginosa</Mark2> beträgt die Resistenzrate gegenüber Ceftazidim 9,1% (n=10.769), gegenüber Piperacillin/Tazobactam 15,6% (n=1.073) und gegenüber Meropenem 8,1% (n=1.081), zählt man bei Meropenem allerdings die intermediären Stämme hinzu, ergibt sich eine Rate von 16,7% intermediär und resistenter Isolate.</Pgraph></TextBlock>
<TextBlock language="en" linked="yes" name="Microbiology and current resistance situation">
<MainHeadline>Microbiology and current resistance situation</MainHeadline><Pgraph>The current recommendations on blood culture diagnostics were published within the scope of the “MiQ guidelines” (Quality standards in microbiological-infectiological diagnostics of the German Society for Hygiene and Microbiology, DGHM). This contains instructions on the collection of blood cultures, the place of collection, the procedure for venipuncture and for sample transport and processing, with and without an automatic detection system. When taking blood cultures, if possible before initiating antibiotic treatment, the following points should be observed in particular:</Pgraph><Pgraph><UnorderedList><ListItem level="1">fresh puncture of a peripheral vein, take samples from existing catheters only in addition</ListItem><ListItem level="1">hygienic hand disinfection</ListItem><ListItem level="1">wipe or spray disinfect the skin on an area of at least 5x 5 cm with alcoholic disinfectant, exposure time <TextGroup><PlainText>1 min</PlainText></TextGroup>.</ListItem><ListItem level="1">second skin disinfection inside out with sterile swab</ListItem><ListItem level="1">wear disposable gloves</ListItem><ListItem level="1">no re-palpation of the puncture site</ListItem><ListItem level="1">venipuncture and removal of 8–10 ml (5–10 ml) of blood per blood culture bottle, i.e. 16–20 ml per blood culture set</ListItem><ListItem level="1">taking three blood culture sets</ListItem><ListItem level="1">wipe septum tops of blood culture bottles with alcoholic disinfectant </ListItem><ListItem level="1">wait for the disinfectant to dry</ListItem><ListItem level="1">inoculate blood culture bottles with fresh cannula (not used!) or use closed sampling system (TRBA!)</ListItem><ListItem level="1">do not aerate the aerobic bottle</ListItem><ListItem level="1">immediately transport blood culture bottles to the lab</ListItem></UnorderedList></Pgraph><Pgraph>The spectrum of sepsis pathogens is broad. In the German SEPNET study, 55% of cases were caused by Gram-positive bacteria, 54% by Gram-negative microorganisms and almost 18% by <Mark2>Candida</Mark2> species. Their sum exceeding 100% is explained by polymicrobial infections <TextLink reference="7"></TextLink>.</Pgraph><Pgraph>Data on the resistance situation in blood culture isolates in Germany are available from the ARS Antibiotic Resistance Surveillance System from 2015 <TextLink reference="44"></TextLink> (see also chapter 2 <TextLink reference="45"></TextLink>).</Pgraph><Pgraph>The proportion of methicillin-resistant strains of <Mark2>Staphylococcus</Mark2> <Mark2>aureus</Mark2> has fallen slightly in recent years, reaching 11.8% (n=7,740). However the proportion of methicillin-resistant isolates in coagulase-negative staphylococci remains high at 58.8% (n=27.804). The proportion of glycopeptide-resistant <Mark2>Enterococcus</Mark2> <Mark2>faecium</Mark2> strains in blood culture isolates stood at 12.2% in 2015 (n=1,729), falling slightly in 2011 from a previous high of 14.8% (n=573).</Pgraph><Pgraph>In the case of <Mark2>Escherichia</Mark2> <Mark2>coli</Mark2>, the proportion of fluoroquinolone-resistant strains has fallen slightly in recent years and for ciprofloxacin was 20.7% (n=11,611). The proportion of cefotaxime-resistant isolates expressing the presence of an ESBL is currently 11.5% (n=9,958). In Klebsiella pneumoniae, the ciprofloxacin resistance rate has remained more or less constant in recent years, reaching 12.1% in 2015 (n=2,051). The rate of ESBL-formers in <Mark2>Klebsiella</Mark2> <Mark2>pneumoniae</Mark2>, again measured by cefotaxime resistance, has also been virtually unchanged in recent years and last year was 13.0% (n=1,796). In the meantime, the first carbapenem-resistant Klebsiella isolates have been detected in blood cultures, even though the proportion of 0.2% (meropenem, n=2,032) is still very low.</Pgraph><Pgraph>In the case of <Mark2>Pseudomonas</Mark2> <Mark2>aeruginosa</Mark2>, the resistance rate to ceftazidime is 9.1% (n=10,769), to piperacillin/tazobactam 15.6% (n=1,073) and to meropenem 8.1% (n=1,081) but if intermediate strains are added to meropenem, this results in 16.7% intermediate and resistant isolates.</Pgraph></TextBlock>
<TextBlock language="de" linked="yes" name="Pharmakokinetik und Pharmakodynamik">
<MainHeadline>Pharmakokinetik und Pharmakodynamik</MainHeadline><Pgraph>Die Pharmakokinetik und Pharmakodynamik von Antibiotika unterscheiden sich bei Patienten mit schwerer Sepsis und septischem Schock teilweise erheblich von den Daten, die bei weniger schwer kranken Patienten erhoben wurden. Die Pharmakokinetik wird durch komplexe, teils gegenläufige Prozesse beeinflusst, so dass die Antibiotika-Spiegel schwer vorherzusagen sind. In der Frühphase der Sepsis dominiert bei vielen Patienten die hyperdyname Kreislaufsituation, bei der es zur gegenüber Gesunden gesteigerten Clearance von renal eliminierten Antiinfektiva kommen kann (augmented renal clearance, ARC). Durch das kapilläre Leck kommt es zusätzlich zur Expansion des Extrazellularraums. Diese beiden Faktoren führen zu unerwartet niedrigen Plasmaspiegeln bei hydrophilen und renal eliminierten Antibiotika, was für die meisten Beta-Lactame, aber auch Aminoglykoside und Vancomycin zutrifft <TextLink reference="46"></TextLink>, <TextLink reference="47"></TextLink>, <TextLink reference="48"></TextLink>. Daraus ergibt sich, dass für diese Antibiotika ein therapeutisches „drug monitoring“ (TDM) durchgeführt werden sollte, das für Aminoglykoside und Vancomycin aufgrund ihres hohen toxischen Potentials ohnehin zwingend erfolgen muss <TextLink reference="49"></TextLink>, <TextLink reference="50"></TextLink>. Für Beta-Lactame wäre ein TDM ebenfalls sinnvoll, es ist aber für die klinische Routine kaum verfügbar. Die Veränderungen der Pharmakokinetik sind für Antibiotika mit großem Verteilungsvolumen (z.B. Fluorchinolone), also vorwiegend intrazellulärer Anreicherung, weniger ausgeprägt <TextLink reference="46"></TextLink>.</Pgraph><Pgraph>Wenn im weiteren Verlauf der Sepsis zunehmend Organfunktionsstörungen – vor allem Niereninsuffizienz – auftreten, kommt es durch verringerte Elimination zu steigenden Plasmaspiegeln und möglicherweise zur Kumulation von meist unwirksamen, aber potenziell toxischen Metaboliten der Arzneistoffe <TextLink reference="47"></TextLink>. Bei Antibiotika mit hoher Eiweißbindung kommt noch die Verdrängung aus der Bindung durch andere Arzneistoffe oder aufgrund von pH-Verschiebungen hinzu. Aus diesen Überlegungen sollte daher bei vorhandenen Alternativen eher auf Antibiotika mit niedrigerer Eiweißbindung und niedrigem toxischen Potenzial ausgewichen werden (z.B. bei MSSA-Sepsis Gabe eines Cephalosporins statt Flucloxacillin, welches zu über 90% an Eiweiß gebunden ist und ein hohes hepatotoxisches Risiko hat).</Pgraph><Pgraph>Offen ist jedoch die Beantwortung der Frage, ob die für die Proteinbindung angegebenen Prozentwerte auf die Situation der Behandlung kritisch kranker Patienten übertragen werden können. So wird diskutiert, ob die Plasmaspiegel der Beta-Lactam-Antibiotika bei Schwerkranken nicht besser während des gesamten Dosierungsintervalls oberhalb der MHK liegen sollten. Darüber hinaus wird angeführt, dass Plasmaspiegel bis zu 4-fach oberhalb der MHK angestrebt werden sollten, um die Gewebepenetration der Antibiotika sicherzustellen. Dies würde in vielen Fällen jedoch eine deutlich höhere als die bisher übliche Dosierung der Beta-Lactam-Antibiotika bedeuten <TextLink reference="32"></TextLink>.</Pgraph><Pgraph>Nach initialer Gabe einer Loading-Dose, mit der rasch der erforderliche Wirkspiegel erreicht werden soll, könnten kontinuierliche Infusionen von Beta-Lactam-Antibiotika vor allem für Erreger mit intermediärer Empfindlichkeit bei schwer kranken Patienten das Behandlungsergebnis verbessern. Neben der Praktikabilität (Haltbarkeit bei Raumtemperatur, Inkompatibilität mit anderen Medikamenten) birgt die Anwendung einer kontinuierlichen Infusion ohne therapeutisches Drug-Monitoring (TDM) jedoch die Gefahr, dass die Plasmaspiegel dauerhaft unterhalb der MHK des (oft unbekannten) Infektionserregers liegen können. Die kontinuierliche Antibiotika-Infusion sollte deshalb nur angewendet werden, wenn ein TDM zeitnah zur Verfügung steht – im Idealfall ergänzt durch die Bestimmung der MHK von dem Antibiotikum für den Erreger (siehe Kapitel 3 <TextLink reference="51"></TextLink>).</Pgraph><Pgraph>Steht kein TDM zur Verfügung, bietet sich die prolongierte Infusion der Beta-Lactame über 3–4 Stunden als sinnvoller Kompromiss an. Auf diese Weise wird der Nachteil der Kurzinfusion mit (unnötig) hohen Spitzenspiegeln und zu raschem Absinken des Wirkspiegels unter die MHK ebenso vermieden wie die mit der kontinuierlichen Infusion verbundene potentielle Gefahr, dass die MHK dauerhaft unterschritten wird. Zur raschen Erzielung eines therapeutischen Wirkspiegels soll die Initialdosis in Form der traditionellen Kurzinfusion gegeben werden. </Pgraph><Pgraph>Um die Erkenntnisse zu den Besonderheiten der Pharmakokinetik und Pharmakodynamik klinisch umsetzen zu können, sollte ein TDM für die wichtigsten Beta-Lactame etabliert werden, die in der betreffenden Klinik bei Patienten mit schwerer Sepsis eingesetzt werden (z.B. Ceftazidim oder Cefepim, Piperacillin/Tazobactam, Meropenem oder Imipenem). Ohne TDM wird von der Anwendung kontinuierlicher Infusionen abgeraten.</Pgraph><Pgraph>In manchen Kliniken ohne Verfügbarkeit eines TDM ist es üblich, bei Patienten in der hyperdynamen Phase der Sepsis bei noch erhaltener Nierenfunktion zumindest am ersten Therapietag höhere Dosierungen anzuwenden. Das Regime kann dann sein, die Initialdosis o.g. Antibiotika bei Indikationsstellung als Kurzinfusion zu applizieren, gefolgt von prolongierten Infusionen zu den auf der Station etablierten Tageszeiten. Einschränkend muss darauf hingewiesen werden, dass lediglich Doripenem – welches wieder vom Markt genommen wurde – die Zulassung zur prolongierten Infusion besaß. Für die anderen Beta-Lactame liegen vielversprechende Einzelstudien und Meta-Analysen vor, die eine bessere klinische Wirksamkeit der kontinuierlichen oder prolongierten Infusion zeigen. Die Meta-Analysen beinhalten neben wenigen prospektiven Studien auch retrospektive und Kohortenstudien mit begrenzter Aussagekraft <TextLink reference="52"></TextLink>, <TextLink reference="53"></TextLink>. In einer neueren Meta-Analyse <TextLink reference="54"></TextLink> wurden randomisierte, prospektive Studien zur kontinuierlichen gegenüber intermittierender Beta-Lactam-Infusion anhand der individuellen Patientendaten ausgewertet <TextLink reference="55"></TextLink>, <TextLink reference="56"></TextLink>, <TextLink reference="57"></TextLink>. Es zeigte sich eine signifikante Reduktion der Sterblichkeit im Krankenhaus bei Anwendung kontinuierlicher Infusionen (19,6% gegenüber 26,3%), die allerdings ohne therapeutisches Drug-Monitoring durchgeführt wurden <TextLink reference="54"></TextLink>.</Pgraph><Pgraph>Trotz überzeugender Daten in vitro und in vivo bleibt es schwierig, in klinischen Studien die Überlegenheit kontinuierlicher oder prolongierter Infusionen zu zeigen. Die Gründe hierfür sind vielfältig und reichen von der Schwierigkeit der Infektionsdiagnose über fehlenden Erregernachweis bis hin zu der Tatsache, dass bei sehr empfindlichen Erregern auch bei traditionell intermittierender Bolus-Gabe ausreichend lange Wirkspiegel oberhalb der MHK erreicht werden können <TextLink reference="58"></TextLink>, <TextLink reference="59"></TextLink>, <TextLink reference="60"></TextLink>.</Pgraph><Pgraph>In Bezug auf die Pharmakodynamik verhalten sich Aminoglykoside geradezu spiegelbildlich zu den Beta-Lactamen. Denn die bakterizide Wirkung wird durch hohe Spitzenspiegel verbessert, gefolgt von ausgeprägten postantibiotischen Effekten, die es erlauben die Plasmaspiegel viele Stunden unter die MHK absinken zu lassen. Ein TDM ist flächendeckend etabliert und aufgrund der hohen Nephrotoxizität und Ototoxizität obligat. Nach Bolus-Gabe der gesamten Tagesdosis wird die nächste Dosis frühestens nach 24 Stunden gegeben, wenn der Talspiegel für Gentamicin oder Tobramycin unter 1 mg/l liegt. </Pgraph><Pgraph>Für Fluorchinolone wird zur Optimierung der Wirksamkeit empfohlen, eine möglichst große Fläche der Zeit-Plasmaspiegel-Kurve oberhalb der MHK zu erzeugen (AUC>MHK). In der klinischen Praxis lässt sich mit diesem komplizierten mathematischen Begriff wenig anfangen. Aufgrund der mathematischen Verknüpfung lassen sich Fluorchinolone eher in Analogie zu den Aminoglykosiden als Spitzenspiegel-abhängige Antibiotika verstehen <TextLink reference="47"></TextLink>.</Pgraph></TextBlock>
<TextBlock language="en" linked="yes" name="Pharmacokinetics and pharmacodynamics">
<MainHeadline>Pharmacokinetics and pharmacodynamics</MainHeadline><Pgraph>The pharmacokinetics and pharmacodynamics of antibiotics in patients with severe sepsis and septic shock are sometimes significantly different from data collected in less severely ill patients. Pharmacokinetics are influenced by complex, sometimes counterproductive processes, so that antibiotic levels are difficult to predict. In the early stages of sepsis, hyperdynamic circulatory conditions dominate in many patients, leading to increased clearance of renally eliminated anti-infective agents (augmented renal clearance, ARC) compared to healthy people. The capillary leak also causes expansion of the extracellular space. These two factors lead to unexpectedly low plasma levels of hydrophilic and renally eliminated antibiotics, affecting most beta-lactams and also aminoglycosides and vancomycin <TextLink reference="46"></TextLink>, <TextLink reference="47"></TextLink>, <TextLink reference="48"></TextLink>. As a result, therapeutic drug monitoring (TDM) should be carried out for these antibiotics, which is mandatory for aminoglycosides and vancomycin in any case because of their high toxic potential <TextLink reference="49"></TextLink>, <TextLink reference="50"></TextLink>. For beta-lactams TDM would also be useful but it is rarely available for routine clinical work. Changes in pharmacokinetics are less pronounced for antibiotics with large volumes of distribution (for example fluoroquinolones), i.e. with predominantly intracellular accumulation <TextLink reference="46"></TextLink>.</Pgraph><Pgraph>As a progressing sepsis leads to more and more organ dysfunction, especially with renal insufficiency, reduced elimination leads to increased plasma levels and possibly the accumulation of mostly ineffective but potentially toxic metabolites of the drugs <TextLink reference="47"></TextLink>. Added to this, for antibiotics with high protein binding, is displacement from binding through other drugs or due to pH shifts . If alternatives exist, consideration should therefore be given to antibiotics with lower protein binding and low toxic potential (for example in MSSA sepsis a cephalosporin instead of flucloxacillin, which is more than 90% protein-bound and has a high hepatotoxic risk).</Pgraph><Pgraph>There is however no answer to the question of whether the percentages given for protein binding can be transferred to the situation of treating critically ill patients. There is a discussion of whether it would not be better for the plasma levels of beta-lactam antibiotics in critically ill patients to be above the MIC during the entire dosing interval. In addition, it is stated that plasma levels should be up to 4 times above the MIC to ensure tissue penetration of the antibiotics. However in many cases this would mean a significantly higher dosage than previously used for beta-lactam antibiotics <TextLink reference="32"></TextLink>.</Pgraph><Pgraph>After initial administration of a loading dose to rapidly achieve the required effective level, continuous infusions of beta-lactam antibiotics, especially for intermediate-susceptibility pathogens, could improve treatment outcomes in critically ill patients. However in addition to practicability (shelf-life at room temperature, incompatibility with other drugs), the use of a continuous infusion without therapeutic drug monitoring (TDM) carries the risk that the plasma levels may be permanently below the MIC of the (often unknown) pathogen. Continuous antibiotic infusion should therefore only be used if TDM is available promptly, ideally complemented by determination of the MIC of the antibiotic for the pathogen (see chapter 3 <TextLink reference="51"></TextLink>).</Pgraph><Pgraph>If TDM is not available, prolonged infusion of beta-lactams over 3–4 hours is a possible sensible compromise. In this way, the disadvantage of short infusion with (unnecessarily) high peak levels and rapid drop of the effective level below the MIC is avoided as well as the potential danger associated with continuous infusion of permanently staying below the MIC. For rapidly reaching a therapeutically effective level, the initial dose should be given in the form of a traditional short infusion. </Pgraph><Pgraph>In order to clinically translate the insights into the peculiarities of pharmacokinetics and pharmacodynamics, TDM should be established for the most important beta-lactams used at the hospital in question in patients with severe sepsis (for example ceftazidime or cefepime, piperacillin/tazobactam, meropenem or imipenem). Without TDM, the use of continuous infusions is discouraged.</Pgraph><Pgraph>In some hospitals where TDM is not available, it is common practice to use higher doses for patients in the hyperdynamic phase of sepsis if the kidneys are still functioning, at least on the first day of treatment. Treatment may then be to administer the initial dose of the antibi<TextGroup><PlainText>o</PlainText></TextGroup>tics mentioned above, when indicated, as a short infusion, followed by prolonged infusions at the usual times on the ward. It should be pointed out that only Doripenem – which was withdrawn from the market – was approved for prolonged infusion. For the other beta-lactams there are promising individual studies and meta-analyzes demonstrating better clinical efficacy of continuous or prolonged infusion. In addition to a few prospective studies, the meta-analyzes also include retrospective and cohort studies with limited significance <TextLink reference="52"></TextLink>, <TextLink reference="53"></TextLink>. A recent meta-analysis <TextLink reference="54"></TextLink> evaluated randomized, prospective studies of continuous versus intermittent beta-lactam infusion based on individual patient data <TextLink reference="55"></TextLink>, <TextLink reference="56"></TextLink>, <TextLink reference="57"></TextLink>. There was a significant reduction in hospital mortality with continuous infusion (19.6% versus 26.3%) but without therapeutic drug monitoring <TextLink reference="54"></TextLink>.</Pgraph><Pgraph>Despite convincing data in vitro and in vivo, it remains difficult to demonstrate the superiority of continuous or prolonged infusions in clinical trials. The reasons for this are manifold, ranging from the difficulty of infection diagnosis to lack of pathogen identification to the fact that, in very sensitive pathogens, effective levels above the MIC can be achieved for a sufficient length of time even with traditional intermittent bolus administration <TextLink reference="58"></TextLink>, <TextLink reference="59"></TextLink>, <TextLink reference="60"></TextLink>.</Pgraph><Pgraph>In terms of pharmacodynamics, aminoglycosides are a mirror image to beta-lactams. This is because the bactericidal effect is improved by high peak levels, followed by pronounced post-antibiotic effects, which allow the plasma levels to drop below the MIC for many hours. TDM is established nationwide and is obligatory due to the high nephrotoxicity and ototoxicity. After bolus administration of the total daily dose, the next dose is given at the earliest after 24 hours, when the trough level for gentamicin or tobramycin is below 1 mg/l. </Pgraph><Pgraph>For fluoroquinolones, in order to optimize efficacy, it is recommended to generate the largest possible area of the time-plasma-mirror curve above the MIC (AUC>MIC). In clinical practice, this complicated mathematical term is of little use. Due to the mathematical link, fluoroquinolones can be better understood as analogous to aminoglycosides as peak-level-dependent antibiotics <TextLink reference="47"></TextLink>.</Pgraph></TextBlock>
<TextBlock language="de" linked="yes" name="Therapieempfehlungen">
<MainHeadline>Therapieempfehlungen</MainHeadline><Pgraph>Bei fast allen Patienten erfolgt die initiale, antimikrobielle Therapie kalkuliert im Sinne der von der Paul-Ehrlich-Gesellschaft empfohlenen Interventionstherapie. Bei einem Teil der Patienten besteht durch einen Erregernachweis mit Antibiogramm die Möglichkeit, die initial begonnene Interventionstherapie zu modifizieren. Die initiale Antiinfektiva-Auswahl wird durch die vermutete Infektionsquelle, die Grunderkrankungen und Risikofaktoren (z.B. die Tatsache, ob eine Infektion ambulant oder nosokomial erworben wurde, den Zeitpunkt des Auftretens der Infektion und eine vorbestehende antimikrobielle Therapie) beeinflusst.</Pgraph><Pgraph>Tabelle 1 <ImgLink imgNo="1" imgType="table"/> zeigt Therapieempfehlungen bei unbekanntem Erreger bezogen auf die Art und Lokalisation der Infektion und Tabelle 2 <ImgLink imgNo="2" imgType="table"/> zeigt Therapieempfehlungen bei nachgewiesenem Erreger. Tabelle 3 <ImgLink imgNo="3" imgType="table"/> weist die Empfehlungsgrade für den Einsatz der Antibiotika in der Indikation „nosokomial erworbene Sepsis bei unbekanntem Erreger und unbekanntem Infektionsort“ aus. Die Vielfalt der in <TextGroup><PlainText>Tabelle 1</PlainText></TextGroup> <ImgLink imgNo="1" imgType="table"/> und Tabelle 2 <ImgLink imgNo="2" imgType="table"/> aufgeführten Therapieoptionen ist durch unterschiedliche Schweregrade des Krankheitsbildes und durch die Risikofaktoren des Patienten begründet. Die Therapiedauer sollte 7–10 Tage betragen. Ausnahmen sind ein langsames Ansprechen auf die Therapie, ein nicht sanierbarer Fokus sowie eine Immunsuppression <TextLink reference="4"></TextLink>. Bei PCT-gesteuerter Antibiotika-Therapie kann die Antibiotika-Therapiedauer auch kürzer als 7 Tage sein, wenn es bis zu diesem Zeitpunkt zu einem PCT-Abfall von mehr als 80% gegenüber dem am höchsten gemessenen Wert gekommen ist bzw. wenn der absolut gemessene PCT-Wert ≤0,25 ng/l beträgt. </Pgraph><Pgraph>Obwohl die Datenlage nicht ausreichend ist, soll bei lebensbedrohlich erkrankten Patienten initial immer eine Kombinationstherapie durchgeführt werden (Tabelle 1 <ImgLink imgNo="1" imgType="table"/>). </Pgraph><Pgraph>Dieses Vorgehen wird u.a. durch die Ergebnisse der Surviving Sepsis Campaign unterstützt. </Pgraph><Pgraph>Dellinger et al. empfehlen die Gabe einer oder mehrerer Substanzen mit breitem Spektrum und gutem Penetrationsvermögen ins Gewebe für die kalkulierte Initialtherapie <TextLink reference="28"></TextLink>.</Pgraph><Pgraph>Nach spätestens 72 Stunden soll diese Strategie evaluiert werden. Explizit wird eine Kombinationstherapie bei Verdacht oder nachgewiesener <Mark2>Pseudomonas</Mark2>-Infektion gefordert <TextLink reference="28"></TextLink>, <TextLink reference="61"></TextLink>. Traditionell waren Aminoglykoside die bevorzugten Kombinationspartner für Beta-Lactam-Antibiotika. Die Option, Fluorchinolone als Kombinationspart<TextGroup><PlainText>n</PlainText></TextGroup>er der Beta-Lactam-Antibiotika einzusetzen, ist durch die Arbeiten von Paul et al. begründet <TextLink reference="62"></TextLink>, <TextLink reference="63"></TextLink>. Fluorchinolone bieten pharmakokinetische Vorteile, sind mit einer geringeren Toxizität assoziiert und es fehlt die Notwendigkeit der Durchführung von regelmäßigen Spiegelbestimmungen. Allerdings sind die Resistenzraten für Fluorchinolone durchweg höher als für die Aminoglykoside. Fosfomycin stellt im Hinblick auf die z.T. hohen Resistenzraten für Fluorchinolone eine weitere Option als Kombinationspartner mit guter Gewebepenetration dar.</Pgraph><Pgraph>In der Indikation Sepsis müssen alle Antiinfektiva intravenös und in hoher Dosierung appliziert werden. Weder eine Sequenztherapie noch eine Dosisreduktion sind in dieser Indikation durch Studien belegt.</Pgraph><Pgraph>Bei schwerer Sepsis bzw. septischem Schock und unbekanntem Sepsis-Fokus sollte bei Risikopatienten und hoher Rate an MRSA mit einem Lipopeptid (Daptomycin) <TextLink reference="7"></TextLink>, <TextLink reference="40"></TextLink>, <TextLink reference="64"></TextLink>, <TextLink reference="65"></TextLink> oder einem Glykopeptid kombiniert werden. Alternativ kann bei diesen Patienten auch Ceftobiprol (Cephalosporin der Gruppe 5) in Kombination mit einem Fluorchinolon oder Fosfomycin eingesetzt werden, da Ceftobiprol eine gute MRSA-Wirksamkeit besitzt. Ob jedoch die zugelassene Dosierung von 3x 500 mg i.v. in Form einer 2-stündigen Infusion bei Patienten mit normaler Nierenfunktion ausreichend ist, ist zu bezweifeln. Nach den von Torres et al. auf der ECCMID 2015 <TextLink reference="66"></TextLink> publizierten Daten ist bei diesen Patienten eine Dosis von <TextGroup><PlainText>3x 1.000 mg</PlainText></TextGroup> Ceftobiprol anzustreben. Auch Ceftolozan/Tazobactam könnte eine sinnvolle Therapieoption in dieser Indikation darstellen. Hier ist jedoch die fehlende Wirksamkeit dieser Substanzkombination gegenüber Staphylokokken und den meisten Anaerobiern zu berücksichtigen. Die Dosis zur Behandlung der Sepsis sollte <TextGroup><PlainText>3x 3 g i.v.</PlainText></TextGroup> betragen.</Pgraph><Pgraph>Bei der Sepsis, die von den Atemwegen ausgeht, muss vor allem mit <Mark2>Streptococcus</Mark2> <Mark2>pneumoniae</Mark2>, <Mark2>Staphylococcus</Mark2> <Mark2>aureus</Mark2> und verschiedenen Enterobacteriaceae sowie bei Aspirationspneumonie zusätzlich mit Anaerobiern gerechnet werden. Bei schwerwiegenden Risikosituationen oder bei einer Verweildauer im Krankenhaus von mehr als <TextGroup><PlainText>5 T</PlainText></TextGroup>agen ist ferner mit <Mark2>Pseudomonas</Mark2> <Mark2>aeruginosa</Mark2>, <Mark2>Acinetobacter</Mark2> spp. und <Mark2>Stenotrophomonas</Mark2> <Mark2>maltophilia</Mark2> zu rechnen. Das Erregerspektrum kann von Institution zu Institution sehr unterschiedlich sein. Eine neuere Untersuchung weist darauf hin, dass gramnegative Erreger bei beatmeten Patienten auch zunehmend bei kurzer Krankenhausverweildauer in Frage kommen <TextLink reference="67"></TextLink>. Bei Risikopatienten mit schwerer Sepsis oder septischem Schock und hoher MRSA-Rate in der Institution sollte mit einem Oxazolidinon (Linezolid) kombiniert werden <TextLink reference="40"></TextLink>. Ceftobiprol, in Kombination mit einem Fluorchinolon oder Fosfomycin, stellt eine sinnvolle Alternative dar. Auch bei der pneumogenen Sepsis kann Ceftobiprol bei geeigneter Dosis (3x 1 g i.v.) <TextLink reference="66"></TextLink> eine Therapieoption darstellen.</Pgraph><Pgraph>Außerdem sollte auf Grund der sehr guten Wirksamkeit gegenüber Pseudomonaden (auch MDR) und der Wirksamkeit gegenüber ESBL-Bildnern Ceftolozan/Tazobactam eine weitere Therapieoption zur kalkulierten Initialtherapie bei Patienten mit schwerer Sepsis bzw. septischem Schock und unbekanntem Sepsis-Fokus sowie bei der pneumogenen Sepsis darstellen. Die Unwirksamkeit gegen Staphylokokken und die Anaerobier-Lücke müssen jedoch durch einen entsprechenden Kombinati<TextGroup><PlainText>o</PlainText></TextGroup>nspartner ausgeglichen werden.</Pgraph><Pgraph>Bei den Harnwegen als Sepsis-Quelle ohne vorausgegangene instrumentelle Intervention sind in erster Linie <Mark2>Escherichia</Mark2> <Mark2>coli</Mark2> und <Mark2>Proteus</Mark2> <Mark2>mirabilis</Mark2> als Sepsis-Erreger zu erwarten. Nach urologischen Eingriffen müssen außerdem andere Enterobacteriaceae, <Mark2>Pseudomonas</Mark2> <Mark2>aeruginosa</Mark2>, Enterokokken und Staphylokokken berücksichtigt werden.</Pgraph><Pgraph>Ist der Ausgangspunkt der Darm oder ein gynäkologisches Organ, muss mit folgenden Erregern gerechnet werden: Enterobacteriaceae, Anaerobier, Enterokokken, <Mark2>Pseudomonas</Mark2> spp., <Mark2>Staphylococcus</Mark2> <Mark2>aureus</Mark2>.</Pgraph><Pgraph>Bei einer biliären Sepsis nehmen die Erregerbesiedlung in den Gallenwegen und damit das Bakteriämie-Risiko mit dem Grad der Abflussbehinderung zu. Beim Verschlussikterus werden bei mehr als 75% der Patienten Erreger im Blut nachgewiesen. Das Spektrum umfasst Enterobacteriaceae, Enterokokken und Anaerobier. Bei postoperativen Bakteriämien, cholangitischer Sepsis und subhepatischen Abszessen sowie bei interventionellen Eingriffen (ERCP oder endoskopischer Papillotomie) lassen sich weitere gramnegative Problemerreger, einschließlich <Mark2>Pseudomonas</Mark2> <Mark2>aeruginosa</Mark2>, nachweisen. Bei den Sepsis-Ausgangspunkten Darm/gynäkologische Organe und Gallenwege kann bei schwerer Sepsis oder septischem Schock mit einem Glycylcyclin (Tigecyclin) <TextLink reference="40"></TextLink>, <TextLink reference="68"></TextLink>, <TextLink reference="69"></TextLink> kombiniert werden. </Pgraph><Pgraph>Ist die Quelle im Bereich der Haut oder des Weichgewebes, sind Infektionen durch <Mark2>Streptococcus</Mark2> <Mark2>pyogenes</Mark2>, <Mark2>Staphylococcus</Mark2> <Mark2>aureus</Mark2> (auch MRSA) sowie Mischinfektionen unter zusätzlicher Beteiligung von Non-A-Streptokokken, Anaerobiern, Enterobacteriaceae bzw. <Mark2>Pseudomonas</Mark2> <Mark2>aeruginosa</Mark2> möglich.</Pgraph><Pgraph>Das Erregerspektrum der Katheter-assoziierten Sepsis umfasst Koagulase-negative Staphylokokken, <Mark2>Staphylococcus</Mark2> <Mark2>aureus</Mark2>, gramnegative Stäbchenbakterien, <Mark2>Candida</Mark2> spp., <Mark2>Corynebacterium</Mark2> <Mark2>jeikeium</Mark2> sowie Propionibakterien. Hier kommt als Therapieoption auch das Lipopeptid Daptomycin <TextLink reference="7"></TextLink>, <TextLink reference="65"></TextLink>, alternativ zum Glykopeptid, zum Einsatz.</Pgraph><Pgraph>Die in Tabelle 1 <ImgLink imgNo="1" imgType="table"/> dargestellten Empfehlungen zur Monotherapie basieren auf den Ergebnissen gut dokumentierter, randomisierter klinischer Studien. Demgegenüber liegt für die Empfehlungen zur Kombinationstherapie in der Regel keine ausreichende Zahl klinischer Studien vor. Demnach basieren diese Empfehlungen auf Expertenmeinungen. Dies gilt insbesondere für die Kombinationsthe<TextGroup><PlainText>ra</PlainText></TextGroup>pie mit einem Fluorchinolon.</Pgraph></TextBlock>
<TextBlock language="en" linked="yes" name="Treatment recommendations">
<MainHeadline>Treatment recommendations</MainHeadline><Pgraph>In almost all patients, the initial, antimicrobial treatment is calculated according to the intervention treatment recommended by the Paul-Ehrlich-Gesellschaft. In some of the patients it is possible to modify initial intervention treatment through detecting the pathogen with an antibiogram. Initial anti-infective selection is influenced by the suspected source of infection, underlying diseases and risk factors (for example whether an infection is community-acquired or nosocomial, time of onset of infection and prior antimicrobial treatment).</Pgraph><Pgraph>Table 1 <ImgLink imgNo="1" imgType="table"/> shows treatment recommendations for unknown pathogens in relation to the type and localization of the infection and Table 2 <ImgLink imgNo="2" imgType="table"/> shows treatment recommendations for cases where the pathogens have been identified. Table 3 <ImgLink imgNo="3" imgType="table"/> shows the recommendation grades for the use of antibiotics in the indication “nosocomially acquired sepsis with unknown pathogen and unknown site of infection”. The wide variety of treatment options listed in <TextGroup><PlainText>Table 1 </PlainText></TextGroup><ImgLink imgNo="1" imgType="table"/> and Table 2 <ImgLink imgNo="2" imgType="table"/> is due to different degrees of severity of the disease and the risk factors of the patient. The duration of treatment should be 7–10 days. Exceptions are slow response to treatment, a non-restorable focus and immunosuppression <TextLink reference="4"></TextLink>. In PCT-directed antibiotic treatment, the duration of antibiotic treatment may also be shorter than 7 days if by that time there has been a PCT decrease of more than 80% compared to the highest measured value or if the absolute PCT has a measured value ≤0.25 ng/l. </Pgraph><Pgraph>Although the data are insufficient, initial combination treatment should always be performed in patients suffering from life-threatening illness (Table 1 <ImgLink imgNo="1" imgType="table"/>). This approach is supported, amongst other things, by the results of the Surviving Sepsis Campaign. Dellinger et al. recommend administration of one or more substances with a broad spectrum and good penetration into tissue for calculated initial treatment <TextLink reference="28"></TextLink>.</Pgraph><Pgraph>This strategy should be evaluated after 72 hours at the latest. Combination treatment is explicitly called for in cases of suspected or proven <Mark2>Pseudomonas</Mark2> infection <TextLink reference="28"></TextLink>, <TextLink reference="61"></TextLink>. Traditionally, aminoglycosides have been the preferred combination partners for beta-lactam antibiotics. The option of using fluoroquinolones as a combination partner of beta-lactam antibiotics is backed up by the work of Paul et al. <TextLink reference="62"></TextLink>, <TextLink reference="63"></TextLink>. Fluoroquinolones offer pharmacokinetic benefits, are associated with lower toxicity, and there is no need to measure levels regularly. However, resistance rates for fluoroquinolones are consistently higher than for aminoglycosides. In view of the occasionally high fluoroquinolones resistance rates, fosfomycin is another option as a combination partner with good tissue penetration.</Pgraph><Pgraph>In cases of sepsis, all anti-infective drugs must be administered intravenously and in high doses. Neither sequential therapy nor dose reduction are proven by studies in this indication.</Pgraph><Pgraph>In severe sepsis or septic shock and with unknown sepsis focus, it should be combined with a lipopeptide (daptomycin) <TextLink reference="7"></TextLink>, <TextLink reference="40"></TextLink>, <TextLink reference="64"></TextLink>, <TextLink reference="65"></TextLink> or a glycopeptide in high-risk patients with a high rate of MRSA. Alternatively, ceftobiprole (group 5 cephalosporin) may also be used in combination with a fluoroquinolone or fosfomycin in these patients since ceftobiprole has good efficacy against MRSA. However it is doubtful whether the approved dosage of 3x 500 mg i.v., in the form of a 2-hour infusion in patients with normal renal function, is adequate. According to the data published in ECCMID 2015 by Torres et al. <TextLink reference="66"></TextLink> one should aim for a dose of 3x 1,000 mg ceftobiprole in such patients. Ceftolozane/tazobactam could also be a useful treatment option in this indication. Here, however, the lack of efficacy of this combination of substances against staphylococci and most anaerobes has to be considered. The dose for the treatment of sepsis should be 3x 3 g i.v.</Pgraph><Pgraph>In addition, anaerobes can be expected in sepsis which originates from the respiratory tract, especially with <Mark2>Streptococcus</Mark2> <Mark2>pneumoniae</Mark2>, <Mark2>Staphylococcus</Mark2> <Mark2>aureus</Mark2> and various Enterobacteriaceae as well as in aspiration pneumonia. In case of serious risk situations or hospital stays of more than 5 days, <Mark2>Pseudomonas</Mark2> <Mark2>aeruginosa</Mark2>, <Mark2>Acinetobacter</Mark2> spp. and <Mark2>Stenotrophomonas</Mark2> <Mark2>maltophilia</Mark2> can be expected. The pathogen spectrum can vary greatly from hospital to hospital. A recent study indicates that Gram-negative pathogens in ventilated patients can increasingly also be expected in short hospital stays <TextLink reference="67"></TextLink>. In high-risk patients with severe sepsis or septic shock and high MRSA hospital rates, it should be combined with oxazolidinone (linezolid) <TextLink reference="40"></TextLink>. Ceftobiprole, in combination with a fluoroquinolone or fosfomycin, is a useful alternative. Ceftobiprole is a treatment option that can also be administered at a suitable dose (3x 1 g i.v.) in cases of pneumogenic sepsis <TextLink reference="66"></TextLink>.</Pgraph><Pgraph>In addition, ceftolozane/tazobactam should be considered as a further option for calculated initial treatment in patients with severe sepsis or septic shock and unknown septic focus as well as in pneumogenic sepsis because of its excellent efficacy against pseudomonads (including MDR) and ESBL-producers. Its ineffectiveness against staphylococci and anaerobics must, however, be compensated by an appropriate combination partner.</Pgraph><Pgraph>If sepsis originates in the urinary tract without previous instrumental intervention, primarily <Mark2>Escherichia</Mark2> <Mark2>coli</Mark2> and <Mark2>Proteus</Mark2> <Mark2>mirabilis</Mark2> are to be expected as sepsis pathogens. After urological interventions other Enterobacteriaceae, <Mark2>Pseudomonas</Mark2> <Mark2>aeruginosa</Mark2>, enterococci and staphylococci must also be considered.</Pgraph><Pgraph>If the starting point is the intestine or a gynecological organ, the following pathogens must be expected: Enterobacteriaceae, anaerobes, enterococci, <Mark2>Pseudomonas</Mark2> spp., <Mark2>Staphylococcus</Mark2> <Mark2>aureus</Mark2>.</Pgraph><Pgraph>In biliary sepsis, pathogen colonization in the bile ducts and thus the risk of bacteremia increases with the degree of outflow obstruction. In occlusive ictus, more than 75% of patients have pathogens in their blood. The spectrum includes Enterobacteriaceae, enterococci and anaerobes. In post-operative bacteremia, cholangiotic sepsis and sub-hepatic abscesses as well as in interventional procedures (ERCP or endoscopic papillotomy), other Gram-negative pathogens, including <Mark2>Pseudomonas</Mark2> <Mark2>aeruginosa</Mark2>, have been identified. If sepsis originates from the gut/gynecological organs and biliary tract, in severe sepsis or septic shock, it can be combined with a glycylcycline (tigecycline) <TextLink reference="40"></TextLink>, <TextLink reference="68"></TextLink>, <TextLink reference="69"></TextLink>. </Pgraph><Pgraph>If the source is the skin or soft tissue, infections by <Mark2>Streptococcus</Mark2> <Mark2>pyogenes</Mark2>, <Mark2>Staphylococcus</Mark2> <Mark2>aureus</Mark2> (also MRSA) and mixed infections with the additional involvement of non-A streptococci, anaerobes, Enterobacteriaceae or <Mark2>Pseudomonas</Mark2> <Mark2>aeruginosa</Mark2> are possible.</Pgraph><Pgraph>The pathogen spectrum of catheter-associated sepsis includes coagulase-negative staphylococci, <Mark2>Staphylococcus</Mark2> <Mark2>aureus</Mark2>, Gram-negative rod bacteria, <Mark2>Candida</Mark2> spp., <Mark2>Corynebacterium</Mark2> <Mark2>jeikeium</Mark2> and propionibacteria. Another therapeutic option is the lipopeptide daptomycin <TextLink reference="7"></TextLink>, <TextLink reference="65"></TextLink> as an alternative to the glycopeptide.</Pgraph><Pgraph>The monotherapy recommendations presented in <TextGroup><PlainText>Table 1 </PlainText></TextGroup><ImgLink imgNo="1" imgType="table"/> are based on the results of well-documented, randomized clinical studies. In contrast, there is a general lack of clinical studies on combination treatment recommendations. Accordingly, these recommendations are based on expert opinions, this is especially true for combination therapy with a fluoroquinolone.</Pgraph></TextBlock>
<TextBlock language="de" linked="yes" name="Anmerkung">
<MainHeadline>Anmerkung</MainHeadline><Pgraph>Dies ist das elfte Kapitel der von der Paul-Ehrlich-Gesellschaft für Chemotherapie e.V. (PEG) herausgegebenen S2k Leitlinie „Kalkulierte parenterale Initialtherapie bakterieller Erkrankungen bei Erwachsenen – Update 2018“ in der 2. aktualisierten Fassung.</Pgraph></TextBlock>
<TextBlock language="en" linked="yes" name="Note">
<MainHeadline>Note</MainHeadline><Pgraph>This is the eleventh chapter of the guideline “Calculated initial parenteral treatment of bacterial infections in adults – update 2018” in the 2<Superscript>nd</Superscript> updated version. The German guideline by the Paul-Ehrlich-Gesellschaft für Chemothe<TextGroup><PlainText>ra</PlainText></TextGroup>pie e.V. (PEG) has been translated to address an international audience.</Pgraph></TextBlock>
<TextBlock language="de" linked="yes" name="Interessenkonflikte">
<MainHeadline>Interessenkonflikte</MainHeadline><Pgraph>Die Autoren erklären, dass sie keine Interessenkonflikte in Zusammenhang mit diesem Artikel haben.</Pgraph></TextBlock>
<TextBlock language="en" linked="yes" name="Competing interests">
<MainHeadline>Competing interests</MainHeadline><Pgraph>The authors declare that they have no competing interests.</Pgraph></TextBlock>
<References linked="yes">
<Reference refNo="45">
<RefAuthor>Kresken M</RefAuthor>
<RefAuthor>Grabein B</RefAuthor>
<RefAuthor>Becker K</RefAuthor>
<RefAuthor>Straube E</RefAuthor>
<RefAuthor>Wichelhaus TA</RefAuthor>
<RefAuthor>Willinger B</RefAuthor>
<RefTitle>Kalkulierte parenterale Initialtherapie bakterieller Infektionen: Mikrobiologie</RefTitle>
<RefYear>2020</RefYear>
<RefJournal>GMS Infect Dis</RefJournal>
<RefPage>Doc18</RefPage>
<RefTotal>Kresken M, Grabein B, Becker K, Straube E, Wichelhaus TA, Willinger B. Kalkulierte parenterale Initialtherapie bakterieller Infektionen: Mikrobiologie [Calculated parenteral initial treatment of bacterial infections: Microbiology]. GMS Infect Dis. 2020;8:Doc18. DOI: 10.3205/id000062</RefTotal>
<RefLink>https://doi.org/10.3205/id000062</RefLink>
</Reference>
<Reference refNo="51">
<RefAuthor>Derendorf H</RefAuthor>
<RefAuthor>Heinrichs T</RefAuthor>
<RefAuthor>Reimers T</RefAuthor>
<RefAuthor>Lebert C</RefAuthor>
<RefAuthor>Brinkmann A</RefAuthor>
<RefTitle>Kalkulierte parenterale Initialtherapie bakterieller Infektionen: Pharmakokinetik und Pharmakodynamik</RefTitle>
<RefYear>2020</RefYear>
<RefJournal>GMS Infect Dis</RefJournal>
<RefPage>Doc17</RefPage>
<RefTotal>Derendorf H, Heinrichs T, Reimers T, Lebert C, Brinkmann A. Kalkulierte parenterale Initialtherapie bakterieller Infektionen: Pharmakokinetik und Pharmakodynamik [Calculated parenteral initial treatment of bacterial infections: Pharmacokinetics and pharmacodynamics]. GMS Infect Dis. 2020;8:Doc17. DOI: 10.3205/id000061</RefTotal>
<RefLink>https://doi.org/10.3205/id000061</RefLink>
</Reference>
<Reference refNo="1">
<RefAuthor>Peterson LR</RefAuthor>
<RefTitle>Bad bugs, no drugs: no ESCAPE revisited</RefTitle>
<RefYear>2009</RefYear>
<RefJournal>Clin Infect Dis</RefJournal>
<RefPage>992-3</RefPage>
<RefTotal>Peterson LR. Bad bugs, no drugs: no ESCAPE revisited. Clin Infect Dis. 2009 Sep;49(6):992-3. DOI: 10.1086/605539</RefTotal>
<RefLink>https://doi.org/10.1086/605539</RefLink>
</Reference>
<Reference refNo="2">
<RefAuthor>Angus DC</RefAuthor>
<RefAuthor>van der Poll T</RefAuthor>
<RefTitle>Severe sepsis and septic shock</RefTitle>
<RefYear>2013</RefYear>
<RefJournal>N Engl J Med</RefJournal>
<RefPage>840-51</RefPage>
<RefTotal>Angus DC, van der Poll T. Severe sepsis and septic shock. N Engl J Med. 2013 Aug;369(9):840-51. DOI: 10.1056/NEJMra1208623</RefTotal>
<RefLink>https://doi.org/10.1056/NEJMra1208623</RefLink>
</Reference>
<Reference refNo="3">
<RefAuthor>Marik PE</RefAuthor>
<RefTitle>Don't miss the diagnosis of sepsis!</RefTitle>
<RefYear>2014</RefYear>
<RefJournal>Crit Care</RefJournal>
<RefPage>529</RefPage>
<RefTotal>Marik PE. Don't miss the diagnosis of sepsis!. Crit Care. 2014 Sep;18(5):529. DOI: 10.1186/s13054-014-0529-6</RefTotal>
<RefLink>https://doi.org/10.1186/s13054-014-0529-6</RefLink>
</Reference>
<Reference refNo="4">
<RefAuthor>Fleischmann C</RefAuthor>
<RefAuthor>Thomas-Rueddel DO</RefAuthor>
<RefAuthor>Hartmann M</RefAuthor>
<RefAuthor>Hartog CS</RefAuthor>
<RefAuthor>Welte T</RefAuthor>
<RefAuthor>Heublein S</RefAuthor>
<RefAuthor>Dennler U</RefAuthor>
<RefAuthor>Reinhart K</RefAuthor>
<RefTitle>Hospital Incidence and Mortality Rates of Sepsis</RefTitle>
<RefYear>2016</RefYear>
<RefJournal>Dtsch Arztebl Int</RefJournal>
<RefPage>159-66</RefPage>
<RefTotal>Fleischmann C, Thomas-Rueddel DO, Hartmann M, Hartog CS, Welte T, Heublein S, Dennler U, Reinhart K. Hospital Incidence and Mortality Rates of Sepsis. Dtsch Arztebl Int. 2016 Mar;113(10):159-66. DOI: 10.3238/arztebl.2016.0159</RefTotal>
<RefLink>https://doi.org/10.3238/arztebl.2016.0159</RefLink>
</Reference>
<Reference refNo="5">
<RefAuthor>SepNet Critical Care Trials Group</RefAuthor>
<RefTitle>Incidence of severe sepsis and septic shock in German intensive care units: the prospective, multicentre INSEP study</RefTitle>
<RefYear>2016</RefYear>
<RefJournal>Intensive Care Med</RefJournal>
<RefPage>1980-1989</RefPage>
<RefTotal>SepNet Critical Care Trials Group. Incidence of severe sepsis and septic shock in German intensive care units: the prospective, multicentre INSEP study. Intensive Care Med. 2016 Dec;42(12):1980-1989. DOI: 10.1007/s00134-016-4504-3</RefTotal>
<RefLink>https://doi.org/10.1007/s00134-016-4504-3</RefLink>
</Reference>
<Reference refNo="6">
<RefAuthor>Fleischmann C</RefAuthor>
<RefAuthor>Scherag A</RefAuthor>
<RefAuthor>Adhikari NK</RefAuthor>
<RefAuthor>Hartog CS</RefAuthor>
<RefAuthor>Tsaganos T</RefAuthor>
<RefAuthor>Schlattmann P</RefAuthor>
<RefAuthor>Angus DC</RefAuthor>
<RefAuthor>Reinhart K</RefAuthor>
<RefAuthor> International Forum of Acute Care Trialists</RefAuthor>
<RefTitle>Assessment of Global Incidence and Mortality of Hospital-treated Sepsis. Current Estimates and Limitations</RefTitle>
<RefYear>2016</RefYear>
<RefJournal>Am J Respir Crit Care Med</RefJournal>
<RefPage>259-72</RefPage>
<RefTotal>Fleischmann C, Scherag A, Adhikari NK, Hartog CS, Tsaganos T, Schlattmann P, Angus DC, Reinhart K; International Forum of Acute Care Trialists. Assessment of Global Incidence and Mortality of Hospital-treated Sepsis. Current Estimates and Limitations. Am J Respir Crit Care Med. 2016 Feb;193(3):259-72. DOI: 10.1164/rccm.201504-0781OC</RefTotal>
<RefLink>https://doi.org/10.1164/rccm.201504-0781OC</RefLink>
</Reference>
<Reference refNo="7">
<RefAuthor>Engel C</RefAuthor>
<RefAuthor>Brunkhorst FM</RefAuthor>
<RefAuthor>Bone HG</RefAuthor>
<RefAuthor>Brunkhorst R</RefAuthor>
<RefAuthor>Gerlach H</RefAuthor>
<RefAuthor>Grond S</RefAuthor>
<RefAuthor>Gruendling M</RefAuthor>
<RefAuthor>Huhle G</RefAuthor>
<RefAuthor>Jaschinski U</RefAuthor>
<RefAuthor>John S</RefAuthor>
<RefAuthor>Mayer K</RefAuthor>
<RefAuthor>Oppert M</RefAuthor>
<RefAuthor>Olthoff D</RefAuthor>
<RefAuthor>Quintel M</RefAuthor>
<RefAuthor>Ragaller M</RefAuthor>
<RefAuthor>Rossaint R</RefAuthor>
<RefAuthor>Stuber F</RefAuthor>
<RefAuthor>Weiler N</RefAuthor>
<RefAuthor>Welte T</RefAuthor>
<RefAuthor>Bogatsch H</RefAuthor>
<RefAuthor>Hartog C</RefAuthor>
<RefAuthor>Loeffler M</RefAuthor>
<RefAuthor>Reinhart K</RefAuthor>
<RefTitle>Epidemiology of sepsis in Germany: results from a national prospective multicenter study</RefTitle>
<RefYear>2007</RefYear>
<RefJournal>Intensive Care Med</RefJournal>
<RefPage>606-18</RefPage>
<RefTotal>Engel C, Brunkhorst FM, Bone HG, Brunkhorst R, Gerlach H, Grond S, Gruendling M, Huhle G, Jaschinski U, John S, Mayer K, Oppert M, Olthoff D, Quintel M, Ragaller M, Rossaint R, Stuber F, Weiler N, Welte T, Bogatsch H, Hartog C, Loeffler M, Reinhart K. Epidemiology of sepsis in Germany: results from a national prospective multicenter study. Intensive Care Med. 2007 Apr;33(4):606-18. DOI: 10.1007/s00134-006-0517-7</RefTotal>
<RefLink>https://doi.org/10.1007/s00134-006-0517-7</RefLink>
</Reference>
<Reference refNo="8">
<RefAuthor>Wisplinghoff H</RefAuthor>
<RefAuthor>Bischoff T</RefAuthor>
<RefAuthor>Tallent SM</RefAuthor>
<RefAuthor>Seifert H</RefAuthor>
<RefAuthor>Wenzel RP</RefAuthor>
<RefAuthor>Edmond MB</RefAuthor>
<RefTitle>Nosocomial bloodstream infections in US hospitals: analysis of 24,179 cases from a prospective nationwide surveillance study</RefTitle>
<RefYear>2004</RefYear>
<RefJournal>Clin Infect Dis</RefJournal>
<RefPage>309-17</RefPage>
<RefTotal>Wisplinghoff H, Bischoff T, Tallent SM, Seifert H, Wenzel RP, Edmond MB. Nosocomial bloodstream infections in US hospitals: analysis of 24,179 cases from a prospective nationwide surveillance study. Clin Infect Dis. 2004 Aug;39(3):309-17. DOI: 10.1086/421946</RefTotal>
<RefLink>https://doi.org/10.1086/421946</RefLink>
</Reference>
<Reference refNo="9">
<RefAuthor>Meyer E</RefAuthor>
<RefAuthor>Geffers C</RefAuthor>
<RefAuthor>Gastmeier P</RefAuthor>
<RefAuthor>Schwab F</RefAuthor>
<RefTitle>No increase in primary nosocomial candidemia in 682 German intensive care units during 2006 to 2011</RefTitle>
<RefYear>2013</RefYear>
<RefJournal>Euro Surveill</RefJournal>
<RefPage>20505</RefPage>
<RefTotal>Meyer E, Geffers C, Gastmeier P, Schwab F. No increase in primary nosocomial candidemia in 682 German intensive care units during 2006 to 2011. Euro Surveill. 2013 Jun 13;18(24). pii: 20505. DOI: 10.2807/ese.18.24.20505-en</RefTotal>
<RefLink>https://doi.org/10.2807/ese.18.24.20505-en</RefLink>
</Reference>
<Reference refNo="10">
<RefAuthor>Seymour CW</RefAuthor>
<RefAuthor>Rosengart MR</RefAuthor>
<RefTitle>Septic Shock: Advances in Diagnosis and Treatment</RefTitle>
<RefYear>2015</RefYear>
<RefJournal>JAMA</RefJournal>
<RefPage>708-17</RefPage>
<RefTotal>Seymour CW, Rosengart MR. Septic Shock: Advances in Diagnosis and Treatment. JAMA. 2015 Aug;314(7):708-17. DOI: 10.1001/jama.2015.7885</RefTotal>
<RefLink>https://doi.org/10.1001/jama.2015.7885</RefLink>
</Reference>
<Reference refNo="11">
<RefAuthor>Schuster HP</RefAuthor>
<RefAuthor>Werdan K</RefAuthor>
<RefTitle></RefTitle>
<RefYear>2000</RefYear>
<RefBookTitle>Intensivtherapie bei Sepsis und Multiorganversagen</RefBookTitle>
<RefPage></RefPage>
<RefTotal>Schuster HP, Werdan K, editors. Intensivtherapie bei Sepsis und Multiorganversagen. Berlin, Heidelberg: Springer; 2000. DOI: 10.1007/978-3-662-07962-1</RefTotal>
<RefLink>https://doi.org/10.1007/978-3-662-07962-1</RefLink>
</Reference>
<Reference refNo="12">
<RefAuthor>Bone RC</RefAuthor>
<RefAuthor>Balk RA</RefAuthor>
<RefAuthor>Cerra FB</RefAuthor>
<RefAuthor>Dellinger RP</RefAuthor>
<RefAuthor>Fein AM</RefAuthor>
<RefAuthor>Knaus WA</RefAuthor>
<RefAuthor>Schein RM</RefAuthor>
<RefAuthor>Sibbald WJ</RefAuthor>
<RefTitle>Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine</RefTitle>
<RefYear>1992</RefYear>
<RefJournal>Chest</RefJournal>
<RefPage>1644-55</RefPage>
<RefTotal>Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM, Knaus WA, Schein RM, Sibbald WJ. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest. 1992; 101(6):1644-55. DOI: 10.1378/chest.101.6.1644</RefTotal>
<RefLink>https://doi.org/10.1378/chest.101.6.1644</RefLink>
</Reference>
<Reference refNo="13">
<RefAuthor>Liu V</RefAuthor>
<RefAuthor>Escobar GJ</RefAuthor>
<RefAuthor>Greene JD</RefAuthor>
<RefAuthor>Soule J</RefAuthor>
<RefAuthor>Whippy A</RefAuthor>
<RefAuthor>Angus DC</RefAuthor>
<RefAuthor>Iwashyna TJ</RefAuthor>
<RefTitle>Hospital deaths in patients with sepsis from 2 independent cohorts</RefTitle>
<RefYear>2014</RefYear>
<RefJournal>JAMA</RefJournal>
<RefPage>90-2</RefPage>
<RefTotal>Liu V, Escobar GJ, Greene JD, Soule J, Whippy A, Angus DC, Iwashyna TJ. Hospital deaths in patients with sepsis from 2 independent cohorts. JAMA. 2014 Jul;312(1):90-2. DOI: 10.1001/jama.2014.5804</RefTotal>
<RefLink>https://doi.org/10.1001/jama.2014.5804</RefLink>
</Reference>
<Reference refNo="14">
<RefAuthor>Kaukonen KM</RefAuthor>
<RefAuthor>Bailey M</RefAuthor>
<RefAuthor>Pilcher D</RefAuthor>
<RefAuthor>Cooper DJ</RefAuthor>
<RefAuthor>Bellomo R</RefAuthor>
<RefTitle>Systemic inflammatory response syndrome criteria in defining severe sepsis</RefTitle>
<RefYear>2015</RefYear>
<RefJournal>N Engl J Med</RefJournal>
<RefPage>1629-38</RefPage>
<RefTotal>Kaukonen KM, Bailey M, Pilcher D, Cooper DJ, Bellomo R. Systemic inflammatory response syndrome criteria in defining severe sepsis. N Engl J Med. 2015 Apr;372(17):1629-38. DOI: 10.1056/NEJMoa1415236</RefTotal>
<RefLink>https://doi.org/10.1056/NEJMoa1415236</RefLink>
</Reference>
<Reference refNo="15">
<RefAuthor>Shankar-Hari M</RefAuthor>
<RefAuthor>Deutschman CS</RefAuthor>
<RefAuthor>Singer M</RefAuthor>
<RefTitle>Do we need a new definition of sepsis? Intensive Care Med</RefTitle>
<RefYear>2015</RefYear>
<RefTotal>Shankar-Hari M, Deutschman CS, Singer M. Do we need a new definition of sepsis? Intensive Care Med. 2015 May;41(5):909-11. DOI: 10.1007/s00134-015-3680-x</RefTotal>
<RefLink>https://doi.org/10.1007/s00134-015-3680-x</RefLink>
</Reference>
<Reference refNo="16">
<RefAuthor>Singer M</RefAuthor>
<RefAuthor>Deutschman CS</RefAuthor>
<RefAuthor>Seymour CW</RefAuthor>
<RefAuthor>Shankar-Hari M</RefAuthor>
<RefAuthor>Annane D</RefAuthor>
<RefAuthor>Bauer M</RefAuthor>
<RefAuthor>Bellomo R</RefAuthor>
<RefAuthor>Bernard GR</RefAuthor>
<RefAuthor>Chiche JD</RefAuthor>
<RefAuthor>Coopersmith CM</RefAuthor>
<RefAuthor>Hotchkiss RS</RefAuthor>
<RefAuthor>Levy MM</RefAuthor>
<RefAuthor>Marshall JC</RefAuthor>
<RefAuthor>Martin GS</RefAuthor>
<RefAuthor>Opal SM</RefAuthor>
<RefAuthor>Rubenfeld GD</RefAuthor>
<RefAuthor>van der Poll T</RefAuthor>
<RefAuthor>Vincent JL</RefAuthor>
<RefAuthor>Angus DC</RefAuthor>
<RefTitle>The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3)</RefTitle>
<RefYear>2016</RefYear>
<RefJournal>JAMA</RefJournal>
<RefPage>801-10</RefPage>
<RefTotal>Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, Bellomo R, Bernard GR, Chiche JD, Coopersmith CM, Hotchkiss RS, Levy MM, Marshall JC, Martin GS, Opal SM, Rubenfeld GD, van der Poll T, Vincent JL, Angus DC. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016 Feb;315(8):801-10. DOI: 10.1001/jama.2016.0287</RefTotal>
<RefLink>https://doi.org/10.1001/jama.2016.0287</RefLink>
</Reference>
<Reference refNo="17">
<RefAuthor>Seymour CW</RefAuthor>
<RefAuthor>Liu VX</RefAuthor>
<RefAuthor>Iwashyna TJ</RefAuthor>
<RefAuthor>Brunkhorst FM</RefAuthor>
<RefAuthor>Rea TD</RefAuthor>
<RefAuthor>Scherag A</RefAuthor>
<RefAuthor>Rubenfeld G</RefAuthor>
<RefAuthor>Kahn JM</RefAuthor>
<RefAuthor>Shankar-Hari M</RefAuthor>
<RefAuthor>Singer M</RefAuthor>
<RefAuthor>Deutschman CS</RefAuthor>
<RefAuthor>Escobar GJ</RefAuthor>
<RefAuthor>Angus DC</RefAuthor>
<RefTitle>Assessment of Clinical Criteria for Sepsis: For the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3)</RefTitle>
<RefYear>2016</RefYear>
<RefJournal>JAMA</RefJournal>
<RefPage>762-74</RefPage>
<RefTotal>Seymour CW, Liu VX, Iwashyna TJ, Brunkhorst FM, Rea TD, Scherag A, Rubenfeld G, Kahn JM, Shankar-Hari M, Singer M, Deutschman CS, Escobar GJ, Angus DC. Assessment of Clinical Criteria for Sepsis: For the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016 Feb;315(8):762-74. DOI: 10.1001/jama.2016.0288</RefTotal>
<RefLink>https://doi.org/10.1001/jama.2016.0288</RefLink>
</Reference>
<Reference refNo="18">
<RefAuthor>Shankar-Hari M</RefAuthor>
<RefAuthor>Phillips GS</RefAuthor>
<RefAuthor>Levy ML</RefAuthor>
<RefAuthor>Seymour CW</RefAuthor>
<RefAuthor>Liu VX</RefAuthor>
<RefAuthor>Deutschman CS</RefAuthor>
<RefAuthor>Angus DC</RefAuthor>
<RefAuthor>Rubenfeld GD</RefAuthor>
<RefAuthor>Singer M</RefAuthor>
<RefAuthor> Sepsis Definitions Task Force</RefAuthor>
<RefTitle>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)</RefTitle>
<RefYear>2016</RefYear>
<RefJournal>JAMA</RefJournal>
<RefPage>775-87</RefPage>
<RefTotal>Shankar-Hari M, Phillips GS, Levy ML, Seymour CW, Liu VX, Deutschman CS, Angus DC, Rubenfeld GD, Singer M; Sepsis Definitions Task Force. 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. 2016 Feb 23;315(8):775-87. DOI: 10.1001/jama.2016.0289</RefTotal>
<RefLink>https://doi.org/10.1001/jama.2016.0289</RefLink>
</Reference>
<Reference refNo="19">
<RefAuthor>Hotchkiss RS</RefAuthor>
<RefAuthor>Monneret G</RefAuthor>
<RefAuthor>Payen D</RefAuthor>
<RefTitle>Sepsis-induced immunosuppression: from cellular dysfunctions to immunotherapy</RefTitle>
<RefYear>2013</RefYear>
<RefJournal>Nat Rev Immunol</RefJournal>
<RefPage>862-74</RefPage>
<RefTotal>Hotchkiss RS, Monneret G, Payen D. Sepsis-induced immunosuppression: from cellular dysfunctions to immunotherapy. Nat Rev Immunol. 2013 Dec;13(12):862-74. DOI: 10.1038/nri3552</RefTotal>
<RefLink>https://doi.org/10.1038/nri3552</RefLink>
</Reference>
<Reference refNo="20">
<RefAuthor>Uhle F</RefAuthor>
<RefAuthor>Lichtenstern C</RefAuthor>
<RefAuthor>Brenner T</RefAuthor>
<RefAuthor>Weigand MA</RefAuthor>
<RefTitle>Sepsis und Multiorganversagen – Pathophysiologie der Sepsis</RefTitle>
<RefYear>2015</RefYear>
<RefJournal>Anasthesiol Intensivmed Notfallmed Schmerzther</RefJournal>
<RefPage>114-22</RefPage>
<RefTotal>Uhle F, Lichtenstern C, Brenner T, Weigand MA. Sepsis und Multiorganversagen – Pathophysiologie der Sepsis [Pathophysiology of sepsis]. Anasthesiol Intensivmed Notfallmed Schmerzther. 2015 Feb;50(2):114-22. DOI: 10.1055/s-0041-100391</RefTotal>
<RefLink>https://doi.org/10.1055/s-0041-100391</RefLink>
</Reference>
<Reference refNo="21">
<RefAuthor>Rhodes A</RefAuthor>
<RefAuthor>Evans LE</RefAuthor>
<RefAuthor>Alhazzani W</RefAuthor>
<RefAuthor>Levy MM</RefAuthor>
<RefAuthor>Antonelli M</RefAuthor>
<RefAuthor>Ferrer R</RefAuthor>
<RefAuthor>Kumar A</RefAuthor>
<RefAuthor>Sevransky JE</RefAuthor>
<RefAuthor>Sprung CL</RefAuthor>
<RefAuthor>Nunnally ME</RefAuthor>
<RefAuthor>Rochwerg B</RefAuthor>
<RefAuthor>Rubenfeld GD</RefAuthor>
<RefAuthor>Angus DC</RefAuthor>
<RefAuthor>Annane D</RefAuthor>
<RefAuthor>Beale RJ</RefAuthor>
<RefAuthor>Bellinghan GJ</RefAuthor>
<RefAuthor>Bernard GR</RefAuthor>
<RefAuthor>Chiche JD</RefAuthor>
<RefAuthor>Coopersmith C</RefAuthor>
<RefAuthor>De Backer DP</RefAuthor>
<RefAuthor>French CJ</RefAuthor>
<RefAuthor>Fujishima S</RefAuthor>
<RefAuthor>Gerlach H</RefAuthor>
<RefAuthor>Hidalgo JL</RefAuthor>
<RefAuthor>Hollenberg SM</RefAuthor>
<RefAuthor>Jones AE</RefAuthor>
<RefAuthor>Karnad DR</RefAuthor>
<RefAuthor>Kleinpell RM</RefAuthor>
<RefAuthor>Koh Y</RefAuthor>
<RefAuthor>Lisboa TC</RefAuthor>
<RefAuthor>Machado FR</RefAuthor>
<RefAuthor>Marini JJ</RefAuthor>
<RefAuthor>Marshall JC</RefAuthor>
<RefAuthor>Mazuski JE</RefAuthor>
<RefAuthor>McIntyre LA</RefAuthor>
<RefAuthor>McLean AS</RefAuthor>
<RefAuthor>Mehta S</RefAuthor>
<RefAuthor>Moreno RP</RefAuthor>
<RefAuthor>Myburgh J</RefAuthor>
<RefAuthor>Navalesi P</RefAuthor>
<RefAuthor>Nishida O</RefAuthor>
<RefAuthor>Osborn TM</RefAuthor>
<RefAuthor>Perner A</RefAuthor>
<RefAuthor>Plunkett CM</RefAuthor>
<RefAuthor>Ranieri M</RefAuthor>
<RefAuthor>Schorr CA</RefAuthor>
<RefAuthor>Seckel MA</RefAuthor>
<RefAuthor>Seymour CW</RefAuthor>
<RefAuthor>Shieh L</RefAuthor>
<RefAuthor>Shukri KA</RefAuthor>
<RefAuthor>Simpson SQ</RefAuthor>
<RefAuthor>Singer M</RefAuthor>
<RefAuthor>Thompson BT</RefAuthor>
<RefAuthor>Townsend SR</RefAuthor>
<RefAuthor>Van der Poll T</RefAuthor>
<RefAuthor>Vincent JL</RefAuthor>
<RefAuthor>Wiersinga WJ</RefAuthor>
<RefAuthor>Zimmerman JL</RefAuthor>
<RefAuthor>Dellinger RP</RefAuthor>
<RefTitle>Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016</RefTitle>
<RefYear>2017</RefYear>
<RefJournal>Crit Care Med</RefJournal>
<RefPage>486-552</RefPage>
<RefTotal>Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R, Kumar A, Sevransky JE, Sprung CL, Nunnally ME, Rochwerg B, Rubenfeld GD, Angus DC, Annane D, Beale RJ, Bellinghan GJ, Bernard GR, Chiche JD, Coopersmith C, De Backer DP, French CJ, Fujishima S, Gerlach H, Hidalgo JL, Hollenberg SM, Jones AE, Karnad DR, Kleinpell RM, Koh Y, Lisboa TC, Machado FR, Marini JJ, Marshall JC, Mazuski JE, McIntyre LA, McLean AS, Mehta S, Moreno RP, Myburgh J, Navalesi P, Nishida O, Osborn TM, Perner A, Plunkett CM, Ranieri M, Schorr CA, Seckel MA, Seymour CW, Shieh L, Shukri KA, Simpson SQ, Singer M, Thompson BT, Townsend SR, Van der Poll T, Vincent JL, Wiersinga WJ, Zimmerman JL, Dellinger RP. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Crit Care Med. 2017 Mar;45(3):486-552. DOI: 10.1097/CCM.0000000000002255</RefTotal>
<RefLink>https://doi.org/10.1097/CCM.0000000000002255</RefLink>
</Reference>
<Reference refNo="22">
<RefAuthor>Kumar A</RefAuthor>
<RefAuthor>Roberts D</RefAuthor>
<RefAuthor>Wood KE</RefAuthor>
<RefAuthor>Light B</RefAuthor>
<RefAuthor>Parrillo JE</RefAuthor>
<RefAuthor>Sharma S</RefAuthor>
<RefAuthor>Suppes R</RefAuthor>
<RefAuthor>Feinstein D</RefAuthor>
<RefAuthor>Zanotti S</RefAuthor>
<RefAuthor>Taiberg L</RefAuthor>
<RefAuthor>Gurka D</RefAuthor>
<RefAuthor>Kumar A</RefAuthor>
<RefAuthor>Cheang M</RefAuthor>
<RefTitle>Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock</RefTitle>
<RefYear>2006</RefYear>
<RefJournal>Crit Care Med</RefJournal>
<RefPage>1589-96</RefPage>
<RefTotal>Kumar A, Roberts D, Wood KE, Light B, Parrillo JE, Sharma S, Suppes R, Feinstein D, Zanotti S, Taiberg L, Gurka D, Kumar A, Cheang M. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med. 2006; 34(6):1589-96. DOI: 10.1097/01.CCM.0000217961.75225.E9</RefTotal>
<RefLink>https://doi.org/10.1097/01.CCM.0000217961.75225.E9</RefLink>
</Reference>
<Reference refNo="23">
<RefAuthor>Sterling SA</RefAuthor>
<RefAuthor>Miller WR</RefAuthor>
<RefAuthor>Pryor J</RefAuthor>
<RefAuthor>Puskarich MA</RefAuthor>
<RefAuthor>Jones AE</RefAuthor>
<RefTitle>The Impact of Timing of Antibiotics on Outcomes in Severe Sepsis and Septic Shock: A Systematic Review and Meta-Analysis</RefTitle>
<RefYear>2015</RefYear>
<RefJournal>Crit Care Med</RefJournal>
<RefPage>1907-15</RefPage>
<RefTotal>Sterling SA, Miller WR, Pryor J, Puskarich MA, Jones AE. The Impact of Timing of Antibiotics on Outcomes in Severe Sepsis and Septic Shock: A Systematic Review and Meta-Analysis. Crit Care Med. 2015 Sep;43(9):1907-15. DOI: 10.1097/CCM.0000000000001142</RefTotal>
<RefLink>https://doi.org/10.1097/CCM.0000000000001142</RefLink>
</Reference>
<Reference refNo="24">
<RefAuthor>Seymour CW</RefAuthor>
<RefAuthor>Gesten F</RefAuthor>
<RefAuthor>Prescott HC</RefAuthor>
<RefAuthor>Friedrich ME</RefAuthor>
<RefAuthor>Iwashyna TJ</RefAuthor>
<RefAuthor>Phillips GS</RefAuthor>
<RefAuthor>Lemeshow S</RefAuthor>
<RefAuthor>Osborn T</RefAuthor>
<RefAuthor>Terry KM</RefAuthor>
<RefAuthor>Levy MM</RefAuthor>
<RefTitle>Time to Treatment and Mortality during Mandated Emergency Care for Sepsis</RefTitle>
<RefYear>2017</RefYear>
<RefJournal>N Engl J Med</RefJournal>
<RefPage>2235-2244</RefPage>
<RefTotal>Seymour CW, Gesten F, Prescott HC, Friedrich ME, Iwashyna TJ, Phillips GS, Lemeshow S, Osborn T, Terry KM, Levy MM. Time to Treatment and Mortality during Mandated Emergency Care for Sepsis. N Engl J Med. 2017 06;376(23):2235-2244. DOI: 10.1056/NEJMoa1703058</RefTotal>
<RefLink>https://doi.org/10.1056/NEJMoa1703058</RefLink>
</Reference>
<Reference refNo="25">
<RefAuthor>Bloos F</RefAuthor>
<RefAuthor>Rüddel H</RefAuthor>
<RefAuthor>Thomas-Rüddel D</RefAuthor>
<RefAuthor>Schwarzkopf D</RefAuthor>
<RefAuthor>Pausch C</RefAuthor>
<RefAuthor>Harbarth S</RefAuthor>
<RefAuthor>Schreiber T</RefAuthor>
<RefAuthor>Gründling M</RefAuthor>
<RefAuthor>Marshall J</RefAuthor>
<RefAuthor>Simon P</RefAuthor>
<RefAuthor>Levy MM</RefAuthor>
<RefAuthor>Weiss M</RefAuthor>
<RefAuthor>Weyland A</RefAuthor>
<RefAuthor>Gerlach H</RefAuthor>
<RefAuthor>Schürholz T</RefAuthor>
<RefAuthor>Engel C</RefAuthor>
<RefAuthor>Matthäus-Krämer C</RefAuthor>
<RefAuthor>Scheer C</RefAuthor>
<RefAuthor>Bach F</RefAuthor>
<RefAuthor>Riessen R</RefAuthor>
<RefAuthor>Poidinger B</RefAuthor>
<RefAuthor>Dey K</RefAuthor>
<RefAuthor>Weiler N</RefAuthor>
<RefAuthor>Meier-Hellmann A</RefAuthor>
<RefAuthor>Häberle HH</RefAuthor>
<RefAuthor>Wöbker G</RefAuthor>
<RefAuthor>Kaisers UX</RefAuthor>
<RefAuthor>Reinhart K</RefAuthor>
<RefAuthor> MEDUSA study group</RefAuthor>
<RefTitle>Effect of a multifaceted educational intervention for anti-infectious measures on sepsis mortality: a cluster randomized trial</RefTitle>
<RefYear>2017</RefYear>
<RefJournal>Intensive Care Med</RefJournal>
<RefPage>1602-1612</RefPage>
<RefTotal>Bloos F, Rüddel H, Thomas-Rüddel D, Schwarzkopf D, Pausch C, Harbarth S, Schreiber T, Gründling M, Marshall J, Simon P, Levy MM, Weiss M, Weyland A, Gerlach H, Schürholz T, Engel C, Matthäus-Krämer C, Scheer C, Bach F, Riessen R, Poidinger B, Dey K, Weiler N, Meier-Hellmann A, Häberle HH, Wöbker G, Kaisers UX, Reinhart K; MEDUSA study group. Effect of a multifaceted educational intervention for anti-infectious measures on sepsis mortality: a cluster randomized trial. Intensive Care Med. 2017 Nov;43(11):1602-1612. DOI: 10.1007/s00134-017-4782-4</RefTotal>
<RefLink>https://doi.org/10.1007/s00134-017-4782-4</RefLink>
</Reference>
<Reference refNo="26">
<RefAuthor>Raman G</RefAuthor>
<RefAuthor>Avendano E</RefAuthor>
<RefAuthor>Berger S</RefAuthor>
<RefAuthor>Menon V</RefAuthor>
<RefTitle>Appropriate initial antibiotic therapy in hospitalized patients with gram-negative infections: systematic review and meta-analysis</RefTitle>
<RefYear>2015</RefYear>
<RefJournal>BMC Infect Dis</RefJournal>
<RefPage>395</RefPage>
<RefTotal>Raman G, Avendano E, Berger S, Menon V. Appropriate initial antibiotic therapy in hospitalized patients with gram-negative infections: systematic review and meta-analysis. BMC Infect Dis. 2015 Sep;15:395. DOI: 10.1186/s12879-015-1123-5</RefTotal>
<RefLink>https://doi.org/10.1186/s12879-015-1123-5</RefLink>
</Reference>
<Reference refNo="27">
<RefAuthor>Kumar A</RefAuthor>
<RefAuthor>Safdar N</RefAuthor>
<RefAuthor>Kethireddy S</RefAuthor>
<RefAuthor>Chateau D</RefAuthor>
<RefTitle>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</RefTitle>
<RefYear>2010</RefYear>
<RefJournal>Crit Care Med</RefJournal>
<RefPage>1651-64</RefPage>
<RefTotal>Kumar A, Safdar N, Kethireddy S, Chateau D. A survival benefit of combination antibiotic therapy for serious infections associated with sepsis and septic shock is contingent only on the risk of death: a meta-analytic/meta-regression study. Crit Care Med. 2010 Aug;38(8):1651-64. DOI: 10.1097/CCM.0b013e3181e96b91</RefTotal>
<RefLink>https://doi.org/10.1097/CCM.0b013e3181e96b91</RefLink>
</Reference>
<Reference refNo="28">
<RefAuthor>Dellinger RP</RefAuthor>
<RefAuthor>Levy MM</RefAuthor>
<RefAuthor>Rhodes A</RefAuthor>
<RefAuthor>Annane D</RefAuthor>
<RefAuthor>Gerlach H</RefAuthor>
<RefAuthor>Opal SM</RefAuthor>
<RefAuthor>Sevransky JE</RefAuthor>
<RefAuthor>Sprung CL</RefAuthor>
<RefAuthor>Douglas IS</RefAuthor>
<RefAuthor>Jaeschke R</RefAuthor>
<RefAuthor>Osborn TM</RefAuthor>
<RefAuthor>Nunnally ME</RefAuthor>
<RefAuthor>Townsend SR</RefAuthor>
<RefAuthor>Reinhart K</RefAuthor>
<RefAuthor>Kleinpell RM</RefAuthor>
<RefAuthor>Angus DC</RefAuthor>
<RefAuthor>Deutschman CS</RefAuthor>
<RefAuthor>Machado FR</RefAuthor>
<RefAuthor>Rubenfeld GD</RefAuthor>
<RefAuthor>Webb SA</RefAuthor>
<RefAuthor>Beale RJ</RefAuthor>
<RefAuthor>Vincent JL</RefAuthor>
<RefAuthor>Moreno R</RefAuthor>
<RefAuthor> Surviving Sepsis Campaign Guidelines Committee including the Pediatric Subgroup</RefAuthor>
<RefTitle>Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012</RefTitle>
<RefYear>2013</RefYear>
<RefJournal>Crit Care Med</RefJournal>
<RefPage>580-637</RefPage>
<RefTotal>Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, Sevransky JE, Sprung CL, Douglas IS, Jaeschke R, Osborn TM, Nunnally ME, Townsend SR, Reinhart K, Kleinpell RM, Angus DC, Deutschman CS, Machado FR, Rubenfeld GD, Webb SA, Beale RJ, Vincent JL, Moreno R; Surviving Sepsis Campaign Guidelines Committee including the Pediatric Subgroup. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med. 2013 Feb;41(2):580-637. DOI: 10.1097/CCM.0b013e31827e83af</RefTotal>
<RefLink>https://doi.org/10.1097/CCM.0b013e31827e83af</RefLink>
</Reference>
<Reference refNo="29">
<RefAuthor>Dellinger RP</RefAuthor>
<RefTitle>The Surviving Sepsis Campaign: Where have we been and where are we going?</RefTitle>
<RefYear>2015</RefYear>
<RefJournal>Cleve Clin J Med</RefJournal>
<RefPage>237-44</RefPage>
<RefTotal>Dellinger RP. The Surviving Sepsis Campaign: Where have we been and where are we going? Cleve Clin J Med. 2015 Apr;82(4):237-44. DOI: 10.3949/ccjm.82gr.15001</RefTotal>
<RefLink>https://doi.org/10.3949/ccjm.82gr.15001</RefLink>
</Reference>
<Reference refNo="30">
<RefAuthor>Garnacho-Montero J</RefAuthor>
<RefAuthor>Gutiérrez-Pizarraya A</RefAuthor>
<RefAuthor>Escoresca-Ortega A</RefAuthor>
<RefAuthor>Corcia-Palomo Y</RefAuthor>
<RefAuthor>Fernández-Delgado E</RefAuthor>
<RefAuthor>Herrera-Melero I</RefAuthor>
<RefAuthor>Ortiz-Leyba C</RefAuthor>
<RefAuthor>Márquez-Vácaro JA</RefAuthor>
<RefTitle>De-escalation of empirical therapy is associated with lower mortality in patients with severe sepsis and septic shock</RefTitle>
<RefYear>2014</RefYear>
<RefJournal>Intensive Care Med</RefJournal>
<RefPage>32-40</RefPage>
<RefTotal>Garnacho-Montero J, Gutiérrez-Pizarraya A, Escoresca-Ortega A, Corcia-Palomo Y, Fernández-Delgado E, Herrera-Melero I, Ortiz-Leyba C, Márquez-Vácaro JA. De-escalation of empirical therapy is associated with lower mortality in patients with severe sepsis and septic shock. Intensive Care Med. 2014 Jan;40(1):32-40. DOI: 10.1007/s00134-013-3077-7</RefTotal>
<RefLink>https://doi.org/10.1007/s00134-013-3077-7</RefLink>
</Reference>
<Reference refNo="31">
<RefAuthor>Roberts JA</RefAuthor>
<RefAuthor>Taccone FS</RefAuthor>
<RefAuthor>Lipman J</RefAuthor>
<RefTitle>Understanding PK/PD</RefTitle>
<RefYear>2016</RefYear>
<RefJournal>Intensive Care Med</RefJournal>
<RefPage>1797-1800</RefPage>
<RefTotal>Roberts JA, Taccone FS, Lipman J. Understanding PK/PD. Intensive Care Med. 2016 Nov;42(11):1797-1800. DOI: 10.1007/s00134-015-4032-6</RefTotal>
<RefLink>https://doi.org/10.1007/s00134-015-4032-6</RefLink>
</Reference>
<Reference refNo="32">
<RefAuthor>Taccone FS</RefAuthor>
<RefAuthor>Laterre PF</RefAuthor>
<RefAuthor>Dugernier T</RefAuthor>
<RefAuthor>Spapen H</RefAuthor>
<RefAuthor>Delattre I</RefAuthor>
<RefAuthor>Wittebole X</RefAuthor>
<RefAuthor>De Backer D</RefAuthor>
<RefAuthor>Layeux B</RefAuthor>
<RefAuthor>Wallemacq P</RefAuthor>
<RefAuthor>Vincent JL</RefAuthor>
<RefAuthor>Jacobs F</RefAuthor>
<RefTitle>Insufficient β-lactam concentrations in the early phase of severe sepsis and septic shock</RefTitle>
<RefYear>2010</RefYear>
<RefJournal>Crit Care</RefJournal>
<RefPage>R126</RefPage>
<RefTotal>Taccone FS, Laterre PF, Dugernier T, Spapen H, Delattre I, Wittebole X, De Backer D, Layeux B, Wallemacq P, Vincent JL, Jacobs F. Insufficient β-lactam concentrations in the early phase of severe sepsis and septic shock. Crit Care. 2010;14(4):R126. DOI: 10.1186/cc9091</RefTotal>
<RefLink>https://doi.org/10.1186/cc9091</RefLink>
</Reference>
<Reference refNo="33">
<RefAuthor>Mouton JW</RefAuthor>
<RefAuthor>Ambrose PG</RefAuthor>
<RefAuthor>Canton R</RefAuthor>
<RefAuthor>Drusano GL</RefAuthor>
<RefAuthor>Harbarth S</RefAuthor>
<RefAuthor>MacGowan A</RefAuthor>
<RefAuthor>Theuretzbacher U</RefAuthor>
<RefAuthor>Turnidge J</RefAuthor>
<RefTitle>Conserving antibiotics for the future: new ways to use old and new drugs from a pharmacokinetic and pharmacodynamic perspective</RefTitle>
<RefYear>2011</RefYear>
<RefJournal>Drug Resist Updat</RefJournal>
<RefPage>107-17</RefPage>
<RefTotal>Mouton JW, Ambrose PG, Canton R, Drusano GL, Harbarth S, MacGowan A, Theuretzbacher U, Turnidge J. Conserving antibiotics for the future: new ways to use old and new drugs from a pharmacokinetic and pharmacodynamic perspective. Drug Resist Updat. 2011 Apr;14(2):107-17. DOI: 10.1016/j.drup.2011.02.005</RefTotal>
<RefLink>https://doi.org/10.1016/j.drup.2011.02.005</RefLink>
</Reference>
<Reference refNo="34">
<RefAuthor>Drusano GL</RefAuthor>
<RefAuthor>Lodise TP</RefAuthor>
<RefTitle>Saving lives with optimal antimicrobial chemotherapy</RefTitle>
<RefYear>2013</RefYear>
<RefJournal>Clin Infect Dis</RefJournal>
<RefPage>245-7</RefPage>
<RefTotal>Drusano GL, Lodise TP. Saving lives with optimal antimicrobial chemotherapy. Clin Infect Dis. 2013 Jan;56(2):245-7. DOI: 10.1093/cid/cis863</RefTotal>
<RefLink>https://doi.org/10.1093/cid/cis863</RefLink>
</Reference>
<Reference refNo="35">
<RefAuthor>Lipman J</RefAuthor>
<RefAuthor>Roberts J</RefAuthor>
<RefTitle>Does Appropriate Antibiotic Therapy Mean Only Adequate Spectrum and Timing?</RefTitle>
<RefYear>2015</RefYear>
<RefJournal>Crit Care Med</RefJournal>
<RefPage>1773-4</RefPage>
<RefTotal>Lipman J, Roberts J. Does Appropriate Antibiotic Therapy Mean Only Adequate Spectrum and Timing? Crit Care Med. 2015 Aug;43(8):1773-4. DOI: 10.1097/CCM.0000000000001060</RefTotal>
<RefLink>https://doi.org/10.1097/CCM.0000000000001060</RefLink>
</Reference>
<Reference refNo="36">
<RefAuthor>Nobre V</RefAuthor>
<RefAuthor>Harbarth S</RefAuthor>
<RefAuthor>Graf JD</RefAuthor>
<RefAuthor>Rohner P</RefAuthor>
<RefAuthor>Pugin J</RefAuthor>
<RefTitle>Use of procalcitonin to shorten antibiotic treatment duration in septic patients: a randomized trial</RefTitle>
<RefYear>2008</RefYear>
<RefJournal>Am J Respir Crit Care Med</RefJournal>
<RefPage>498-505</RefPage>
<RefTotal>Nobre V, Harbarth S, Graf JD, Rohner P, Pugin J. Use of procalcitonin to shorten antibiotic treatment duration in septic patients: a randomized trial. Am J Respir Crit Care Med. 2008 Mar;177(5):498-505. DOI: 10.1164/rccm.200708-1238OC</RefTotal>
<RefLink>https://doi.org/10.1164/rccm.200708-1238OC</RefLink>
</Reference>
<Reference refNo="37">
<RefAuthor>Bouadma L</RefAuthor>
<RefAuthor>Luyt CE</RefAuthor>
<RefAuthor>Tubach F</RefAuthor>
<RefAuthor>Cracco C</RefAuthor>
<RefAuthor>Alvarez A</RefAuthor>
<RefAuthor>Schwebel C</RefAuthor>
<RefAuthor>Schortgen F</RefAuthor>
<RefAuthor>Lasocki S</RefAuthor>
<RefAuthor>Veber B</RefAuthor>
<RefAuthor>Dehoux M</RefAuthor>
<RefAuthor>Bernard M</RefAuthor>
<RefAuthor>Pasquet B</RefAuthor>
<RefAuthor>Régnier B</RefAuthor>
<RefAuthor>Brun-Buisson C</RefAuthor>
<RefAuthor>Chastre J</RefAuthor>
<RefAuthor>Wolff M</RefAuthor>
<RefAuthor> PRORATA trial group</RefAuthor>
<RefTitle>Use of procalcitonin to reduce patients’ exposure to antibiotics in intensive care units (PRORATA trial): a multicentre randomised controlled trial</RefTitle>
<RefYear>2010</RefYear>
<RefJournal>Lancet</RefJournal>
<RefPage>463-74</RefPage>
<RefTotal>Bouadma L, Luyt CE, Tubach F, Cracco C, Alvarez A, Schwebel C, Schortgen F, Lasocki S, Veber B, Dehoux M, Bernard M, Pasquet B, Régnier B, Brun-Buisson C, Chastre J, Wolff M; PRORATA trial group. Use of procalcitonin to reduce patients’ exposure to antibiotics in intensive care units (PRORATA trial): a multicentre randomised controlled trial. Lancet. 2010 Feb 6;375(9713):463-74. DOI: 10.1016/S0140-6736(09) 61879-1</RefTotal>
<RefLink>https://doi.org/10.1016/S0140-6736(09) 61879-1</RefLink>
</Reference>
<Reference refNo="38">
<RefAuthor>Wacker C</RefAuthor>
<RefAuthor>Prkno A</RefAuthor>
<RefAuthor>Brunkhorst FM</RefAuthor>
<RefAuthor>Schlattmann P</RefAuthor>
<RefTitle>Procalcitonin as a diagnostic marker for sepsis: a systematic review and meta-analysis</RefTitle>
<RefYear>2013</RefYear>
<RefJournal>Lancet Infect Dis</RefJournal>
<RefPage>426-35</RefPage>
<RefTotal>Wacker C, Prkno A, Brunkhorst FM, Schlattmann P. Procalcitonin as a diagnostic marker for sepsis: a systematic review and meta-analysis. Lancet Infect Dis. 2013 May;13(5):426-35. DOI: 10.1016/S1473-3099(12) 70323-7</RefTotal>
<RefLink>https://doi.org/10.1016/S1473-3099(12) 70323-7</RefLink>
</Reference>
<Reference refNo="39">
<RefAuthor>Bodmann KF</RefAuthor>
<RefTitle>Diagnostische Marker und Effektivitätsbewertung in der antibakteriellen Therapie</RefTitle>
<RefYear>2014</RefYear>
<RefJournal>Med Klin Intensivmed Notfmed</RefJournal>
<RefPage>187-90</RefPage>
<RefTotal>Bodmann KF. Diagnostische Marker und Effektivitätsbewertung in der antibakteriellen Therapie [Diagnostic markers and assessment of efficacy of antibacterial therapy]. Med Klin Intensivmed Notfmed. 2014 Apr;109(3):187-90. DOI: 10.1007/s00063-013-0312-5</RefTotal>
<RefLink>https://doi.org/10.1007/s00063-013-0312-5</RefLink>
</Reference>
<Reference refNo="40">
<RefAuthor>Dellit TH</RefAuthor>
<RefAuthor>Owens RC</RefAuthor>
<RefAuthor>McGowan JE Jr</RefAuthor>
<RefAuthor>Gerding DN</RefAuthor>
<RefAuthor>Weinstein RA</RefAuthor>
<RefAuthor>Burke JP</RefAuthor>
<RefAuthor>Huskins WC</RefAuthor>
<RefAuthor>Paterson DL</RefAuthor>
<RefAuthor>Fishman NO</RefAuthor>
<RefAuthor>Carpenter CF</RefAuthor>
<RefAuthor>Brennan PJ</RefAuthor>
<RefAuthor>Billeter M</RefAuthor>
<RefAuthor>Hooton TM</RefAuthor>
<RefAuthor> Infectious Diseases Society of America</RefAuthor>
<RefAuthor> Society for Healthcare Epidemiology of America</RefAuthor>
<RefTitle>Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America guidelines for developing an institutional program to enhance antimicrobial stewardship</RefTitle>
<RefYear>2007</RefYear>
<RefJournal>Clin Infect Dis</RefJournal>
<RefPage>159-77</RefPage>
<RefTotal>Dellit TH, Owens RC, McGowan JE Jr, Gerding DN, Weinstein RA, Burke JP, Huskins WC, Paterson DL, Fishman NO, Carpenter CF, Brennan PJ, Billeter M, Hooton TM; Infectious Diseases Society of America; Society for Healthcare Epidemiology of America. Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America guidelines for developing an institutional program to enhance antimicrobial stewardship. Clin Infect Dis. 2007 Jan;44(2):159-77. DOI: 10.1086/510393</RefTotal>
<RefLink>https://doi.org/10.1086/510393</RefLink>
</Reference>
<Reference refNo="41">
<RefAuthor>Deutsche Gesellschaft für Infektiologie (DGI)</RefAuthor>
<RefAuthor></RefAuthor>
<RefTitle></RefTitle>
<RefYear>2013</RefYear>
<RefBookTitle>Strategien zur Sicherung rationaler Antibiotika-Anwendung im Krankenhaus. S3 - Guideline. AWMF-Registernummer 092-001</RefBookTitle>
<RefPage></RefPage>
<RefTotal>Deutsche Gesellschaft für Infektiologie (DGI), et al. Strategien zur Sicherung rationaler Antibiotika-Anwendung im Krankenhaus. S3 - Guideline. AWMF-Registernummer 092-001. AWMF; 2013. Available from: http://www.awmf.org/uploads/tx_szleitlinien/092-001l_S3_Antibiotika_Anwendung_im_Krankenhaus_2013-verlaengert.pdf</RefTotal>
<RefLink>http://www.awmf.org/uploads/tx_szleitlinien/092-001l_S3_Antibiotika_Anwendung_im_Krankenhaus_2013-verlaengert.pdf</RefLink>
</Reference>
<Reference refNo="42">
<RefAuthor>Bai AD</RefAuthor>
<RefAuthor>Showler A</RefAuthor>
<RefAuthor>Burry L</RefAuthor>
<RefAuthor>Steinberg M</RefAuthor>
<RefAuthor>Ricciuto DR</RefAuthor>
<RefAuthor>Fernandes T</RefAuthor>
<RefAuthor>Chiu A</RefAuthor>
<RefAuthor>Raybardhan S</RefAuthor>
<RefAuthor>Science M</RefAuthor>
<RefAuthor>Fernando E</RefAuthor>
<RefAuthor>Tomlinson G</RefAuthor>
<RefAuthor>Bell CM</RefAuthor>
<RefAuthor>Morris AM</RefAuthor>
<RefTitle>Impact of Infectious Disease Consultation on Quality of Care, Mortality, and Length of Stay in Staphylococcus aureus Bacteremia: Results From a Large Multicenter Cohort Study</RefTitle>
<RefYear>2015</RefYear>
<RefJournal>Clin Infect Dis</RefJournal>
<RefPage>1451-61</RefPage>
<RefTotal>Bai AD, Showler A, Burry L, Steinberg M, Ricciuto DR, Fernandes T, Chiu A, Raybardhan S, Science M, Fernando E, Tomlinson G, Bell CM, Morris AM. Impact of Infectious Disease Consultation on Quality of Care, Mortality, and Length of Stay in Staphylococcus aureus Bacteremia: Results From a Large Multicenter Cohort Study. Clin Infect Dis. 2015 May;60(10):1451-61. DOI: 10.1093/cid/civ120</RefTotal>
<RefLink>https://doi.org/10.1093/cid/civ120</RefLink>
</Reference>
<Reference refNo="43">
<RefAuthor>Bretonnière C</RefAuthor>
<RefAuthor>Leone M</RefAuthor>
<RefAuthor>Milési C</RefAuthor>
<RefAuthor>Allaouchiche B</RefAuthor>
<RefAuthor>Armand-Lefevre L</RefAuthor>
<RefAuthor>Baldesi O</RefAuthor>
<RefAuthor>Bouadma L</RefAuthor>
<RefAuthor>Decré D</RefAuthor>
<RefAuthor>Figueiredo S</RefAuthor>
<RefAuthor>Gauzit R</RefAuthor>
<RefAuthor>Guery B</RefAuthor>
<RefAuthor>Joram N</RefAuthor>
<RefAuthor>Jung B</RefAuthor>
<RefAuthor>Lasocki S</RefAuthor>
<RefAuthor>Lepape A</RefAuthor>
<RefAuthor>Lesage F</RefAuthor>
<RefAuthor>Pajot O</RefAuthor>
<RefAuthor>Philippart F</RefAuthor>
<RefAuthor>Souweine B</RefAuthor>
<RefAuthor>Tattevin P</RefAuthor>
<RefAuthor>Timsit JF</RefAuthor>
<RefAuthor>Vialet R</RefAuthor>
<RefAuthor>Zahar JR</RefAuthor>
<RefAuthor>Misset B</RefAuthor>
<RefAuthor>Bedos JP</RefAuthor>
<RefAuthor> Société de Réanimation de Langue Française (SRLF)</RefAuthor>
<RefAuthor> Société Française d’Anesthésie et de Réanimation (SFAR)</RefAuthor>
<RefTitle>Strategies to reduce curative antibiotic therapy in intensive care units (adult and paediatric)</RefTitle>
<RefYear>2015</RefYear>
<RefJournal>Intensive Care Med</RefJournal>
<RefPage>1181-96</RefPage>
<RefTotal>Bretonnière C, Leone M, Milési C, Allaouchiche B, Armand-Lefevre L, Baldesi O, Bouadma L, Decré D, Figueiredo S, Gauzit R, Guery B, Joram N, Jung B, Lasocki S, Lepape A, Lesage F, Pajot O, Philippart F, Souweine B, Tattevin P, Timsit JF, Vialet R, Zahar JR, Misset B, Bedos JP; Société de Réanimation de Langue Française (SRLF); Société Française d’Anesthésie et de Réanimation (SFAR). Strategies to reduce curative antibiotic therapy in intensive care units (adult and paediatric). Intensive Care Med. 2015 Jul;41(7):1181-96. DOI: 10.1007/s00134-015-3853-7</RefTotal>
<RefLink>https://doi.org/10.1007/s00134-015-3853-7</RefLink>
</Reference>
<Reference refNo="44">
<RefAuthor>Robert-Koch-Institute</RefAuthor>
<RefTitle></RefTitle>
<RefYear></RefYear>
<RefBookTitle>ARS - Antibiotic Resistance Surveillance [cited 2017 Feb 13]</RefBookTitle>
<RefPage></RefPage>
<RefTotal>Robert-Koch-Institute. ARS - Antibiotic Resistance Surveillance. [Timestamp: 22.8.2016]. [cited 2017 Feb 13]. Available from: https://ars.rki.de</RefTotal>
<RefLink>https://ars.rki.de</RefLink>
</Reference>
<Reference refNo="46">
<RefAuthor>Roberts JA</RefAuthor>
<RefAuthor>Paul SK</RefAuthor>
<RefAuthor>Akova M</RefAuthor>
<RefAuthor>Bassetti M</RefAuthor>
<RefAuthor>De Waele JJ</RefAuthor>
<RefAuthor>Dimopoulos G</RefAuthor>
<RefAuthor>Kaukonen KM</RefAuthor>
<RefAuthor>Koulenti D</RefAuthor>
<RefAuthor>Martin C</RefAuthor>
<RefAuthor>Montravers P</RefAuthor>
<RefAuthor>Rello J</RefAuthor>
<RefAuthor>Rhodes A</RefAuthor>
<RefAuthor>Starr T</RefAuthor>
<RefAuthor>Wallis SC</RefAuthor>
<RefAuthor>Lipman J</RefAuthor>
<RefAuthor> DALI Study</RefAuthor>
<RefTitle>DALI: defining antibiotic levels in intensive care unit patients: are current β-lactam antibiotic doses sufficient for critically ill patients?</RefTitle>
<RefYear>2014</RefYear>
<RefJournal>Clin Infect Dis</RefJournal>
<RefPage>1072-83</RefPage>
<RefTotal>Roberts JA, Paul SK, Akova M, Bassetti M, De Waele JJ, Dimopoulos G, Kaukonen KM, Koulenti D, Martin C, Montravers P, Rello J, Rhodes A, Starr T, Wallis SC, Lipman J; DALI Study. DALI: defining antibiotic levels in intensive care unit patients: are current β-lactam antibiotic doses sufficient for critically ill patients? Clin Infect Dis. 2014 Apr;58(8):1072-83. DOI: 10.1093/cid/ciu027</RefTotal>
<RefLink>https://doi.org/10.1093/cid/ciu027</RefLink>
</Reference>
<Reference refNo="47">
<RefAuthor>Roberts JA</RefAuthor>
<RefAuthor>Abdul-Aziz MH</RefAuthor>
<RefAuthor>Lipman J</RefAuthor>
<RefAuthor>Mouton JW</RefAuthor>
<RefAuthor>Vinks AA</RefAuthor>
<RefAuthor>Felton TW</RefAuthor>
<RefAuthor>Hope WW</RefAuthor>
<RefAuthor>Farkas A</RefAuthor>
<RefAuthor>Neely MN</RefAuthor>
<RefAuthor>Schentag JJ</RefAuthor>
<RefAuthor>Drusano G</RefAuthor>
<RefAuthor>Frey OR</RefAuthor>
<RefAuthor>Theuretzbacher U</RefAuthor>
<RefAuthor>Kuti JL</RefAuthor>
<RefAuthor> International Society of Anti-Infective Pharmacology and the Pharmacokinetics and Pharmacodynamics Study Group of the European Society of Clinical Microbiology and Infectious Diseases</RefAuthor>
<RefTitle>Individualised antibiotic dosing for patients who are critically ill: challenges and potential solutions</RefTitle>
<RefYear>2014</RefYear>
<RefJournal>Lancet Infect Dis</RefJournal>
<RefPage>498-509</RefPage>
<RefTotal>Roberts JA, Abdul-Aziz MH, Lipman J, Mouton JW, Vinks AA, Felton TW, Hope WW, Farkas A, Neely MN, Schentag JJ, Drusano G, Frey OR, Theuretzbacher U, Kuti JL; International Society of Anti-Infective Pharmacology and the Pharmacokinetics and Pharmacodynamics Study Group of the European Society of Clinical Microbiology and Infectious Diseases. Individualised antibiotic dosing for patients who are critically ill: challenges and potential solutions. Lancet Infect Dis. 2014; 14(6):498-509. DOI: 10.1016/S1473-3099(14) 70036-2</RefTotal>
<RefLink>https://doi.org/10.1016/S1473-3099(14) 70036-2</RefLink>
</Reference>
<Reference refNo="48">
<RefAuthor>Udy AA</RefAuthor>
<RefAuthor>Lipman J</RefAuthor>
<RefAuthor>Jarrett P</RefAuthor>
<RefAuthor>Klein K</RefAuthor>
<RefAuthor>Wallis SC</RefAuthor>
<RefAuthor>Patel K</RefAuthor>
<RefAuthor>Kirkpatrick CM</RefAuthor>
<RefAuthor>Kruger PS</RefAuthor>
<RefAuthor>Paterson DL</RefAuthor>
<RefAuthor>Roberts MS</RefAuthor>
<RefAuthor>Roberts JA</RefAuthor>
<RefTitle>Are standard doses of piperacillin sufficient for critically ill patients with augmented creatinine clearance?</RefTitle>
<RefYear>2015</RefYear>
<RefJournal>Crit Care</RefJournal>
<RefPage>28</RefPage>
<RefTotal>Udy AA, Lipman J, Jarrett P, Klein K, Wallis SC, Patel K, Kirkpatrick CM, Kruger PS, Paterson DL, Roberts MS, Roberts JA. Are standard doses of piperacillin sufficient for critically ill patients with augmented creatinine clearance? Crit Care. 2015 Jan;19:28. DOI: 10.1186/s13054-015-0750-y</RefTotal>
<RefLink>https://doi.org/10.1186/s13054-015-0750-y</RefLink>
</Reference>
<Reference refNo="49">
<RefAuthor>Hao JJ</RefAuthor>
<RefAuthor>Chen H</RefAuthor>
<RefAuthor>Zhou JX</RefAuthor>
<RefTitle>Continuous versus intermittent infusion of vancomycin in adult patients: A systematic review and meta-analysis</RefTitle>
<RefYear>2016</RefYear>
<RefJournal>Int J Antimicrob Agents</RefJournal>
<RefPage>28-35</RefPage>
<RefTotal>Hao JJ, Chen H, Zhou JX. Continuous versus intermittent infusion of vancomycin in adult patients: A systematic review and meta-analysis. Int J Antimicrob Agents. 2016 Jan;47(1):28-35. DOI: 10.1016/j.ijantimicag.2015.10.019</RefTotal>
<RefLink>https://doi.org/10.1016/j.ijantimicag.2015.10.019</RefLink>
</Reference>
<Reference refNo="50">
<RefAuthor>Kumpf O</RefAuthor>
<RefAuthor>Braun JP</RefAuthor>
<RefAuthor>Brinkmann A</RefAuthor>
<RefAuthor>Bause H</RefAuthor>
<RefAuthor>Bellgardt M</RefAuthor>
<RefAuthor>Bloos F</RefAuthor>
<RefAuthor>Dubb R</RefAuthor>
<RefAuthor>Greim C</RefAuthor>
<RefAuthor>Kaltwasser A</RefAuthor>
<RefAuthor>Marx G</RefAuthor>
<RefAuthor>Riessen R</RefAuthor>
<RefAuthor>Spies C</RefAuthor>
<RefAuthor>Weimann J</RefAuthor>
<RefAuthor>Wöbker G</RefAuthor>
<RefAuthor>Muhl E</RefAuthor>
<RefAuthor>Waydhas C</RefAuthor>
<RefTitle>Quality indicators in intensive care medicine for Germany – third edition 2017</RefTitle>
<RefYear>2017</RefYear>
<RefJournal>Ger Med Sci</RefJournal>
<RefPage>Doc10</RefPage>
<RefTotal>Kumpf O, Braun JP, Brinkmann A, Bause H, Bellgardt M, Bloos F, Dubb R, Greim C, Kaltwasser A, Marx G, Riessen R, Spies C, Weimann J, Wöbker G, Muhl E, Waydhas C. Quality indicators in intensive care medicine for Germany – third edition 2017. Ger Med Sci. 2017 Aug 1;15:Doc10. DOI: 10.3205/000251</RefTotal>
<RefLink>https://doi.org/10.3205/000251</RefLink>
</Reference>
<Reference refNo="52">
<RefAuthor>Chant C</RefAuthor>
<RefAuthor>Leung A</RefAuthor>
<RefAuthor>Friedrich JO</RefAuthor>
<RefTitle>Optimal dosing of antibiotics in critically ill patients by using continuous/extended infusions: a systematic review and meta-analysis</RefTitle>
<RefYear>2013</RefYear>
<RefJournal>Crit Care</RefJournal>
<RefPage>R279</RefPage>
<RefTotal>Chant C, Leung A, Friedrich JO. Optimal dosing of antibiotics in critically ill patients by using continuous/extended infusions: a systematic review and meta-analysis. Crit Care. 2013 Nov 29;17(6):R279. DOI: 10.1186/cc13134</RefTotal>
<RefLink>https://doi.org/10.1186/cc13134</RefLink>
</Reference>
<Reference refNo="53">
<RefAuthor>Falagas ME</RefAuthor>
<RefAuthor>Tansarli GS</RefAuthor>
<RefAuthor>Ikawa K</RefAuthor>
<RefAuthor>Vardakas KZ</RefAuthor>
<RefTitle>Clinical outcomes with extended or continuous versus short-term intravenous infusion of carbapenems and piperacillin/tazobactam: a systematic review and meta-analysis</RefTitle>
<RefYear>2013</RefYear>
<RefJournal>Clin Infect Dis</RefJournal>
<RefPage>272-82</RefPage>
<RefTotal>Falagas ME, Tansarli GS, Ikawa K, Vardakas KZ. Clinical outcomes with extended or continuous versus short-term intravenous infusion of carbapenems and piperacillin/tazobactam: a systematic review and meta-analysis. Clin Infect Dis. 2013 Jan;56(2):272-82. DOI: 10.1093/cid/cis857</RefTotal>
<RefLink>https://doi.org/10.1093/cid/cis857</RefLink>
</Reference>
<Reference refNo="54">
<RefAuthor>Roberts JA</RefAuthor>
<RefAuthor>Abdul-Aziz MH</RefAuthor>
<RefAuthor>Davis JS</RefAuthor>
<RefAuthor>Dulhunty JM</RefAuthor>
<RefAuthor>Cotta MO</RefAuthor>
<RefAuthor>Myburgh J</RefAuthor>
<RefAuthor>Bellomo R</RefAuthor>
<RefAuthor>Lipman J</RefAuthor>
<RefTitle>Continuous versus Intermittent β-Lactam Infusion in Severe Sepsis. A Meta-analysis of Individual Patient Data from Randomized Trials</RefTitle>
<RefYear>2016</RefYear>
<RefJournal>Am J Respir Crit Care Med</RefJournal>
<RefPage>681-91</RefPage>
<RefTotal>Roberts JA, Abdul-Aziz MH, Davis JS, Dulhunty JM, Cotta MO, Myburgh J, Bellomo R, Lipman J. Continuous versus Intermittent β-Lactam Infusion in Severe Sepsis. A Meta-analysis of Individual Patient Data from Randomized Trials. Am J Respir Crit Care Med. 2016 Sep;194(6):681-91. DOI: 10.1164/rccm.201601-0024OC</RefTotal>
<RefLink>https://doi.org/10.1164/rccm.201601-0024OC</RefLink>
</Reference>
<Reference refNo="55">
<RefAuthor>Dulhunty JM</RefAuthor>
<RefAuthor>Roberts JA</RefAuthor>
<RefAuthor>Davis JS</RefAuthor>
<RefAuthor>Webb SA</RefAuthor>
<RefAuthor>Bellomo R</RefAuthor>
<RefAuthor>Gomersall C</RefAuthor>
<RefAuthor>Shirwadkar C</RefAuthor>
<RefAuthor>Eastwood GM</RefAuthor>
<RefAuthor>Myburgh J</RefAuthor>
<RefAuthor>Paterson DL</RefAuthor>
<RefAuthor>Lipman J</RefAuthor>
<RefTitle>Continuous infusion of beta-lactam antibiotics in severe sepsis: a multicenter double-blind, randomized controlled trial</RefTitle>
<RefYear>2013</RefYear>
<RefJournal>Clin Infect Dis</RefJournal>
<RefPage>236-44</RefPage>
<RefTotal>Dulhunty JM, Roberts JA, Davis JS, Webb SA, Bellomo R, Gomersall C, Shirwadkar C, Eastwood GM, Myburgh J, Paterson DL, Lipman J. Continuous infusion of beta-lactam antibiotics in severe sepsis: a multicenter double-blind, randomized controlled trial. Clin Infect Dis. 2013 Jan;56(2):236-44. DOI: 10.1093/cid/cis856</RefTotal>
<RefLink>https://doi.org/10.1093/cid/cis856</RefLink>
</Reference>
<Reference refNo="56">
<RefAuthor>Dulhunty JM</RefAuthor>
<RefAuthor>Roberts JA</RefAuthor>
<RefAuthor>Davis JS</RefAuthor>
<RefAuthor>Webb SA</RefAuthor>
<RefAuthor>Bellomo R</RefAuthor>
<RefAuthor>Gomersall C</RefAuthor>
<RefAuthor>Shirwadkar C</RefAuthor>
<RefAuthor>Eastwood GM</RefAuthor>
<RefAuthor>Myburgh J</RefAuthor>
<RefAuthor>Paterson DL</RefAuthor>
<RefAuthor>Starr T</RefAuthor>
<RefAuthor>Paul SK</RefAuthor>
<RefAuthor>Lipman J</RefAuthor>
<RefAuthor> BLING II Investigators for the ANZICS Clinical Trials Group</RefAuthor>
<RefTitle>A Multicenter Randomized Trial of Continuous versus Intermittent β-Lactam Infusion in Severe Sepsis</RefTitle>
<RefYear>2015</RefYear>
<RefJournal>Am J Respir Crit Care Med</RefJournal>
<RefPage>1298-305</RefPage>
<RefTotal>Dulhunty JM, Roberts JA, Davis JS, Webb SA, Bellomo R, Gomersall C, Shirwadkar C, Eastwood GM, Myburgh J, Paterson DL, Starr T, Paul SK, Lipman J; BLING II Investigators for the ANZICS Clinical Trials Group. A Multicenter Randomized Trial of Continuous versus Intermittent β-Lactam Infusion in Severe Sepsis. Am J Respir Crit Care Med. 2015 Dec 1;192(11):1298-305. DOI: 10.1164/rccm.201505-0857OC</RefTotal>
<RefLink>https://doi.org/10.1164/rccm.201505-0857OC</RefLink>
</Reference>
<Reference refNo="57">
<RefAuthor>Abdul-Aziz MH</RefAuthor>
<RefAuthor>Sulaiman H</RefAuthor>
<RefAuthor>Mat-Nor MB</RefAuthor>
<RefAuthor>Rai V</RefAuthor>
<RefAuthor>Wong KK</RefAuthor>
<RefAuthor>Hasan MS</RefAuthor>
<RefAuthor>Abd Rahman AN</RefAuthor>
<RefAuthor>Jamal JA</RefAuthor>
<RefAuthor>Wallis SC</RefAuthor>
<RefAuthor>Lipman J</RefAuthor>
<RefAuthor>Staatz CE</RefAuthor>
<RefAuthor>Roberts JA</RefAuthor>
<RefTitle>Beta-Lactam Infusion in Severe Sepsis (BLISS): a prospective, two-centre, open-labelled randomised controlled trial of continuous versus intermittent beta-lactam infusion in critically ill patients with severe sepsis</RefTitle>
<RefYear>2016</RefYear>
<RefJournal>Intensive Care Med</RefJournal>
<RefPage>1535-1545</RefPage>
<RefTotal>Abdul-Aziz MH, Sulaiman H, Mat-Nor MB, Rai V, Wong KK, Hasan MS, Abd Rahman AN, Jamal JA, Wallis SC, Lipman J, Staatz CE, Roberts JA. Beta-Lactam Infusion in Severe Sepsis (BLISS): a prospective, two-centre, open-labelled randomised controlled trial of continuous versus intermittent beta-lactam infusion in critically ill patients with severe sepsis. Intensive Care Med. 2016 Oct;42(10):1535-1545. DOI: 10.1007/s00134-015-4188-0</RefTotal>
<RefLink>https://doi.org/10.1007/s00134-015-4188-0</RefLink>
</Reference>
<Reference refNo="58">
<RefAuthor>Lipman J</RefAuthor>
<RefAuthor>Boots R</RefAuthor>
<RefTitle>A new paradigm for treating infections: “go hard and go home”</RefTitle>
<RefYear>2009</RefYear>
<RefJournal>Crit Care Resusc</RefJournal>
<RefPage>276-81</RefPage>
<RefTotal>Lipman J, Boots R. A new paradigm for treating infections: “go hard and go home”. Crit Care Resusc. 2009 Dec;11(4):276-81.</RefTotal>
</Reference>
<Reference refNo="59">
<RefAuthor>Krueger WA</RefAuthor>
<RefAuthor>Bulitta J</RefAuthor>
<RefAuthor>Kinzig-Schippers M</RefAuthor>
<RefAuthor>Landersdorfer C</RefAuthor>
<RefAuthor>Holzgrabe U</RefAuthor>
<RefAuthor>Naber KG</RefAuthor>
<RefAuthor>Drusano GL</RefAuthor>
<RefAuthor>Sörgel F</RefAuthor>
<RefTitle>Evaluation by monte carlo simulation of the pharmacokinetics of two doses of meropenem administered intermittently or as a continuous infusion in healthy volunteers</RefTitle>
<RefYear>2005</RefYear>
<RefJournal>Antimicrob Agents Chemother</RefJournal>
<RefPage>1881-9</RefPage>
<RefTotal>Krueger WA, Bulitta J, Kinzig-Schippers M, Landersdorfer C, Holzgrabe U, Naber KG, Drusano GL, Sörgel F. Evaluation by monte carlo simulation of the pharmacokinetics of two doses of meropenem administered intermittently or as a continuous infusion in healthy volunteers. Antimicrob Agents Chemother. 2005 May;49(5):1881-9. DOI: 10.1128/AAC.49.5.1881-1889.2005</RefTotal>
<RefLink>https://doi.org/10.1128/AAC.49.5.1881-1889.2005</RefLink>
</Reference>
<Reference refNo="60">
<RefAuthor>Lorente L</RefAuthor>
<RefAuthor>Lorenzo L</RefAuthor>
<RefAuthor>Martín MM</RefAuthor>
<RefAuthor>Jiménez A</RefAuthor>
<RefAuthor>Mora ML</RefAuthor>
<RefTitle>Meropenem by continuous versus intermittent infusion in ventilator-associated pneumonia due to gram-negative bacilli</RefTitle>
<RefYear>2006</RefYear>
<RefJournal>Ann Pharmacother</RefJournal>
<RefPage>219-23</RefPage>
<RefTotal>Lorente L, Lorenzo L, Martín MM, Jiménez A, Mora ML. Meropenem by continuous versus intermittent infusion in ventilator-associated pneumonia due to gram-negative bacilli. Ann Pharmacother. 2006 Feb;40(2):219-23. DOI: 10.1345/aph.1G467</RefTotal>
<RefLink>https://doi.org/10.1345/aph.1G467</RefLink>
</Reference>
<Reference refNo="61">
<RefAuthor>Briegel J</RefAuthor>
<RefTitle>Update der Surviving Sepsis Campaign Guidelines 2008</RefTitle>
<RefYear>2008</RefYear>
<RefJournal>Anaesthesist</RefJournal>
<RefPage>284-6</RefPage>
<RefTotal>Briegel J. Update der Surviving Sepsis Campaign Guidelines 2008 [Update of the Surviving Sepsis Campaign guidelines 2008]. Anaesthesist. 2008 Mar;57(3):284-6. DOI: 10.1007/s00101-008-1335-9</RefTotal>
<RefLink>https://doi.org/10.1007/s00101-008-1335-9</RefLink>
</Reference>
<Reference refNo="62">
<RefAuthor>Paul M</RefAuthor>
<RefAuthor>Benuri-Silbiger I</RefAuthor>
<RefAuthor>Soares-Weiser K</RefAuthor>
<RefAuthor>Leibovici L</RefAuthor>
<RefTitle>Beta lactam monotherapy versus beta lactam-aminoglycoside combination therapy for sepsis in immunocompetent patients: systematic review and meta-analysis of randomised trials</RefTitle>
<RefYear>2004</RefYear>
<RefJournal>BMJ</RefJournal>
<RefPage>668</RefPage>
<RefTotal>Paul M, Benuri-Silbiger I, Soares-Weiser K, Leibovici L. Beta lactam monotherapy versus beta lactam-aminoglycoside combination therapy for sepsis in immunocompetent patients: systematic review and meta-analysis of randomised trials. BMJ. 2004 Mar;328(7441):668. DOI: 10.1136/bmj.38028.520995.63</RefTotal>
<RefLink>https://doi.org/10.1136/bmj.38028.520995.63</RefLink>
</Reference>
<Reference refNo="63">
<RefAuthor>Paul M</RefAuthor>
<RefAuthor>Lador A</RefAuthor>
<RefAuthor>Grozinsky-Glasberg S</RefAuthor>
<RefAuthor>Leibovici L</RefAuthor>
<RefTitle>Beta lactam antibiotic monotherapy versus beta lactam-aminoglycoside antibiotic combination therapy for sepsis</RefTitle>
<RefYear>2014</RefYear>
<RefJournal>Cochrane Database Syst Rev</RefJournal>
<RefPage>CD003344</RefPage>
<RefTotal>Paul M, Lador A, Grozinsky-Glasberg S, Leibovici L. Beta lactam antibiotic monotherapy versus beta lactam-aminoglycoside antibiotic combination therapy for sepsis. Cochrane Database Syst Rev. 2014 Jan 7;(1):CD003344. DOI: 10.1002/14651858.CD003344.pub3</RefTotal>
<RefLink>https://doi.org/10.1002/14651858.CD003344.pub3</RefLink>
</Reference>
<Reference refNo="64">
<RefAuthor>Cosgrove SE</RefAuthor>
<RefAuthor>Fowler VG Jr</RefAuthor>
<RefTitle>Management of methicillin-resistant Staphylococcus aureus bacteremia</RefTitle>
<RefYear>2008</RefYear>
<RefJournal>Clin Infect Dis</RefJournal>
<RefPage>S386-93</RefPage>
<RefTotal>Cosgrove SE, Fowler VG Jr. Management of methicillin-resistant Staphylococcus aureus bacteremia. Clin Infect Dis. 2008 Jun 1;46 Suppl 5:S386-93. DOI: 10.1086/533595</RefTotal>
<RefLink>https://doi.org/10.1086/533595</RefLink>
</Reference>
<Reference refNo="65">
<RefAuthor>Cunha BA</RefAuthor>
<RefTitle>Sepsis and septic shock: selection of empiric antimicrobial therapy</RefTitle>
<RefYear>2008</RefYear>
<RefJournal>Crit Care Clin</RefJournal>
<RefPage>313-34, ix</RefPage>
<RefTotal>Cunha BA. Sepsis and septic shock: selection of empiric antimicrobial therapy. Crit Care Clin. 2008 Apr;24(2):313-34, ix. DOI: 10.1016/j.ccc.2007.12.015</RefTotal>
<RefLink>https://doi.org/10.1016/j.ccc.2007.12.015</RefLink>
</Reference>
<Reference refNo="66">
<RefAuthor>Torres A</RefAuthor>
<RefAuthor>Sanches-Garcia M</RefAuthor>
<RefAuthor>Demeyer I</RefAuthor>
<RefAuthor>Saulay M</RefAuthor>
<RefAuthor>Schmitt-Hoffmann AH</RefAuthor>
<RefAuthor>Engelhardt M</RefAuthor>
<RefAuthor></RefAuthor>
<RefTitle>Pharmacokinetics, safety and tolerability of high-dose ceftobiprole medocaril administrered as prolonged infusion in intensive-car-unit (ICU) patients [Abstract]</RefTitle>
<RefYear></RefYear>
<RefBookTitle>25th European Congress of Clinical Microbiology and Infectious Diseases; 2015 Apr 25-28; Copenhagen. O199.</RefBookTitle>
<RefPage></RefPage>
<RefTotal>Torres A, Sanches-Garcia M, Demeyer I, Saulay M, Schmitt-Hoffmann AH, Engelhardt M, et al. Pharmacokinetics, safety and tolerability of high-dose ceftobiprole medocaril administrered as prolonged infusion in intensive-car-unit (ICU) patients [Abstract]. In: 25th European Congress of Clinical Microbiology and Infectious Diseases; 2015 Apr 25-28; Copenhagen. O199.</RefTotal>
</Reference>
<Reference refNo="67">
<RefAuthor>Gastmeier P</RefAuthor>
<RefAuthor>Sohr D</RefAuthor>
<RefAuthor>Geffers C</RefAuthor>
<RefAuthor>Rüden H</RefAuthor>
<RefAuthor>Vonberg RP</RefAuthor>
<RefAuthor>Welte T</RefAuthor>
<RefTitle>Early- and late-onset pneumonia: is this still a useful classification?</RefTitle>
<RefYear>2009</RefYear>
<RefJournal>Antimicrob Agents Chemother</RefJournal>
<RefPage>2714-8</RefPage>
<RefTotal>Gastmeier P, Sohr D, Geffers C, Rüden H, Vonberg RP, Welte T. Early- and late-onset pneumonia: is this still a useful classification? Antimicrob Agents Chemother. 2009 Jul;53(7):2714-8. DOI: 10.1128/AAC.01070-08</RefTotal>
<RefLink>https://doi.org/10.1128/AAC.01070-08</RefLink>
</Reference>
<Reference refNo="68">
<RefAuthor>Dellinger RP</RefAuthor>
<RefAuthor>Levy MM</RefAuthor>
<RefAuthor>Carlet JM</RefAuthor>
<RefAuthor>Bion J</RefAuthor>
<RefAuthor>Parker MM</RefAuthor>
<RefAuthor>Jaeschke R</RefAuthor>
<RefAuthor>Reinhart K</RefAuthor>
<RefAuthor>Angus DC</RefAuthor>
<RefAuthor>Brun-Buisson C</RefAuthor>
<RefAuthor>Beale R</RefAuthor>
<RefAuthor>Calandra T</RefAuthor>
<RefAuthor>Dhainaut JF</RefAuthor>
<RefAuthor>Gerlach H</RefAuthor>
<RefAuthor>Harvey M</RefAuthor>
<RefAuthor>Marini JJ</RefAuthor>
<RefAuthor>Marshall J</RefAuthor>
<RefAuthor>Ranieri M</RefAuthor>
<RefAuthor>Ramsay G</RefAuthor>
<RefAuthor>Sevransky J</RefAuthor>
<RefAuthor>Thompson BT</RefAuthor>
<RefAuthor>Townsend S</RefAuthor>
<RefAuthor>Vender JS</RefAuthor>
<RefAuthor>Zimmerman JL</RefAuthor>
<RefAuthor>Vincent JL</RefAuthor>
<RefAuthor> International Surviving Sepsis Campaign Guidelines Committee</RefAuthor>
<RefAuthor> American Association of Critical-Care Nurses</RefAuthor>
<RefAuthor> American College of Chest Physicians</RefAuthor>
<RefAuthor> American College of Emergency Physicians</RefAuthor>
<RefAuthor> Canadian Critical Care Society</RefAuthor>
<RefAuthor> European Society of Clinical Microbiology and Infectious Diseases</RefAuthor>
<RefAuthor> European Society of Intensive Care Medicine</RefAuthor>
<RefAuthor> European Respiratory Society</RefAuthor>
<RefAuthor> International Sepsis Forum</RefAuthor>
<RefAuthor> Japanese Association for Acute Medicine</RefAuthor>
<RefAuthor> Japanese Society of Intensive Care Medicine</RefAuthor>
<RefAuthor> Society of Critical Care Medicine</RefAuthor>
<RefAuthor> Society of Hospital Medicine</RefAuthor>
<RefAuthor> Surgical Infection Society</RefAuthor>
<RefAuthor> World Federation of Societies of Intensive and Critical Care Medicine</RefAuthor>
<RefTitle>Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008</RefTitle>
<RefYear>2008</RefYear>
<RefJournal>Crit Care Med</RefJournal>
<RefPage>296-327</RefPage>
<RefTotal>Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, Jaeschke R, Reinhart K, Angus DC, Brun-Buisson C, Beale R, Calandra T, Dhainaut JF, Gerlach H, Harvey M, Marini JJ, Marshall J, Ranieri M, Ramsay G, Sevransky J, Thompson BT, Townsend S, Vender JS, Zimmerman JL, Vincent JL; International Surviving Sepsis Campaign Guidelines Committee; American Association of Critical-Care Nurses; American College of Chest Physicians; American College of Emergency Physicians; Canadian Critical Care Society; European Society of Clinical Microbiology and Infectious Diseases; European Society of Intensive Care Medicine; European Respiratory Society; International Sepsis Forum; Japanese Association for Acute Medicine; Japanese Society of Intensive Care Medicine; Society of Critical Care Medicine; Society of Hospital Medicine; Surgical Infection Society; World Federation of Societies of Intensive and Critical Care Medicine. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med. 2008 Jan;36(1):296-327. DOI: 10.1097/01.CCM.0000298158.12101.41</RefTotal>
<RefLink>https://doi.org/10.1097/01.CCM.0000298158.12101.41</RefLink>
</Reference>
<Reference refNo="69">
<RefAuthor>Garnacho-Montero J</RefAuthor>
<RefAuthor>Sa-Borges M</RefAuthor>
<RefAuthor>Sole-Violan J</RefAuthor>
<RefAuthor>Barcenilla F</RefAuthor>
<RefAuthor>Escoresca-Ortega A</RefAuthor>
<RefAuthor>Ochoa M</RefAuthor>
<RefAuthor>Cayuela A</RefAuthor>
<RefAuthor>Rello J</RefAuthor>
<RefTitle>Optimal management therapy for Pseudomonas aeruginosa ventilator-associated pneumonia: an observational, multicenter study comparing monotherapy with combination antibiotic therapy</RefTitle>
<RefYear>2007</RefYear>
<RefJournal>Crit Care Med</RefJournal>
<RefPage>1888-95</RefPage>
<RefTotal>Garnacho-Montero J, Sa-Borges M, Sole-Violan J, Barcenilla F, Escoresca-Ortega A, Ochoa M, Cayuela A, Rello J. Optimal management therapy for Pseudomonas aeruginosa ventilator-associated pneumonia: an observational, multicenter study comparing monotherapy with combination antibiotic therapy. Crit Care Med. 2007 Aug;35(8):1888-95. DOI: 10.1097/01.CCM.0000275389.31974.22</RefTotal>
<RefLink>https://doi.org/10.1097/01.CCM.0000275389.31974.22</RefLink>
</Reference>
<Reference refNo="70">
<RefAuthor>Grabein B</RefAuthor>
<RefAuthor>Ebenhoch M</RefAuthor>
<RefAuthor>Kühnen E</RefAuthor>
<RefAuthor>Thalhammer F</RefAuthor>
<RefTitle>Kalkulierte parenterale Initialtherapie bakterieller Infektionen: Infektionen durch multiresistente gramnegative Stäbchen – ESBL-Bildner, Carbapenemase-bildende Enterobacteriaceae, Carbapenem-resistente Acinetobacter baumannii</RefTitle>
<RefYear>2020</RefYear>
<RefJournal>GMS Infect Dis</RefJournal>
<RefPage>Doc04</RefPage>
<RefTotal>Grabein B, Ebenhoch M, Kühnen E, Thalhammer F. Kalkulierte parenterale Initialtherapie bakterieller Infektionen: Infektionen durch multiresistente gramnegative Stäbchen – ESBL-Bildner, Carbapenemase-bildende Enterobacteriaceae, Carbapenem-resistente Acinetobacter baumannii [Calculated parenteral initial treatment of bacterial infections: Infections with multi-resistant Gram-negative rods – ESBL producers, carbapenemase-producing Enterobacteriaceae, carbapenem-resistant Acinetobacter baumannii]. GMS Infect Dis. 2020;8:Doc04. DOI: 10.3205/id000048</RefTotal>
<RefLink>https://doi.org/10.3205/id000048</RefLink>
</Reference>
</References>
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<Caption language="de"><Pgraph><Mark1>Tabelle 1: Empfehlungen zur Therapie der Sepsis bei unbekanntem Erreger. (Die Therapieempfehlungen richten sich nicht an immunsuprimierte und neutropenische Patienten.)</Mark1></Pgraph></Caption>
<Caption language="en"><Pgraph><Mark1>Table 1: Recommendations for the treatment of sepsis with unknown pathogen. (Treatment recommendations are not intended for immunosuppressed and neutropenic patients.)</Mark1></Pgraph></Caption>
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<MediaNo>2</MediaNo>
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<Caption language="de"><Pgraph><Mark1>Tabelle 2: Empfehlungen zur gezielten Antibiotika-Therapie der Sepsis bei bekanntem Erreger</Mark1></Pgraph></Caption>
<Caption language="en"><Pgraph><Mark1>Table 2: Recommendations for antibiotic treatment of sepsis where the pathogen is known</Mark1></Pgraph></Caption>
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<Table format="png">
<MediaNo>3</MediaNo>
<MediaID language="de">3de</MediaID>
<MediaID language="en">3en</MediaID>
<Caption language="de"><Pgraph><Mark1>Tabelle 3: Empfehlungsgrade für den Einsatz der Antibiotika in der Indikation „nosokomial erworbene Sepsis bei unbekanntem Erreger und unbekanntem Infektionsort“</Mark1></Pgraph></Caption>
<Caption language="en"><Pgraph><Mark1>Table 3: Recommendation grade for the use of antibiotics in the indication “nosocomial acquired sepsis with unknown pathogen and unknown site of infection”</Mark1></Pgraph></Caption>
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<Caption language="de"><Pgraph><Mark1>Abbildung 1: Flowchart zur Identifizierung von Patienten mit Sepsis und septischem Schock</Mark1></Pgraph></Caption>
<Caption language="en"><Pgraph><Mark1>Figure 1: Flowchart to identify patients with sepsis and septic shock</Mark1></Pgraph></Caption>
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